interleukin-8 and Pulmonary-Disease--Chronic-Obstructive

Chronic obstructive pulmonary disease (COPD) is currently one of the highest morbidity and mortality worldwide, a serious public health problem. Pulmonary hypertension is a common complication of COPD. At present, the pathogenesis of pulmonary hypertension is not clear. A concise overview of the known factors contributing to pulmonary hypertension in COPD includes hypoxia and inflammation. Hypoxia, resulting from lung damage and inadequate oxygen supply, can lead to pulmonary vasoconstriction and increased vascular resistance, thus contributing to the development of pulmonary hypertension in COPD patients. Inflammation also plays a significant role in the progression of pulmonary hypertension. COPD patients exhibit inflammatory responses in their lung tissues, with the release of various inflammatory mediators. These mediators can stimulate abnormal proliferation of endothelial cells and smooth muscle cells within the pulmonary arteries, leading to vascular wall thickening and restricted blood flow. This paper focuses on the pathogenesis of four inflammatory factors, namely interleukin (IL-1β), IL-6, IL-8, and tumor necrosis factor (TNF)-α, in pulmonary hypertension. IL-1β, IL-6, IL-8, and TNF-α are known as pro-inflammatory cytokines that play crucial roles in the inflammatory response. In the context of pulmonary hypertension, these inflammatory factors have been implicated in the remodeling of the pulmonary vasculature, leading to increased vascular resistance and impaired blood flow. The research presented in this paper will delve into the current scientific knowledge surrounding IL-1β, IL-6, IL-8, and TNF-α, and their roles in pulmonary vascular remodeling, endothelial dysfunction, smooth muscle cell proliferation, and inflammation. The goal is to provide a comprehensive overview of their involvement in pulmonary hypertension and how these factors may be influenced by the hypoxic environment prevalent in high-altitude regions. By focusing on the relevance of these inflammatory factors in high-altitude areas, we hope to contribute valuable insights that can inform clinical management strategies, prevention approaches, and potential therapeutic interventions for individuals residing in such regions who are at an increased risk of developing pulmonary hypertension.

Topics: Altitude; Endothelial Cells; Humans; Hypertension, Pulmonary; Hypoxia; Inflammation; Interleukin-6; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Asthma is a complex, heterogeneous condition that affects over 350 million people globally. It is characterised by bronchial hyperreactivity and airways inflammation. A subset display marked airway neutrophilia, associated with worse lung function, higher morbidity and poor response to treatment. In these individuals, recent metagenomic studies have identified persistent bacterial infection, particularly with non-encapsulated strains of the Gram-negative bacterium

Topics: Asthma; Cell Adhesion Molecule-1; Cytokines; Haemophilus influenzae; Humans; Inflammasomes; Interleukin-12; Interleukin-17; Interleukin-6; Interleukin-8; Macrolides; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Disease, Chronic Obstructive; Respiratory System; Tumor Necrosis Factors

Topics: Asthma; Humans; Inflammation; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Quality of Life

Asthma and chronic obstructive pulmonary disease (COPD) cause significant morbidity and mortality worldwide. In the context of disease pathogenesis, both asthma and COPD involve chronic inflammation of the lung and are characterised by the abnormal release of inflammatory cytokines, dysregulated immune cell activity and remodelling of the airways. To date, current treatments still only manage symptoms and do not reverse the primary disease processes. In recent work, interleukin (IL)-1α and IL-1β have been suggested to play important roles in both asthma and COPD. In this review, we summarise overwhelming pre-clinical evidence for dysregulated signalling of IL-1α and IL-1β contributing to disease pathogenesis and discuss the paradox of IL-1 therapeutic studies in asthma and COPD. This is particularly important given recent completed and ongoing clinical trials with IL-1 biologics that have had varying degrees of failure and success as therapeutics for disease modification in asthma and COPD.

Topics: Asthma; Humans; Interleukin-8; Lung; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death nowadays, and its underdiagnosis is still a great challenge. More effective diagnosis method is in urgent need since the traditional spirometry has many limitations in the practical application. The electrochemical (EC) detection methods have their unique advantages of high accuracy, short response time and easy integration of the system. In this review, recent works on the EC methods for COPD biomarkers including interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP) are summarized. Five types of EC methods are highlighted in this study, as enzyme-labelled immunosensors, nanoparticle-labelled immunosensors, capacitive or impedimetric immunosensors, magnetoimmunosensors, and field effect transistor (FET) immunosensors. To date, EC immunosensors have been exhibiting high analytical performance with a detection limit that can achieve several pg/mL or even lower. The simplicity of EC immunosensors makes them a perfect solution for a future point-of-care device to use in settings for COPD diagnosis and follow-up. Nevertheless, more efforts need to be paid on the simultaneous detection of multiple biomarkers, a demand for the clinical diagnosis, and processes of assay simplification towards achieving one-step detection.

Topics: Animals; Biomarkers; Biosensing Techniques; C-Reactive Protein; Electrochemical Techniques; Equipment Design; Humans; Immunoassay; Interleukin-6; Interleukin-8; Point-of-Care Systems; Pulmonary Disease, Chronic Obstructive; Saliva

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease associated with significant morbidity and mortality. Current diagnostic criteria based on the presence of fixed airflow obstruction and symptoms do not integrate the complex pathological changes occurring within the lung and they do not define different airway inflammatory patterns. The current management of COPD is based on 'one size fits all' approach and does not take the importance of heterogeneity in COPD population into account. The available treatments aim to alleviate symptoms and reduce exacerbation frequency but do not alter the course of the disease. Recent advances in molecular biology have furthered our understanding of inflammatory pathways in pathogenesis of COPD and have led to development of targeted therapies (biologics and small molecules) based on predefined biomarkers. Herein we shall review the trials of biologics in COPD and potential future drug developments in the field.

Topics: Airway Remodeling; Antibodies, Monoclonal, Humanized; Biological Products; Eosinophils; Etanercept; Humans; Infliximab; Interleukin-1; Interleukin-13; Interleukin-5; Interleukin-8; Molecular Targeted Therapy; Pulmonary Disease, Chronic Obstructive; Pyrimidines; Receptors, Interleukin-1 Type I; Receptors, Interleukin-5; Receptors, Interleukin-8B; Sulfonamides; Tumor Necrosis Factor-alpha

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; 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Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Chronic obstructive pulmonary disease (COPD) is a prevalent chronic disease of the upper airways and it is the fourth cause of death in the Polish population. COPD is characterized by not fully reversible constriction of air flow, which is a consequence of inflammation caused by noxious fumes and gases, particularly tobacco smoke. It seems that among mediators of inflammation, chemokine CXCL8 (interleukin 8) may play a pivotal role. CXCL8 is a member of the chemokine family and is a major chemoattractant to neutrophils, which are responsible for inducing and sustaining the inflammatory state. It was shown that there is a correlation between the number of neutrophils in induced sputum in COPD patients, the CXCL8 level, and clinical outcome of the illness. Increased frequency of exacerbation may be a result of increased secretion of mucus caused by increased expression of genes encoding mucins (MUC5AC and MUCB), which is stimulated by high levels of CXCL8. Activation of the CXCL8-encoding gene depends on pro-inflammatory cytokines such as tumor necrosis factor, interleukin 1 and lipopolysaccharide which activate transcription factor NF-κB. Inhibitors of CXCL8 (such as N-acetyl-L-cysteine) cause a decrease of exacerbation frequency and clinical symptoms. The data presented in the review suggest that CXCL8 plays a major role in the inflammatory process leading to COPD.

Topics: Animals; Biomarkers; Humans; Inflammation; Interleukin-8; Neutrophils; NF-kappa B; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive; Smoke; Tumor Necrosis Factor-alpha

Oxidation of low-density lipoprotein (LDL) has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO) is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNF α and IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis.

Topics: Apolipoprotein B-100; Atherosclerosis; Endocytosis; Erectile Dysfunction; Fatty Liver; Female; Fibrinolysis; Humans; Hydrogen Peroxide; Inflammation; Interleukin-8; Lipoproteins, LDL; Macrophages; Male; Oxygen; Peroxidase; Pulmonary Disease, Chronic Obstructive; Renal Dialysis; Sleep Wake Disorders; Tumor Necrosis Factor-alpha

Two applications claim CXCR2 receptor antagonists respectively incorporating arylcarbonyl and arylsulfonyl substituted 2-hydroxyaniline scaffolds. The first application claims both N-aryl,N'-aryl urea and squaramide derivatives, the second focuses on squaramide derivatives. Several examples of the latter scaffold with nanomolar affinity are provided and indicate an alternative modification of the squaramide scaffold that has been explored extensively by other groups.

Topics: Aminophenols; Chemotaxis; Humans; Inflammation; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8B; Structure-Activity Relationship; Sulfonamides

Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal persistent inflammatory response to noxious environmental stimuli, particularly cigarette smoke. The determinants of the dysregulated immune responses, which play a role both in the onset and continuation of COPD, are largely unknown. We examined several molecular mechanisms regulating the inflammatory pathway, such as cytokine polymorphisms, miRNA expression, and DNA methylation in COPD and aging, with the aim to provide evidence supporting the view that aging of the immune system may predispose to COPD.. The incidence of COPD increases with age. The pathogenesis of the disease is linked to a chronic inflammation and involves the recruitment and regulation of innate and adaptive immune cells. A chronic systemic inflammation characterizes aging and has been correlated with many diseases, most of them age-related.. COPD and aging are associated with significant dysregulation of the immune system that leads to a chronic inflammatory response. The similar molecular mechanisms and the common genetic signature shared by COPD and aging suggest that immunosenescence may contribute to the development of COPD.

Topics: Aged; Aged, 80 and over; Aging; DNA Methylation; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; MicroRNAs; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Smoking; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem. It is predicted by the World Health Organization to become the third most common cause of death and the fifth most common cause of disability in the world by 2020. COPD is a complex inflammatory disease involving several types of inflammatory cells and multiple inflammatory mediators. Although abnormal numbers of inflammatory cells such as macrophages, dendritic cells, neutrophils, and T lymphocytes have been documented in COPD, the relationship between these cell types and the sequence of their appearance and persistence is largely unknown. Alveolar macrophages have been identified as one of the major cell types that plays a key role in orchestrating the inflammatory events associated with the pathophysiology of COPD. One of the major functions of macrophages is the secretion of chemotactic factors and this function is markedly increased on exposure to cigarette smoke (CS). This enhanced release of chemoattractants results in increased lung neutrophil infiltration, which is thought to be a key event in the development of COPD. The molecular basis for this amplified inflammatory response is not very clear, but it could be due to an alteration in signal transduction pathways within the macrophage. Based on existing literature, an attempt has been made to create a comprehensive review of the signal transduction pathways that link the activation of macrophages with the increased recruitment of neutrophils into the airways. Some of the major stimuli that activate macrophages and cause them to secrete chemotactic factors have been identified as CS, wood smoke, ozone, bacterial endotoxin, and proinflammatory cytokines such as interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. These stimuli seem to activate mainly redox-sensitive transcription factors such as nuclear factor (NF)-kappa B and activator protein (AP)-1, both of which play a major role in the synthesis and secretion of chemotactic factors such as IL-8 and leukotriene B(4) (LTB(4)). The pathways involved in the synthesis and secretion of other factors such as macrophage chemotactic protein-1 (MCP-1) and growth-related oncogene-alpha (Gro-alpha) have also been reviewed.

Topics: Animals; Chemotactic Factors; Humans; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Lung; Macrophage Activation; Macrophages, Alveolar; Models, Biological; Neutrophils; Pulmonary Disease, Chronic Obstructive; Risk Factors; Signal Transduction; Smoking; Tumor Necrosis Factor-alpha

Inhaled air is contaminated with pathogens and particulates that may deposit in the airways and damage the host. In response to these invaders, the airway epithelium has developed innate immune responses that provide a defence against the invaders and protect the airway structure and function. Thus, the epithelium of conducting airways becomes the "battleground" between the invaders and the host. Recent evidence suggests that airway epithelial surface signalling through the epidermal growth factor receptor (EGFR) is a convergent pathway producing innate immune responses to a variety of infectious and noninfectious noxious stimuli. In the present review, the EGFR signalling pathways leading to airway mucin production, neutrophil recruitment (via interleukin-8 production) and airway epithelial repair were examined. The importance of these findings in human airway diseases was also investigated. The current authors suggest that the exaggerated innate immune responses found in chronic inflammatory airway diseases (e.g. chronic obstructive pulmonary disease, cystic fibrosis and severe asthma) contribute to the pathogenesis or the aggravation of these diseases. Potential therapies include inhibition of the various elements of the described epidermal growth factor receptor cascade. In considering each therapeutic intervention, the potential benefits must be considered in relation to potential deleterious effects.

Topics: Animals; Asthma; Cystic Fibrosis; ErbB Receptors; Humans; Immunity, Innate; Interleukin-8; Ligands; Models, Biological; Mucins; Neutrophils; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Signal Transduction

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, antiinflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-beta, tumor necrosis factor-alpha, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-kappaB, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.

Topics: Animals; Chemokine CCL2; Chemokine CXCL1; Cytokines; Fibroblast Growth Factors; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-8; Macrophages; Models, Biological; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Transforming Growth Factor beta; Treatment Outcome; Vascular Endothelial Growth Factor A

Morbidity and mortality of chronic obstructive pulmonary disease (COPD) are considerable and still increasing. The disease is gaining increasing socioeconomic importance. The knowledge of underlying mechanisms is of special relevance because of the lack of a curative therapy. Respiratory infections have been identified as the most important triggers of acute exacerbations but recent data suggest that they might also play an important role in COPD pathogenesis. This knowledge might offer new therapeutic perspectives in the future. The aim of this review is, therefore, to describe the inflammatory processes involved and to specify the role of respiratory infections in this context.

Topics: Asthma; Bacterial Infections; Bronchitis; Common Cold; Disease Progression; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Neutrophils; Picornaviridae Infections; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections; Rhinovirus; Tumor Necrosis Factor-alpha

Diagnosis and assessment of treatment effect in chronic obstructive pulmonary disease (COPD) have relied primarily on the examination of a complex set of symptoms and the use of spirometry. However, these methods require long periods of assessment to determine whether patients show clinically relevant improvements after intervention. We therefore wanted to determine how existing clinical and laboratory measures change with COPD severity and identify disease markers that can serve as better endpoints for diagnosis and assessment of COPD progression and treatment effect.. Using standard COPD keywords and terms, we searched PubMed, ISI Web of Science, and Cochrane Review databases for retrospective and prospective clinical studies published since 1966. We identified 652 studies (n = 146,255) from 1978 to September 2003 based on the availability of spirometric and demographic data, investigation of possible markers, absence of acute exacerbations and co-morbidities, and the withdrawal of standard COPD medication. Central tendencies and dispersions of subject baseline measures were collected according to study sample size, smoking status, and mild, moderate and severe COPD stages. A fixed effect meta-analysis was then conducted on each measure at various disease stages.. Arterial oxygen tension, sputum neutrophils and IL-8, and serum TNF-alpha and C-Reactive Protein showed a trend toward separation between COPD stages. Other measures such as pack-years and St George's Respiratory Questionnaire only distinguished between disease and disease-free states.. We observed little separation between disease stages for many measures used in COPD diagnosis and clinical trials. This demonstrates the poor sensitivity of such endpoints to define a patient's clinical status and to quantify treatment effect. Therefore, we recommend that longitudinal studies and disease modelling be the primary methods for assessing whether potential markers of disease progression can be used for COPD diagnosis and clinical trials.

Topics: Biomarkers; C-Reactive Protein; Disease Progression; Humans; Interleukin-6; Interleukin-8; Macrophages; Neutrophils; PubMed; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Severity of Illness Index; Sputum; Tumor Necrosis Factor-alpha

Topics: Adult; Aged; Humans; Interleukin-8; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Smoking

Airway mucus hypersecretion is a serious and presently untreatable symptom of COPD. Over the past several years, emerging evidence has implicated epidermal growth factor receptor (EGFR) expression and activation in mucin production by airway epithelial (goblet) cells. Activated neutrophils recruited to the airways (and their secreted products) play several key roles in EGFR-dependent mucus hypersecretion: (i) activated neutrophils secrete tumor necrosis factor (TNF)-alpha, which induces EGFR expression in airway epithelial cells; (ii) activated neutrophils release reactive oxygen species, which activate EGFR; (iii) neutrophil elastase cleaves the EGFR proligand, pro-transforming growth factor (TGF)-alpha, releasing mature TGF alpha which activates EGFR in a ligand-dependent fashion; and (iv) neutrophil elastase causes potent goblet cell degranulation. The secretion of active products by neutrophils appears carefully regulated. The local release of neutrophil elastase requires close contact between the neutrophil and another cell, mediated by surface adhesion molecules, thus limiting proteolysis to the immediate pericellular environment. In the airway lumen, neutrophils undergo apoptosis and are cleared by macrophages without releasing their intracellular contents. In contrast, neutrophils that die by necrosis disgorge proteases and reactive oxygen species into the lumen. In COPD, conditions within the airway lumen promote neutrophil necrosis. It is concluded that neutrophil death via necrosis leads to the high concentrations of free neutrophil elastase and reactive oxygen species in the sputum of patients with airway neutrophilia and mucus hypersecretion. Inflammatory cells (neutrophils), molecules (neutrophil elastase and reactive oxygen species), signaling pathways (EGFR), and cellular processes (neutrophil necrosis) contribute to mucus hypersecretion in COPD, and are potential targets for therapy. Interventions that target EGFR, neutrophil elastase, and reactive oxygen species exist and can be evaluated as treatments for neutrophil-dependent mucus hypersecretion.

Topics: Antioxidants; ErbB Receptors; Goblet Cells; Humans; Interleukin-8; Models, Biological; Mucins; Myeloblastin; Neutrophils; Protein-Tyrosine Kinases; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Serine Endopeptidases; Serpins

Chronic obstructive pulmonary disease(COPD) is a chronic airway disorder characterized by obstructive airflow limitation which is not completely reversible with treatment. Inflammatory changes in the peripheral airways, especially those with the diameter less than 2 mm(so-called small airway disease) have been speculated to be initial steps of COPD. However, it remains unclear which types of the cells play an essential role in the pathogenesis of these lesions. Studies with bronchoalveolar lavage demonstrated an increase in neutrophil numbers and the neutrophil chemoattractant interleukin-8. Tobacco smoke-induced IL-8 expression in the airway epithelial cells and macrophages results in neutrophil accumulation and activation. Immunohistochemical analysis recently demonstrated that T lymphocytes, especially CD8(+) cells are increased in the pathologic lesions. However, their role in the pathogenesis of inflammatory changes remains unelucidated. Further studies are necessary for the new development of treatment for this progressive lung disease.

Topics: Bronchi; Bronchoalveolar Lavage Fluid; CD8-Positive T-Lymphocytes; Chemotaxis, Leukocyte; Epithelial Cells; Humans; Interleukin-8; Lymphocyte Activation; Macrophages, Alveolar; Neutrophil Activation; Neutrophils; Pulmonary Disease, Chronic Obstructive; Smoking

Neutrophils have been implicated in the pathogenesis of many inflammatory lung diseases, including the acute respiratory distress syndrome, chronic obstructive pulmonary disease and asthma. The CXC chemokine interleukin (IL)-8, is a potent neutrophil recruiting and activating factor and the detection of IL-8 in clinical samples from patients with these diseases has led clinicians to believe that antagonism of IL-8 may be a practicable therapeutic strategy for disease management. Work over the last decade has concentrated on both the molecular mechanisms by which IL-8 is produced in the inflammatory setting and also on the manner in which IL-8 activates the neutrophil. Expression of the IL-8 gene appears to be controlled by several components of the inflammatory milieu. Whilst lipopolysaccharide, IL-1beta and tumor necrosis factor-alpha are capable of augmenting IL-8 production, IL-10 is a potent inhibitor of IL-8 synthesis and appears to play an auto-regulatory role. Regulation of the IL-8 gene is under the control of nuclear factor kappaB which appears to be a primary target for corticosteroid-mediated repression of IL-8 production. IL-8 exerts is effects on neutrophils by binding with high affinity to two receptors on its cell surface, the chemokine receptors CXCR1 and CXCR2. These closely related receptors belong to the superfamily of G-protein coupled receptors, proteins that historically have proved amenable to antagonism by small molecules. The recent descriptions in the literature of highly potent small molecule antagonists of CXCR2 and their success in blocking in vivo trafficking of neutrophils suggest that antagonism of IL-8 at the receptor level is a viable therapeutic strategy. Clinical trials of such compounds will ultimately provide crucial information currently lacking and will define whether or not IL-8 blockade provides future therapy in pulmonary disease.

Topics: Asthma; Humans; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Respiratory Distress Syndrome

Airway inflammation with eosinophils is now reported to occur not only in asthma but in other airway diseases such as cough variant asthma, chronic cough, atopic cough, episodic symptoms without asthma, allergic rhinitis, and COPD. Although the prevalence of eosinophilic bronchitis (EB) is less than in asthma, the causes, mechanisms and treatment of EB in these conditions appears to be similar to asthma where allergen induced IL-5 secretion and symptoms are readily responsive to inhaled corticosteroids. The prognosis of EB without asthma is not known but it may be a precursor for asthma and, if so, recognition of this syndrome may permit effective treatment and reduction in the rising prevalence of asthma. Induced sputum analysis allows recognition of EB in clinical practice. The place of the asthma treatment paradigm with early and sustained corticosteroid treatment needs to be defined in EB without asthma. Airway wall remodelling can occur in rhinitis, COPD, and cough variant asthma with EB. The mechanisms and long term implications of this complication in EB without asthma need to be clarified.

Topics: Asthma; Bronchitis; Chronic Disease; Cough; Eosinophilia; Humans; Interleukin-5; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Rhinitis, Allergic, Perennial

Some patients with COPD are prone to frequent exacerbations, which are an important determinant of health status. Such patients have elevated airway cytokine levels, suggesting the presence of increased inflammation that may increase their susceptibility to exacerbation. The inflammatory response during a COPD exacerbation is variable, but increases in interleukin-6 levels during the exacerbation are related to the presence of a common cold. Rhinovirus infection is the most important etiologic factor in COPD exacerbations and is an important target for preventive therapy. The reduction of COPD exacerbations will have an important impact on the considerable morbidity and mortality associated with COPD.

Topics: Endothelin-1; Environmental Pollution; Humans; Inflammation; Interleukin-6; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections

COPD is a major health problem, with patients showing a progressively declining, largely irreversible, change in lung function. This is associated with chronic airways inflammation and structural remodeling, including loss of alveolar walls, and goblet cell metaplasia with mucus hypersecretion. Inflammatory cells may contribute to the airway remodeling via secretion of proteases, fibrotic or mitogenic growth factors, and cytokines. In turn, airway remodeling may contribute to the clinical symptoms of COPD. Currently available therapies are directed to improvement of clinical symptoms and reduction of the airways inflammation. The commonly used glucocorticosteroids are expected to reduce the inflammation by acting on kinases or transcription factors necessary for expression of pro-inflammatory cytokines or chemokines. However, several long-term and short-term studies showed that glucocorticosteroids are rather ineffective in improving lung function and reducing the airway inflammation in patients with COPD. New therapeutic strategies may reduce the inflammation and alleviate the clinical symptoms of COPD. Tumor necrosis factor-alpha, interleukin-8, and monocyte chemoattractant protein-1 are important chemotactic proteins for macrophages and neutrophils, the predominant inflammatory cells associated with COPD. As lung levels of these cytokines are higher in COPD compared to non-COPD patients, they may represent targets for novel therapies.

Topics: Animals; Chemokine CCL2; Cytokines; Glucocorticoids; Humans; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) is characterized by chronic obstruction of expiratory flow affecting peripheral airways, associated with chronic bronchitis (mucus hypersecretion with goblet cell and submucosal gland hyperplasia) and emphysema (destruction of airway parenchyma), together with fibrosis and tissue damage, and inflammation of the small airways. Cytokines are extracellular signalling proteins. Increased levels of interleukin (IL)-6, IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and IL-8 have been measured in sputum, with further increases during exacerbations, and the bronchiolar epithelium over-expresses monocyte chemotactic protein (MCP)-1 and IL-8. IL-8 can account for some chemotactic activity of sputum, and sputum IL-8 levels correlate with airway bacterial load and blood myeloperoxidase levels. The expression of chemokines such as regulated on activation, normal T-cell expressed and secreted (RANTES) may underlie the airway eosinophilia observed in some COPD patients. Cytokines may be involved in tissue remodelling. TNF-alpha and IL-1beta stimulate macrophages to produced matrix metalloproteinase-9 (MMP-9), and bronchial epithelial cells to produce extracellular matrix glycoproteins such as tenascin. Increased expression of transforming growth factor-beta (TGFbeta) and of epidermal growth factor (EGF) occurs in the epithelium and submucosal cells of patients with chronic bronchitis. TGFbeta and EGF activate proliferation of fibroblasts, while activation of the EGF receptor leads to mucin gene expression. The cytokine profile seen in chronic obstructive pulmonary disease is different from that observed in asthma. The role of these cytokines needs to be defined and there is a potential for anticytokine therapy in chronic obstructive pulmonary disease.

Topics: Cytokines; Eosinophils; Epidermal Growth Factor; Female; Humans; Inflammation; Interleukin-1; Interleukin-8; Male; Prognosis; Pulmonary Disease, Chronic Obstructive; Sensitivity and Specificity; Severity of Illness Index; Transforming Growth Factor beta

This paper's goal is to review the relationship between infections and chronic respiratory disease, with particular reference to periodontal disease. The link between oral diseases in general, periodontal disease, and respiratory disease remains somewhat controversial. However, with cooperation between dentistry and medicine, the nature of the connection between dental and medical pathology can be better defined. An overview of respiratory disease and some of the factors that can contribute to respiratory infection is presented below, with special reference to infections related to aspiration.

Topics: Bacteria; Cough; Deglutition; Humans; Interleukin-8; Lung; Periodontal Diseases; Pneumonia, Aspiration; Pneumonia, Bacterial; Pulmonary Disease, Chronic Obstructive; Respiratory Physiological Phenomena; Respiratory Tract Diseases; Respiratory Tract Infections; Risk Factors; Saliva; Smoking

Several microbiologic and epidemiologic studies have suggested an association between dental plaque, poor oral health, and respiratory diseases such as nosocomial pneumonia and chronic obstructive pulmonary disease (COPD). A number of hypotheses are suggested to help explain how oral bacteria may participate in the pathogenesis of respiratory infection. Resident bacteria in oral secretions are likely aspirated along with respiratory pathogens and may affect the adhesion of the later organisms to the respiratory epithelium. Preliminary studies performed in our laboratory suggest that oral bacteria may modulate the adhesion of respiratory pathogens to epithelial cell lines. In addition, oral bacterial products or cytokines in oral/pharyngeal aspirates may stimulate cytokine production from respiratory epithelial cells, resulting in recruitment of inflammatory cells. The resulting inflamed epithelium may be more susceptible to respiratory infection. Further preliminary data are presented that some species of oral bacteria may induce the release of proinflammatory cytokines from epithelial cell lines to an extent similar to that seen for respiratory pathogens.

Topics: Aggregatibacter actinomycetemcomitans; Analysis of Variance; Bacterial Adhesion; Cell Line; Chemotaxis, Leukocyte; Cytokines; Dental Plaque; Epithelial Cells; Haemophilus influenzae; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Linear Models; Mouth; Pneumonia, Bacterial; Porphyromonas gingivalis; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Respiratory Tract Infections; Streptococcus; Streptococcus pneumoniae; Tumor Necrosis Factor-alpha

Bradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx.. In a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of pulmonary oedema.. After LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups.. Treatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model.. The study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408).

Topics: Albumins; Biomarkers; Bradykinin; Bronchoalveolar Lavage Fluid; Humans; Inflammation; Interleukin-8; Lipopolysaccharides; Pneumonia; Pulmonary Disease, Chronic Obstructive; Smokers

The respiratory system is the first line of defense against outside pollutants. Recently, respiratory health has been receiving increasing attention due to the increase in fine dust, which reduces respiratory function and increases incidence of chronic obstructive pulmonary disease, and in coronavirus pandemic, which can cause severe acute respiratory syndrome.. This clinical pilot trial was designed to secure evidence for a main clinical trial and to confirm the efficacy and safety of Liriope platyphylla (LP) extract for improving respiratory function. We conducted a double-blind randomized placebo-controlled trial with 22 participants from June 30, 2021, to August 25, 2021. The primary outcome was Breathlessness, Cough, and Sputum Scale score. Secondary outcomes included forced vital capacity, forced expiratory volume at 1 second (FEV1), forced expiratory volume at 1 s/forced vital capacity ratio, cough assessment test score, chronic obstructive pulmonary disease assessment test score, peripheral blood mononuclear cell counts (white blood cells, eosinophils, T cells, and B cells), high-sensitivity C-reactive protein level, erythrocyte sedimentation rate, cytokine (interleukin-1β, interleukin-4, tumor necrosis factor-α, interleukin-6, interleukin-8, interferon-γ, and immunoglobulin E) levels, antioxidant (glutathione peroxidase and superoxide dismutase) levels, and nitric oxide level.. A total of 22 participants were randomly assigned to 2 groups: the LP group (n = 11), who took 1000 mg of LP extract per day, and the placebo group, who took 1000 mg of dextrin per day. Participants took 1 capsule twice a day for 4 weeks. For the Breathlessness, Cough, and Sputum Scale, the interaction between group and visit was statistically significant in a blend of analyses of variance. interleukin-8, tumor necrosis factor-α, and interferon-γ levels decreased more in the LP group than in the placebo group. The sample size required for large-scale clinical trials in the future was 50. There were no side effects.. LP extract can enhance respiratory function. The detailed data we obtained support conducting the future main large-scale clinical trial.

Topics: Antioxidants; C-Reactive Protein; Cough; Dextrins; Dust; Dyspnea; Glutathione Peroxidase; Humans; Immunoglobulin E; Interferon-gamma; Interleukin-1beta; Interleukin-4; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Nitric Oxide; Pilot Projects; Plant Extracts; Pulmonary Disease, Chronic Obstructive; Superoxide Dismutase; Tumor Necrosis Factor-alpha

A Chinese herb formula Yufeining (YFN) has showed promise in the treatment of stable chronic obstructive pulmonary disease (COPD), less is known that the impact of YFN in combination with standard Western treatments on lung inflammation. This study evaluated the safety and efficacy of YFN as a treatment for stable COPD and as an anti-inflammatory agent.. Sixty patients with stable COPD were randomly assigned to two treatment groups (YFN treatment, N = 30; placebo treatment, N = 30). Both groups received inhaled steroids and bronchodilators during an 8-week intervention, and patient status was assessed at 8 weeks later and 4 months after treatment. The primary outcome included clinical efficacy. The secondary outcomes involved CAT score, mMRC grade, six-minute walking distance (6MWD). IL-8, TNF-α, IL-17A, LTB4, TGF-β1 and CRP were also detection in peripheral serum, as well as adverse reaction conditions.. The YFN group demonstrated a significant improvement in clinical efficacy (compare 89.3% to 63.3% in the placebo group; P < 0.05). CAT scores and mMRC grades significantly decreased (P < 0.05, P < 0.01), and 6MWD significantly increased (P<0.05), after YFN treatment. The levels of IL-8, TNF-α, LTB4 and CRP decreased significantly after 8 weeks of treatment compared to baseline levels in both groups. Only in the YFN treatment group, the levels of IL-17A decreased significantly after treatment compared to baseline levels (P < 0.05). No changes were observed inTGF-β1 from pre-to post-treatment in either group (P > 0.05). Serum levels of IL-8, TNF-α, IL-17A, LTB4 and CRP decreased significantly after YFN treatment compared to the placebo group (P < 0.05).. A combinatorial treatment approach with YFN, inhaled steroids and bronchodilators produced a clinically effective treatment for stable COPD, leading to a significant decrease in circulating inflammatory mediators. The study appeared YFN was safety.. No. ChiCTR-IOR-17013577.

Topics: Administration, Inhalation; Aged; Anti-Inflammatory Agents; Bronchodilator Agents; C-Reactive Protein; Double-Blind Method; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Interleukin-17; Interleukin-8; Leukotriene B4; Male; Medicine, Chinese Traditional; Middle Aged; Pulmonary Disease, Chronic Obstructive; Steroids; Treatment Outcome; Tumor Necrosis Factor-alpha; Walk Test

In this Beijing Indoor Air Purifier StudY (BIAPSY), we conducted a randomized crossover intervention trial in a panel of 35 non-smoking senior participants with free-living, with and without chronic obstructive pulmonary disease (COPD). Portable air filtration units were randomly allocated to active-(filter in) for 2weeks and sham-mode (filter out) for 2weeks in the households. We examined the differences in indoor air pollutant concentrations in 20 study homes and a suite of cardio-respiratory biomarker levels in study participants between filtration modes, with and without adjustment for potential confounders. Following active filtration, we observed significant reductions from 60±45 to 24±15μg/m

Topics: Aged; Air Pollutants; Air Pollution, Indoor; Beijing; Blood Pressure; Cardiovascular System; Cross-Over Studies; Female; Filtration; Heart Rate; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Particulate Matter; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Respiratory System

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Little is known about the effects of long-term nasal low-flow oxygen (NLFO) on mucus and symptoms and how this variable is affected by dry or cold humidified gas. The aim of this study was to investigate the effects of dry-NLFO and cold bubble humidified-NLFO on nasal mucociliary clearance (MCC), mucus properties, inflammation, and symptoms in subjects with chronic hypoxemia requiring long-term domiciliary oxygen therapy.. Eighteen subjects (mean age, 68 years; 7 male; 66% with COPD) initiating NLFO were randomized to receive dry-NLFO (n = 10) or humidified-NLFO (n = 8). Subjects were assessed at baseline, 12 h, 7 days, 30 days, 12 months, and 24 months by measuring nasal MCC using the saccharin transit test, mucus contact angle (surface tension), inflammation (cells and cytokine concentration in nasal lavage), and symptoms according to the Sino-Nasal Outcome Test-20.. Nasal MCC decreased significantly (40% longer saccharin transit times) and similarly in both groups over the study period. There was a significant association between impaired nasal MCC and decline in lung function. Nasal lavage revealed an increased proportion of macrophages, interleukin-8, and epidermal growth factor concentrations with decreased interleukin-10 during the study. No changes in the proportion of ciliated cells or contact angle were observed. Coughing and sleep symptoms decreased similarly in both groups. There were no outcome differences comparing dry vs cold bubble humidified NLFO.. In subjects receiving chronic NLFO, cold bubble humidification does not adequately humidify inspired oxygen to prevent deterioration of MCC, mucus hydration, and pulmonary function. The unheated bubble humidification performed no better than no humidification.. ClinicalTrials.gov; No.: NCT02515786; URL: www.clinicaltrials.gov.

Topics: Aged; Aged, 80 and over; Bronchiectasis; Cough; Cytokines; Disease Progression; Epidermal Growth Factor; Female; Humans; Humidifiers; Humidity; Hypertension, Pulmonary; Interleukin-10; Interleukin-8; Macrophages; Male; Middle Aged; Mucociliary Clearance; Mucus; Nasal Lavage Fluid; Oxygen Inhalation Therapy; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Respiratory Function Tests; Surface Tension

COPD is characterized by chronic inflammation. In vitro and ex vivo observations suggest that this inflammatory response is partially resistant to the effect of corticosteroids and that low-dose theophylline can restore this response via enhancement of histone deacetylase (HDAC) activity. Whether this occurs in vivo and what its potential clinical consequences are is unclear.. The objective of this trial was to determine whether low-dose theophylline on top of inhaled long-acting β2-agonists and inhaled corticosteroids (ICS) in patients with COPD (1) enhances HDAC activity and the antiinflammatory effects of ICS in vivo, (2) reduces the concentration of inflammatory markers, and (3) reduces exacerbation frequency.. In this prospective, double-blind, placebo-controlled clinical trial, we randomized patients with COPD (FEV1 < 50% predicted plus at least one hospitalization due to exacerbation in the previous year) to ICS plus theophylline 100 mg bid or matched placebo. We determined the following at baseline and at the end of 52 weeks of follow-up: (1) HDAC activity in blood monocytes and sputum macrophages, (2) the concentration of several inflammatory markers (IL-8, IL-6, IL-1β, and tumor necrosis factor -α) in serum and sputum supernatant, and (3) the rates of exacerbations and adverse effects.. Seventy patients were randomized-36 to theophylline and 34 to placebo. HDAC activity and inflammatory marker levels were not different in the two arms either at baseline or after 52 weeks. Likewise, the rate of exacerbations during follow-up was similar in both groups.. The combination of low-dose oral theophylline and ICS did not enhance the antiinflammatory properties of ICS in vivo or influence exacerbation rate.. ClinicalTrials.gov; No.: NCT01599871; URL: www.clinicaltrials.gov.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Anti-Inflammatory Agents; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Symptom Flare Up; Theophylline; Treatment Outcome

Corticosteroids have been shown to improve the outcome of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, whether inhaled corticosteroids (IC) alone have similar effects with systemic corticosteroid (SCS) is still unclear.. To compare the efficacy of inhaled budesonide and systemic methylprednisolone on systemic inflammation of AECOPD.. 30 AECOPD patients were randomly divided into two group. Budesonide group (15 cases) were treated with inhaled budesonide (3 mg Bid); methylprednisolone group (15 cases) were treated with systemic methylprednisolone (methylprednisolone acetate injectable suspension 40 mg Qd for three days and then methylprednisolone tablets 8 mg Bid). Observe symptoms, lung function, blood gas analysis and adverse effects of the patients in two groups. Peripheral blood samples were collected before and after treatment for 1 day, 4 days and 7 days. Interleukin-8 (IL-8) and TNF-α levels were determined by an enzyme linked immunosorbent assay (ELISA). Hs-CRP levels were detected by automatic biochemical analyzer. Western blotting was used to determine histone deacetylase 2 (HDAC2) protein expression.. Symptoms, pulmonary function and blood gas analysis were significantly improved after treatment in the two groups (P < 0.05) and no significant differences between the two groups (P > 0.05). There were no significant differences of IL-8, TNF-α and hs-CRP levels in the two groups (P > 0.05). Besides, the levels of HDAC2 protein expression before treatment were significantly lower comparing to that after treatment for 4 and 7 days. Incidence of adverse events (heart rate, blood pressure, glycemic, sleep condition, gastrointestinal symptoms) in budesonide group was lower than methylprednisolone group (P < 0.05).. Inhaled budesonide and systemic methylprednisolone have the same effects on systemic inflammation of AECOPD. Inhaled corticosteroid alone could instead systemic corticosteroid in AECOPD treatment.

Topics: Aged; Anti-Inflammatory Agents; Blood Gas Analysis; Budesonide; C-Reactive Protein; Drug Administration Routes; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Interleukin-8; Male; Methylprednisolone; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Severity of Illness Index; Tumor Necrosis Factor-alpha

More than two-fifths of the world's population uses solid fuels, mostly biomass, for cooking. The resulting biomass smoke exposure is a major cause of chronic obstructive pulmonary disease (COPD) among women in developing countries.. To assess whether lower woodsmoke exposure from use of a stove with a chimney, compared to open fires, is associated with lower markers of airway inflammation in young women.. We carried out a cross-sectional analysis on a sub-cohort of participants enrolled in a randomized controlled trial in rural Guatemala, RESPIRE.. We recruited 45 indigenous women at the end of the 18-month trial; 19 women who had been using the chimney stove for 18-24 months and 26 women still using open fires.. We obtained spirometry and induced sputum for cell counts, gene expression of IL-8, TNF-α, MMP-9 and 12, and protein concentrations of IL-8, myeloperoxidase and fibronectin. Exhaled carbon monoxide (CO) and 48-hr personal CO tubes were measured to assess smoke exposure.. MMP-9 gene expression was significantly lower in women using chimney stoves. Higher exhaled CO concentrations were significantly associated with higher gene expression of IL-8, TNF-α, and MMP-9. Higher 48-hr personal CO concentrations were associated with higher gene expression of IL-8, TNF- α, MMP-9 and MMP-12; reaching statistical significance for MMP-9 and MMP-12.. Compared to using an open wood fire for cooking, use of a chimney stove was associated with lower gene expression of MMP-9, a potential mediator of airway remodeling. Among all participants, indoor biomass smoke exposure was associated with higher gene expression of multiple mediators of airway inflammation and remodeling; these mechanisms may explain some of the observed association between prolonged biomass smoke exposure and COPD.

Topics: Adult; Air Pollutants; Carbon Monoxide; Cohort Studies; Cross-Sectional Studies; Female; Fibronectins; Guatemala; Humans; Inflammation; Interleukin-8; Matrix Metalloproteinase 12; Matrix Metalloproteinase 9; Peroxidase; Pulmonary Disease, Chronic Obstructive; Rural Population; Smoke; Spirometry; Tumor Necrosis Factor-alpha; Young Adult

The study aims to evaluate the efficacy and safety of two Chinese herbal formulae for the treatment of stable COPD.. A multicenter, double-blind, double-dummy, and randomized controlled trial (RCT) was conducted. All groups were treated with additional conventional medicines. There were a 6-month treatment and a 12-month follow-up for 5 times. Primary outcomes included lung function test, exacerbation frequency, score of SGRQ. Second outcomes consisted of 6MWD, BODE index, psychological field score, inflammatory factors and cortisol.. A total of 331 patients were randomly divided into two active treatment groups (Bushen Yiqi (BY) granule group, n = 109; Bushen Fangchuan (BF) tablet group, n = 109) and a placebo group (n = 113). Finally 262 patients completed the study. BY granule & BF tablet increased the values of VC, FEV1 (%) and FEV1/FVC (%), compared with placebo. BY granule improved PEF. Both treatments reduced acute exacerbation frequency (P = 0.067), BODE index and psychological field score, while improved 6MWD. In terms of descent rang of SGRQ score, both treatments increased (P = 0.01). Both treatments decreased inflammatory cytokines, such as IL-8, and IL-17(P = 0.0219). BY granule obviously descended IL-17(P<0.05), IL-1β (P = 0.05), IL-6, compared with placebo. They improved the level of IL-10 and cortisol. BY granule raised cortisol (P = 0.07) and decreased TNF-α. Both treatments slightly descended TGF-β1. In terms of safety, subject compliance and drug combination, there were no differences (P>0.05) among three groups.. BY granule and BF tablet were positively effective for the treatment of COPD, and the former performed better in general.. Chinese Clinical Trial Register center ChiCTR-TRC-09000530.

Topics: Adult; Aged; Double-Blind Method; Drugs, Chinese Herbal; Female; Humans; Interleukin-10; Interleukin-17; Interleukin-6; Interleukin-8; Male; Medicine, Chinese Traditional; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Chronic Obstructive Pulmonary Disease (COPD) is a progressive airway disease characterised by neutrophilic airway inflammation or bronchitis. Neutrophilic bronchitis is associated with both bacterial colonisation and lung function decline and is common in exacerbations of COPD. Despite current available therapies to control inflammation, neutrophilic bronchitis remains common. This study tested the hypothesis that azithromycin treatment, as an add-on to standard medication, would significantly reduce airway neutrophil and neutrophils chemokine (CXCL8) levels, as well as bacterial load. We conducted a randomised, double-blind, placebo-controlled study in COPD participants with stable neutrophilic bronchitis.. Eligible participants (n = 30) were randomised to azithromycin 250 mg daily or placebo for 12 weeks in addition to their standard respiratory medications. Sputum was induced at screening, randomisation and monthly for a 12 week treatment period and processed for differential cell counts, CXCL8 and neutrophil elastase assessment. Quantitative bacteriology was assessed in sputum samples at randomisation and the end of treatment visit. Severe exacerbations where symptoms increased requiring unscheduled treatment were recorded during the 12 week treatment period and for 14 weeks following treatment. A sub-group of participants underwent chest computed tomography scans (n = 15).. Nine participants with neutrophilic bronchitis had a potentially pathogenic bacteria isolated and the median total bacterial load of all participants was 5.22×107 cfu/mL. Azithromycin treatment resulted in a non-significant reduction in sputum neutrophil proportion, CXCL8 levels and bacterial load. The mean severe exacerbation rate was 0.33 per person per 26 weeks in the azithromycin group compared to 0.93 exacerbations per person in the placebo group (incidence rate ratio (95%CI): 0.37 (0.11,1.21), p = 0.062). For participants who underwent chest CT scans, no alterations were observed.. In stable COPD with neutrophilic bronchitis, add-on azithromycin therapy showed a trend to reduced severe exacerbations sputum neutrophils, CXCL8 levels and bacterial load. Future studies with a larger sample size are warranted.. Australian New Zealand Clinical Trials Registry ACTRN12609000259246.

Topics: Adult; Aged; Anti-Bacterial Agents; Azithromycin; Double-Blind Method; Female; Humans; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Sputum

Moderate-intensity exercise training improves skeletal muscle aerobic capacity and increased oxidative enzyme activity, as well as exercise tolerance in COPD patients.. To investigate whether the home-based exercise training program can reduce inflammatory biomarkers in patients with COPD, twelve patients using mobile phone assistance and 14 with free walk were assessed by incremental shuttle walk test (ISWT), spirometry, strength of limb muscles, and serum C-reactive protein (CRP) and inflammatory cytokines.. Patients in the mobile phone group improved their ISWT walking distance, with decrease in serum CRP after 2 months, and sustained at 6 months. Patients in the control group had no improvement. Serum IL-8 in the mobile phone group was significantly reduced at 2, 3 and 6 months after doing home exercise training compared to baseline. IL-6 and TNF-α were significantly elevated at 3 and 6 months in control group, while there were no changes in mobile phone group. The strength of limb muscles was significantly greater compared to baseline at 3 and 6 months in the mobile phone group.. A mobile-phone-based system can provide an efficient home endurance exercise training program with improved exercise capacity, strength of limb muscles and a decrease in serum CRP and IL-8 in COPD patients. Decreased systemic inflammation may contribute to these clinical benefits. (Clinical trial registration No.: NCT01631019).

Topics: Aged; Biomarkers; C-Reactive Protein; Cell Phone; Cytokines; Exercise Test; Exercise Therapy; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Mobile Applications; Muscle Strength; Muscle, Skeletal; Physical Conditioning, Human; Physical Endurance; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Spirometry; Tumor Necrosis Factor-alpha; Walking

To study the therapeutic effect Bufei granule, which is a traditional Chinese drug that can enhance the immune function of the lung, on patients with stable chronic obstructive pulmonary disease (COPD).. This is a randomized, double blinded, placebo-controlled, and multicenter clinical study. Three medical centers in Tianjin, China, participated in the trial. A total of 140 patients with stable COPD were enrolled and randomized into two groups, with 70 patients in each. The treatment group was treated with Bufei granule, while the control group received Bufei placebo. The pharmacological treatment lasted for 12 weeks from the date of enrollment. Then, the indexes of patients were observed. Data were analyzed to study the effect of Bufei granule, with the frequency of acute exacerbation as the primary outcome. Traditional Chinese Medicine syndromes, Modified British Medical Research Council dyspnea scale score, St. George's respiratory questionnaire scores, pulmonary function, and serum inflammatory marker levels [including interleukin-6 (IL-6), interleukin-8, tumor necrosis factor-alpha, and transformation growth factor-beta1] were the secondary outcomes.. During the 12-week treatment, treatment and control groups had no adverse reactions. The analysis of the indexes obtained from all patients showed that the therapeutic effect in the treatment group was significantly better than that in the control group because most of the similar probabilities of primary and secondary outcomes were less than 0.05, except for the level of IL-6.. Bufei granule can treat patients with stable COPD by lowering the frequency of acute exacerbation, improving the quality of life, and alleviating the severity of inflammation.

Topics: Adult; China; Drugs, Chinese Herbal; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Young Adult

Selectins, a family of cell adhesion molecules, are involved in leukocyte extravasation to sites of inflammation. We investigated the safety and efficacy of the inhaled pan-selectin antagonist Bimosiamose in patients with chronic obstructive pulmonary disease (COPD). 77 COPD patients (mean forced expiratory volume in 1 s, 57% pred.) were enrolled in a cross-over, double-blind, randomized, Placebo-controlled, multi-center trial. Bimosiamose (10 mg) or Placebo was inhaled twice daily via the breath actuated nebulizer Akita2 Apixneb™ for 28 days on top of standard bronchodilator therapy. Efficacy was assessed by measurement of inflammatory parameters in induced sputum (differential cell count, interleukin-8, matrix-metalloproteinase-9, myeloperoxidase) and lung function at day 28 of both treatment periods. The total adverse event ratio of Bimosiamose compared to Placebo treatment was balanced. Compared to Placebo, treatment with Bimosiamose led to a decrease of the interleukin-8 concentration (-9.49 ng/mL, 95%CI -18.8 to -2.7 ng/mL, p = 0.008), for the neutrophil count a difference of -0.368 × 10(6) cells/mL (95%CI -1.256 to 0.407 × 10(6)/mL, p = 0.313) was found. The macrophage count decreased by -0.200 × 10(6) cells/mL (95%CI -0.365 to -0.044 × 10(6) cells/mL, p = 0.012). Most lung function parameters showed a small numeric increase. Inhalation of Bimosiamose for 28 days was safe and well tolerated in patients with COPD. It led to an attenuation of airway inflammation (EudraCT 2009-017257-35; NCT ID: NCT01108913).

Topics: Administration, Inhalation; Aged; Asthma; Cross-Over Studies; Double-Blind Method; Female; Hexanes; Humans; Interleukin-8; Male; Mannose; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Selectins

Epidemiological evidence supports a positive relationship between fruit and vegetable (FV) intake, lung function and chronic obstructive pulmonary disease (COPD). Increasing FV intake may attenuate the oxidative stress and inflammation associated with COPD. An exploratory randomised controlled trial to examine the effect of increased consumption of FV on oxidative stress and inflammation in moderate-to-severe COPD was conducted. 81 symptomatically stable patients with a habitually low FV intake (two or fewer portions of FV per day) were randomised to the intervention group (five or more portions of FV per day) or the control group (two or fewer portions of FV per day). Each participant received self-selected weekly home deliveries of FV for 12 weeks. 75 participants completed the intervention. There was a significant between-group change in self-reported FV intake and biomarkers of FV intake (zeaxanthin (p = 0.034) and β-cryptoxanthin (p = 0.015)), indicating good compliance; post-intervention intakes in intervention and control groups were 6.1 and 1.9 portions of FV per day, respectively. There were no significant changes in biomarkers of airway inflammation (interleukin-8 and myeloperoxidase) and systemic inflammation (C-reactive protein) or airway and systemic oxidative stress (8-isoprostane). This exploratory study demonstrated that patients with moderate-to-severe COPD were able to comply with an intervention to increase FV intake; however, this had no significant effect on airway or systemic oxidative stress and inflammation.

Topics: Aged; Aged, 80 and over; Anticarcinogenic Agents; Biomarkers; C-Reactive Protein; Cryptoxanthins; Diet; Dinoprost; Feeding Behavior; Female; Fruit; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Oxidative Stress; Patient Compliance; Peroxidase; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Sputum; Vegetables; Xanthophylls; Zeaxanthins

Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).. Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p<0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice.. Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.

Topics: Biomarkers; C-Reactive Protein; Cohort Studies; Cross-Sectional Studies; Fibrinogen; Humans; Interleukin-6; Interleukin-8; Leukocyte Count; Phenotype; Pulmonary Disease, Chronic Obstructive; Smoking; Spirometry; Surveys and Questionnaires; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Interleukin-8 (IL-8/CXCL8) is an important neutrophil chemoattractant known to be elevated in the airways of cigarette smokers and in patients with chronic obstructive pulmonary disease (COPD). We examined the acute effect of aqueous cigarette smoke extract (CSE) on IL-8 expression in primary human pulmonary cells, in particular in normal human bronchial smooth muscle cells (HBSMCs). IL-8 mRNA levels increased upon CSE exposure in a concentration- and time-dependent manner, and such an effect was accompanied by IL-8 secretion. CSE-evoked elevation of IL-8 mRNA was mimicked by its component acrolein. Both CSE and acrolein induced p38 mitogen-activated protein kinase (MAPK) phosphorylation, accompanied by the phosphorylation of MAPK-activated kinase 2 (MK2), a known downstream substrate of the p38 MAPK, both in HBSMCs and in human airway epithelial cells. Furthermore, pharmacological inhibition of p38 MAPK or MK2 strongly accelerated the decay of IL-8 mRNA levels upon stimulation with CSE or acrolein and subsequent blockade of mRNA neosynthesis with actinomycin D in pulmonary structural cells (HBSMCs and airways epithelial cells) as well as in human alveolar macrophages. Conversely, pharmacological inhibition of ERK1/2 signaling inhibited CSE-induced steady-state levels of IL-8 mRNA without affecting mRNA stability, thus suggesting inhibition at the transcriptional level. In sum, p38 MAPK/MK2 signaling is an important posttranscriptional mechanism underlying upregulation of IL-8 mRNA levels elicited by CSE and acrolein. Given the pivotal role of IL-8 in neutrophil chemotaxis and activation, our results shed light on the mechanisms through which cigarette smoke can initiate inflammation in the lung.

Topics: Acrolein; Bronchi; Cells, Cultured; Chemotaxis; Dactinomycin; Epithelial Cells; Female; Humans; Interleukin-8; Intracellular Signaling Peptides and Proteins; Male; MAP Kinase Signaling System; Middle Aged; Myocytes, Smooth Muscle; Neutrophil Activation; Neutrophils; Nucleic Acid Synthesis Inhibitors; p38 Mitogen-Activated Protein Kinases; Pneumonia; Protein Serine-Threonine Kinases; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; RNA Stability; RNA, Messenger; Tobacco Smoke Pollution

A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility.. To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD.. GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10(-8)), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated.. Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009-0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001-0.049), although these COPD associations were not replicated in two additional cohorts.. Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

Topics: C-Reactive Protein; Female; Fibrinogen; Genetic Markers; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Quantitative Trait Loci; Tumor Necrosis Factor-alpha; Uteroglobin

Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD.. Twenty-eight patients (age 58 ± 7.8 yr, packyears 40 ± 15.5, post-bronchodilator FEV1 77 ± 14.0%predicted, no inhaled steroids ≥4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum.. There was a positive correlation between RDR to mannitol and eosinophil numbers (r = 0.47, p = 0.03) and level of IL-8 (r = 0.46, p = 0.04) in hypertonic saline-induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r = 0.71, p = 0.001), level of ECP (r = 0.72, p = 0.001), IL-8 (r = 0.57, p = 0.015) and MPO (r = 0.64, p = 0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum.. In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD.. Netherlands Trial Register (NTR): NTR1283.

Topics: Administration, Inhalation; Aged; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchoconstriction; Cross-Sectional Studies; Female; Forced Expiratory Volume; Humans; Inflammation Mediators; Interleukin-8; Male; Mannitol; Middle Aged; Netherlands; Peroxidase; Pneumonia; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Pulmonary Eosinophilia; ROC Curve; Severity of Illness Index; Sputum; Treatment Outcome

Our recent studies showed that one session of transcutaneous electrical nerve stimulation on acupoints (Acu-TENS) improved forced expiratory volume in 1s (FEV(1)) in patients with chronic obstructive pulmonary disease (COPD). This study investigated the effect of 4-week Acu-TENS on physical and psychosocial function in these patients. Twenty-eight patients were randomly allocated to receive 4-weeks of 45-min, 5-days/week, of either Acu-TENS (over Dingchuan), Placebo-TENS (same protocol without electrical output), or Sham-TENS (over the patellae). Variables measured before and after intervention included FEV(1), forced vital capacity (FVC), 6-min walk distance (6MWD), St. George's Respiratory Questionnaire score (SGRQ), beta-endorphin and blood inflammatory marker levels. Only the Acu-TENS group attained significant improvement in FEV(1) (p=0.046), physical activity (p=0.007) and total SGRQ score (p=0.028). The increase in beta-endorphin (p=0.012) correlated positively with the improvement in FEV(1) (r=0.526, p=0.008). To conclude, 4 weeks of Acu-TENS improved the functional capacity of patients with COPD, probably due to the bronchodilation induced by beta-endorphin elevation.

Topics: Acupuncture Points; Aged; Analysis of Variance; beta-Endorphin; C-Reactive Protein; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Interleukin-8; Male; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Surveys and Questionnaires; Time Factors; Transcutaneous Electric Nerve Stimulation; Treatment Outcome; Tumor Necrosis Factor-alpha; Vital Capacity

The first aim of this study was to investigate the effects of nutritional supplementation combined with low-intensity exercise on body components, exercise tolerance, and health-related quality of life (HRQOL) in malnourished patients with COPD. The second aim of this study was to examine the degree of systemic inflammation and the actual changes in levels of systemic CRP, TNFα, IL-6 and IL-8 actual changes after a combination of nutritional supplementation and low-intensity exercise in these patients.. A prospective randomized trial.. Thirty-two moderate to severe, clinically stable malnourished COPD patients.. Patients were randomly divided into a nutritional supplementation with low-intensity exercise group and a control group. Lung function, maximum inspiratory and expiratory muscle force, the Chronic Respiratory Disease Questionnaire (CRQ), the 6-min walking distance (6MWD), and the Borg scale were measured at baseline and were re-assessed at 3 months after intervention. The degree of systemic inflammation and the changes in levels of systemic CRP, TNFα, IL-6 and IL-8 were assessed before and after a combination nutritional supplementation with low-intensity exercise.. Body weight and FFM increased significantly after 12 weeks of nutritional supplementation therapy in patients with COPD. The dietary intake energy increased and the REE:REEpred ratio decreased significantly in the nutrition with low-intensity exercise group. PI(max), Quadriceps muscle force and the 6-min walking distance (6MWD) increased significantly from baseline through week 12. Health status, as assessed by CRQ, improved in the domains of dyspnea and total sores significantly in the nutrition with low-intensity exercise group after intervention. In this group, hsCRP, IL-6, IL-8, and TNFα, decreased significantly after intervention compared with the control group.. The combination of nutritional supplementation with low-intensity exercise training was successful in increasing weight and energy intake as well as exercise capacity and health-related QOL in our patients. Moreover, REE and major inflammatory cytokines decreased significantly after nutritional supplementation with low-intensity exercise training. The present study results suggest a potential role for the combination of nutritional supplementation and low-intensity exercise in the management of malnourished patients with COPD.

Topics: Aged; Body Weight; Dietary Supplements; Exercise Tolerance; Female; Humans; Interleukin-6; Interleukin-8; Japan; Male; Malnutrition; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Surveys and Questionnaires; Tumor Necrosis Factor-alpha

The anti-inflammatory effects of salmeterol/fluticasone (SFP), tiotropium/fluticasone (Tio+FP) and tiotropium (Tio) alone were investigated on the inflammatory cells and mediators in sputum induced from chronic obstructive pulmonary disease patients. Subjects were either newly diagnosed or had not taken any medication for 3 months prior to the study. Subjects (n = 99) were randomised (not double blinded) and received either SFP (100/1,000 microg daily), Tio+FP (18/1,000 microg daily) or Tio (18 microg daily) for 12 weeks. Induced sputum and serum C-reactive protein (CRP) were analysed prior to and at the end of treatment. The results showed that treatment with SFP caused a significant reduction in interleukin (IL)-8 and matrix metalloprotease (MMP)-9 in induced sputum, compared with treatment with Tio alone. There were no treatment differences between the SFP and Tio+FP groups in decreasing IL-8 and MMP-9 levels. The reduction in IL-8 showed significant association with the reduction in MMP-9. All treatment groups failed to significantly reduce the numbers of total cells, neutrophils, macrophages and eosinophils in induced sputum; in addition, there were no treatment differences in terms of improvement of forced expiratory volume in one second, forced vital capacity, CRP or quality of life between the three groups. The anti-inflammatory effects of salmeterol/fluticasone probably contribute to the clinical benefits seen in chronic obstructive pulmonary disease patients.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Biomarkers; C-Reactive Protein; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Fluticasone; Humans; Inflammation; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Sputum; Tiotropium Bromide

To explore the effects of Tanreqing injection, a traditional Chinese herbal preparation for clearing heat and resolving phlegm, in treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) by improving airway inflammation and airway mucus hypersecretion.. A randomized controlled trial (RCT) was designed. Ninety AECOPD patients were randomly divided into Tanreqing group, ambroxol hydrochloride group and control group. The patients in the three groups were all treated with conventional therapy. Furthermore, intravenous drip infusion of 20 ml Tanreqing injection (once daily) and 15 mg ambroxol hydrochloride injection (twice daily) were administered respectively to the patients in the Tanreqing group and ambroxol hydrochloride group. They were all treated for 10 days. Symptom score of traditional Chinese medicine (TCM), plasma concentrations of interleukin-8 (IL-8), IL-10 and neutrophil elastase (NE) were detected before and after treatment.. Cough, sputum amount, expectoration, dyspnea, fever, coated tongue and pulse tracings were improved obviously in Tanreqing group (P<0.05), and the effects of Tanreqing on improving cough, sputum amount and expectoration were better than the conventional therapy (P<0.05), while there was no significant difference between Tanreqing group and ambroxol hydrochloride group (P>0.05). Compared with ambroxol hydrochloride group and the control group, the coated tongue was improved obviously in Tanreqing group (P>0.05). After treatment, plasma concentrations of IL-8, IL-10 and NE were decreased in Tanreqing group and ambroxol hydrochloride group (P<0.05), and the levels of IL-8 and IL-10 in the control group were decreased (P<0.05). The change of IL-8 level before and after treatment in Tanreqing group was greater than that in ambroxol hydrochloride group and the control group. The changes of IL-10 and NE levels in ambroxol hydrochloride group were greater than those in Tanreqing group and the control group, while there was no significant difference in the changes of serum levels of IL-8, IL-10 and NE among the three groups (P>0.05). Total response rates in Tanreqing group and ambroxol hydrochloride group were higher than that in the control group (P<0.05), while there was no significant difference in total response rate between Tanreqing group and ambroxol hydrochloride group (P>0.05). There was no significant difference in total response rate among the three groups (P>0.05).. Tanreqing injection can improve TCM signs and symptoms in AECOPD patients, and the mechanism maybe due to the decrease of serum levels of IL-8 and NE and improvement of IL-10 level.

Topics: Aged; Ambroxol; Anti-Inflammatory Agents; Diagnosis, Differential; Drug Therapy, Combination; Drugs, Chinese Herbal; Expectorants; Female; Humans; Interleukin-10; Interleukin-8; Leukocyte Elastase; Male; Medicine, Chinese Traditional; Middle Aged; Mucus; Phytotherapy; Pulmonary Disease, Chronic Obstructive

A subset of patients with chronic obstructive pulmonary disease (COPD) may respond more favorably to inhaled corticosteroids (ICS), but no simple method is currently utilized to predict the presence or absence of ICS responses in patients with COPD.We evaluated the ability of exhaled nitric oxide (FENO) and serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], and interleukin-8 [IL-8]) to independently predict spirometric responses to ICS in patients with COPD.. Among 60 ex-smokers with severe COPD (mean FEV1 1.07 L, 36% of predicted), we conducted a single-arm, open-label study. Participants spent four weeks free of any ICS, followed by four weeks of ICS use (fluticasone propionate 500 mcg twice daily). FENO, CRP, IL-6, IL-8, and pre-bronchodilator spirometry were measured immediately before and after the four weeks of ICS use.. Baseline FENO, CRP, IL-6, and IL-8 showed no correlations to FEV1 responses to ICS. ICS responders (increase in FEV1 > or = 200 mL after four weeks of ICS) did have significantly higher baseline FENO levels compared with non-responders (46.5 parts per billion [ppb] vs. 25 ppb, p = 0.028). The receiver operating characteristic curve for FENO to discriminate responders from non-responders had an area under curve of 0.72. Baseline serum inflammatory markers did not differ between responders and non-responders.. In ex-smokers with severe COPD, a measure of local pulmonary inflammation, FENO, may be more closely associated with FEV1 responses to four weeks of ICS than are standard markers of systemic inflammation, serum CRP, IL-6, and IL-8.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Biomarkers; Bronchodilator Agents; C-Reactive Protein; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Nitric Oxide; Prospective Studies; Pulmonary Disease, Chronic Obstructive; ROC Curve; Salmeterol Xinafoate; Severity of Illness Index; Spirometry

Airway inflammation plays a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Endogenous hydrogen sulfide (H2S) is involved in the physiological and pathophysiological process in systemic inflammation and may be involved in the pathogenesis of airway inflammation and airflow obstruction in COPD. The non-selective phosphodiesterase inhibitor theophylline has bronchodilator/anti-inflammatory properties and is widely used in the treatment of airways diseases. It is not fully understood whether endogenous H2S mediates the mechanism of theophylline anti-inflammatory effect.. The effect of short-term theophylline treatment on airway inflammation and endogenous H2S production was prospectively studied in thirty-seven patients with stable COPD. Patients were randomly divided into theophylline-treatment group (nineteen patients, orally given sustained theophylline tablets for 1 month, 0.2g, q 12h) and control group (eighteen patients, not given any theophylline). Symptom score, lung function, total and differential cell counts in sputum, serum H2S and nitric oxide (NOx) levels, sputum and serum IL-8 levels were measured at baseline and 1 month later.. No significant difference was found in symptom scores, lung function and other investigated experimental parameters at baseline between treatment and control groups, and between baseline and a month follow-up in control patients. Symptom scores were significantly lowered only in the treated patients after treatment, compared with those before (P<0.01). The proportion of neutrophils in sputum was significantly decreased (P<0.05) while that of macrophages was markedly increased (P<0.01) in the treated patients after treatment, compared with that before. No significant change was found in serum H2S and NOx levels, serum and sputum IL-8 levels before and after experiment in treatment group. Serum H2S level correlated positively with percentage of predicted FEV1 (r=0.465, P=0.005), and with proportion of sputum macrophages (r=0.349, P=0.05), but negatively with proportion of sputum neutrophils (r=-0.351, P=0.049) in all patients at baseline.. Short-term theophylline treatment improved symptoms and decreased sputum neutrophils in COPD, while serum H2S levels were not affected in our study population. Large samples will be needed to illustrate the effect of long-term theophylline treatment on inflammatory mediators and H2S generation in COPD.

Topics: Aged; Blood Cell Count; Bronchodilator Agents; Female; Humans; Hydrogen Sulfide; Interleukin-8; Male; Middle Aged; Nitric Oxide; Phosphodiesterase Inhibitors; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum; Theophylline

Anti-oxidant interventions consist in reduction of direct oxidant damage by removing oxidant agents and/or by supplementing reducing agents with anti-oxidant effects.. Aim of the present study was to investigate the anti-oxidant effects of erdosteine, a recent drug currently used in chronic obstructive pulmonary disease (COPD) for its rheological activity. At present, no data are available on current smokers with COPD to our knowledge.. Two groups of 10 persons matched for sex; age (65.0 yr+/-8.4 S.D. and 65.3 yr+/-6.5 S.D.); basal FEV1 (88.7% pred +/-6.8 S.D. and 85.2% pred +/-5.8 S.D.); and cigarette consumption (25.4 pack/yr+/-3.5 S.D. and 28.1 pack/yr+/-2.3 S.D.) entered a controlled, double blind, parallel groups study. They were randomized to receive erdosteine 600 mg daily or placebo for 10 days. IL-6; IL-8; TNFalpha were measured in bronchial secretions in bsln, after 4, 7, and 10 days of Erdosteine or placebo; e-NO and both ROS and 8-Isoprostane in blood were also measured at the same experimental times.. ANOVA: a t-test with Bonferroni correction; p<0.05 was accepted.. Blood ROS and IL-8 in bronchial secretions dropped significantly following erdosteine starting from day 4 (both p<0.01), while 8-isoprostane drop was significant only after day 10 (p<0.02), and the e-NO decrease proved evident but not significant. No significant changes were observed in the placebo group.. Erdosteine affects substantially some pro-inflammatory cytokines specifically involved in oxidative stress in current smokers with mild COPD. Effects appeared differently time-dependent. Further long-term studies are needed to confirm these pilot data and to assess their long-term clinical relevance.

Topics: Aged; Analysis of Variance; Antioxidants; Breath Tests; Bronchi; Cytokines; Dinoprost; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Nitric Oxide; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Smoking; Thioglycolates; Thiophenes; Time Factors; Tumor Necrosis Factor-alpha

The non-selective phosphodiesterase inhibitor theophylline has bronchodilator/anti-inflammatory properties and is widely used in the treatment of airways diseases. We determined the effect of long-term theophylline treatment on airway inflammation in patients with chronic obstructive pulmonary disease (COPD).. Seventeen stable COPD patients were enrolled in the 12-month study. Theophylline was administered at 400mg/day. We studied changes in symptoms, spirometry, sputum volume, and sputum inflammatory cytokines levels. We also examined the effects of theophylline on the release of inflammatory cytokines in vitro by measuring interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha levels from lipopolysaccharide (LPS)-stimulated neutrophils and THP-1 cells.. Forced vital capacity was increased and sputum IL-8 levels decreased after 4 weeks of theophylline treatment. After 6 months of theophylline treatment, forced expiratory volume in 1s was increased, and neutrophils counts and TNF-alpha levels in sputum were reduced. Levels of IL-8 and TNF-alpha released by LPS-stimulated THP-1 cells were reduced by treatment with theophylline at 10microg/ml. In contrast, IL-8 levels released by LPS-stimulated neutrophils were reduced by treatment with theophylline at 100microg/ml.. Our clinical study of small population showed that long-term treatment with theophylline seems to reduce airway inflammation in stable COPD patients.

Topics: Administration, Oral; Aged; Bronchodilator Agents; Cell Line; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Interleukin-8; Lipopolysaccharides; Male; Neutrophils; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Spirometry; Sputum; Theophylline; Time Factors; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation. Tiotropium has been shown to reduce exacerbation frequency, but its effect on airway inflammation is unknown. The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency. Patients (n = 142) were randomised to receive tiotropium or placebo in addition to their usual medication for 1 yr. Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary. There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups, but sputum IL-8 level was increased in the tiotropium arm. There was no difference between start and end of study in serum IL-6 or C-reactive protein level. Tiotropium was associated with a 52% reduction in exacerbation frequency (1.17 versus 2.46 exacerbations.yr(-1)). Of patients on tiotropium, 43% experienced at least one exacerbation, compared with 64% on placebo. The total number of exacerbation days was reduced compared with placebo (17.3 versus 34.5 days). Tiotropium reduces exacerbation frequency in chronic obstructive pulmonary disease, but this effect does not appear to be due to a reduction in airway or systemic inflammation.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; C-Reactive Protein; Cytokines; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Peroxidase; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sputum; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Inhaled corticosteroids have a high level of topical anti-inflammatory activity. However, in patients with COPD these drugs have been reported to exert limited effects. A reduction in histone deacetylase (HDAC) activity is suggested to prevent the anti-inflammatory action of corticosteroids. Cigarette smoke is known to reduce HDAC expression. The aim of this study is to compare the outcome of corticosteroid therapy in both smoking and non-smoking COPD patients. Twenty-three smoking patients and 18 ex-smoking patients with COPD were treated with inhaled corticosteroids for a period of 2 months. Blood and induced sputum samples were collected before and after treatment. Values of FEV(1) %-predicted did not change upon the therapy, but there was a trend to improve in the ex-smokers (63.1 -> 64.8%-pred.), compared with a decrease in the smokers (63.3 -> 61.6%-pred.). The levels of the pro-inflammatory cytokine IL-8 increased in the group of smokers from 379 +/-78 to 526 +/-118 ng/ml. Although not significant, a slight decrease from 382 +/-70 to 342 +/-62 ng/ml was observed in the group of ex-smokers. The neutrophil related elastase activity showed similar effects after steroid treatment, it went up from 36.4 +/-12.0 to 113.5 +/-9.7 nmol/l in smokers, and decreased from 346.2 +/-72.1 to 131.1 +/-6.5 nmol/l in ex-smokers with COPD. These results support the evidence that inhaled corticosteroids have no anti-inflammatory effects in COPD patients, but only when these patients are still smoking. Smoking cessation seems the best therapy for COPD patients.

Topics: Adrenal Cortex Hormones; Aged; Albumins; Androstadienes; Anti-Inflammatory Agents; Budesonide; Cell Count; Female; Fluticasone; Forced Expiratory Volume; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Pancreatic Elastase; Peroxidase; Pulmonary Disease, Chronic Obstructive; Smoking; Smoking Cessation; Sputum; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is accompanied by both airway and systemic inflammation and by oxidative stress. This study aimed to characterise the relationship between oxidative stress and inflammatory components in induced sputum and blood.. We studied blood and sputum samples from stable COPD patients (mean FEV1 60.5+/-7.5% predicted) at baseline (no treatment) and after 10 weeks treatment with either inhaled steroid, fluticasone propionate (FP) (1000 microg/d) or 10 weeks treatment with N-acetylcysteine (600mg/d) (NAC). We assessed the inflammatory markers (IL-8, ECP, sICAM-1, NE) in sputum and serum and we compared them with blood markers of oxidative stress (SOD, GPx, TEAC, albumin, vitamin E and A).. At baseline blood sICAM-1 correlated with IL-8 levels (P<0.01, r = 0.62) and negatively with GPx (P<0.01, r = -0.63) and with TEAC (P<0.05, r = -0.53). TEAC correlated positively with GPx (P<0.01, r = 0.70). Correlation between sICAM and IL-8 disappeared after NAC treatment. The correlation between sICAM and GPx disappeared after FP treatment. The correlation between TEAC and GPx was maintained after both NAC and FP.. The relationship between markers of inflammation, adhesion and antioxidant capacity is significantly modulated by treatment with N-acetylcysteine or inhaled corticosteroids.

Topics: Administration, Inhalation; Aged; Androstadienes; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Bronchitis; Cross-Over Studies; Female; Fluticasone; Forced Expiratory Volume; Humans; Interleukin-8; Male; Middle Aged; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Spirometry; Sputum; Vital Capacity

An association between the sputum eosinophil count and the response to a 2 week course of prednisolone has previously been reported in patients with chronic obstructive pulmonary disease (COPD). Whether the response to inhaled corticosteroids is related to the presence of eosinophilic inflammation is unclear.. A randomised, double blind, crossover trial of placebo and mometasone furoate (800 microg/day), each given for 6 weeks with a 4 week washout period, was performed in subjects with COPD treated with bronchodilator therapy only. Spirometric tests, symptom scores, chronic respiratory disease questionnaire (CRQ), and induced sputum were performed before and after each treatment phase.. Ninety five patients were recruited of which 60 were randomised. Overall there were no treatment associated changes in forced expiratory volume in 1 second (FEV(1)), total CRQ, or sputum characteristics. After stratification into tertiles by baseline eosinophil count, the net improvement in post-bronchodilator FEV(1) increased with mometasone compared with placebo progressively from the least to the most eosinophilic tertile. The mean change in post-bronchodilator FEV(1) with mometasone compared with placebo in the highest tertile was 0.11 l (95% CI 0.03 to 0.19). This improvement was not associated with a fall in the sputum eosinophil count.. An increased sputum eosinophil count is related to an improvement in post-bronchodilator FEV(1) following treatment with inhaled mometasone in COPD, but the improvement is not associated with a reduction in the sputum eosinophil count.

Topics: Administration, Inhalation; Aged; Anti-Inflammatory Agents; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Eosinophilia; Eosinophils; Female; Forced Expiratory Volume; Humans; Interleukin-8; Leukocyte Count; Male; Mometasone Furoate; Pregnadienediols; Pulmonary Disease, Chronic Obstructive; Sputum

To explore the effect and the mechanism of yifei jianpi recipe (YFJPR) on patients with chronic obstructive pulmonary disease (COPD).. Forty patients with COPD in stable phase were randomly divided into two groups, the treated group and the control group. Indexes including the total and differential count of inflammatory cell in sputum, levels of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), as well as the percentage of forced expiratory volume in one second in its predicted value (FEV1%) and ratio of FEV1/forced vital capacity (FVC) in patients were measured before and after treatment, and compared with those in 20 healthy subjects.. All the indexes measured in patients before and after treatment were significantly different from those in healthy subjects (P < 0.01). Differential count of polymorphonuclear neutrophil (PMN) and levels of IL-8 and TNF-alpha in sputum in the treated group significantly decreased after treatment (P < 0.01), while the non-PMN differential count and levels of FEV1% and FEV1/FVC significantly increased (P < 0.01). But in the control group, changes only showed in increasing of FEV1% and FEV1/FVC (P < 0.05 or P < 0.01). And the effects in the treated group were better than those in the control group (P < 0.01).. YFJPR can play a therapeutic role on patients with COPD by way of reducing the airway inflammatory reaction.

Topics: Adult; Aged; Drugs, Chinese Herbal; Female; Humans; Interleukin-8; Leukocyte Count; Male; Middle Aged; Neutrophils; Phytotherapy; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammatory process in the large and small airways, as well as in the lung parenchyma. Although the role of oral corticosteroids in the management of acute exacerbations of COPD is well documented, its role in stable COPD is not clear. We examined the anti-inflammatory effect of inhaled budesonide on the percentage of neutrophils and on interleukin-8 (IL-8) levels in bronchoalveolar lavage (BAL) and their correlation with spirometry and symptom scores. Twenty-six patients with stable COPD were randomised, in a double-blinded, placebo-controlled trial with either 800 microg of inhaled budesonide or placebo for a 6-month period. The budesonide-treated subjects had significant reductions in IL-8 levels in the BAL after therapy (mean+/-sem, 1.53+/-0.72 at baseline vs. 0.70+/-0.48 ng/ml at 6 months, P=0.004) and a reduction in the mean percentages of neutrophils (17.16+/-2.67% vs. 13.25+/-2.28% P=0.002). The improvement in sputum production was of borderline (P=0.058) significance but there was no improvement in lung function. In stable patients with COPD, treatment with inhaled budesonide for a period of 6 months has a positive effect on markers of lung inflammation, as assessed by reduction in percentage neutrophils and IL-8 concentration in BAL.

Topics: Administration, Inhalation; Aged; Biomarkers; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Budesonide; Double-Blind Method; Female; Glucocorticoids; Humans; Interleukin-8; Lymphocyte Count; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Spirometry; Statistics, Nonparametric; Time Factors

The anti-inflammatory potential of azithromycin in chronic obstructive pulmonary disease (COPD) patients was explored following a standard oral dosing regimen. Patients with moderate and severe COPD were treated with azithromycin (500 mg, n=16) or placebo (n=8) once daily for 3 days in a randomized, double blind design, to compare effects on inflammation markers with those seen in a previous study in healthy volunteers. A battery of tests was made on serum, blood neutrophils and sputum on days 1 (baseline), 3, 4, 11, 18 and 32. In comparison to placebo, azithromycin resulted in an early transient increase in serum nitrites plus nitrates (day 3), associated with a tendency towards an increase in the blood neutrophil oxidative burst to phorbol myristic acetate. Subsequently, prolonged decreases in blood leukocyte and platelet counts, serum acute phase protein (including C reactive protein) and soluble E-selectin and blood neutrophil lactoferrin concentrations and a transient decrease in serum interleukin-8 were observed. Blood neutrophil glutathione peroxidase activity showed a prolonged increase after azithromycin treatment. The biphasic facilitatory-then-inhibitory response to azithromycin seen in healthy volunteers is not so clearly detectable in COPD patients, only potential anti-inflammatory effects. Treatment for longer periods may give therapeutic anti-inflammatory benefit in these patients.

Topics: Adult; Aged; Anti-Inflammatory Agents; Azithromycin; Biomarkers; Blood Cell Count; C-Reactive Protein; Cell Count; Double-Blind Method; E-Selectin; Glutathione; Glutathione Peroxidase; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Humans; Inflammation; Interleukin-6; Interleukin-8; Lactoferrin; Male; Middle Aged; Neutrophils; Nitrates; Nitrites; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Respiratory Burst; Respiratory Function Tests; Serum Amyloid A Protein; Sputum; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

To evaluate the effect of Yufeining, a traditional Chinese medicine, on induced sputum interleukin-8 (IL-8) in patients with chronic obstructive pulmonary disease (COPD) at the stable phase.. Thirty-six patients with COPD were divided into trial group (18 cases) and control group (18 cases) randomly. The trial group was treated with Yufeining pills taken orally for half a year; the control group was not given any medicine. Routine lung function was recorded before and after treatment. Total cell count (TCC), differential cell counts (DCCs) and IL-8 in induced sputum were determined at the baseline and 6 months later.. The indices of lung function improved significantly after 6 months' treatment in trial group (P < 0.05); TCC and absolute neutrophil count decreased significantly compared with baseline in the trial group (P < 0.05); Sputum IL-8 concentration dropped significantly after 6 months' treatment, from a mean of 5.216 +/- 2.914 microg/L to 4.222 +/- 2.140 microg/L (P < 0.05). There were insignificant changes in the parameters in the control group between baseline and 6 months later.. Yufeining could improve lung function, decrease sputum TCC, absolute neutrophil count and IL-8 concentration, and relieve airway inflammation in patients with COPD in the stable phase.

Topics: Aged; Drugs, Chinese Herbal; Female; Humans; Interleukin-8; Male; Medicine, Chinese Traditional; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum

Inhaled corticosteroids (ICS) are widely used for the treatment of COPD despite of controversial statements concerning their efficacy. The use of N-acetylcysteine (NAC), a mucolytic drug with antioxidant properties, is less clear, but it may counteract the oxidant-antioxidant imbalance in COPD. The aim of this study was to evaluate whether treatment of COPD patients with ICS or NAC is able to improve inflammatory indices and to enhance lung function. ICS treatment enhanced protective markers for oxidative stress such as glutathione peroxidase (GPx) (51.2 +/-5.8 vs. 62.2 +/-8.6 U/g Hb, P<0.02) and trolox-equivalent antioxidant capacity (TEAC) (1.44 +/-0.05 vs. 1.52 +/-0.06 mM, P<0.05). NAC decreased sputum eosinophil cationic protein (318 +/-73 vs. 163 +/-30 ng/ml, P<0.01) and sputum IL-8 (429 +/-80 vs. 347 +/-70 ng/ml, P<0.05). The increased antioxidant capacity prevented an up-regulation of adhesion molecules, since the levels of intracellular adhesion molecule 1 (ICAM-1) correlated negatively with GPx (P<0.0001) and TEAC (P<0.0001). On the other hand, expression of adhesion molecules was promoted by inflammation, reflected by a positive correlation between the levels of IL-8 and ICAM-1 (P<0.0001). The effects of treatment on lung function were only reflected in the FEV(1) values. The absolute value of FEV(1), both before and after salbutamol inhalation, increased from 1690 +/-98 to 1764 +/-110 ml, and 1818 +/-106 to 1906 +/-116 ml, respectively, after ICS (P<0.05) . Ten weeks after treatment, FEV(1) values dropped to 1716 +/-120 ml post-salbutamol (P<0.05). When followed by treatment with NAC, these values decreased even further to 1666 +/-84 ml. These results suggest that ICS improved lung function in COPD patients with moderate airflow obstruction, beside a minor improvement in the oxidant-antioxidant imbalance leading to a lesser expression of ICAM-1. Treatment with NAC decreased some inflammatory parameters and had indirectly an inhibitory effect on the expression of adhesion molecules.

Topics: Acetylcysteine; Administration, Inhalation; Adrenal Cortex Hormones; Adult; Androstadienes; Anti-Inflammatory Agents; Antioxidants; Double-Blind Method; Eosinophil Cationic Protein; Expectorants; Female; Fluticasone; Forced Expiratory Volume; Glutathione Peroxidase; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum; Treatment Outcome

Clarithromycin is an antimicrobial agent that can be used for treatment of chronic obstructive pulmonary disease (COPD) exacerbations with bronchodilator therapy. However, it has also been shown that clarithromycin has antiinflammatory effects by the inhibition of cytokine production.. To evaluate the antiinflammatory effect of clarithromycin on serum and sputum interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and leukotriene B4 levels in patients with COPD.. Thirty men with mild to moderate COPD were enrolled in this prospective, single-center, double-blind, placebo-controlled study. None of the patients was receiving systemic or inhaled corticosteroids during the study. Subjects received either clarithromycin or placebo for 14 days. Before and after this treatment period, spirometric tests and arterial blood gas analysis were performed, blood was drawn for measurement of serum inflammatory markers, and sputum was induced.. There were no statistically significant differences in baseline clinical or laboratory parameters between the groups. After the treatment, the induced sputum total cell counts, and IL-8 and TNF-alpha levels decreased significantly in the clarithromycin group compared with pretreatment levels (mean +/- SD IL-8 1606 +/- 367.3 vs 882 +/- 143.6 pg/mL, p = 0.001; TNF-alpha 638.2 +/- 287.5 vs 390 +/- 235 pg/mL, p = 0.001). Similarly, decreases in serum inflammatory markers were found in the clarithromycin group while there was no significant change in the placebo group.. This study demonstrated that the decrease in IL-8 and TNF-alpha levels might be related to the antiinflammatory effect of clarithromycin. Thus, we suggest that the use of clarithromycin in COPD exacerbations may either treat the infection or help control the inflammation. Future studies are needed to determine the clinical significance of these findings.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Biomarkers; Clarithromycin; Double-Blind Method; Humans; Inflammation Mediators; Interleukin-8; Leukotriene B4; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Sputum; Tumor Necrosis Factor-alpha

To investigate the efficacy and safety of a fully human monoclonal antibody recognizing the chemokine interleukin (IL)-8 in patients with COPD.. Randomized, double-blind, parallel-group, placebo-controlled trial.. Eighteen clinics/hospitals in the United States.. One hundred nine patients with stable COPD.. Three IV infusions of either monoclonal antibody recognizing IL-8 (800-mg loading dose; 400-mg subsequent doses) or active buffer solution administered monthly over a 3-month period.. The differences in the transition dyspnea index (TDI) total score, the primary outcome measure, between fully human monoclonal IgG(2) antibody directed against IL-8 and placebo were 0.8, 1.0, 0.8, and 0.3 at week 2 (p = 0.046) and months 1 to 3, respectively. At all time points, the proportion of patients achieving >/= 1 point improvement in the TDI was greater for the monoclonal antibody group compared with the placebo group: 28% vs 11% at week 2 (p = 0.028). There were no significant differences observed for lung function, health status, 6-min walking distance, and adverse events between groups.. The results of this phase 2 study suggest that neutralization of IL-8 with monoclonal antibody therapy may improve dyspnea in patients with COPD. These results support the further investigation of monoclonal antibody therapy targeting IL-8 for the treatment of this disease.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Dose-Response Relationship, Drug; Double-Blind Method; Dyspnea; Female; Humans; Infusions, Intravenous; Interleukin-8; Male; Middle Aged; Neutrophil Activation; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8A; Respiratory Function Tests

To compare efficacy of atrovent alone and in combination with erespal in patients with chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD).. Of 80 participants of the trial (51 male and 29 female--63.75 and 36.25%, respectively) who had CB or COPD, 39 patients (28 with CB and 11 with COPD) received 6-month combined treatment with erespal (160 mg/day) and atrovent (160 mcg/day) and 41 patients (32 with CB and 9 with COPD) received atrovent monotherapy in the same dosage.. Combined therapy produced positive changes in dyspnea, sputum characteristics and its discharge, cough, monotherapy improved sputum discharge and relieved cough; pulmonary ventilation improved in both groups especially in those on monotherapy. CB patients showed low cytosis, percentage and absolute count of neutrophils, absolute count of lymphocytes and eosinophils in induced sputum. In CB patients percentage of lymphocytes reduced while count of macrophages went up. Combined treatment including erespal also promoted a significant fall of serum and sputum TNFalpha and IL-8 reduction in the sputum.. Erespal+atrovent treatment proved more effective than atrovent alone. It is recommended for both CB and COPD patients without marked disorders of external respiration function.

Topics: Adult; Aged; Anti-Inflammatory Agents; Blood Cell Count; Bronchitis, Chronic; Bronchodilator Agents; Disulfiram; Drug Therapy, Combination; Female; Humans; Interleukin-8; Ipratropium; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Sputum; Treatment Outcome; Tumor Necrosis Factor-alpha

The prevalent theory concerning the pathogenesis of chronic obstructive pulmonary disease (COPD) is of an imbalance between oxidants and antioxidants in the lung. It has recently been reported that the production of peroxynitrite, an extremely potent oxidant, is increased in the airways of patients with COPD. A study was undertaken of the imbalance between the levels of nitrogen oxides and antioxidant activity against peroxynitrite in the airways of patients with COPD.. Sputum induction was performed in 30 patients with COPD and 15 normal control subjects. Levels of nitrogen oxides, percentage of neutrophils, and interleukin 8 (IL-8) levels were measured in sputum samples, and peroxynitrite inhibitory activity was assayed by monitoring rhodamine formation.. Nitrite and nitrate levels in induced sputum were significantly higher in patients with COPD than in normal controls (949 (133) microM v 621 (89) microM, p<0.001). In contrast, peroxynitrite inhibitory activity in induced sputum was significantly lower in patients with COPD than in normal controls (47.4 (12.7)% v 92.9 (3.9)%, p<0.001). There was a negative correlation between nitrite and nitrate levels and peroxynitrite inhibitory activity in induced sputum (r=-0.775, p<0.001). Peroxynitrite inhibitory activity was also significantly correlated with forced expiratory volume in 1 second (FEV(1)) % predicted (r=0.539, p=0.004), FEV(1)/FVC (r=0.512, p=0.006), and carbon monoxide transfer factor (TLCO) (r=0.486, p=0.009). Moreover, there was a significant negative correlation between peroxynitrite inhibitory activity and the degree of neutrophilic inflammation (percentage of neutrophils: r=-0.754, p<0.001; IL-8 levels: r=-0.497, p=0.007).. Reduced peroxynitrite inhibitory activity and increased levels of nitrogen oxides are found in induced sputum from patients with COPD. An imbalance in nitrogen oxides and antioxidant defence may contribute to the pathogenesis of COPD.

Topics: Female; Forced Expiratory Volume; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Nitrogen Oxides; Peroxynitrous Acid; Pulmonary Disease, Chronic Obstructive; Sputum; Vital Capacity

Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at five further visits. Interleukin-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils, CD8+ and CD4+ T-lymphocyte subsets, and CD68+ macrophages. Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified. Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1. However, bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8+ (p = 0.001; ANOVA) and CD68+ cells (p < 0.05; ANOVA). In addition, by Poisson analysis, comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8+ (48% p < 0.01) and CD68+ (47% p = 0.001) cells. This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD. Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biopsy; Bronchodilator Agents; Carboxylic Acids; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Interleukin-8; Leukocyte Count; Leukocyte Elastase; Male; Middle Aged; Nitriles; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Sputum; Treatment Outcome

s: Induced sputum is used to investigate pulmonary diseases. Low-output ultrasonic nebulizers have become available and have potential advantages over high-output nebulizers. We hypothesized that a low-output nebulizer would give comparable results to a high-output nebulizer, with an acceptable safety profile.. Randomized, crossover study.. University teaching hospital.. Ten normal subjects and 10 patients with COPD.. Participants attended for sputum induction on two occasions in random order using low-output and high-output nebulizers.. Lung function and oxygen saturation were measured during sputum induction, and tolerability of the procedure was assessed. Cell counts, interleukin 8, and neutrophil elastase were measured in sputum. Use of the high-output nebulizer resulted in a greater FEV(1) (mean +/- SEM, 0.29 +/- 0.04 L vs 0.21 +/- 0.04 L; p = 0.04) and percentage drop in FEV(1) (25.8 +/- 2.6% vs 19.5 +/- 2.9%, respectively; p = 0.02) compared with the low-output nebulizer in patients with COPD. There was a shorter tolerated nebulization time with the high-output nebulizer compared with the low-output nebulizer: 12.7 +/- 2.0 min vs 16.5 +/- 1.8 min, respectively (p = 0.02). Modified Borg scores were lower with the low-output nebulizer than the high-output nebulizer in normal subjects: median, 0 (interquartile range [IQR], 0 to 1) vs median, 1.5 (IQR, 0 to 2), respectively (p = 0.05). There were no differences in cell counts and soluble markers of inflammation.. The low-output ultrasonic nebulizer is comparable to high-output nebulizer for cellular and soluble markers of inflammation, results in a smaller reduction in FEV(1), is better tolerated, and is a suitable tool for investigating airway inflammation in patients with COPD.

Topics: Adult; Aged; Cell Count; Cross-Over Studies; Equipment Design; Female; Forced Expiratory Volume; Humans; Interleukin-8; Leukocyte Elastase; Male; Mast Cells; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Reference Values; Sputum

As a traditional medicine, seeds of Ginkgo biloba L. (Gbs) have been used to treat cough or asthma for a long time. It is commonly used in clinic for lung diseases. However, its mechanism of lung protection is not completely clear.. This research was designed to explore the protective effects of Gbs on antioxidant and inflammation during the chronic obstructive pulmonary disease (COPD) pathological process provoked by cigarette smoking (CS) in rats.. Six random groups including control group, CS model group, Gbs intervention groups (25 mg/kg, 50 mg/kg, and 100 mg/kg) and aminophylline group were composed of forty-eight rats. Smoking and intratracheal instillation of lipopolysaccharide (LPS) were used to establish the COPD rat model. Glutathione peroxidase (GSH-PX), malondialdehyde (MDA), superoxide dismutase (SOD), and enzyme-linked immunosorbent assay (ELISA) was used for quantifying the inflammatory factors such as IL-8, IL-6, IL-10, IL-17 and TNF-α. Western blotting were used for detecting the protein expressions of Nrf2, Keap1 and HO-1 in the lung tissues.. Gbs inhibits lung histological changes and decreased the inflammatory factors in both bronchoalveolar lavage fluid (BALF) and serum of CS-exposed rats, including IL-10, IL-17, IL-6, IL-8 and TNF-α. Gbs also inhibited the MDA level, increased SOD and GSH-PX activity in serum and changed expressions of Nrf2, Keap1 and HO-1 in the lung tissues.. Gbs inhibit oxidative stress and inflammation induced by cigarette smoke in COPD rats through the Nrf2 Pathway.

Topics: Animals; Antioxidants; Cigarette Smoking; Ginkgo biloba; Inflammation; Interleukin-10; Interleukin-17; Interleukin-6; Interleukin-8; Kelch-Like ECH-Associated Protein 1; Lung; NF-E2-Related Factor 2; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Rats; Seeds; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Our previous studies have suggested that bromodomain protein 4 (BRD4) is increased in the lung of stable chronic obstructive pulmonary disease (COPD) patients, which has been shown to be involved in inflammatory responses. We investigated its role in the viral exacerbation of COPD.. BRD4, interleukin (IL)-6 and IL-8 were measured in the blood and sputum of stable COPD patients and patients with viral exacerbation. Mice were exposed to cigarette smoke (CS) and/or infected with influenza virus as an in vivo model. BRD4, IL-6 and keratinocyte-derived chemokine (KC) were measured in the lung. BEAS-2B cells were treated with CS extract and/or influenza virus as an in vitro model. BRD4, IL-6 and IL-8 were measured in the cells and/or culture supernatant.. BRD4 was increased in COPD patients with viral exacerbation compared with those in stable condition and its expression was correlated with IL-6 and IL-8 expression. Inflammatory cells, IL-6, KC and BRD4 were synergistically induced in the lung of mice by viral infection and CS exposure, and the former three were decreased by JQ1 (BRD4 inhibitor) treatment. IL-6, IL-8 and BRD4 were significantly induced by CS extract and influenza virus in bronchial epithelial cells, and this upregulation was suppressed by knockdown of BRD4 expression.. Our findings indicate that CS and viruses may synergistically induce IL-6 and IL-8 expression through their synergistic induction of BRD4 expression, which might contribute to the enhanced inflammatory response in the viral exacerbation of COPD.

Topics: Animals; Cell Cycle Proteins; Humans; Interleukin-6; Interleukin-8; Mice; Nuclear Proteins; Pulmonary Disease, Chronic Obstructive; Transcription Factors

Alpha-1-antitrypsin deficient (AATD) individuals are prone to develop early age of onset chronic obstructive pulmonary disease (COPD) more severe than non-genetic COPD. Here, we investigated the characteristics of lower respiratory tract of AATD individuals prior to the onset of clinically significant COPD.. Bronchoalveolar lavage was performed on 22 AATD with normal lung function and 14 healthy individuals. Cell counts and concentrations of proteases, alpha-1-antitrypsin and proinflammatory mediators were determined in the bronchoalveolar lavage fluid from study subjects. In order to determine the airway inflammation, we also analyzed immune cell components of the large airways from bronchial biopsies using immunohistochemistry in both study subjects. Finally, we made comparisons between airway inflammation and lung function rate of decline using four repeated lung function tests over one year in AATD individuals.. AATD individuals with normal lung function had 3 folds higher neutrophil counts, 2 folds increase in the proteases levels, and 2-4 folds higher levels of IL-8, IL-6, IL-1β, and leukotriene B4 in their epithelial lining fluid compared to controls. Neutrophil elastase levels showed a positive correlation with the levels of IL-8 and neutrophils in AATD epithelial lining fluid. AATD individuals also showed a negative correlation of baseline FEV. Mild inflammation is present in the lower respiratory tract and airways of AATD individuals despite having normal lung function. A declining trend was also noticed in the lung function of AATD individuals which was correlated with pro-inflammatory phenotype of their lower respiratory tract. This results suggest the presence of proinflammatory phenotype in AATD lungs. Therefore, early anti-inflammatory therapies may be a potential strategy to prevent progression of lung disease in AATD individuals.

Topics: alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Humans; Inflammation; Interleukin-8; Leukocyte Elastase; Lung; Pneumonia; Pulmonary Disease, Chronic Obstructive

COPD is a lifestyle-related disease resulting from irreversible damage to respiratory tissues mostly due to chronic exposure to environmental pollutants, including cigarette smoke. Environmental pathogens and pollutants induce the acquired dysfunction of the CFTR Cl

Topics: Cystic Fibrosis Transmembrane Conductance Regulator; Environmental Exposure; Environmental Pollutants; Humans; Interleukin-8; Polymorphism, Genetic; Pulmonary Disease, Chronic Obstructive

Smoking can lead to airway inflammation and mucus secretion through the nucleotide-binding domain-like receptor protein 3/caspase-1 pathway. In this study, z-VaD-Ala-Asp-fluoromethyl ketone(Z-VAD), a pan-caspase inhibitor, and acetyl-Asp-Glu-Val-Asp-aldehyde(Ac-DEVD), a caspase-3 inhibitor, were used to investigate the effect of caspase inhibitors on the expression of interleukin(IL)-1β and IL-8, airway inflammation, and mucus secretion in mice exposed to cigarette smoke(CS).. Thirty-two C57BL/6J male mice were divided into a control group, Smoke group, Z-VAD group, and Ac-DEVD group. Except for the control group, the animals were all exposed to CS for three months. After the experiment, lung function was measured and hematoxylin and eosin staining and periodic acid-Schiff staining were performed. The levels of IL-1β, IL-8, and mucin 5ac(Muc5ac) in serum and bronchoalveolar lavage fluid(BALF) were determined by enzyme-linked immunosorbent assay.. Compared with the control group, the lung function of mice exposed to smoke was poorer, with a large number of inflammatory cells infiltrating around the airway, collapse of alveoli, expansion and fusion of distal alveoli, and formation of emphysema. The Z-VAD group was relieved compared with the smoke group. Airway inflammation was also reduced in the Ac-DEVD group compared with the Smoke group, but the degree of emphysema was not significantly improved. Although Z-VAD relieved airway inflammation and emphysema, Ac-DEVD only relieved inflammation. Z-VAD and Ac-DEVD decreased serum IL-1β and IL-8 levels. In BALF, IL-1β was decreased in Z-VAD group and IL-8 was highest in Smoke +Ac-DEVD group compared with control group and Ac-DEVD group. There was no significant difference in the expression of Muc5ac in serum. However, in BALF, levels of Muc5ac were higher in the smoking group and the lowest in the Ac-DEVD group.. Mice exposed to smoke had decreased lung function and significant cilia lodging, epithelial cell shedding, and inflammatory cell infiltration, with significant emphysema formation. The pan-caspase inhibitor, Z-VAD, improved airway inflammation and emphysema lesions in the mice exposed to smoke and reduced IL-1β and IL-8 levels in serum. The caspase-3 inhibitor, Ac-DEVD, reduced airway inflammation, serum IL-1β and IL-8 levels, and Muc5ac levels in BALF, but it did not improve emphysema.

Topics: Animals; Caspase 3; Cigarette Smoking; Inflammation; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Mucus; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema

Epithelial cytokines are involved in the orchestration of T1/T2 inflammatory patterns. We question the persistence of this trait in air-liquid interface (ALI) epithelial cultures and whether this local orientation can be related to systemic patterns (e.g., blood eosinophil counts [BECs]). We investigated alarmin release related to high versus low T2 phenotypes associated with chronic airway diseases. ALIs were reconstituted from 32 control, 40 chronic obstructive pulmonary disease, and 20 asthmatic patients. Interleukin-8 (IL-8; a T1-cytokine), IL-25, IL-33, and thymic stromal lymphopoietin (T2-alarmins) concentrations were assessed in subnatants at steady state and used to explain blood neutrophil and eosinophil counts. IL-25 and IL-8 levels were highest in asthma ALI-subnatants, whereas IL-33 was sparsely detected. Thymic stromal lymphopoietin levels were similar among groups. All asthma cell cultures were T1-high/T2-high, while chronic obstructive pulmonary disease and controls tended to be mixed. BECs were independently explained by both disease and in-culture T2-alarmin levels, irrespective of the T2-alarmin considered. The epithelial ALI-T2 signature was more frequently high in patients with a BEC > 300/mm

Topics: Alarmins; Asthma; Cytokines; Eosinophils; Humans; Interleukin-33; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Thymic Stromal Lymphopoietin

Transforming growth factor-β2 (TGF-β2) plays an important role in pleiotropic functions and has been reported to be involved in the pathogenesis of chronic obstructive lung disease. The role of TGF-β2 in regulating cigarette smoke (CS)-induced lung inflammation and injury has not been investigated, and its underlying mechanism remains unclear.. Primary bronchial epithelial cells (PBECs) were treated with cigarette smoke extract (CSE), and the signaling pathway of TGF-β2 regulating lung inflammation was investigated. Mice were exposed to CS and treated with TGF-β2 i.p. or bovine whey protein extract containing TGF-β2 p.o., and the role of TGF-β2 in alleviating lung inflammation/injury was studied.. In vitro, we demonstrated that TGF-β2 attenuated CSE-induced IL-8 production from PBECs through the TGF-β receptor I (TGF-βRI), Smad3, and mitogen-activated protein kinase signaling pathways. Selective TGF-βRI inhibitor (LY364947) and antagonist of Smad3 (SIS3) abolished the effect of TGF-β2 on alleviating CSE-induced IL-8 production. In vivo, CS exposure for 4 weeks in mice increased the levels of total protein, inflammatory cell counts, and monocyte chemoattractant protein-1 in bronchoalveolar fluid and induced lung inflammation/injury, as revealed by immunohistochemistry. Administration of TGF-β2 through intraperitoneal injection or oral feeding with bovine whey protein extract containing TGF-β2 significantly reduced CS-induced lung inflammation and injury.. We concluded that TGF-β2 reduced CSE-induced IL-8 production through the Smad3 signaling pathway in PBECs and alleviated lung inflammation/injury in CS-exposed mice. The anti-inflammatory effect of TGF-β2 on CS-induced lung inflammation in humans deserves further clinical study.

Topics: Animals; Cattle; Cigarette Smoking; Humans; Inflammation; Interleukin-8; Lung; Mice; Nicotiana; Pneumonia; Pulmonary Disease, Chronic Obstructive; Transforming Growth Factor beta2; Transforming Growth Factors; Whey Proteins

To explore the mechanism of. Serum samples were collected from 40 SD rats treated with. At the optimal concentration of 20%, treatment with the medicated serum for 24 h significantly lowered the mRNA and protein expressions of TLR4, NF- κB, MUC5AC, MUC7, and MUC8 in CSE- exposed 16HBE cells, and these effects were further enhanced by TLR4 silencing in the cells. In 16HBE cells with TLR4 overexpression, the expressions of TLR4, NF-κB, MUC5AC, MUC7, and MUC8 were significantly increased after CSE exposure and were lowered following treatment with the medicated serum (

Topics: Animals; Cigarette Smoking; Epithelial Cells; Humans; Interleukin-6; Interleukin-8; Mucus; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Topics: Biomarkers; Cyclic Nucleotide Phosphodiesterases, Type 4; Humans; Interleukin-8; Longitudinal Studies; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) causes organic damage as well as anxiety, depression, fear, and other psychological disorders, which seriously affect the quality of life and prognosis of patients and cause a huge economic burden to the family and society.. The aim of this study was to investigate the correlation between an imbalance of serum Th1/Th2 indicators and psychiatric depression in elderly patients with COPD and analyze its implications for clinical management.. From January 2018 to May 2022, 120 elderly patients with COPD treated at our hospital were categorized into two groups based on the self-rating depression scale (SDS): COPD with depression (SDS score ⩾ 50) and COPD alone (SDS score < 50). Blood gas analysis, pulmonary function, and serum Th1/Th2 index were determined. Receiver operating characteristic (ROC) curves were analyzed to explore the diagnostic value of serum Th1/Th2 ratios for COPD complicated by depression.. Compared with the group without depression, the partial pressure of carbon dioxide and COPD assessment test scores were significantly higher, and the oxygenation index, forced expiratory volume in one second (FEV1), and percent predicted FEV1 were significantly lower in the COPD with depression group (P< 0.05). Interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) were significantly higher in the COPD with depression group than in the group without depression (P< 0.05). Logistic regression analysis indicated that the imbalance of serum IL-1β, IL-2, IL-6, IL-8, IL-10, and TNF-α was a risk factor for mental depression in elderly patients with COPD. When comparing prognostic indices, the interval before the first onset of clinically noticeable deterioration (CID-C) in the COPD with depression group was noticeably shorter than that in the COPD without depression group; the incidence of CID-C within 6 months was noticeably higher in the COPD with depression group than in the group without depression.. Elderly patients with COPD and depression had reduced pulmonary function and higher serum Th1/Th2 levels, and an imbalance in serum Th1/Th2 indicators was a potential risk factor for depression. Moreover, elderly patients with COPD and depression were at a higher risk of disease progression and had a worse prognosis. Thus, an imbalance in serum Th1/Th2 indicators is a potential prognostic factor for evaluating depression in patients with COPD.

Topics: Aged; Depression; Humans; Interleukin-10; Interleukin-2; Interleukin-6; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tumor Necrosis Factor-alpha

Lung cancer frequently affects patients with Chronic Obstructive Pulmonary Disease (COPD). Cigarette smoke (CS) fosters cancer progression by increasing oxidative stress and by modulating epithelial-mesenchymal transition (EMT) processes in cancer cells. Formoterol (FO), a long-acting β2-agonist widely used for the treatment of COPD, exerts antioxidant activities. This study explored in a lung adenocarcinoma cell line (A549) whether FO counteracted the effects of cigarette smoke extract (CSE) relative to oxidative stress, inflammation, EMT processes, and cell migration and proliferation. A549 was stimulated with CSE and FO, ROS were evaluated by flow-cytometry and by nanostructured electrochemical sensor, EMT markers were evaluated by flow-cytometry and Real-Time PCR, IL-8 was evaluated by ELISA, cell migration was assessed by scratch and phalloidin test, and cell proliferation was assessed by clonogenic assay. CSE significantly increased the production of ROS, IL-8 release, cell migration and proliferation, and SNAIL1 expression but significantly decreased E-cadherin expression. FO reverted all these phenomena in CSE-stimulated A549 cells. The present study provides intriguing evidence that FO may exert anti-cancer effects by reverting oxidative stress, inflammation, and EMT markers induced by CS. These findings must be validated in future clinical studies to support FO as a valuable add-on treatment for lung cancer management.

Topics: Adenocarcinoma of Lung; Cigarette Smoking; Epithelial Cells; Epithelial-Mesenchymal Transition; Formoterol Fumarate; Humans; Inflammation; Interleukin-8; Lung Neoplasms; Nicotiana; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species

In the present study, we investigated effects of Puerarin on the early oxidative and inflammatory responses in the lung triggered by acute cigarette smoking (ACS). C57BL/6 mice were exposed to ACS for 1 hr in the presence or absence of Puerarin and harvested at 2, 6, and 24 hours. ACS induced significant increases in superoxide production in mouse lungs at 2 and 6 hours; and superoxide production was also elevated in a time and concentration dependent manner in cigarette smoke extract (CSE) stimulated human small airway epithelial cells (HSAECs), which was dose-dependently abrogated by Puerarin. ACS exposure upregulated NOX1, NOX2, and NOX4 protein expression in mouse lungs. Likewise, NOX1 and NOX4 were upregulated in CSE-stimulated HSAECs. These responses were significantly or completely attenuated by Puerarin. ACS induced significant infiltrations of neutrophils and macrophages in mouse lung parenchyma and BAL fluid, which were completely or significantly abrogated by Puerarin, so was the activation of the NF-

Topics: Animals; Cyclooxygenase 2; Inflammation Mediators; Interleukin-8; Isoflavones; Mice; Mice, Inbred C57BL; NADPH Oxidases; Nicotiana; Oxidation-Reduction; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Signal Transduction; Superoxides

The main risk factor for chronic obstructive pulmonary disease (COPD) is cigarette smoke (CS). It can alter many immune cells functions such as phagocytosis, efferocytosis and cytokine production. Cytokines play a role in the orchestration of inflammation in COPD. The JAK/STAT pathways are among the most important signalling components of cytokines. The objective of this work was to investigate the role of the JAK/STAT pathway with regard to cytokine release and microsphere uptake capacity (to minimize the non-specific scavenging) in human monocyte-derived-macrophages (MDMs). The MDMs were stimulated by cigarette smoke extract (CSE) alone or in combination with lipopolysaccharide (LPS). CSE alone was not associated with significant changes in the cytokine, with the exception of IL-8/CXCL8 production. However, CSE disturbed cytokine production in LPS-stimulated MDMs. CSE increase CXCL-8 and CCL2 release in LPS-stimulated monocyte-derived macrophages and suppressed the production of IL-6 and CXCL1 in these cells. CSE also decreased microsphere uptake capacity by MDMs. Then, CSE + LPS-stimulated MDMs were treated with two different JAK inhibitors. AG490 (specific inhibitor of JAK2) and ruxolitinib (inhibitor of JAK1 and JAK2). JAK/STAT inhibitors, particularly ruxolitinib, attenuated in cytokine production without completely inhibiting when compared with dexamethasone. On the other hand, the cells exposed to dexamethasone are nearly unable to capture the microspheres, while both JAK inhibitors do not affect the uptake capacity. In summary, our results showed the versatility of ruxolitinib which might bring a better balance disturbance of cytokine release and uptake capacity. The information regarding the distinctive effect of JAK/STAT inhibitors may be useful in the development of novel treatments for COPD.

Topics: Cigarette Smoking; Cytokines; Dexamethasone; Humans; Interleukin-6; Interleukin-8; Janus Kinase Inhibitors; Janus Kinases; Lipopolysaccharides; Macrophages; Monocytes; Nicotiana; Nitriles; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Pyrimidines; Signal Transduction; STAT Transcription Factors

The omega-3 polyunsaturated fatty acids (PUFAs) have an anti-inflammatory effect, beneficial for allergies, asthma, chronic obstructive pulmonary disease (COPD), reduce cholesterol and triglyceride levels and blood inflammatory parameters [C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α)]. The aim of our cross-sectional study was to monitor omega-3 supplementation in patients with severe COPD and assess its association with quality of life, nutritional status, inflammatory parameters, lipid profile, comorbidities, exercise tolerance and inhaled medications.. Our questionnaire on dietary supplement habits and our validated self-completion questionnaires were filled in by 400 patients with COPD at the National Koranyi Institute of Pulmonology, Hungary, mean age 67 [61-73] years; forced expiratory volume in one second (FEV1) (ref%): 46 [34-58]; 47.5% male, 52.5% female. We used the disease-specific COPD Assessment Test (CAT) questionnaire to measure quality of life.. More than half of the study participants (61%) did not consume fish or oilseeds at all. Nineteen patients (4.75%) took omega-3 supplementation regularly, mainly on medical advice (0.5 g/day). We observed significantly lower serum CRP levels [6.0 (1-7.3) vs. 9.7 (7.4-14.4); P=0.044], more favourable lipid profile [triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol] with higher mean body mass index (BMI) [28.1 (22.0-35.3) vs. 24.7 (24.5-30.1); P=0.118], better quality of life {CAT: 25 [21-30.5] vs. 26 [20-31]; P=0.519}, lower inhaled short-acting bronchodilators use [short-acting beta-agonists (SABAs): 6 (31.58) vs. 209 (54.86); P=0.047], lower number of exacerbations in the previous half year [0 (0-1) vs. 1 (0-2); P=0.023], and higher 6-minute walking distance (6MWD) {300 [177-387] vs. 251 [150-345]; P=0.120} in the group with omega-3 supplementation.. PUFAs are anti-inflammatory and affect the immune system. Our study shows that omega-3 intake of COPD patients is insufficient, and there is an urgent need to develop new anti-inflammatory strategies because only one drug (such as corticosteroids) cannot ease the chronically progressive inflammatory process of COPD.

Topics: Adrenal Cortex Hormones; Bronchodilator Agents; C-Reactive Protein; Cholesterol; Cross-Sectional Studies; Dietary Supplements; Exercise Tolerance; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Humans; Interleukin-6; Interleukin-8; Lipoproteins, HDL; Lipoproteins, LDL; Male; Nutritional Status; Pulmonary Disease, Chronic Obstructive; Quality of Life; Triglycerides; Tumor Necrosis Factor-alpha

Cigarette smoke is a major risk factor for chronic obstructive pulmonary disease (COPD), leading to chronic inflammation, while bacterial components lipopolysaccharide (LPS) and lipoteichoic acid (LTA) are often present in airways of COPD patients, especially during exacerbations.We hypothesised that extracellular heat shock protein 70 (eHsp70), a damage-associated molecular pattern elevated in serum of COPD patients, induces inflammation and alters cigarette smoke and LPS/LTA-induced inflammatory effects in the airway epithelium.We used 16HBE cells exposed to recombinant human (rh)Hsp70 and its combinations with cigarette smoke extract (CSE), LPS or LTA to investigate those assumptions, and we determined pro-inflammatory cytokines' secretion as well as TLR2 and TLR4 gene expression.rhHsp70 and CSE alone stimulated IL-6, IL-8 and TNF-α secretion. CSE and rhHsp70 had antagonistic effect on IL-6 secretion, while combinations of LPS or LTA with rhHsp70 showed antagonistic effect on TNF-α release. By using specific inhibitors, we demonstrated that effects of rhHsp70 on cytokines' secretion were mediated via NF-κB and/or MAPK signalling pathways. rhHsp70 increased, and CSE decreased TLR2 gene expression compared to untreated cells, but their combinations increased it compared to CSE alone. LPS and rhHsp70 combinations decreased TLR2 gene expression compared to untreated cells. TLR4 expression was not induced by any of the treatments.In conclusion, we demonstrated that extracellular Hsp70 modulates pro-inflammatory responses of human airway epithelial cells to cigarette smoke and bacterial components LPS and LTA. Simultaneous presence of those compounds and their interactions might lead to inappropriate immune responses and adverse consequences in COPD.

Topics: Cigarette Smoking; HSP70 Heat-Shock Proteins; Humans; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; NF-kappa B; Nicotiana; Pulmonary Disease, Chronic Obstructive; Teichoic Acids; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Cigarette smoke (CS) is one of the major risk factors for chronic obstructive pulmonary disease (COPD) and increases the risk of lung cancer (LC). Anemoside B4 (B4) is the main bioactive ingredient in Pulsatilla chinensis (P. chinensis), a traditional medicinal herb for various diseases. It has a wide range of anti-inflammatory, anti-oxidation and anti-cancer activities. However, in recent years, there is no relevant literature report on the therapeutic effect of B4 on COPD, and the anti-inflammatory and inhibitory effects of anemoside B4 on basal cell hyperplasia in CS-induced COPD have not been clearly established.. In the present study, we investigated whether anemoside B4 could alleviate CS or cigarette smoke extract (CSE) induced inflammation of COPD and further prevent basal cell hyperplasia, hoping to find its possible mechanism.. In this study, a COPD mouse model was established in C57BL mice by CS exposure 3 months. Bronchial pathology and basal cell hyperplasia were observed by HE staining and immunostaining. The contents of glutathione peroxidase catalase (GSH-PX), malondialdehyde (MDA) and superoxide dismutase (MPO) were determined by GSH-PX, MDA and SOD assay kits, respectively. 16HBE cells were cultured with 5% CSE with or without treatment with B4 (1, 10, 100 μM) or DEX (20 μM) in vitro. Cell viability was assessed by a cell counting kit 8 (CCK-8). Reactive oxygen species (ROS) generation was tested by DCFH-DA. Moreover, anti-inflammatory mechanism of anemoside B4 was further determined by pro-inflammatory cytokines production using RT-PCR. Protein expression levels of MAPK/AP-1/TGF-β signaling pathway were measured by western blot.. Anemoside B4 improved the lung function of mice, relieved lung inflammation and reduced the MDA, MPO and GSH-Px in the plasma. At the same time, B4 repressed the oxidative stress response and played a role in balancing the levels of protease and anti-protease. During the process of bronchial basal cell hyperplasia, B4 alleviated the degree of cell hyperplasia, and prevented further deterioration of hyperplasia through increased P53 and inhibited FHIT protein. In addition, B4 reduced ROS levels in human bronchial epithelial cells stimulated by CSE in vitro study. Meanwhile, B4 treatment also significantly attenuated increased IL-1β, TGF-β, IL-8 and TNF-α from CSE treated human bronchial epithelial cells. The expression of p-P38, AP-1(c-fos, and c-Jun), TGF-β proteins in MAPK/AP-1/TGF-β signaling pathway were decreased and the signal cascade reaction was blocked.. Anemoside B4 protects against CS-induced COPD. These findings indicated that B4 may have therapeutic potential for the prevention and treatment of COPD.

Topics: Animals; Anti-Inflammatory Agents; Catalase; Cigarette Smoking; Glutathione Peroxidase; Humans; Hyperplasia; Inflammation; Interleukin-8; Malondialdehyde; Mice; Mice, Inbred C57BL; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Saponins; Superoxide Dismutase; Transcription Factor AP-1; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

Genes involved in lung development may become dysregulated in adult life and contribute to the pathogenesis of lung diseases. Multiple genes regulate lung development, including Forkhead box protein P1-4 (FoxP1-4).. We examined the association between variants in the FoxP1-4 genes and lung function using data from a GWAS that included close to 400,000 individuals and 20 million SNPs.. More than 100 variants in the FoxP1 gene, but none in the FoxP2-4 genes, are associated with lung function. The sentinel variant in the FoxP1 gene associated with FEV1 was rs1499894 (C > T), while the sentinel variant in the FoxP1 gene associated with FVC was rs35480566 (A > G). Those with the T allele instead of the C allele for rs1499894, or the G allele instead of the A allele for rs35480566 had increased FoxP1 mRNA levels in transcriptomic data, higher FEV1 and FVC, and reduced odds of being diagnosed with idiopathic pulmonary fibrosis. Further, knockdown of FoxP1 in lung epithelial cells by RNA interference led to increased mRNA levels for matrix metalloproteinases 1, 2, 3 and pro-inflammatory cytokines IL-6 & IL-8, as well as reduced cell viability after exposure to cigarette smoke-all processes implicated in the pathogenesis of COPD and IPF.. Our results suggest that the protein encoded by the FoxP1 gene may protect against the development of COPD and IPF. A causal role for FoxP1 in the pathogenesis of COPD and IPF may warrant further investigation, and FoxP1 may be a novel therapeutic target for these lung disorders.

Topics: Adult; Forkhead Transcription Factors; Humans; Idiopathic Pulmonary Fibrosis; Inflammation Mediators; Interleukin-6; Interleukin-8; Lung; Matrix Metalloproteinases; Pulmonary Disease, Chronic Obstructive; Repressor Proteins; RNA, Messenger

Cationic antimicrobial protein of 37 kDa (CAP37), a neutrophil-derived protein originally identified for its antimicrobial activity, is now known to have many regulatory effects on host cells. However, its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) has not been studied. We therefore investigated the expression of CAP37 in COPD and its effects on airway structural cells, including bronchial epithelial cells, smooth muscle cells, and fibroblasts.. CAP37 was detected in the lung tissue, sputum, and plasma of COPD patients and the control subjects, as well as in the neutrophils stimulated by cigarette smoke extract (CSE). BEAS-2B cells, human bronchial smooth muscle cells (HBSMCs), and MRC-5 cells were treated with CAP37 or an anti-CAP37 antibody plus CAP37. Interleukin (IL)-6 and IL-8 were detected in the BEAS-2B cells. The cell proliferation was analyzed in the HBSMCs. Collagens were also detected in the MRC-5 cells.. The expression of CAP37 was increased in the lung tissue and sputum supernatant of the COPD patients compared with the control subjects. The sputum supernatant CAP37 levels were inversely correlated with the forced expiratory volume in the first second percentage predicted in COPD. CAP37 was induced by CSE stimulation in the peripheral blood neutrophils from healthy non-smokers. CAP37 induced expression of IL-6 and IL-8 in BEAS-2B cells, and collagen expression of lung fibroblasts (MRC-5 cells). However, CAP37 did not significantly alter the proliferation of the HBSMCs.. Our findings indicated that neutrophil-derived CAP37 may be involved in airway inflammation and fibrosis in COPD via affecting the bronchial epithelial cells, and fibroblasts, thus suggesting a possible role of CAP37 in the development and progression of COPD.

Topics: Anti-Infective Agents; Collagen; Humans; Interleukin-6; Interleukin-8; Nicotiana; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with respiratory symptoms and narrowing of airways.. We examined the effect and potential molecular action mechanism of GJT in a mouse model of COPD induced by cigarette smoke (CS) plus lipopolysaccharide (LPS).. COPD was induced in C57BL/6J mice via daily exposure to CS for 1 h for 8 weeks and intranasal administration of LPS on weeks 1, 3, 5, and 7. GJT (100 or 200 mg/kg) or roflumilast (5 mg/kg) was administrated daily for the final 4 weeks of COPD induction.. Administration of GJT significantly suppressed the CS/LPS-induced increases in: the numbers of total cells and macrophages in bronchoalveolar lavage fluid; the expression levels of tumour necrosis factor-α, interleukin (IL)-6, IL-1β, and IL-8; the activities (phosphorylation) of nuclear factor kappa B and signal transducer and activator of transcription 3; and the expression levels of the structural remodelling markers, transforming growth factor beta, matrix metallopeptidase (MMP)-7, and MMP-9.. These results demonstrate that GJT prevents the lung inflammation and airway remodelling induced by CS plus LPS exposure in mice, suggesting that GJT may have therapeutic potential for the treatment of COPD.

Topics: Animals; Anti-Inflammatory Agents; Cigarette Smoking; Disease Models, Animal; Interleukin-8; Lipopolysaccharides; Lung; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; NF-kappa B; Nicotiana; Pulmonary Disease, Chronic Obstructive; STAT3 Transcription Factor; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

In patients with chronic obstructive pulmonary disease, the levels of cytokines IL-1β, IL-4, IL-8, TNFα, and IFNγ depended on the degree of bronchial obstruction and severity and period of the disease. The maximum levels of IL-4, IL-8, and TNFα were observed in severe chronic obstructive pulmonary disease during exacerbation. The highest concentration of IL-1β and IFNγ were recorded during activation of inflammation in patients with moderate bronchial obstruction. The revealed correlations between the tested cytokines and spirometry parameters make it possible to consider the levels of these proteins as quantitative markers of systemic inflammation progression.

Topics: Cytokines; Humans; Inflammation; Interferon-gamma; Interleukin-4; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) is characterized by accelerated lung aging. Smoking is the critical risk factor for COPD. Cellular senescence of airway epithelial cells is the cytological basis of accelerated lung aging in COPD, and the regulation of microRNAs (miRNAs) is the central epigenetic mechanism of cellular senescence. Resveratrol (Res) is a polyphenol with anti-aging properties. This study investigated whether Res attenuates cigarette smoke extract (CSE)-induced cellular senescence in human airway epithelial cells (BEAS-2B) through the miR-34a/SIRT1/nuclear factor-kappaB (NF-κB) pathway. BEAS-2B cells were treated with Res, CSE and transfected with miR-34a-5p mimics. Cellular senescence was evaluated by senescence -related β-galactosidase (SA-β-gal) staining and expression of senescence-related genes (p16, p21, and p53). The expressions of miR-34a-5p, SIRT1, and NF-κB p65 were examined using quantitative real time polymerase chain reaction and western blotting. The senescence-associated secretory phenotype (SASP) cytokines (IL-1β, IL-6, IL-8, TNF-α) were assessed by enzyme-linked immunosorbent assay. The binding between miR-34a-5p and SIRT1 was confirmed by dual-luciferase reporter assay. The results showed that CSE dose-dependently decreased cell viability and elevated cellular senescence, characterized by increased SA-β-gal staining and senescence-related gene expressions (p16, p21, and p53). Further, CSE dose-dependently increased the expression of miR-34a-5p and SASP cytokines (IL-1β, IL-6, IL-8, TNF-α) in BEAS-2B cells. Pretreatment with Res inhibited CSE-induced cellular senescence and secretion of SASP cytokines (IL-1β, IL-6, IL-8, TNF-α) in a dose-dependent manner. Moreover, Res reversed the CSE-induced down-regulation of SIRT1 and up-regulation of miR-34a-5p and NF-κB p65. SIRT1 is a target of miR-34a-5p. Overexpression of miR-34a-5p via transfection with miR-34a-5p mimic in BEAS-2B cells attenuated the inhibitory effect of Res on cellular senescence, accompanied by reversing the expression of SIRT1 and NF-κB p65. In conclusion, Res attenuated CSE-induced cellular senescence in BEAS-2B cells by regulating the miR-34a/SIRT1/NF-κB pathway, which may provide a new approach for COPD treatment.

Topics: Cellular Senescence; Cigarette Smoking; Epithelial Cells; Humans; Interleukin-6; Interleukin-8; MicroRNAs; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Resveratrol; Sirtuin 1; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

Chitinases and chitinase-like proteins are thought to play a role in innate inflammatory responses. Our study aimed to assess whether chitinase concentration and activity in induced sputum (IS) of patients exposed to tobacco smoke are related to the level of airway inflammation including the level and activity of chitinases and chitinase-like proteins. The study included 22 patients with chronic obstructive pulmonary disease (COPD), 12 non-COPD smokers, and nine nonsmoking subjects. Sputum CHIT1 and YKL-40 levels and chitinolytic activity were compared with sputum IL-6, IL-8, IL-18, and MMP-9 levels. A hierarchical cluster analysis was also performed. Sputum YKL-40 was higher in COPD patients than in the control groups. Sputum CHIT1 and YKL-40 levels correlated with IS inflammatory cell count as well as with MMP-9 and IL-8 levels. Two main clusters were revealed: Cluster 1 had lower chitinase levels and activity, lower IS macrophage and neutrophil count, and lower IS IL-8, IL-18, and MMP-9 than Cluster 2. Comparison of COPD patients from both clusters revealed significant differences in the IS inflammatory profile despite comparable clinical and functional data. Our findings seem to confirm the involvement of chitinases in smoking-associated chronic airway inflammation and show that airway chitinases may be a potential novel marker in COPD phenotyping.

Topics: Chitinases; Humans; Inflammation; Interleukin-18; Interleukin-8; Matrix Metalloproteinase 9; Pulmonary Disease, Chronic Obstructive; Tobacco Smoke Pollution

Chronic obstructive pulmonary disease (COPD) is related to inflammation and obstruction of the lungs and airways. Protein arginine methyltransferase 5 (PRMT5) that promotes arginine methylation of histones is associated with inflammation of endothelial cell and is implicated in lung branching morphogenesis and progression of lung cancer. The mechanism of PRMT5 in inflammatory response of COPD was explored in this study.. Human bronchial epithelial cells, 16HBE, were treated with cigarette smoke extract for 24 h to establish cell model of COPD. Cell viability was examined by MTT assay. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays were used to explore expression of PRMT5. Expression of Interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α), and IL-1β were investigated by enzyme-linked-ithe mmunosorbent serologic assay.. Cigarette smoke extract treatment induced cytotoxity of 16HBE with reduced cell viability. PRMT5 was enhanced in cigarette smoke extract-induced 16HBE. Knockdown of PRMT5 increased cell viability of cigarette smoke extract-induced 16HBE, and attenuated cigarette smoke extract-induced increase of IL-6, IL-8, TNF-α, and IL-1β. Up-regulation of C-X-C Motif Chemokine 10 (CXCL10) in cigarette smoke extract-induced 16HBE was restored by knockdown of PRMT5. Over-expression of CXCL10 counteracted with the suppressive effect of PRMT5 silence on expression of IL-6, IL-8, TNF-α, and IL-1β. Moreover, PRMT5 silence-induced increase of cell viability in cigarette smoke extract-induced 16HBE was reversed by over-expression of CXCL10.. Knockdown of PRMT5 promoted cell viability of cigarette smoke extract-induced 16HBE, and reduced inflammation through down-regulation of CXCL10.

Topics: Chemokine CXCL10; Epithelial Cells; Humans; Inflammation; Interleukin-6; Interleukin-8; Protein-Arginine N-Methyltransferases; Pulmonary Disease, Chronic Obstructive; Smoking; Tumor Necrosis Factor-alpha; Up-Regulation

The role of PAR-1 expression and activation was described in epithelial cells from the central and distal airways of COPD patients using an ex vivo/in vitro model. PAR-1 immunoreactivity was studied in epithelial cells from surgical specimens of the central and distal airways of COPD patients and healthy control (HC). Furthermore, PAR-1 expression and activation were measured in both the human bronchial epithelial cell line (16HBE) and normal human bronchial epithelial cells (NHBEs) exposed to cigarette smoke extract (CSE) (10%) or thrombin. Finally, cell proliferation, apoptosis, and IL-8 release were detected in stimulated NHBEs. We identified higher levels of PAR-1 expression/activation in epithelial cells from the central airways of COPD patients than in HC. Active PAR-1 increased in epithelial cells from central and distal airways of COPD, with higher levels in COPD smokers (correlated with pack-years) than in COPD ex-smokers. 16HBE and NHBEs exposed to CSE or thrombin showed increased levels of active PAR-1 (localized in the cytoplasm) than baseline conditions, while NHBEs treated with thrombin or CSE showed increased levels of IL-8 proteins, with an additional effect when used in combination. Smoking habits generate the upregulation of PAR-1 expression/activation in airway epithelial cells, and promoting IL-8 release might affect the recruitment of infiltrating cells in the airways of COPD patients.

Topics: Apoptosis; Biomarkers; Case-Control Studies; Cell Line; Cell Proliferation; Disease Susceptibility; Epithelial Cells; Fluorescent Antibody Technique; Gene Expression; Humans; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Receptor, PAR-1; Respiratory Mucosa; Smoking

BACKGROUND The aim of this study was to investigate the correlations of silent information regulator of transcription 1 (SIRT1) expression, inflammatory factors, and oxidative stress with pulmonary function in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). MATERIAL AND METHODS Bronchoalveolar lavage fluid (BALF) was collected from 188 patients with COPD (83 in stable phase and 105 in acute exacerbation phase) and 56 healthy controls. Subsequently, the SIRT1 expression levels, the IL-6 and IL-8 levels (the representatives of inflammatory factors), and the MDA and SOD levels (indicative of oxidative stress) were detected via enzyme-linked immunosorbent assay. Correlations of SIRT1 expression, inflammatory factors, and oxidative stress with pulmonary function parameters [forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) and FEV1] were measured via Spearman's correlation analysis. RESULTS The levels of inflammatory factors and oxidative stress were elevated and SIRT1 expression remarkably declined in patients with AECOPD compared with those in healthy controls and stable COPD patients (P<0.05). Spearman's correlation analysis revealed that SIRT1 expression, interleukin (IL)-6, and IL-8 were strongly associated with pulmonary function parameters (FEV1/FVC and FEV1) in patients with AECOPD (P<0.001), while no such obvious correlation was observed in stable COPD patients. CONCLUSIONS Oxidative stress and expression levels of inflammatory factors are evidently elevated and SIRT1 expression declines in patients with AECOPD. Moreover, SIRT1 expression is positively associated with pulmonary function parameters, while IL-6 and IL-8 exhibit negative correlations with pulmonary function parameters.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Case-Control Studies; China; Disease Progression; Female; Forced Expiratory Volume; Gene Expression; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sirtuin 1; Superoxide Dismutase; Vital Capacity

Lower airway bacterial colonisation (LABC) in COPD patients is associated with increased exacerbation frequency and faster lung function decline. Defective macrophage phagocytosis in COPD drives inflammation, but how defective macrophage function contributes to exacerbations is not clear. This study investigated the association between macrophage phagocytosis and exacerbation frequency, LABC and clinical parameters.. Monocyte-derived macrophages (MDM) were generated from 92 stable COPD patients, and at the onset of exacerbation in 39 patients. Macrophages were exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, then phagocytosis measured by fluorimetry and cytokine release by ELISA. Sputum bacterial colonisation was measured by PCR.. Phagocytosis of H. influenzae was negatively correlated with exacerbation frequency (r = 0.440, p < 0.01), and was significantly reduced in frequent vs. infrequent exacerbators (1.9 × 10. Impaired COPD macrophage phagocytosis of H. influenzae, but not S. pneumoniae is associated with exacerbation frequency, resulting in pro-inflammatory macrophages that may contribute to disease progression. Targeting these frequent exacerbators with drugs that improve macrophage phagocytosis may prove beneficial.

Topics: Aged; Case-Control Studies; Cells, Cultured; Disease Progression; Female; Haemophilus influenzae; Humans; Inflammation Mediators; Interleukin-8; Lung; Macrophages; Male; Phagocytosis; Phenotype; Pulmonary Disease, Chronic Obstructive; Streptococcus pneumoniae; Tumor Necrosis Factor-alpha

Inflammation, oxidative stress, and protease-antiprotease imbalance have been suggested to be a pathogenic triad in chronic obstructive pulmonary disease (COPD). However, it is not clear how proteases interact with components of inflammatory pathways. Therefore, this study aimed to evaluate the effect of neutrophil elastase (NE) on lipopolysaccharide (LPS)-induced interleukin 8 (IL-8) production and determine the molecular mechanism in human bronchial epithelial cells (HBECs). Immortalized bronchial epithelial cells and primary HBECs were used to investigate the impact of NE on LPS-induced IL-8 production. The molecular mechanism by which NE modulated LPS-induced IL-8 production was confirmed in elastase-treated C57BL/6 mice and primary HBECs obtained from COPD patients and healthy controls. The results showed that NE treatment synergistically augmented LPS-induced IL-8 production in both immortalized bronchial epithelial cells and primary HBECs. NE partially degraded peroxisome proliferator-activated receptor gamma (PPARγ), which is known to regulate IL-8 production in the nucleus. Treatment with a PPARγ agonist and overexpression of PPARγ reversed the NE-induced synergistic increase in LPS-induced IL-8 production. Moreover, PPARγ levels were lower in lung homogenates and lung epithelial cells from elastase-treated mice than in those from saline-treated mice. In accordance with the findings in mice, PPARγ levels were lower in primary HBECs from COPD patients than in those from healthy never-smokers or healthy smokers. In conclusion, a vicious cycle of mutual augmentation of protease activity and inflammation resulting from PPARγ degradation plays a role in the pathogenesis of COPD.

Topics: Animals; Biomarkers; Cell Line; Cells, Cultured; Disease Susceptibility; Epithelial Cells; Female; Gene Expression Regulation; Humans; Interleukin-8; Leukocyte Elastase; Lipopolysaccharides; Mice; NF-kappa B; Peptide Hydrolases; PPAR gamma; Proteolysis; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Signal Transduction; Toll-Like Receptor 4

Among immunologically normal hosts, patients with chronic obstructive pulmonary disease (COPD) are considered to be at high risk of invasive pulmonary aspergillosis (IPA), and early diagnosis and treatment are the key to improving the prognosis of patients. Here we aimed to evaluate whether interleukin (IL)-6 and IL-8 might be used in the detection and diagnosis of IPA in patients with COPD. We prospectively collected 106 patients with COPD and divided them into non-IPA (n=74), probable/possible IPA (n=26) and proven IPA (n=6). Platelia Aspergillus kit was used to detect galactomannan in bronchoalveolar lavage fluid (BALF), and serum and ELISA kit was used to detect IL-6 and IL-8 levels. Diagnostic efficiency of IL-6, IL-8 and galactomannan in serum and BALF was evaluated by receiver operating characteristic curve. Compared with the non-IPA group, the proven/probable IPA group showed significantly elevated levels of IL-6 and IL-8 in both serum and BALF, which were positively correlated with galactomannan levels. The sensitivity and specificity of IL-6 for diagnosing IPA were 74.32% and 81.25% (cut-off at 92.82 pg/mL, area under the curve (AUC)=0.8366) in serum and 68.92% and 71.88% (cut-off at 229.4 pg/mL, AUC=0.7694) in BALF. The sensitivity and specificity of IL-8 for diagnosing IPA were 83.78% and 81.25% (cut-off at 93.46 pg/mL, AUC=0.8756) in serum and 85.14% and 75.00% (cut-off at 325.4 pg/mL, AUC=0.8252) in BALF. The elevated levels of IL-6 and IL-8 in patients with IPA with COPD could be used as auxiliary indicators to diagnose IPA in addition to galactomannan.

Topics: Bronchoalveolar Lavage Fluid; Galactose; Humans; Interleukin-6; Interleukin-8; Invasive Pulmonary Aspergillosis; Mannans; Pulmonary Disease, Chronic Obstructive; Sensitivity and Specificity

The health effects of e-cigarettes in patients with pre-existing lung disease are unknown. The aim of this study was to investigate whether aerosols from a fourth-generation e-cigarette produces similar in-vitro cytotoxic, DNA damage and inflammatory effects on bronchial epithelial cells (BECs) from patients with COPD, as cigarette smoke.. BECs from patients with COPD who underwent surgery for lung cancer and comparator (immortalised 16HBE) cells were grown at air liquid interface (ALI). BECs were exposed to aerosols from a JUUL® e-cigarette (Virginia Tobacco and Menthol pods at 5% nicotine strength) or reference 3R4F cigarette for 30 min at ALI. Cell cytotoxicity, DNA damage and inflammation were measured.. In response to the Virginia Tobacco and Menthol flavoured e-cigarette aerosols, COPD BECs showed comparable LDH release (cell cytotoxicity, p = 0.59, p = 0.67 respectively), DNA damage (p = 0.41, p = 0.51) and inflammation (IL-8, p = 0.20, p = 0.89 and IL-6, p = 0.24, p = 0.93), to cigarette smoke. 16HBE cells also showed comparable cellular responses to cigarette smoke.. In airway cells from patients with COPD, aerosols from a fourth-generation e-cigarette were associated with similar toxicity to cigarette smoke. These results have potential implications for the safety of e-cigarette use in patients with lung disease.

Topics: Aerosols; Aged; Bronchi; Cell Line; Cell Survival; DNA Damage; Electronic Nicotine Delivery Systems; Epithelial Cells; Flavoring Agents; Humans; Interleukin-6; Interleukin-8; Male; Menthol; Middle Aged; Nicotiana; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Tobacco Products

Chronic obstructive pulmonary disease (COPD) often tends to respond poorly to glucocorticoid (GC) therapy. Reduced Histone deacetylase-2 (HDAC-2) activity is an important mechanism behind this GC insensitivity. In this study, we investigated the effects of three phosphodiesterase inhibitors (PDEIs), with an anti-inflammatory propensity, on cigarette smoke (CS)-induced pulmonary inflammation and HDAC-2 activity. Male C57BL/6 mice were exposed to cigarette smoke (CS) over the course of 30 weeks. Administration of the PDEIs commenced from the 29th week and followed a schedule of once daily treatments, 5 days a week, for 2 weeks. Roflumilast (ROF) was administered intragastrically (5 mg·kg

Topics: Aminopyridines; Animals; Anti-Inflammatory Agents; Benzamides; Cyclopropanes; Disease Models, Animal; Histone Deacetylase 2; Interleukin-8; Lung; Male; Mice, Inbred C57BL; Nicotiana; Pentoxifylline; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Smoke; Smoking; Theophylline; Tumor Necrosis Factor-alpha

Within the pathogenesis of the chronic obstructive pulmonary disease (COPD) there are interactions between different inflammatory mediators that are enhanced during an exacerbation. Arginase is present in bronchial epithelial cells, endothelial, fibroblasts and alveolar macrophages, which make it a probable key enzyme in the regulation of inflammation and remodelling. We aimed to find a potential relationship between arginase activity, inflammatory mediators in COPD patients in stable phase and during exacerbations.. We performed a prospective, observational study of cases and controls, with 4 study groups (healthy controls, stable COPD, COPD during an exacerbation and COPD 3 months after exacerbation). We measured arginase, inflammation markers (IL-6, IL-8, TNF-∝, IFN-γ and C reactive protein), and mediators of immunity: neutrophils, monocytes, total TCD3 + lymphocytes (CD3ζ), CD4 + T cells, CD8 + T cells, NK cells.. A total of 49 subjects were recruited, average age of 69.73 years (59.18% male). Arginase activity is elevated during an exacerbation of COPD, and this rise is related to an increase in IL-6 production. The levels of IL-6 and IL-8 remained elevated in patients with COPD at 3 months after hospital exacerbation. We did not find a clear relationship between arginase activity, immunity or with the degree of obstruction in COPD patients.. Arginase activity is elevated during an exacerbation of COPD, and it could be related to an increase in the production of IL-6. Levels of IL-6, IL-8, and arginase activity remain elevated in patients with COPD at 3 months after hospital exacerbation. Arginase activity could contribute to the development of COPD.

Topics: Aged; Aged, 80 and over; Arginase; Biomarkers; Case-Control Studies; Disease Progression; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Linear Models; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive

Respiratory infections are a leading cause of global morbidity and mortality and are of significant concern for individuals with chronic inflammatory lung diseases. There is an urgent need for novel antimicrobials. Antimicrobial peptides (AMPs) are naturally occurring innate immune response peptides with therapeutic potential. However, therapeutic development has been hindered by issues with stability and cytotoxicity. Availing of direct drug delivery to the affected site, for example the lung, can reduce unwanted systemic side effects and lower the required dose. As cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) lungs typically exhibit elevated protease levels, the aim of this study was to assess their impact on snake-derived AMPs. Peptide cleavage was determined using SDS-PAGE and antimicrobial and anti-inflammatory activities of neutrophil elastase (NE)-incubated peptides were assessed using a radial diffusion assay (RDA) and an in vitro LPS-induced inflammation model, respectively. Although the snake-derived AMPs were found to be susceptible to cleavage by lung proteases including NE, several retained their function following NE-incubation. This facilitated the design of novel truncated derivatives that retained functionality following NE incubation. Snake-derived AMPs are tractable candidate treatments for use in environments that feature elevated NE levels, such as the CF airways.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Cystic Fibrosis; Humans; Immunity, Innate; Inflammation; Inhibitory Concentration 50; Interleukin-6; Interleukin-8; Leukocyte Elastase; Lipopolysaccharides; Lung; Macrophages; Monocytes; Peptide Hydrolases; Peptides; Pore Forming Cytotoxic Proteins; Protein Structure, Secondary; Pseudomonas aeruginosa; Pulmonary Disease, Chronic Obstructive; Snakes; THP-1 Cells

Thrombin plays a crucial role in lung inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Thrombin induces the release of interleukin-8 (IL-8)/CXCL8 by lung epithelial cells, and this phenomenon plays a vital role in lung inflammation. Our previous studies have indicated that thrombin stimulates IL-8/CXCL8 expression through PI3K/Akt/IκB kinase (IKK)α/β/nuclear factor-κB (NF-κB) and p300 pathways in human lung epithelial cells. In the present study, we explored the roles of mammalian target of rapamycin (mTOR) and p70S6 kinase (p70S6K) in thrombin-induced NF-κB activation and IL-8/CXCL8 release in human lung epithelial cells. In this study, we found that rapamycin (an mTOR inhibitor) and p70S6K siRNA diminished thrombin-induced IL-8/CXCL8 release. Thrombin induced mTOR Ser2448 phosphorylation and p70S6K Thr389 phosphorylation in a time-dependent manner. Moreover, rapamycin attenuated thrombin-stimulated p70S6K phosphorylation. We also found that transfection of cells with the dominant negative mutant of Akt (Akt DN) reduced the thrombin-induced increase in mTOR phosphorylation and p70S6K phosphorylation. Moreover, thrombin-stimulated p300 phosphorylation was attenuated by Akt DN, rapamycin, and p70S6K siRNA. Thrombin triggered p70S6K translocation from the cytosol to the nucleus in a time-dependent manner. Thrombin induced the complex formation of p70S6K, p300, and p65; acetylation of p65 Lys310, and recruitment of p70S6K, p300, and p65 to the κB-binding site of the IL-8/CXCL8 promoter region. In conclusion, these results indicate that thrombin initiates the Akt-dependent mTOR/p70S6K signaling pathway to promote p300 phosphorylation and NF-κB activation and finally induces IL-8/CXCL8 release in human lung epithelial cells.

Topics: A549 Cells; Asthma; E1A-Associated p300 Protein; Epithelial Cells; Humans; Interleukin-8; Lung; Phosphorylation; Pulmonary Disease, Chronic Obstructive; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Thrombin; TOR Serine-Threonine Kinases; Transcription Factor RelA

Glucocorticoids are commonly prescribed to treat inflammation of the respiratory system; however, they are mostly ineffective for controlling chronic obstructive pulmonary disease (COPD)-associated inflammation. This study aimed to elucidate the molecular mechanisms responsible for such glucocorticoid inefficacy in COPD, which may be instrumental to providing better patient outcomes. Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor with anti-inflammatory properties in severe COPD patients who have a history of exacerbations. Roflumilast has a suggested ability to mitigate glucocorticoid resistance, but the mechanism is unknown.. To understand the mechanism that mediates roflumilast-induced restoration of glucocorticoid sensitivity in COPD, we tested the role of glucocorticoid receptor α (GRα). Roflumilast's effects on GRα expression and transcriptional activity were assessed in bronchial epithelial cells from COPD patients.. We found that both GRα expression and activity are downregulated in bronchial epithelial cells from COPD patients and that roflumilast stimulates both GRα mRNA synthesis and GRα's transcriptional activity in COPD bronchial epithelial cells. We also demonstrate that roflumilast enhances dexamethasone's ability to suppress pro-inflammatory mediator production, in a GRα-dependent manner.. Our findings highlight the significance of roflumilast-induced GRα upregulation for COPD therapeutic strategies by revealing that roflumilast restores glucocorticoid sensitivity by sustaining GRα expression.

Topics: Aminopyridines; Benzamides; Cells, Cultured; Cyclopropanes; Dexamethasone; Drug Resistance; Epithelial Cells; Glucocorticoids; Humans; Inflammation Mediators; Interleukin-8; Lung; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Receptors, Glucocorticoid; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Up-Regulation

The eosinophilic chronic obstructive pulmonary disease (COPD) is known to be more sensitive to corticosteroid. The sputum microbiome has been shown to affect COPD prognosis, but its role in acute exacerbations of eosinophilic COPD is unclear. This study aimed to investigate the dynamic changes of the airway microbiome in patients with acute exacerbations of eosinophilic COPD.. Fifty-seven patients with acute exacerbations of COPD from the First Affiliated Hospital of Guangxi Medical University between June 2017 and June 2018 were divided into two groups. Patients with eosinophils ≥300 cells/μL in the peripheral venous blood were assigned to the eosinophilic group (Eos) and the rest to the non-eosinophilic group (Noneos). All patients received similar treatment including inhaled budesonide according to the guidelines. The induced sputum microbiome was analyzed on the 1st and 7th day of treatment using the 16S ribosomal RNA (rRNA) method. The levels of interleukin (IL)-6 and IL-8 were measured in the plasma and the sensitivity to corticosteroids was determined in isolated peripheral blood mononuclear cells. Quantitative data were compared between the two groups using the independent samples t test or Mann-Whitney U test. Categorical data were evaluated using Chi-squared test or Fisher's exact test.. Twenty-six patients were classified into Eos group and 31 patients were classified into Noneos group. Prior to treatment, the alpha diversity (Shannon index) (2.65 ± 0.63 vs. 2.56 ± 0.54, t = 0.328, P = 0.747) and the structure of the sputum microbiome were similar in the Eos group and the Noneos group. After 7 days of treatment, alpha diversity increased in both groups, while the microbiome richness (Ace index) was significantly lower in the Eos group (561.87 ± 109.13 vs. 767.88 ± 148.48, t = -3.535, P = 0.002). At the same time, IL-6 (12.09 ± 2.85 pg/mL vs. 15.54 ± 2.45 pg/mL, t = -4.913, P < 0.001) and IL-8 (63.64 ± 21.69 pg/mL vs. 78.97 ± 17.13 pg/mL, t = -2.981, P = 0.004) decreased more significantly in the Eos group, and the percentages of inhibition of IL-8 at dexamethasone concentrations 10 to 10 mol/L were significantly higher in the Eos group than those in the Noneos group (all P < 0.05).. The induced sputum microbiome richness decreased more significantly following treatment in the Eos patients compared to the Noneos patients. The lower plasma inflammatory factor levels and the higher percentage of inhibition of IL-8 might be due to higher corticosteroid sensitivity in Eos patients.

Topics: Adrenal Cortex Hormones; Aged; Cytokines; Humans; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Middle Aged; Pulmonary Disease, Chronic Obstructive; RNA, Ribosomal; RNA, Ribosomal, 16S; Sputum

Topics: Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Hesperidin; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Mice; NF-kappa B; Oxidative Stress; Peroxidase; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Sirtuin 1; Smoke; Superoxide Dismutase; Transcription Factor RelA

Chronic obstructive pulmonary disease (COPD) skeletal muscle dysfunction is a prevalent malady that significantly affects patients' prognosis and quality of life. Although the study of this disease has attracted considerable attention, a definite animal model is yet to be established. This study investigates whether smoke exposure could lead to the development of a COPD skeletal muscle dysfunction model in rats.. Sprague Dawley rats were randomly divided into model (MG, n = 8) and control groups (CG, n = 6). The MG was exposed to cigarette smoke for 16 weeks while the CG was not. The body weight and forelimb grip strength of rats were monitored monthly. The pulmonary function and the strength of tibialis anterior muscle were assessed in vitro and compared after establishing the model. The histological changes in lung and gastrocnemius muscles were observed. The expressions of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α were detected by ELISA, while the expressions of Atrogin-1 and MuRF1 in the gastrocnemius muscle were determined by Western blotting.. Smoke exposure slowly increases the body weight and forelimb grip strength of MG rats, compared to CG rats. However, it significantly decreases the pulmonary ventilation function and the skeletal muscle contractility of the MG in vitro. Histologically, the lung tissues of MG show typical pathological manifestations of emphysema, while the skeletal muscles present muscular atrophy. The expressions of IL-6, IL-8, and TNF-α in MG rats are significantly higher than those measured in CG rats. Increased levels of Atrogin-1 and MuRF1 were also detected in the gastrocnemius muscle tissue of MG.. Progressive smoking exposure decreases the contractile function of skeletal muscles, leading to muscular atrophy. It also increases the expressions of inflammatory and muscle protein degradation factors in COPD rats. This indicates that smoke exposure could be used to establish a COPD skeletal muscle dysfunction model in rats.

Topics: Animals; Cigarette Smoking; Disease Models, Animal; Interleukin-6; Interleukin-8; Lung; Male; Muscle Contraction; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

The Global Initiative classification (GOLD) for chronic obstructive pulmonary disease (COPD), which relies on the practical issues of treatment of this complex and heterogeneous disease, may not be reliable in predicting disease severity and prognosis as the term of inflammation is excluded from the definition.. The aim of this study was to determine systemic inflammatory markers in GOLD ABCD groups and to compare these parameters according to clinical and functional features.. The study included 60 COPD patients and 59 healthy subjects. Comparisons were made with the pulmonary function test, transthoracic echocardiography and the six-minute walk test (6MWT). The COPD assessment test (CAT), modified Medical Research Council (mMRC), and index scores of body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) were recorded. The systemic inflammatory state was assessed using C-reactive protein, fibrinogen, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8 and IL-18.. The levels of all serum inflammatory markers were higher in the COPD group than in the control group. TNF-α and IL-6 were significantly higher in the symptomatic groups (B and D) than in the less symptomatic groups (A and C) (P < 0.05). Spirometric parameters were more severe in Group D, followed by groups C, B and A, respectively. The 6MWT and the BODE scores were worst in Group D, followed by groups B, C and A.. The results suggest that bronchodilator treatment alone might be insufficient in Group B patients, as the systemic inflammatory markers in addition to exercise capacity and mortality predictors were at the worst level in Groups D and B.

Topics: Aged; Biomarkers; Body Mass Index; C-Reactive Protein; Case-Control Studies; Cross-Sectional Studies; Dyspnea; Echocardiography; Exercise Tolerance; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Severity of Illness Index; Spirometry; Tumor Necrosis Factor-alpha; Walk Test

In chronic obstructive pulmonary disease (COPD), the bronchial epithelium is the first immune barrier that is triggered by cigarette smoke. Although vitamin D (vitD) has proven anti-inflammatory and antimicrobial effects in alveolar macrophages, little is known about the direct role of vitD on cigarette smoke-exposed bronchial epithelial cells. We examined the effects of vitD on a human bronchial epithelial cell line (16HBE) and on air-liquid culture of primary bronchial epithelial cells (PBEC) of COPD patients and controls exposed for 24 h to cigarette smoke extract (CSE). VitD decreased CSE-induced IL-8 secretion by 16HBE cells, but not by PBEC. VitD significantly increased the expression of the antimicrobial peptide cathelicidin in 16HBE and PBEC of both COPD subjects and controls. VitD did not affect epithelial to mesenchymal transition or epithelial MMP-9 expression and was not able to restore impaired wound healing by CSE in 16HBE cells. VitD increased the expression of its own catabolic enzyme CYP24A1 thereby maintaining its negative feedback. In conclusion, vitD supplementation may potentially reduce infectious exacerbations in COPD by the upregulation of cathelicidin in the bronchial epithelium.

Topics: Aged; Antimicrobial Cationic Peptides; Bronchi; Case-Control Studies; Cathelicidins; Cell Line; Epithelial Cells; Female; Humans; Interleukin-8; Male; Pulmonary Disease, Chronic Obstructive; Receptors, Calcitriol; Smoke; Tobacco Products; Vitamin D; Vitamin D3 24-Hydroxylase

Topics: Anti-Inflammatory Agents; Bronchi; Cell Line; Disease Progression; Epithelial Cells; Flagellin; Humans; Inflammation; Interleukin-6; Interleukin-8; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pseudomonas aeruginosa; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Toll-Like Receptor 5

To investigate the effect of Daiqin phlegm-expelling pill, prepared with Traditional Chinese Medicine (TCM), on the development of inflammation in Sprague-Dawley (SD) rats with chronic obstructive pulmonary disease (COPD) induced by lipopolysaccharide (LPS) and smoke, and to identity the possible underlying mechanism.. Sixty male rats were divided into 6 groups (healthy control group, untreated group, Daiqin phlegm-expelling pill low, middle and high dose, and ambroxol hydrochloride tablet group). COPD was established in SD rats by sootiness and tracheal instillation with LPS. The rats were treated with Daiqin phlegm-expelling pill at the indicated doses for 28 d, the inflammatory cells in bronchoalveolar lavage fluid (BALF), the concentration of tumor necrosis factor-α (TNF-α), interleukin (IL)-8 and IL-6 in blood and the inflammation in lung were evaluated.. The number of inflammatory cells in the BALF and TNF-α, IL-8 and IL-6 level in plasma were significantly reduced in rats with COPD when treated with Daiqin phlegm-expelling pill or ambroxol hydrochloride tablet, compared with those without any treatment. The Daiqin phlegm-expelling pill treated rats with COPD had a attenuated inflammation in lung tissue, compared with the untreated group.. Daiqin phlegm-expelling pill can significantly restrain the airway inflammation in rats with LPS-smoke induced COPD.

Topics: Animals; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Drugs, Chinese Herbal; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Male; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Smoke; Tumor Necrosis Factor-alpha

Extracellular Hsp70 (eHsp70) can activate immune cells via Toll-like receptors (TLR) 2 and 4, and induce cytokine synthesis. The aim of this study was to explore inflammation-associated effects of eHsp70 alone and in combination with cigarette smoke extract (CSE) in primary bronchial epithelial cells. We assessed IL-6 and IL-8 concentrations, TLR2, TLR4 and Hsp70 mRNA expressions, and mitogen-activated protein kinases (MAPKs) activation induced by recombinant human (rh) Hsp70, CSE or their combinations in normal human bronchial epithelial cells (NHBE) obtained commercially, and primary bronchial epithelial cells isolated from non-COPD lung donors (PBEC) or COPD patients (PBEC COPD). Baseline levels of IL-6 and IL-8 were significantly higher in PBEC COPD than in non-COPD PBECs. Upon rhHsp70 stimulation, IL-6 and IL-8 were significantly increased, with the strongest response in COPD-derived PBECs. CSE alone elevated cytokine secretion in all examined cells. rhHsp70 and CSE had antagonistic interactions on IL-8 release in PBECs from COPD patients, while the addition of rhHsp70 further increased CSE-induced IL-6 secretion in NHBE cells. rhHsp70 and CSE alone decreased TLR2 and TLR4 mRNA expression in COPD-derived PBECs. In non-COPD PBECs, combined treatments decreased only TLR2 mRNA expression. Hsp70 mRNA expression, as indicator of intracellular Hsp70, which may have anti-inflammatory effects, was reduced in COPD-derived cells upon exposure to CSE and rhHsp70 alone, but not with their combinations. Contrary to this, in PBECs from lung donors only combined treatments supressed Hsp70 gene expression. CSE activated JNK and p38 MAPKs, while rhHsp70 increased activation of c-Jun kinase in NHBE cells. Collectively, both eHsp70 and CSE induce pro-inflammatory responses in PBECs from non-COPD as well as COPD donors, but in combination antagonistic effects were observed in COPD-derived cells. These effects may be related to the regulation of TLR2/4 and might lead to modulation of inflammation with possible deleterious consequences for COPD patients.

Topics: Epithelial Cells; Female; HSP70 Heat-Shock Proteins; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Tobacco Smoke Pollution; Toll-Like Receptor 2; Toll-Like Receptor 4

Chronic obstructive pulmonary disease (COPD) is a common chronic airway inflammatory disease. MicroRNAs are shown to be involved in the regulation of inflammation. We investigated the role of microRNA-29b (miR-29b) in the airway inflammation in COPD. The expression of miR-29b in the lung and plasma was examined. The target of miR-29b, bromodomain protein 4 (BRD4), was predicted by online algorithms and verified in human bronchial epithelial (HBE) cells. The expression of BRD4, interleukin (IL)-8, and IL-6 in the lung was also examined. The role of miR-29b in the inflammatory cytokine expression of airway epithelial cells was studied using an in vitro model system. In total, 60 subjects were recruited, including 10 nonsmokers, 24 smokers, and 26 patients with COPD. Both lung and plasma miR-29b are decreased in patients with COPD, and miR-29b expression levels are correlated with pulmonary function and inflammation. BRD4 is increased in the lung of patients with COPD and is correlated with miR-29b and IL-8 expression. miR-29b regulates cigarette smoke extract (CSE)-induced IL-8 expression by targeting BRD4 in HBE cells. The antioxidant N-acetylcysteine prevents CSE-induced miR-29b downregulation and BRD4 and IL-8 upregulation. Our findings indicate that miR-29b may participate in the airway inflammation in COPD by regulating inflammatory cytokine expression through targeting BRD4, plasma miR-29b may serve as a biomarker for disease severity in COPD, and oxidative stress may contribute to the decrease of miR-29b induced by cigarette smoke.

Topics: Biomarkers, Tumor; Cell Cycle Proteins; Cell Line; Cytokines; Down-Regulation; Humans; Inflammation; Interleukin-8; Lung; Male; MicroRNAs; Middle Aged; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Smoking; Transcription Factors

The airway epithelium represents a fragile environmental interface potentially disturbed by cigarette smoke (CS), the major risk factor for developing chronic obstructive pulmonary disease (COPD). CS leads to bronchial epithelial damage on ciliated, goblet, and club cells, which could involve calcium (Ca

Topics: Adult; Aged; Benzamides; Bronchi; Calcium; Calcium Channels; Calcium Signaling; Cells, Cultured; Cilia; Cytokines; Endoplasmic Reticulum; Epithelial Cells; Female; Gene Expression Regulation; Humans; Interleukin-8; Male; Middle Aged; Mucin 5AC; Mucus; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Respiratory Mucosa; Signal Transduction; Smoke; Smokers; Smoking

The aim of this study was to identify the association polymorphism (rs11536889) in the 3'-untranslated region (3'-UTR) of Toll-like receptors 4 (TLR4) and the risk for ventilator-associated pneumonia (VAP). miRNA database online and luciferase assays were used to validate TLR4 as the target gene of miR-1236. Enzyme-linked immunosorbent assay analysis and western blot were used to analyze the level of TLR4 in different genotype groups. In the present study, miR-1236 was predicted to bind to the rs11536889 G allele rather than the rs11536889 C allele, which was further confirmed by the luciferase activity suppressed by a fragment of 3'-UTR containing the rs11536889 G allele induced by lipopolysaccharide (LPS) and interleukin-6 (IL-6). Bronchial epithelial cells isolated from participants genotyped as GG, GC, and CC, with no remarkable difference in TLR4 messenger RNA (mRNA) levels were observed among these genotype groups. After stimulating by LPS, a TLR4 ligand, the CC-genotyped cells expressed higher levels of IL-8, IL-6, and tumor necrosis factor alpha (TNF-α) on their surfaces than cells with the other genotypes. Finally, the western blot analysis results showed that the expression level of IL-8, IL-6, and TNF-α protein was much higher in the CC group than the GC and GG groups subsequent to stimulation by LPS, and the IL-8, IL-6, and TNF-α protein levels in the GC were grouped much lower compared with the GG group. These findings indicated the regulatory association of miR-1236 with TLR4 and the abnormal expression of TLR4 caused by the presence of rs11536889 in the 3'-UTR of mRNA, which interfere with its interaction with the miR-1236, contributing to the risk of VAP.

Topics: 3' Untranslated Regions; Alleles; Alveolar Epithelial Cells; Cells, Cultured; Female; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; MicroRNAs; Middle Aged; Pneumonia, Ventilator-Associated; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Respiration, Artificial; RNA, Messenger; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Extracellular Hsp70 (eHsp70) can act as pro-inflammatory mediator and is elevated in blood of chronic obstructive pulmonary disease (COPD) patients. Most of those patients are smokers, and it was suggested previously that cigarette smoke might induce Hsp70 secretion from the circulating cells. Therefore, we aimed to explore inflammation-associated effects of cigarette smoke extract (CSE) and its combinations with eHsp70 in monocyte-derived macrophages (MDMs) and THP-1 cell line, used as systemic component models of COPD. We hypothesized that eHsp70 induces inflammation, but that it can also modulate cigarette smoke extract (CSE)-stimulated inflammatory responses. We assessed IL-8 secretion, TLR2, TLR4 and Hsp70 expressions, MAPKs and NF-κB activation, and cytotoxicity after treating the cells with CSE (2.5 and 5%) and its combinations with low-endotoxin recombinant human (rh) Hsp70, used to mimic eHsp70 effects. CSE induced IL-8 secretion from both cell types, but its combinations with rhHsp70 increased IL-8 release compared to CSE alone only from MDMs. In THP-1, combinations of rhHsp70 with 2.5% CSE induced TLR2 and TLR4 mRNA, while 5% CSE decreased TLR2 expression. In MDMs, CSE alone attenuated TLR2, while rhHsp70 increased TLR2 and lowered TLR4 gene expression. Hsp70 mRNA expression was suppressed in THP-1 with rhHsp70 and CSE; however, the same treatments increased its level in MDMs. CSE had cytotoxic effect only on MDMs, but cytotoxicity was reduced in co-treatments with rhHsp70, which also triggered apoptosis. CSE and rhHsp70 activated p38 and JNK, while ERK was activated only by rhHsp70 in MDMs. In THP-1, 2.5% CSE activated ERK, and 5% CSE activated p38. Inhibition of NF-κB and JNK in MDMs, and ERK and JNK in THP-1 cells, attenuated IL-8 release after rhHsp70 treatment. In conclusion, rhHsp70 provoked pro-inflammatory effects and could also modulate inflammatory response to CSE on protein and gene expression levels in THP-1 cells and MDMs, which suggests that eHsp70 might be implicated in systemic inflammation induced by cigarette smoke.

Topics: Apoptosis; Cell Differentiation; Cell Line; Epithelial Cells; HSP70 Heat-Shock Proteins; Humans; Inflammation; Interleukin-8; Macrophages; NF-kappa B; Nicotiana; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Smoke; Smoking; THP-1 Cells; Toll-Like Receptor 4

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by a progressive and irreversible deterioration of lung function. Exacerbations of COPD have prolonged negative effects on pulmonary function and a major impact on health status and outcomes. NLRP3 inflammasome is a cardinal component of the inflammatory response, with marked evidence in stable and exacerbations of COPD. The aim of our study was to evaluate the NLRP3 inflammasome activity during COPD exacerbation by using an in vitro model.. A549 cells were stimulated with different concentrations (10%, 4%, 2%) of cigarette smoke extract (CSE) with or without LPS (0.1μg/ml) for 24 hours. Cell viability was assessed by using XTT test. Levels of inflammatory cytokines (IL-8, MCP-1, and IL-1β) were measured by ELISA and the activity level of NLRP-3 was evaluated by flow cytometry.. Cells exposed to CSE present an increase in inflammatory cytokines (IL-8 and MCP-1) production in a dose-dependent manner. Incubation with LPS to these cells results in higher levels of IL-8 and MCP-1 compared to stimulation of CSE alone. NLRP3 inflammasome activity and IL-1β levels were significantly increased in cells exposed to both CSE and LPS compared to CSE alone.. NLRP3 inflammasome is upregulated in an in-vitro model of COPD and COPD exacerbation. Our findings provide novel biomarkers for COPD exacerbation and may present new targets for future research.

Topics: A549 Cells; Cell Survival; Chemokine CCL2; Humans; Inflammasomes; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Models, Biological; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Disease, Chronic Obstructive; Smoke; Up-Regulation

Various biomarkers have emerged as potential surrogates to represent various subgroups of chronic obstructive pulmonary disease (COPD), which manifest with different phenotypes. However, the biomarkers representing never-smokers with COPD have not yet been well elucidated. The aim of this study was to evaluate the associations of certain serum and radiological biomarkers with the presence of COPD in never-smokers. To explore the associations of serum and radiological biomarkers with the presence of COPD in never-smokers, we conducted a cross-sectional patient cohort study composed of never-smokers from the COPD in Dusty Areas (CODA) cohort, consisting of subjects living in dusty areas near cement plants in South Korea. Of the 131 never-smokers in the cohort, 77 (58.8%) had COPD. There were no significant differences in the number of subjects with high levels of inflammatory biomarkers (>90th percentile of never-smokers without COPD), including white blood cell count, total bilirubin, interleukin (IL)-6, IL-8, and C-reactive protein, or radiologic measurements (including emphysema index and mean wall area percentage) between never-smokers with COPD and those without COPD. However, the number of subjects with high uric acid was significantly higher in never-smokers with COPD than never-smokers without COPD (31.2% (24/77) vs. 11.1% (6/54); p = 0.013). In addition, multivariate analysis revealed that high uric acid was significantly associated with the presence of COPD in never-smokers (adjusted relative risk: 1.63; 95% confidence interval: 1.21, 2.18; p = 0.001). Our study suggests that high serum levels of uric acid might be a potential biomarker for assessing the presence of COPD in never-smokers.

Topics: Aged; Bilirubin; C-Reactive Protein; Case-Control Studies; Cohort Studies; Cross-Sectional Studies; Dust; Dyspnea; Female; Forced Expiratory Volume; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Male; Manufacturing and Industrial Facilities; Non-Smokers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Republic of Korea; Residence Characteristics; Tomography, X-Ray Computed; Uric Acid; Vital Capacity

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by abnormal inflammation, persistent and progressive lung function decline. The anti-inflammatory actions of tanshinone IIA, which is the most important active component from Chinese herbal medicine Danshen, have been well studied. However, it remains unknown whether sodium tanshinone IIA sulfonate (STS) protects against the development of COPD. Here we found that STS inhalation (5 mg/kg, 30 min per session, twice a day) significantly attenuated lung function decline, airspace enlargement, mucus production, bronchial collagen deposition, inflammatory responses and oxidative stress caused by cigarette smoke (CS) and lipopolysaccharide (LPS) exposures in mice. Moreover, treatment with STS (10 μg/ml) reduced CS extract (CSE)-induced IL-6 and IL-8 secretion in human bronchial epithelial (16HBE) cells. The anti-inflammatory actions of STS were associated with inhibition of ERK1/2 and NF-κB activations. Interestingly, STS inhibited CS-induced reduction of cystic fibrosis transmembrane conductance regulator (CFTR) in mouse lungs and in 16HBE cells. Treatment with a specific CFTR inhibitor CFTR-Inh172 augmented CSE-induced ERK1/2 and NF-κB-dependent inflammatory responses, but abolished the inhibitory action of STS on IL-6 and IL-8 secretion in 16HBE cells. These results demonstrate that CS-induced COPD and down-regulation of CFTR are prevented by STS.

Topics: Animals; Cell Line; Cystic Fibrosis Transmembrane Conductance Regulator; Down-Regulation; Humans; Interleukin-6; Interleukin-8; Male; Mice; Phenanthrenes; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Tobacco Smoke Pollution

Inflammation and ageing are intertwined in chronic obstructive pulmonary disease (COPD). The histone deacetylase SIRT1 and the related activation of FoxO3 protect from ageing and regulate inflammation. The role of SIRT1/FoxO3 in COPD is largely unknown. This study evaluated whether cigarette smoke, by modulating the SIRT1/FoxO3 axis, affects airway epithelial pro-inflammatory responses. Human bronchial epithelial cells (16HBE) and primary bronchial epithelial cells (PBECs) from COPD patients and controls were treated with/without cigarette smoke extract (CSE), Sirtinol or FoxO3 siRNA. SIRT1, FoxO3 and NF-κB nuclear accumulation, SIRT1 deacetylase activity, IL-8 and CCL20 expression/release and the release of 12 cytokines, neutrophil and lymphocyte chemotaxis were assessed. In PBECs, the constitutive FoxO3 expression was lower in patients with COPD than in controls. Furthermore, CSE reduced FoxO3 expression only in PBECs from controls. In 16HBE, CSE decreased SIRT1 activity and nuclear expression, enhanced NF-κB binding to the IL-8 gene promoter thus increasing IL-8 expression, decreased CCL20 expression, increased the neutrophil chemotaxis and decreased lymphocyte chemotaxis. Similarly, SIRT1 inhibition reduced FoxO3 expression and increased nuclear NF-κB. FoxO3 siRNA treatment increased IL-8 and decreased CCL20 expression in 16HBE. In conclusion, CSE impairs the function of SIRT1/FoxO3 axis in bronchial epithelium, dysregulating NF-κB activity and inducing pro-inflammatory responses.

Topics: Bronchi; Chemokine CCL20; Cigarette Smoking; Epithelial Cells; Forkhead Box Protein O3; Gene Expression Regulation; Humans; Immunity, Cellular; Inflammation; Interleukin-8; NF-kappa B; Nicotiana; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Sirtuin 1

The aim of this study was to investigate the predicting value of miR-146a/b for acute exacerbation chronic obstructive pulmonary disease (AECOPD) and COPD, and to explore their associations with inflammatory cytokines in AECOPD and stable COPD patients.One hundred six AECOPD, 122 stable COPD patients, and 110 health volunteers with age and sex matched to total COPD patients (AECOPD and stable COPD) were enrolled. Blood samples were collected from all participants. Relative expression of miR-146a/b was determined by real-time polymerase chain reaction. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), leukotriene B4 (LTB-4) expression in serum from AECOPD and stable COPD patients were assessed using commercial ELISA kit.Serum levels of miR-146a and miR-146b were down regulated in AECOPD patients compared with stable COPD patients and HCs. miR-146a and miR-146b are of good values for predicting the risk of AECOPD in HCs with AUC of 0.702 and 0.715. Additionally, miR-146a and miR-146b could distinguish AECOPD from stable COPD patients with AUC of 0.670 and 0.643. In AECOPD patients, levels of miR-146a in AECOPD patients were negatively associated with TNF-α, IL-6, IL-8, and LTE-4 expression. In stable COPD patients, miR-146a expressions were negatively correlated with TNF-α, IL-1β, IL-6, IL-8, and LTE-4 levels. And, the expressions of miR-146b in AECOPD patients were negatively associated with IL-1β and LTB-4 expression. While in stable COPD patients, miR-146b expressions were only negatively correlated with TNF-α level.In conclusion, miR-146a and miR-146b were negatively correlated with inflammatory cytokines, and could be promising biomarkers for predicting the risk of AECOPD in stable COPD patients and healthy individuals.

Topics: Acute Disease; Aged; Biomarkers; Case-Control Studies; Cytokines; Disease Progression; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukotriene B4; Male; MicroRNAs; Middle Aged; Pulmonary Disease, Chronic Obstructive; Real-Time Polymerase Chain Reaction; Risk Factors; Tumor Necrosis Factor-alpha

Airway epithelial cell death and inflammation are pathological features of chronic obstructive pulmonary disease (COPD). Mechanistic target of rapamycin (MTOR) is involved in inflammation and multiple cellular processes, e.g., autophagy and apoptosis, but little is known about its function in COPD pathogenesis. In this article, we illustrate how MTOR regulates cigarette smoke (CS)-induced cell death, airway inflammation, and emphysema. Expression of MTOR was significantly decreased and its suppressive signaling protein, tuberous sclerosis 2 (TSC2), was increased in the airway epithelium of human COPD and in mouse lungs with chronic CS exposure. In human bronchial epithelial cells, CS extract (CSE) activated TSC2, inhibited MTOR, and induced autophagy. The TSC2-MTOR axis orchestrated CSE-induced autophagy, apoptosis, and necroptosis in human bronchial epithelial cells; all of which cooperatively regulated CSE-induced inflammatory cytokines IL-6 and IL-8 through the NF-κB pathway. Mice with a specific knockdown of

Topics: Animals; Apoptosis; Autophagy; Bronchi; Cell Death; Cell Line; Epithelial Cells; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Mice; Mice, Inbred C57BL; NF-kappa B; Nicotiana; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Smoke; Smoking; TOR Serine-Threonine Kinases

Chronic obstructive pulmonary disease (COPD) is a common inflammatory lung disease characterized by inflammatory cells activation and production of inflammatory mediators. Methyl-CpG-binding domain protein 2 (MBD2) plays an important role in diverse immunological disorders by regulating immune cell functions, such as differentiation and mediator secretion. However, the role of MBD2 in COPD remains unknown.. MBD2 protein expression in lung tissues of patients with COPD and cigarette smoke (CS)-exposed mice were evaluated by Western blot and immunohistochemistry. The role of MBD2 in cigarette smoke extract (CSE)-induction of inflammatory mediator expression in the human bronchial epithelial (HBE) cell line was assessed by silencing MBD2 expression in vitro. The involvement of signaling pathways in mediation of inflammation was tested with signaling inhibitors.. Compared with controls, MBD2 expression was distinctly reduced in the bronchial epithelium of both patients with COPD and CS-exposed mice. Moreover, MBD2 expression was decreased in HBE after CSE stimulation in vitro. Moreover, MBD2 knockdown enhanced interleukin (IL)-6 and IL-8 expression in HBE in the presence and absence of CSE treatment by the ERK signaling pathway.. MBD2 protein expression was reduced in the airway epithelium of COPD. In HBE, this reduced expression was associated with increased levels of IL-6 and IL-8 mediated by the ERK pathway. These results suggest that MBD2 could contribute to chronic airway inflammation in COPD.

Topics: Animals; Bronchi; Case-Control Studies; Cells, Cultured; Disease Models, Animal; DNA-Binding Proteins; Down-Regulation; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Forced Expiratory Volume; Humans; Interleukin-6; Interleukin-8; Male; Mice, Inbred C57BL; Pneumonia; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Smoke; Smoking; Time Factors; Vital Capacity

Electronic cigarettes (e-cigs) are used to help smoking cessation. However, these devices contain harmful chemicals, and there are safety concerns. We have investigated the effects of e-cigs on the inflammatory response and viability of COPD bronchial epithelial cells (BECs).. BECs from COPD patients and controls were exposed to e-cig vapor extract (ECVE) and the levels of interleukin (IL)-6, C-X-C motif ligand 8 (CXCL8), and lactate dehydrogenase release were measured. We also examined the effect of ECVE pretreatment on polyinosinic:polycytidylic acid (poly I:C)-stimulated cytokine release from BECs. Parallel experiments using Calu-3 cells were performed. Comparisons were made with cigarette smoke extract (CSE).. ECVE and CSE caused an increase in the release of IL-6 and CXCL8 from Calu-3 cells. ECVE only caused toxicity in BECs and Calu-3 cells. Furthermore, ECVE and CSE dampened poly I:C-stimulated C-X-C motif ligand 10 release from both cell culture models, reaching statistical significance for CSE at an optical density of 0.3.. ECVE caused toxicity and reduced the antiviral response to poly I:C. This raises concerns over the safety of e-cig use.

Topics: Aged; Antiviral Agents; Bronchi; Case-Control Studies; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Electric Impedance; Electronic Nicotine Delivery Systems; Epithelial Cells; Female; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; L-Lactate Dehydrogenase; Male; Middle Aged; Poly I-C; Pulmonary Disease, Chronic Obstructive; Smoke; Tobacco Smoking; Vaping; Volatilization

Chronic obstructive pulmonary disease (COPD) is a respiratory disorder characterized by a progressive and irreversible airflow limitation. COPD is associated to a chronic inflammatory response with infiltration of inflammatory cells in the surface epithelium of large airways and abnormalities in structure and functions of cilia. Thyme (Thymus vulgaris L.) is a traditional medicinal plant of the Mediterranean area used to treat respiratory disorders. We previously evidenced that thyme extract reduce IL-1beta and IL-8, by downregulating the activated NF-κB levels, suggesting its potential therapeutically use in COPD. Cilia beating frequency (CBF) is dramatically impaired in COPD and different pharmacological agents can modulate cilia function. Herein we evaluated the effect of a commercial thyme extract in modulating CBF by measuring its activity in stimulating cAMP, Ca

Topics: Bronchi; Calcium; Cell Line; Cilia; Cyclic AMP; Down-Regulation; Epithelial Cells; Humans; Interleukin-1beta; Interleukin-8; Lung; NF-kappa B; Plant Extracts; Pulmonary Disease, Chronic Obstructive; Thymus Plant

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by inflammatory cell activation and the release of inflammatory mediators. By measuring microRNA expression in the plasma of COPD subjects, we aimed to identify the clinical relevance of plasma miRNA levels in these patients.. A total of 40 COPD patients and 40 healthy controls were enrolled in the study. The COPD model of C57BL/6 mice was also developed by exposing them to cigarette smoke (CS). The expression of microRNA-218-5p was detected by qRT-PCR in all the subjects and mice. The serum level of IL-18 and TGF-β1 was also detected via ELISA kit. To investigate the effects of miR-218-5p, 10 mg/kg of miR-218-5p inhibitor (miR-218-5p antagonist), a scrambled control or PBS (solvent) was intranasally administered on the first and the fourth exposure day, before the start of CS exposure.. The results showed that miR-218-5p was significantly down-regulated in patients with COPD, compared to normal subjects. There was a negative correlation between the plasma miR-218-5p level and the duration of disease since diagnosis in COPD ex-smokers. CS-induced COPD mice experiments with a miR-218-5p inhibitor demonstrated a protective role of miR-218-5p in cigarette smoke-induced inflammation and COPD.. These findings supported that miR-218-5p may, therefore, play an important role in the pathogenesis of COPD.

Topics: Aged; Animals; Bronchoalveolar Lavage Fluid; Case-Control Studies; Disease Models, Animal; Down-Regulation; Female; Humans; Interleukin-8; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Middle Aged; Pulmonary Disease, Chronic Obstructive; Smokers; Transforming Growth Factor beta1

Neutrophilic airway inflammation plays a central role in chronic obstructive pulmonary disease (COPD). CXC chemokine ligand (CXCL)1 is a neutrophil chemokine involved in the pathogenesis of COPD. However, its clinical significance in COPD patients is poorly understood.. To assess the production of CXCL1 by bronchial epithelial cells in response to lipopolysaccharide (LPS) and tumor necrosis factor (TNF)α.. We measured sputum CXCL1 and CXCL8 levels in patients with COPD, asthma, and asthma-COPD overlap (ACO), and compared them to those of patients with interstitial pneumonia (IP). Using primary human bronchial epithelial cells and BEAS-2B cells, CXCL1 protein release and mRNA expression were measured after LPS or TNFα stimulation. We evaluated signal transduction mechanisms for CXCL1 production using nuclear factor-κ B (NF-kB) and mitogen-activated protein kinase (MAPK) inhibitors, and examined the effects of anti-inflammatory agents on CXCL1 production in BEAS-2B cells.. Sputum CXCL1 levels in COPD and ACO patients were higher than in IP patients, whereas sputum CXCL8 levels were not. Sputum CXCL1 levels were not affected by inhaled corticosteroid usage, whereas sputum CXCL8 levels tended to be affected. LPS and TNFα stimulated CXCL1 production and mRNA expression in bronchial epithelial cells. NF-kB and MAPK p38 were involved in LPS-induced CXCL1 production. Therapeutic anti-inflammatory agents minimally attenuated CXCL1 production and considerably inhibited CXCL8 production in BEAS-2B cells.. Sputum CXCL1 levels is a potentially better diagnostic marker for COPD than sputum CXCL8 levels, which is explained by that CXCL1 production in bronchial epithelial cells is less affected by therapeutic anti-inflammatory agents than CXCL8 production.

Topics: Bronchi; Cell Line; Cells, Cultured; Chemokine CXCL1; Epithelial Cells; Humans; Interleukin-8; Lipopolysaccharides; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

We previously reported that epithelial-derived interleukin (IL)-1α drives fibroblast-derived inflammation in the lung epithelial-mesenchymal trophic unit. Since miR-146a-5p has been shown to negatively regulate IL-1 signalling, we investigated the role of miR-146a-5p in the regulation of IL-1α-driven inflammation in chronic obstructive pulmonary disease (COPD).Human bronchial epithelial (16HBE14o-) cells were co-cultured with control and COPD-derived primary human lung fibroblasts (PHLFs), and miR-146a-5p expression was assessed with and without IL-1α neutralising antibody. Genomic DNA was assessed for the presence of the single nucleotide polymorphism (SNP) rs2910164. miR-146a-5p mimics were used for overexpression studies to assess IL-1α-induced signalling and IL-8 production by PHLFs.Co-culture of PHLFs with airway epithelial cells significantly increased the expression of miR-146a-5p and this induction was dependent on epithelial-derived IL-1α. miR-146a-5p overexpression decreased IL-1α-induced IL-8 secretion in PHLFs

Topics: Alleles; Antibodies, Neutralizing; Bronchi; Cell Line, Tumor; Cigarette Smoking; Coculture Techniques; Culture Media, Conditioned; Epithelial Cells; Epithelium; Fibroblasts; Humans; Inflammation; Interleukin-1alpha; Interleukin-8; MicroRNAs; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Tobacco Products

Present treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time.. In this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40-80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1-4) on the basis of post-bronchodilator FEV. 2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas 567 (51%) had none. 82 (7%) of 1105 patients had at least one acute exacerbation each year, whereas only 23 (2%) had two or more acute exacerbations in each year. An inconsistent pattern (both years with and without acute exacerbations) was common (456 [41%] of the group), particularly among GOLD stages 3 and 4 patients (256 [56%] of 456). In logistic regression, consistent acute exacerbations (≥1 event per year for 3 years) were associated with higher baseline symptom burden, previous exacerbations, greater evidence of small airway abnormality on CT, lower interleukin-15 concentrations, and higher interleukin-8 concentrations, than were no acute exacerbations.. Although acute exacerbations are common, the exacerbation status of most individuals varies markedly from year to year. Among patients who had any acute exacerbation over 3 years, very few repeatedly had two or more events per year. In addition to symptoms and history of exacerbations in the year before study enrolment, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, and interleukin-15 and interleukin-8 concentrations.. National Institutes of Health, and National Heart, Lung, and Blood Institute.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Female; Forced Expiratory Volume; Humans; Interleukin-15; Interleukin-8; Logistic Models; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Spirometry; Time Factors; Tomography, X-Ray Computed

Chronic obstructive pulmonary disease (COPD) is a common inflammatory lung disease. Sialic acid-binding immunoglobulin-type lectins 9 (Siglec-9) is predominantly expressed on innate immune cells and has been shown to exert regulatory effect on immune cells through glycan recognition. Soluble Siglec-9 (sSiglec-9), the extracellular region of Siglec-9, might fulfill its function partly by competitive inhibiting siglec-9 binding to its ligands; however, the role of Siglec-9 and sSiglec-9 in the pathogenesis COPD remain largely unknown. In this study, we showed that Siglec-9 expression in alveolar and peripheral blood neutrophil were increased in COPD patients by immunofluorescence and flow cytometry, respectively. Plasma levels of sSiglelc-9 were elevated in COPD patients by ELISA. In vitro, Siglec-9 expression and/or sSiglelc-9 levels were up-regulated by cigarette smoke extract (CSE), lipopolysaccharide (LPS), some cytokines, and dexamethasone (DEX). Recombinant sSiglce-9 increased oxidative burst in neutrophil and enhanced neutrophil chemotaxis toward IL-8 independent on CXCR1 and CXCR2 expression, but it did not affect neutrophil apoptosis or secretions of inflammatory cytokines. In conclusion, Siglec-9 was complementarily increased to induce a negative feedback loop to limit neutrophil activation in COPD, sSiglce-9 enhanced neutrophil ROS and chemotaxis toward IL-8 likely via competitively inhibiting ligands binding to Siglec-9.

Topics: Antigens, CD; Apoptosis; Cells, Cultured; Chemotaxis; Dexamethasone; Female; Humans; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Neutrophils; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Sialic Acid Binding Immunoglobulin-like Lectins; Tobacco Smoke Pollution

Alterations in microRNA (miRNA) expression may contribute to COPD pathogenesis. In COPD, lung fibroblast repair functions are altered in multiple ways, including extracellular mediator release. Our prior study revealed miR-503 expression is decreased in COPD lung fibroblasts, although the exact role played by miR-503 is undetermined. The current study examined a role of miR-503 in cytokine, growth factor and fibronectin production by lung fibroblasts from patients with and without COPD. Primary adult lung fibroblasts were isolated from patients with or without COPD. MiR-503 expression and interleukin (IL)-6, -8, PGE2, HGF, KGF, VEGF and fibronectin release were examined with or without inflammatory cytokines, IL-1β and tumor necrosis factor (TNF)-α. MiR-503 expression was decreased in COPD lung fibroblasts. The expression of miR-503 was positively correlated with %FVC, %FEV1, and %DLco as well as IL-6, -8, PGE2, HGF, KGF, and VEGF in the absence or presence of IL-1ß/TNF-α. In addition, IL-8 and VEGF release from COPD lung fibroblasts were increased compared to those from control. Exogenous miR-503 inhibited VEGF release from primary adult and fetal lung fibroblasts but not IL-8 release. As expected, COPD fibroblasts proliferated more slowly than control fibroblasts. MiR-503 did not affect proliferation of either control or COPD lung fibroblasts. MiR-503 inhibition of VEGF protein production and mRNA was mediated by direct binding to the 3' untranslated region of VEGF mRNA. Endogenous miR-503 was differently regulated by exogenous stimulants associated with COPD pathogenesis, including IL-1ß/TNF-α, TGF-ß1 and PGE2. Endogenous miR-503 inhibition augmented VEGF release by IL-1ß/TNF-α and TGF-ß1 but not by PGE2, demonstrating selectivity of miR-503 regulation of VEGF. In conclusions, reduced miR-503 augments VEGF release from lung fibroblasts from patients with COPD. Since VEGF contributes to disturbed vasculature in COPD, altered miR-503 production might play a role in modulating fibroblast-mediated vascular homeostasis in COPD.

Topics: 3' Untranslated Regions; Adult; Base Sequence; Case-Control Studies; Cells, Cultured; Chronic Disease; Dinoprostone; Extracellular Matrix; Female; Fibroblasts; Fibronectins; Gene Expression Regulation; Humans; Interleukin-1beta; Interleukin-8; Lung; Male; MicroRNAs; Middle Aged; Protein Binding; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Oxidative stress and inflammation are hypothesized to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Resveratrol (trans-3,5,4'-trihydroxystilbene) is known for its antioxidant and anti-inflammatory properties. The study aimed to investigate the effects of resveratrol in a rat model with COPD on the regulation of oxidative stress and inflammation via the activation of Sirtuin1 (SIRTl) and proliferator-activated receptor-γ coactivator-1α (PGC-1α). Thirty Wistar rats were randomly divided into three groups: control group, COPD group and resveratrol intervention group. The COPD model was established by instilling with lipopolysaccharide (LPS) and challenging with cigarette smoke (CS). The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in serum were measured. The levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured. The expression levels of SIRT1 and PGC-1α in the lung tissues were examined by immunohistochemistry as well as real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and western blotting analysis. After the treatment with resveratrol (50 mg/kg), compared with the COPD group, alleviation of inflammation and reconstruction in the small airways of the lungs were seen. Resveratrol might be correlated not only with the lower level of MDA and the higher activity of SOD, but also with the upregulation of SIRT1 and PGC-1α expression. Resveratrol treatment decreased serum levels of IL-6 and IL-8. Our findings indicate that resveratrol had a therapeutic effect in our rat COPD model, which is related to the inhibition of oxidative stress and inflammatory response. The mechanism may be related to the activation and upgrading of the SIRT1/PGC-1α signaling pathways. Thus resveratrol might be a therapeutic modality in COPD.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Gene Expression Regulation; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Malondialdehyde; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pulmonary Disease, Chronic Obstructive; Rats; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Superoxide Dismutase

The respiratory pathogen nontypeable Haemophilus influenzae (NTHi) is an important cause of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) that requires efficient treatments. A previous screening for host genes differentially expressed upon NTHi infection identified sirtuin-1, which encodes a NAD-dependent deacetylase protective against emphysema and is activated by resveratrol. This polyphenol concomitantly reduces NTHi viability, therefore highlighting its therapeutic potential against NTHi infection at the COPD airway. In this study, resveratrol antimicrobial effect on NTHi was shown to be bacteriostatic and did not induce resistance development in vitro. Analysis of modulatory properties on the NTHi-host airway epithelial interplay showed that resveratrol modulates bacterial invasion but not subcellular location, reduces inflammation without targeting phosphodiesterase 4B gene expression, and dampens β defensin-2 gene expression in infected cells. Moreover, resveratrol therapeutics against NTHi was evaluated in vivo on mouse respiratory and zebrafish septicemia infection model systems, showing to decrease NTHi viability in a dose-dependent manner and reduce airway inflammation upon infection, and to have a significant bacterial clearing effect without signs of host toxicity, respectively. This study presents resveratrol as a therapeutic of particular translational significance due to the attractiveness of targeting both infection and overactive inflammation at the COPD airway.

Topics: A549 Cells; Administration, Intranasal; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; beta-Defensins; Cells, Cultured; Drug Resistance, Bacterial; Epithelial Cells; Gene Expression Regulation, Neoplastic; Haemophilus Infections; Haemophilus influenzae; Humans; Immunologic Factors; Interleukin-8; Mice; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections; Resveratrol; Zebrafish

Chlamydia pneumoniae is an obligatory human pathogen involved in lower and upper airway infections, including pneumonia, bronchitis. Asymptomatic C. pneumoniae carriage is also relatively common. The association of C. pneumoniae infections with the chronic obstructive pulmonary disease (COPD) course is unclear.. The aim of the study was to investigate the association between chronic C. pneumoniae infection and clinical features of COPD, markers of inflammation and metabolic dysfunction.. The study included 59 patients with stable COPD who had no, or had ≥2 acute exacerbations during last year. The level of IgA and IgG antibody against C. pneumoniae, IL-6, IL-8, resistin, insulin, adiponectin and acyl ghrelin was measured in serum by enzyme-linked immunosorbent assay (ELISA).. No differences in clinical and functional data were observed between COPD patients without serological features of C. pneumoniae infection and chronic C. pneumoniae infection. The level of anti C. pneumoniae IgA significantly correlated with IL-8, IL-6, resistin concentration in group of frequent exacerbators. IgG level correlated negatively with acetyl ghrelin and body mass index (BMI) in patients without frequent exacerbations, in contrast to frequent COPD exacerbation group where significant correlations between IgG level and BMI was demonstrated. Serum IL-6 correlated positively with resistin and insulin and negatively with adiponectin in group of patients with serological features of chronic C. pneumoniae infection only.. Our study showed that chronic C. pneumoniae infection does not influence the clinical course of COPD in the both study groups. Chronic C. pneumoniae infections might be associated with a distinct COPD phenotype that affects metabolic dysfunction.

Topics: Aged; Biomarkers; Chlamydial Pneumonia; Chlamydophila pneumoniae; Cross-Sectional Studies; Diet; Female; Humans; Immunoglobulin A; Immunoglobulin G; Insulin; Interleukin-6; Interleukin-8; Male; Middle Aged; Nutritional Status; Pulmonary Disease, Chronic Obstructive; Resistin; Retrospective Studies

Serious problems on muscle strength and functional status can be seen in bedridden-patients with chronic obstructive pulmonary diseases (COPD) receiving mechanical ventilation. We aimed to investigate the impact of active extremity mobilization and neuromuscular electrical stimulation (NMES) on weaning processes, discharge from hospital and inflammatory mediators in COPD patients receiving mechanical ventilation.. Thirty conscious COPD patients (F/M:15/15) hospitalized in the intensive care unit (ICU) with diagnosis of respiratory failure were enrolled to this study. Patients were randomized into three groups, including 10 patients for each. Active extremity-exercise training and NMES were applied to Group-1, only NMES was applied to Group-2 and active extremity exercise training was applied to Group-3. Muscle strengths, mobilization duration and weaning situation were evaluated. Serum cytokine levels were evaluated.. Lower extremity muscle-strength was significantly improved in Group-1 (from 3.00 to 5.00, P = 0.014) and 2 (from 4.00 to 5.00, P = 0.046). Upper extremity muscle strength was also significantly improved in all three groups (from 4.00 to 5.00 for all groups, P = 0.038, P = 0.046 and P = 0.034, respectively). Duration of mobilization and discharge from the ICU were similar among groups. There was a significant decrease in serum interleukin (IL)-6 level in Group-1 and in serum IL-8 level in Group-1 and Group-2 after rehabilitation.. This study indicates that pulmonary rehabilitation can prevent loss of muscle strength in ICU. Nevertheless, we consider that further studies with larger populations are needed to examine the impact of NMES and/or active and passive muscle training in bedridden ICU patients who are mechanically ventilated.

Topics: Aged; Aged, 80 and over; Biomarkers; Cytokines; Electric Stimulation Therapy; Exercise; Female; Humans; Intensive Care Units; Interleukin-6; Interleukin-8; Length of Stay; Male; Middle Aged; Muscle Strength; Muscle Weakness; Pulmonary Disease, Chronic Obstructive; Respiration, Artificial; Respiratory Insufficiency; Ventilator Weaning

Chronic obstructive pulmonary disease (COPD) is caused by the build-up of oxidative stress-induced damages due to cigarette smoking, but how monoamine oxidase (MAO)-B signaling is involved remains unclear. This study aims to establish the involvement of MAO-B signaling pathways in cigarette smoke medium (CSM)-induced oxidative stress and inflammation in human airway epithelial cells (AECs). CSM treatment increased MAO-B activity, ROS levels and IL-8 release in AECs. Pretreatment with MAO-B selective inhibitor selegiline reversed the CSM-induced changes in MAO-B activity, ROS levels and IL-8 release in a dose-dependent manner. Selegiline also reversed CSM-induced changes of anti-oxidant enzymes superoxide dismutase (SOD) and catalase (CAT) activities, GSH/GSSG ratio, as well expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). The effects of selegiline are partially driven through the nuclear factor erythroid 2 related factor 2 (Nrf2) and cytosol translocation of its negative regulator, BTB and CNC homolog 1 (Bach1). Nevertheless, selegiline fully reversed the CSM-induced effects on IKK, cytoplasmic IκB expression, and nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit. Our study demonstrated that in AECs, inhibition of MAO-B using selegiline reversed the CSM-induced oxidative stress and inflammation. These data may provide a novel strategy for therapy in COPD.

Topics: Anti-Inflammatory Agents; Antioxidants; Bronchi; Cell Line; Cytoprotection; Dose-Response Relationship, Drug; Epithelial Cells; Humans; Inflammation Mediators; Interleukin-8; Monoamine Oxidase; Monoamine Oxidase Inhibitors; NF-kappa B; Oxidative Stress; Pneumonia; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Selegiline; Signal Transduction; Smoke; Smoking

Antimicrobial proteins and peptides (AMPs) are a central component of the antibacterial activity of airway epithelial cells. It has been proposed that a decrease in antibacterial lung defense contributes to an increased susceptibility to microbial infection in smokers and patients with chronic obstructive pulmonary disease (COPD). However, whether reduced AMP expression in the epithelium contributes to this lower defense is largely unknown. We investigated the bacterial killing activity and expression of AMPs by air-liquid interface-cultured primary bronchial epithelial cells from COPD patients and non-COPD (ex-)smokers that were stimulated with nontypeable Haemophilus influenzae (NTHi). In addition, the effect of cigarette smoke on AMP expression and the activation of signaling pathways was determined. COPD cell cultures displayed reduced antibacterial activity, whereas smoke exposure suppressed the NTHi-induced expression of AMPs and further increased IL-8 expression in COPD and non-COPD cultures. Moreover, smoke exposure impaired NTHi-induced activation of NF-κB, but not MAP-kinase signaling. Our findings demonstrate that the antibacterial activity of cultured airway epithelial cells induced by acute bacterial exposure was reduced in COPD and suppressed by cigarette smoke, whereas inflammatory responses persisted. These findings help to explain the imbalance between protective antibacterial and destructive inflammatory innate immune responses in COPD.

Topics: Antimicrobial Cationic Peptides; Bacteriolysis; Cells, Cultured; Cigarette Smoking; Haemophilus Infections; Haemophilus influenzae; Humans; Immunity; Immunomodulation; Interleukin-8; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Signal Transduction

Idiopathic pulmonary fibrosis (IPF) is a rare lung disease of unknown origin leading rapidly to death. This paper addresses the issue of whether sputum induction is a suitable tool to study respiratory tract inflammation and potential biomarkers in IPF compared to COPD, a fibrosing airway wall disease.. In a cross-sectional analysis, 15 IPF patients, 32 COPD and 30 healthy subjects underwent sputum induction. Total sputum cell counts and the amount of TGF- β, IGF-1, IGF-2, IGFBP-1, IGFBP-2, IGFBP-3, IL-8, IL-13, MMP-7, MMP-9, YKL-40, TNF-α and KL-6 in sputum supernatant were analysed. We also profiled gene expression of cells in the induced sputum for TGF-β, MMP-7, YKL-40, IGFBP-2, IL-6, IL-8 and TNF-α.. IPF patients, like COPD, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to HS. IPF sputum supernatants had increased concentrations of IGFBP-2, IL-8, TGF-β, MMP-7, MMP-9 and KL-6 (p<0.05, p<0.0001, p<0.05, p<0.05, p<0.0001, p<0.05 respectively) when compared to healthy subjects where COPD had higher IL-6 and TNF-α levels than IPF (p<0.05 and p<0.05 respectively) and HS (p<0.0001 and p<0.001 respectively) and higher IL-8 and MMP-9 than HS (p<0.0001 and p<0.001 respectively). Conversely to IL-6 and TNF-α, MMP-7 was increased in IPF compared to COPD (p<0.05). The KL-6 and MMP-7 protein levels in sputum were inversely correlated with total lung capacity (TLC, % of predicted) in IPF patients (r = -0.73 and r = -0.53 respectively). Sputum gene expression analysis identified a significant increase for IGFBP-2, IL-6, IL-8 and MMP-7 in IPF compared to HS (p<0.05, p<0.01, p<0.05 and p<0.0001 respectively) and for IGFBP-2, YKL-40, IL-6, IL-8 and MMP-7 compared to COPD (p<0.01, p<0.01, p<0.05, p<0.01 and p<0.0001 respectively). Furthermore, gene expression of TGF-β was increased in IPF compared to COPD (p<0.001) but not to HS.. Our data show clear increase in expression and production of IGFBP-2, IL-8 and MMP-7 in sputum from patients with IPF that may contribute to the disease.

Topics: Biomarkers; Cross-Sectional Studies; Female; Gene Expression; Humans; Idiopathic Pulmonary Fibrosis; Insulin-Like Growth Factor Binding Protein 2; Interleukin-8; Leukocyte Count; Male; Matrix Metalloproteinase 7; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum

Patients with Acute Hypercapnic Respiratory Failure (AHRF) who are unresponsive to appropriate medical treatment, are often treated with Noninvasive Positive Pressure Ventilation (NPPV). Clinical predictors of the outcome of this treatment are scarce. Therefore, we evaluated the role of the biomarkers IL-8 and GDF-15 in predicting 28-day mortality in patients with AHRF who receive treatment with NPPV.. The study population were 46 patients treated with NPPV for AHRF. Clinical and background data was registered and blood samples taken for analysis of inflammatory biomarkers. IL-8 and GDF-15 were selected for analysis, and related to risk of 28-day mortality (primary endpoint) using Cox proportional hazard models adjusted for gender, age and various clinical parameters.. Of the 46 patients, there were 3 subgroup in regards to primary diagnosis: Acute Exacerbation of COPD (AECOPD, n = 34), Acute Heart Failure (AHF, n = 8) and Acute Exacerbation in Obesity Hypoventilation Syndrome (AEOHS, n = 4). There was significant difference in the basic characteristic of the subgroups, but not in the clinical parameters that were used in treatment decisions. 13 patients died within 28 days of admission (28%). The Hazard Ratio for 28-days mortality per 1-SD increment of IL-8 was 3.88 (95% CI 1.86-8.06, p < 0.001). When IL-8 values were divided into tertiles, the highest tertile had a significant association with 28 days mortality, HR 10.02 (95% CI 1.24-80.77, p for trend 0.03), compared with the lowest tertile. This correlation was maintained when the largest subgroup with AECOPD was analyzed. GDF-15 was correlated in the same way, but when put into the same model as IL-8, the significance disappeared.. IL-8 is a target to explore further as a predictor of 28 days mortality, in patients with AHRF treated with NPPV.

Topics: Acute Disease; Aged; Aged, 80 and over; Biomarkers; Female; Growth Differentiation Factor 15; Humans; Hypercapnia; Interleukin-8; Kaplan-Meier Estimate; Male; Middle Aged; Noninvasive Ventilation; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Respiratory Insufficiency; Sweden

Airway and lung inflammation is a fundamental hallmark of chronic obstructive pulmonary disease (COPD). Activating transcription factor 3 (ATF3) has been reported to negatively regulate many pro-inflammatory cytokines and chemokines. However, little is known about the impact of ATF3 on the inflammatory response of COPD. Since cigarette smoke (CS) is considered to be the most important risk factor in the etiology of COPD, we attempted to investigate the effects and molecular mechanisms of ATF3 in CS-induced inflammation. We observed an increase in the expression of ATF3 in the lung tissues of CS-exposed mice and CS extract (CSE)-treated human bronchial epithelial (HBE) cells. In vitro results indicated that ATF3 inhibition significantly increased the expression of proinflammatory cytokines interleukin 6 (IL6) and interleukin 8 (IL8) in CSE-stimulated HBE cells. Furthermore, in vivo data verified that CS induced inflammatory cell recruitment around the bronchus. In addition, neutrophil infiltration in bronchoalveolar lavage fluid (BALF) of CS-exposed Atf3

Topics: Activating Transcription Factor 3; Animals; Bronchi; Bronchoalveolar Lavage Fluid; Cell Line; Down-Regulation; Epigenetic Repression; Epithelial Cells; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; NF-kappa B; Pulmonary Disease, Chronic Obstructive; RNA, Small Interfering; Smoking; Up-Regulation

To reveal the effects on expression of airway mucus-associated proteins in rats with\ chronic obstructive pulmonary disease (COPD) and a cold-dryness symptom pattern induced by elastase\ and smoking.. The COPD model was established with an elastase dose into the trachea combined with\ exposure to smoking; the COPD model cold-dryness symptom pattern was further developed by\ exposure to a cold, dry environment. After 90 days, pathologic lung sections, inflammatory cytokine\ levels (measured by enzyme linked immunosorbent assay), mRNA and protein expression of \ mucus-associated proteins and aquaporins (measured by real-time polymerase chain reaction and western\ blots) were examined.. Cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) in\ the COPD and the cold-dryness symptom pattern COPD groups were all significantly higher than in\ controls (each P < 0.01). IL-6 and IL-8 levels were higher in the cold-dryness symptom pattern COPD\ group than in the COPD group (each P < 0.05). The AQP5 mRNA expression in the cold-dryness symptom\ pattern COPD and COPD groups was lower than in the control group (P < 0.01), and that in the\ cold-dryness symptom pattern COPD group was lower than the COPD group (P < 0.05). The expression\ of MUC5AC and MUC5B mRNAs in the cold-dryness symptom pattern COPD group and\ COPD group was higher than in the control group (each P < 0.01), and that in the cold-dryness symptom\ pattern COPD group was higher than the COPD group (P < 0.01, and P < 0.05, respectively).\ The ratio of MUC5AC mRNA/MUC5B mRNA was COPD group < the cold-dryness symptom pattern\ COPD group < the control group. AQP4 and AQP5 protein expression in the cold-dryness symptom\ pattern COPD group was lower than that in the COPD group which was lower again than in the\ control group. MUC5AC and MUC5B expression in the cold-dryness symptom pattern COPD group\ was higher than in the COPD group and higher again than in the control group.. Cold-dryness affects the expression of mucus-associated protein mRNA and its corresponding proteins, reducing the secretion of aquaporins and increasing the secretion of mucins. Imbalance\ in aquaporins and mucins can affect the function of mucus, increasing airway obstruction.

Topics: Animals; Humans; Interleukin-6; Interleukin-8; Lung; Male; Mucin 5AC; Mucus; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Viral infection is a significant cause of chronic obstructive pulmonary disease (COPD) and acute exacerbation of COPD. Retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I and melanoma differentiation associated gene 5 (MDA-5), are important pattern recognition receptors for viral elimination.. The study aims to investigate the role of RIG-I and MDA-5 in COPD pathogenesis.. We examined the expression of RIG-I and MDA-5 by immunohistochemistry, real-time PCR and Western blots in COPD patients and control subjects.. Our results showed that MDA-5 expression was upregulated in lung tissues and peripheral blood mononuclear cells of COPD patients and there was a negative correlation between MDA-5 mRNA levels and forced expiratory volume in 1 s %pred. COPD patients had higher interleukin (IL)-1 and IL-8 mRNA expression levels, and these inflammatory cytokines positively correlate with MDA-5 levels. However, there was no difference in the expression of RIG-I between COPD patients and control subjects.. Our results suggested that MDA-5, but not RIG-I, may play a critical role in airway inflammation in COPD.

Topics: Aged; DEAD Box Protein 58; DEAD-box RNA Helicases; Female; Forced Expiratory Volume; Humans; Inflammation; Interferon-Induced Helicase, IFIH1; Interleukin-1; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Receptors, Immunologic; Up-Regulation

Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases. It is a chronic inflammatory process characterised by airway obstruction and progressive lung inflammation, associated with difficulty breathing and insensitivity to corticosteroid therapy. Although there is some preliminary evidence to suggest a beneficial effect of acupuncture on COPD, its mechanism of action has not been investigated. Our aim was to examine the anti-inflammatory effects of acupuncture in a rat model of COPD induced by exposure to cigarette smoke (CS).. Sixty Sprague-Dawley rats were exposed to the smoke of 15 cigarettes for 1 h/day, 6 days/week for 3 months to induce COPD and treated with acupuncture at BL13 (Feishu), BL23 (Shenshu) and Dingchuan (COPD+Acupuncture, n=15), sham acupuncture (COPD+Sham, n=15) or left untreated (n=15). Exposed rats were compared with controls not exposed to CS (control, n=15). Pulmonary function was measured, and tumour necrosis factor-α (TNF-α) and interleukin-8 (IL-8) levels were determined in bronchoalveolar lavage fluid by ELISA. Histone deacetylase 2 (HDAC2) protein and mRNA expression were examined in lung tissue and in bronchus.. Acupuncture treatment appeared to protect pulmonary function and reduce the COPD-induced inflammatory response by decreasing cell inflammation and the production of TNF-α and IL-8. Acupuncture also enhanced HDAC2 mRNA and protein expression, suggesting a possible direct effect on protein structure through post-translational modifications.. Our results suggest that acupuncture regulates inflammatory cytokines and contributes to lung protection in a rat model of smoke-induced COPD by modulating HDAC2.

Topics: Acupuncture Points; Acupuncture Therapy; Animals; Bronchoalveolar Lavage Fluid; Humans; Interleukin-8; Lung; Male; Muscle, Smooth; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Smoke; Time Factors; Tumor Necrosis Factor-alpha

Although pharmacological treatment of COPD exacerbation (COPDE) includes antibiotics and systemic steroids, a proportion of patients show worsening of symptoms during hospitalization that characterize treatment failure. The aim of our study was to determine in-hospital predictors of treatment failure (≤ 7 days). Prospective data on 110 hospitalized COPDE patients, all treated with antibiotics and systemic steroids, were collected; on the seventh day of hospitalization, patients were divided into treatment failure (n = 16) or success (n = 94). Measures of inflammatory serum biomarkers were recorded at admission and at day 3; data on clinical, laboratory, microbiological, and severity, as well data on mortality and readmission, were also recorded. Patients with treatment failure had a worse lung function, with higher serum levels of C-reactive protein (CRP), procalcitonin (PCT), tumour necrosis factor-alpha (TNF-α), interleukin (IL) 8, and IL-10 at admission, and CRP and IL-8 at day 3. Longer length of hospital stay and duration of antibiotic therapy, higher total doses of steroids and prevalence of deaths and readmitted were found in the treatment failure group. In the multivariate analysis, +1 mg/dL of CRP at admission (OR, 1.07; 95% CI, 1.01 to 1.13) and use of penicillins or cephalosporins (OR, 5.63; 95% CI, 1.26 to 25.07) were independent variables increasing risk of treatment failure, whereas cough at admission (OR, 0.20; 95% CI, 0.05 to 0.75) reduces risk of failure. In hospitalized COPDE patients CRP at admission and use of specific class of antibiotics predict in-hospital treatment failure, while presence of cough has a protective role.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cohort Studies; Disease Progression; Female; Forced Expiratory Volume; Glucocorticoids; Hospitalization; Humans; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Length of Stay; Logistic Models; Male; Mental Status Schedule; Middle Aged; Mortality; Multivariate Analysis; Patient Readmission; Pneumonia, Bacterial; Prognosis; Prospective Studies; Protein Precursors; Pulmonary Disease, Chronic Obstructive; Risk Factors; Time Factors; Treatment Failure; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) is the leading cause of cigarette smoke-related death worldwide. Acrolein, a crucial reactive electrophile found in cigarette smoke mimics many of the toxic effects of cigarette smoke-exposure in the lung. In macrophages, cigarette smoke is known to hinder histone deacetylases (HDACs), glucocorticoid-regulated enzymes that play an important role in the pathogenesis of glucocorticoid resistant inflammation, a common feature of COPD. Thus, we hypothesize that acrolein plays a role in COPD-associated glucocorticoid resistance. To examine the role of acrolein on glucocorticoid resistance, U937 monocytes, differentiated with PMA to macrophage-like cells were treated with acrolein for 0.5h followed by stimulation with hydrocortisone for 8h, or treated simultaneously with LPS and hydrocortisone for 8h without acrolein. GSH and nuclear HDAC activity were measured, or gene expression was analyzed by qPCR. Acrolein-mediated TNFα gene expression was not suppressed by hydrocortisone whereas LPS-induced TNFα expression was suppressed. Acrolein also significantly inhibited nuclear HDAC activity in macrophage-like cells. Incubation of recombinant HDAC2 with acrolein led to the formation of an HDAC2-acrolein adduct identified by mass spectrometry. Therefore, these results suggest that acrolein-induced inflammatory gene expression is resistant to suppression by the endogenous glucocorticoid, hydrocortisone.

Topics: Acrolein; Cell Line, Tumor; Cells, Cultured; Drug Resistance; Gene Expression; Glucocorticoids; Glutathione; Histone Deacetylase 2; Humans; Hydrocortisone; Inflammation; Interleukin-8; Lipopolysaccharides; Lung; Macrophages; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; Smoking; Tumor Necrosis Factor-alpha; Up-Regulation

Topics: Asthma; Comorbidity; Eosinophilia; Humans; Inflammation; Interleukin-8; Phenotype; Prevalence; Pulmonary Disease, Chronic Obstructive; Rhinitis; Syndrome

Rhinoviruses (RV) replicate in both upper and lower airway epithelial cells. We evaluated the possibility of using nasal epithelial cells (NEC) as surrogate of bronchial epithelial cells (BEC) for RV pathogenesis cell culture studies.. We used primary paired NEC and BEC cultures established from healthy subjects and compared the replication of RV belonging to the major (RV16) and minor (RV1B) group, and the cellular antiviral and proinflammatory cytokine responses towards these viruses. We related antiviral and pro-inflammatory responses of NEC isolated from CF and COPD patients with those of BEC.. RV16 replication and major group surface receptor (ICAM-1) expression were higher in healthy NEC compared with BEC (P < 0.05); RV1B replication and minor group surface receptor (LDLR) expression were similar. Healthy NEC and BEC produced similar levels of IFN-β and IFN-λ2/3 upon RV infection or after simulation with poly(IC). IL-8 production was similar between healthy NEC and BEC. IL-6 release at baseline (P < 0.01) and upon infection with RV16 (P < 0.05) and poly(IC) stimulation (P < 0.05) was higher in NEC. RV1B viral load in NEC was related to RV1B viral load in BEC (r = 0.49, P = 0.01). There was a good correlation of IFN levels between NEC and BEC (r = 0.66, P = 0.0004 after RV1B infection). IL-8 production in NEC was related to IL-8 production in BEC (r = 0.48, P = 0.02 after RV1B infection).. NEC are a suitable alternative cellular system to BEC to study the pathophysiology of RV infections and particularly to investigate IFN responses induced by RV infection.

Topics: Adolescent; Aged; Cells, Cultured; Child; Child, Preschool; Cystic Fibrosis; Epithelial Cells; Female; Humans; Immunity, Innate; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Picornaviridae Infections; Pulmonary Disease, Chronic Obstructive; Respiratory System; Rhinovirus

Increasing evidence suggests that the lung microbiome plays an important role in chronic obstructive pulmonary disease (COPD) severity. However, the dynamics of the lung microbiome during COPD exacerbations and its potential role in disease aetiology remain poorly understood.We completed a longitudinal 16S ribosomal RNA survey of the lung microbiome on 476 sputum samples collected from 87 subjects with COPD at four visits defined as stable state, exacerbation, 2 weeks post-therapy and 6 weeks recovery.Our analysis revealed a dynamic lung microbiota where changes appeared to be associated with exacerbation events and indicative of specific exacerbation phenotypes. Antibiotic and steroid treatments appear to have differential effects on the lung microbiome. We depict a microbial interaction network for the lung microbiome and suggest that perturbation of a few bacterial operational taxonomic units, in particular Haemophilus spp., could greatly impact the overall microbial community structure. Furthermore, several serum and sputum biomarkers, in particular sputum interleukin-8, appear to be highly correlated with the structure and diversity of the microbiome.Our study furthers the understanding of lung microbiome dynamics in COPD patients and highlights its potential as a biomarker, and possibly a target, for future respiratory therapeutics.

Topics: Administration, Oral; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Biomarkers; Chemokines; Female; Humans; Interleukin-8; Longitudinal Studies; Lung; Male; Microbiota; Middle Aged; Phenotype; Principal Component Analysis; Pulmonary Disease, Chronic Obstructive; Quality Control; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Sputum

We studied the role of PGE2, its biosynthetic enzymes and its receptors, in regulating the functions of lung fibroblasts through the production of Vascular Endothelial Growth Factor (VEGF) and Interleukin-8 (IL-8) in COPD subjects. Lung fibroblasts from Control (C) (n=6), Smoker (HS) (n=6) and COPD patients (n=8) were cultured, and basal PGE2, VEGF, and IL-8 measured in supernatants by ELISA. COX-1/COX-2 and EP receptors expression were assessed by western blot and by RT-PCR. Release of VEGF and IL-8 by human fetal lung fibroblasts (HFL-1; lung, diploid, human) was evaluated under different conditions. PGE2, VEGF, and IL-8 levels, COX-2, EP2, and EP4 protein expression and mRNA were increased in COPD when compared to Controls. Low concentrations of synthetic PGE2 increased the release of VEGF in HFL-1, but higher concentrations were needed to induce the release of IL-8. This effect was mimicked by an EP2 agonist and modulated by an EP4 antagonist. In the airways of COPD subjects, fibroblast-derived PGE2 may regulate angiogenesis and inflammation through the production of VEGF and IL-8 respectively, suggesting that the increase in expression of COX-2, EP2 and EP4 observed in COPD fibroblasts may contribute to steering the role of PGE2 from homeostatic to pro-inflammatory.

Topics: Aged; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Female; Fibroblasts; Gene Expression Regulation; Humans; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Vascular Endothelial Growth Factor A

To compare pulmonary and systemic inflammatory mediator release, pre- and poststimulation, ex vivo, in cells from Japanese patients with chronic obstructive pulmonary disease (COPD), non-COPD smoking controls, and non-COPD nonsmoking controls (NSC).. This was a nontreatment study with ten subjects per group. Inflammatory biomarker release, including interleukin (IL)-6 and -8, matrix metalloproteinase-9, and tumor necrosis factor (TNF)-α, was measured in peripheral blood mononuclear cells (PBMC) and sputum cells with and without lipopolysaccharide or TNF-α stimulation.. In PBMC, basal TNF-α release (mean ± standard deviation) was significantly different between COPD (81.6±111.4 pg/mL) and nonsmoking controls (9.5±5.2 pg/mL) (P<0.05). No other significant differences were observed. Poststimulation biomarker release tended to increase, with the greatest changes in the COPD group. The greatest mean increases were seen in the lipopolysaccharide-induced release of matrix metalloproteinase-9, TNF-α, and IL-6 from PBMC. Pre- and poststimulation data from sputum samples were more variable and less conclusive than from PBMC. In the COPD group, induced sputum neutrophil levels were higher and macrophage levels were lower than in either control group. Significant correlations were seen between the number of sputum cells (macrophages and neutrophils) and biomarker levels (IL-8, IL-6, and TNF-α).. This was the first study to compare cellular inflammatory mediator release before and after stimulation among Japanese COPD, smoking controls, and nonsmoking controls populations. Poststimulation levels tended to be higher in patients with COPD. The results suggest that PBMC are already preactivated in the circulation in COPD patients. This provides further evidence that COPD is a multicomponent disease, involving both airway and systemic inflammation.

Topics: Aged; Biomarkers; Cells, Cultured; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Leukocyte Count; Leukocytes, Mononuclear; Male; Matrix Metalloproteinase 9; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Smoking; Sputum; Statistics as Topic; Tumor Necrosis Factor-alpha

COPD is a progressive chronic lung disease characterized by pulmonary inflammation. Several recent studies indicate aberrant expression of WNT ligands and Frizzled receptors in the disease. For example, WNT-5A/B ligand expression was recently found to be increased in lung fibroblasts of COPD patients. However, possible effects of WNT-5A and WNT-5B on inflammation have not been investigated yet. In this study, we assessed the regulation of inflammatory cytokine release in response to WNT-5A/B signaling in human lung fibroblasts. Primary human fetal lung fibroblasts (MRC-5), and primary lung fibroblasts from COPD patients and non-COPD controls were treated with recombinant WNT-5A or WNT-5B to assess IL-6 and CXCL8 cytokine secretion and gene expression levels. Following WNT-5B, and to a lesser extent WNT-5A stimulation, fibroblasts showed increased IL-6 and CXCL8 cytokine secretion and mRNA expression. WNT-5B-mediated IL-6 and CXCL8 release was higher in fibroblasts from COPD patients than in non-COPD controls. In MRC-5 fibroblasts, WNT-5B-induced CXCL8 release was mediated primarily via the Frizzled-2 receptor and TAK1 signaling, whereas canonical β-catenin signaling was not involved. In further support of noncanonical signaling, we showed activation of JNK, p38, and p65 NF-κB by WNT-5B. Furthermore, inhibition of JNK and p38 prevented WNT-5B-induced IL-6 and CXCL8 secretion, whereas IKK inhibition prevented CXCL8 secretion only, indicating distinct pathways for WNT-5B-induced IL-6 and CXCL8 release. WNT-5B induces IL-6 and CXCL8 secretion in pulmonary fibroblasts. In summary, WNT-5B mediates this via Frizzled-2 and TAK1. As WNT-5 signaling is increased in COPD, this WNT-5-induced inflammatory response could represent a therapeutic target.

Topics: Case-Control Studies; Cell Line; Fibroblasts; Frizzled Receptors; Gene Expression; Humans; Interleukin-6; Interleukin-8; Lung; Pulmonary Disease, Chronic Obstructive; Wnt Proteins; Wnt Signaling Pathway

IL-17A plays a key role in the persistence of airway inflammation, oxidative stress, and reduction of steroid-sensitivity in COPD. We studied the effect of IL-17A on chromatin remodeling and IL-8 production.. We measured the levels of IL-8 and IL-17A in induced sputum supernatants (ISS) from healthy controls (HCs), healthy smokers (HSs), and COPD patients by enzyme-linked immunosorbent assay (ELISA). A human bronchial epithelial cell line (16HBE) was stimulated with ISS from HCs, HSs, or COPD subjects. IL-8 was evaluated in 16HBE by Western blot and real-time polymerase chain reaction (PCR). Histone deacetylase 2 (HDAC2), acetyl histone H3 (Ac-His H3) (k9) and inhibitor kappa kinase alpha (IKKα) levels were evaluated in the nuclear extract by Western blot. Finally, we evaluated the effect of IL-17A depletion in ISS, the silencing of IKKα, and the anti-inflammatory effects of Tiotropium Spiriva® (100nM) on 16HBE.. IL-8 and IL-17A levels were higher in ISS from COPD patients and HSs than from HCs. IL-8 protein and messenger RNA (mRNA) levels were increased in 16HBE stimulated with ISS from COPD patients compared with untreated cells. Furthermore, ISS from COPD patients reduced the nuclear levels of HDAC2 while increasing the activity of both Ac-His H3 (k9) and IKKα in stimulated 16HBE. IL-17A depletion in ISS and the IKKα silencing in 16HBE significantly increased the nuclear levels of HDAC2, reduced Ac-His H3 (k9), and promoted IL-8 synthesis in stimulated 16HBE. Tiotropium controls the proinflammatory activity generated by ISS from COPD patients in 16HBE.. IL-17A present in the airway of COPD patients, which induces chromatin remodeling, promotes the release of IL-8 in the bronchial epithelium. Tiotropium is able to control this proinflammatory activity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Bronchi; Cells, Cultured; Chromatin Assembly and Disassembly; Epithelial Cells; Histone Deacetylase 2; Histones; Humans; Interleukin-17; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Smoking; Sputum; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is a common, highly debilitating disease of the airways, primarily caused by smoking. Chronic inflammation and structural remodelling are key pathological features of this disease, in part caused by the aberrant function of airway smooth muscle (ASM) cells under the regulation of transforming growth factor (TGF)-β. miRNA are short, noncoding gene transcripts involved in the negative regulation of specific target genes, through their interactions with mRNA. Previous studies have proposed that mRNA-145 (miR-145) may interact with SMAD3, an important downstream signalling molecule of the TGF-β pathway. TGF-β was used to stimulate primary human ASM cells isolated from healthy nonsmokers, healthy smokers and COPD patients. This resulted in a TGF-β-dependent increase in CXCL8 and IL-6 release, most notably in the cells from COPD patients. TGF-β stimulation increased SMAD3 expression, only in cells from COPD patients, with a concurrent increased miR-145 expression. Regulation of miR-145 was found to be negatively controlled by pathways involving the MAP kinases, MEK-1/2 and p38 MAPK. Subsequent, overexpression of miR-145 (using synthetic mimics) in ASM cells from patients with COPD suppressed IL-6 and CXCL8 release, to levels comparable to the nonsmoker controls. Therefore, this study suggests that miR-145 negatively regulates pro-inflammatory cytokine release from ASM cells in COPD by targeting SMAD3.

Topics: Aged; Case-Control Studies; Cells, Cultured; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Male; MAP Kinase Signaling System; MicroRNAs; Middle Aged; Muscle, Smooth; Pulmonary Disease, Chronic Obstructive; Smad3 Protein

To investigate the effects of short-term exposure to traffic-related air pollution on airway oxidative stress and inflammation in chronic obstructive pulmonary diseases (COPD) patients.. A panel of forty-five diagnosed COPD patients were recruited and followed with repeated measurements of biomarkers reflecting airway oxidative stress and inflammation in exhaled breath condensate (EBC), including nitrate and nitrite, 8-isoprostane, interleukin-8 and acidity of EBC (pH), between 5(th) September in 2014 and 26(th) May in 2015. The associations between air pollution and biomarkers were analyzed with mixed-effects models, controlling for confounding covariates.. The concentration of PM2.5, black carbon, NO2 and number concentration of particles with diameter less than 100 nm (PNC100), and particles in size ranges between 100 nm to 200 nm (PNC100-200) during the first follow-up were (156.5±117.7), (10.7±0.7), (165.9±66.0)μg/m(3) and 397 521±96 712, 79 421±44 090 per cubic meter, respectively; the concentration were (67.9±29.6), (3.4±1.3), (126.1±10.9) μg/m(3) and (295 682±39 430), (24 693±12 369) per cubic meter, respectively during the second follow-up. The differences were of significance, with t value being 3.10, 4.42, 2.61, 4.02, 5.12, respectively and P value being 0.005,<0.001, 0.016, <0.001 and <0.001, respectively. In our COPD-patient panel, per interquartile range (IQR) increase in PNC100-200, we observed an increase of 65% (95% CI: 8%-152%) in nitrate and nitrite in EBC reflecting airway oxidative stress. For an IQR increase in PM2.5, black carbon and PNC100-200, respective increases of 0.17 ng/ml (95% CI: 0.02-0.33), 0.12 ng/ml (95% CI: 0.01-0.24) and 0.13 ng/ml (95% CI:0.02-0.24) in interleukin-8 in EBC reflecting airway inflammation were also observed. An IQR increase in ozone was also associated with a 0.24 (95%CI: 0.05-0.42) decrease in pH of EBC reflecting increased airway inflammation. No significant association observed between air pollution and 8-isoprostane in EBC in COPD patients.. Our results suggested that short-term exposure to traffic-related air pollution was responsible for exacerbation of airway oxidative stress and inflammation in COPD patients.

Topics: Air Pollutants; Air Pollution; Biomarkers; Dinoprost; Environmental Exposure; Female; Humans; Inflammation; Interleukin-8; Longitudinal Studies; Male; Motor Vehicles; Oxidative Stress; Particulate Matter; Pulmonary Disease, Chronic Obstructive; Respiratory System; Soot; Urban Population; Vehicle Emissions; Young Adult

COPD is characterized by persistent airflow limitation, neutrophilia and oxidative stress from endogenous and exogenous insults. Current COPD therapy involving anticholinergics, β2-adrenoceptor agonists and/or corticosteroids, do not specifically target oxidative stress, nor do they reduce chronic pulmonary inflammation and disease progression in all patients. Here, we explore the effects of Sul-121, a novel compound with anti-oxidative capacity, on hyperresponsiveness (AHR) and inflammation in experimental models of COPD. Using a guinea pig model of lipopolysaccharide (LPS)-induced neutrophilia, we demonstrated that Sul-121 inhalation dose-dependently prevented LPS-induced airway neutrophilia (up to ~60%) and AHR (up to ~90%). Non-cartilaginous airways neutrophilia was inversely correlated with blood H2S, and LPS-induced attenuation of blood H2S (~60%) was prevented by Sul-121. Concomitantly, Sul-121 prevented LPS-induced production of the oxidative stress marker, malondialdehyde by ~80%. In immortalized human airway smooth muscle (ASM) cells, Sul-121 dose-dependently prevented cigarette smoke extract-induced IL-8 release parallel with inhibition of nuclear translocation of the NF-κB subunit, p65 (each ~90%). Sul-121 also diminished cellular reactive oxygen species production in ASM cells, and inhibited nuclear translocation of the anti-oxidative response regulator, Nrf2. Our data show that Sul-121 effectively inhibits airway inflammation and AHR in experimental COPD models, prospectively through inhibition of oxidative stress.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cell Line, Transformed; Chromans; Complex Mixtures; Disease Models, Animal; Gene Expression Regulation; Guinea Pigs; Humans; Hydrogen Sulfide; Hypersensitivity; Inflammation; Interleukin-8; Lipopolysaccharides; Lung; Male; Malondialdehyde; Myocytes, Smooth Muscle; Neutrophils; NF-E2-Related Factor 2; Oxidative Stress; Piperazines; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Tars; Transcription Factor RelA

To investigate the relationship between the expression of histone acetylation enzyme 2 (HDAC2), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α) in lung adenocarcinoma tissues and smoking.. A total of 73 cases of lung adenocarcinoma confirmed by pathological examination after surgical removals were collected in the First Affiliated Hospital and Affiliated Tumor Hospital of Guangxi Medical University from April 2014 to March 2015. All patients received preoperative lung function test. Lung adenocarcinoma and para-cancer tissues were cut by the sharp blade and stored in liquid nitrogen and the sampling time was less than 30 minutes. Smokers were defined as people who had smoked more than 100 cigarettes or inhaled the smoke of cigarettes at least one day a week (more than 15 minutes every day) more than three years. According to the lung function and whether smoking or not, the cases of lung adenocarcinoma were divided into three groups: smoking without chronic obstructive pulmonary disease (COPD) group (33 cases), without smoking and COPD group (19 cases), smoking with COPD group (21 cases). The levels of HDAC2, IL-8 and TNF-α mRNA in lung adenocarcinoma and para-cancer tissues of groups were detected by real-time polymerase chain reaction (PCR) and the expression of HDAC2 protein was detected by Western blotting, and statistical analysis was carried out.. The expression of HDAC2, IL-8 and TNF-α in lung adenocarcinoma tissues and TNM stage of lung adenocarcinoma showed no significant differences with respect to age and gender (P>0.05). Compared with the para-cancer tissues of 73 cases, the expression of HDAC2 at mRNA and protein levels in lung adenocarcinoma tissues were significantly lower (t=4.15, 8.006, all P<0.01). and the content of IL-8 and TNF-α at mRNA levels were increased (t=-4.252, -5. 576, all P<0.01). The expression of HDAC2 mRNA and protein in lung adenocarcinoma tissues in smoking without COPD group and smoking with COPD group were significantly lower than in without smoking and COPD group (0.38±0.11, 0.35±0.12 vs 0.45±0.10 and 0.26±0.09, 0.24±0.06 vs 0.33±0.10; all P<0.05), and it was the lowest expression in smoking with COPD group. IL-8 and TNF-α at mRNA levels in lung adenocarcinoma tissues in smoking without COPD group and smoking with COPD group were significantly higher than in without smoking and COPD group (0.96±0.19, 1.10±0.18 vs 0.71±0.13 and 0.62±0.21, 0.64±0.20 vs 0.45±0.14; all P<0.05), and the up-regulation was more obvious in smoking with COPD group. The TNM stage of lung adenocarcinoma in smoking group (smoking without COPD group and smoking with COPD group) was higher than without smoking group (without smoking and COPD group)(P=0.038).. HDAC2 is down-regulated and IL-8, TNF-α are up-regulated in lung adenocarcinoma tissues. They are influenced by smoking and especially when combined with chronic obstructive pulmonary disease.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Down-Regulation; Histone Deacetylase 2; Humans; Interleukin-8; Lung; Lung Neoplasms; Pulmonary Disease, Chronic Obstructive; Real-Time Polymerase Chain Reaction; Respiratory Function Tests; RNA, Messenger; Smoking; Tumor Necrosis Factor-alpha

Alveolar macrophages (AMs) are equipped with innate immune receptors such as toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4). In primary bronchial epithelial cells, exposure of toll-like receptor (TLR) ligands or tumor necrosis factor-alpha (TNF-α) increased TLR2 mRNA expression and reduced interleukin-8 (IL-8) release when coincubated with glucocorticosteroids. The aim of this study was to compare TLR2 and TLR4 expression levels and the effect of a glucocorticosteroid after stimulation with TLR ligands on AMs from smokers with and without COPD compared with the healthy controls.. Bronchoalveolar lavage was performed, and AMs were isolated from smokers with (n=10) and without COPD (n=11) and healthy controls (n=10) and stimulated ex vivo with peptidoglycan (PGN), lipopolysaccharide (LPS), or TNF-α ± budesonide (Bud). Blocking antibodies to TLR2 or TLR4 were added before stimulation with LPS or PGN ± Bud, respectively. The release of proinflammatory cytokine (TNF-α), chemoattractant (CXCL8), and TLR expression was analyzed by enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction.. LPS, PGN, and TNF-α induced an increased release of IL-8 and TNF-α in the AMs in all the groups independent of smoking or disease. These responses were inhibited by a glucocorticosteroid (Bud) in all the three groups, except PGN-induced IL-8 secretion in smokers without COPD. Bud increased TLR2 expression in the healthy controls and smokers without COPD. Costimulation of TLR ligands and Bud significantly enhanced TLR2 mRNA expression in both groups of smokers compared with TLR ligands alone. In smokers, costimulation with PGN and Bud significantly increased TLR2 expression when compared with Bud alone. On stimulation with the TLR4 agonist, LPS downregulated TLR4 mRNA expression in all the three groups.. The combination of glucocorticosteroids with TLR ligands can increase TLR2 expression, thereby improving host defense in smokers. Also this combination can decrease the secretion of proinflammatory cytokines and chemokines as an anti-inflammatory response. Our findings indicate that glucocorticosteroid therapy strengthens immune defense pathways, which may have implication during exacerbation caused by microorganisms.

Topics: Adult; Aged; Anti-Inflammatory Agents; Budesonide; Case-Control Studies; Female; Glucocorticoids; Humans; Immunity, Innate; Interleukin-8; Ligands; Lipopolysaccharides; Macrophages, Alveolar; Male; Middle Aged; Peptidoglycan; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Smoking; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) has been associated with aberrant epithelial-mesenchymal interactions resulting in inflammatory and remodelling processes. We developed a co-culture model using COPD and control-derived airway epithelial cells (AECs) and lung fibroblasts to understand the mediators that are involved in remodelling and inflammation in COPD.AECs and fibroblasts obtained from COPD and control lung tissue were grown in co-culture with fetal lung fibroblast or human bronchial epithelial cell lines. mRNA and protein expression of inflammatory mediators, pro-fibrotic molecules and extracellular matrix (ECM) proteins were assessed.Co-culture resulted in the release of pro-inflammatory mediators interleukin (IL)-8/CXCL8 and heat shock protein (Hsp70) from lung fibroblasts, and decreased expression of ECM molecules (e.g. collagen, decorin) that was not different between control and COPD-derived primary cells. This pro-inflammatory effect was mediated by epithelial-derived IL-1α and increased upon epithelial exposure to cigarette smoke extract (CSE). When exposed to CSE, COPD-derived AECs elicited a stronger IL-1α response compared with control-derived airway epithelium and this corresponded with a significantly enhanced IL-8 release from lung fibroblasts.We demonstrate that, through IL-1α production, AECs induce a pro-inflammatory lung fibroblast phenotype that is further enhanced with CSE exposure in COPD, suggesting an aberrant epithelial-fibroblast interaction in COPD.

Topics: Bronchi; Cell Line; Coculture Techniques; Epithelial Cells; Epithelium; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Inflammation; Interleukin-1alpha; Interleukin-8; Lung; Nicotiana; Phenotype; Pulmonary Disease, Chronic Obstructive; Smoke; Smoking

Cigarette smoke (CS) exposure is a major risk factor for chronic obstructive pulmonary disease (COPD). We investigated whether CS-induced damage-associated molecular pattern (DAMP) release or DAMP-mediated inflammation contributes to susceptibility for COPD. Samples, including bronchial brushings, were collected from young and old individuals, susceptible and nonsusceptible for the development of COPD, before and after smoking, and used for gene profiling and airway epithelial cell (AEC) culture. AECs were exposed to CS extract (CSE) or specific DAMPs. BALB/cByJ and DBA/2J mice were intranasally exposed to LL-37 and mitochondrial (mt)DAMPs. Functional gene-set enrichment analysis showed that CS significantly increases the airway epithelial gene expression of DAMPs and DAMP receptors in COPD patients. In cultured AECs, we observed that CSE induces necrosis and DAMP release, with specifically higher galectin-3 release from COPD-derived compared with control-derived cells. Galectin-3, LL-37, and mtDAMPs increased CXCL8 secretion in AECs. LL-37 and mtDAMPs induced neutrophilic airway inflammation, exclusively in mice susceptible for CS-induced airway inflammation. Collectively, we show that in airway epithelium from COPD patients, the CS-induced expression of DAMPs and DAMP receptors in vivo and the release of galectin-3 in vitro is exaggerated. Furthermore, our studies indicate that a predisposition to release DAMPs and subsequent induction of inflammation may contribute to the development of COPD.

Topics: Administration, Intranasal; Adult; Alarmins; Animals; Antimicrobial Cationic Peptides; Cathelicidins; Cell Death; Epithelial Cells; Epithelium; Galectin 3; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Inflammation; Interleukin-8; Mice, Inbred C57BL; Mice, Inbred DBA; Mitochondria; Neutrophils; Pneumonia; Pulmonary Disease, Chronic Obstructive; Smoking

Chronic obstructive pulmonary disease (COPD) patients are at higher risk of developing lung cancer and its metastasis, but no suitable biomarker has been reported for differential diagnosis of these patients. Levels of serum biomarkers (VEGF, IL-8, MMP-9 and MMP-2) were analyzed in these patients, which were compared with healthy donors (HD). Levels of VEGF (P < 0.005) and MMP-9 (P < 0.05) were significantly higher in COPD patients than HD. Compared to HD, a decrease in IL-8 (~8.1 folds; P < 0.0001) but an increase in MMP-9 (~1.6 folds; P < 0.05) levels were observed in the lung cancer patients. Cancer patients showed significantly (P < 0.005) lower levels of serum VEGF (1.9 folds) and IL-8 (~9 folds) than the COPD patients. VEGF level was significantly higher (2.6 folds; P < 0.0005) in metastatic than non-metastatic cancer patients. However, MMP-2 didn't show significant variation in these patients. The Youden's index (YI) values for lung cancer diagnosis in HD using IL-8 was 0.55 with 83.3% overall accuracy. VEGF was able to diagnose COPD in HD with better YI (0.38) and overall accuracy (70.6%). IL-8 was able to diagnose cancer in COPD patients and HD with YI values of 0.35, 0.55 with 71% and 83.3% overall accuracy, respectively.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Diagnosis, Differential; Female; Humans; Interleukin-8; Lung Neoplasms; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Vascular Endothelial Growth Factor A

Chronic obstructive pulmonary disease (COPD) is a common and frequently occurring respiratory disease. At present, western medicine treatment of COPD mainly focuses on symptomatic treatment. Using Chinese medicines or integrated Chinese and Western medicines to treat stable COPD has significant efficacy. In this study, we aimed to observe the effect of Radix Stemonae concentrated decoction on the lung tissue pathology and inflammatory mediators in COPD rats and explore its possible mechanism.. SD rats were randomized into blank group, COPD model group and Radix Stemonae group, 10 cases in each group. Rats were fed for 112 days. Before the rats were sacrificed, lung function of the animals was tested. The right lower lung was fixed for morphologic observation. The inflammatory mediators in serum were determined using enzyme-linked immuno sorbent assay.. Body weight of animals in the model group was significantly decreased compared with blank group (P < 0.05). After gavage therapy with Radix Stemonae, body weight was significantly increased (P < 0.05). Compared with the blank group, pulmonary functions of rats in the model group were significantly abnormal (P < 0.05), while in Radix Stemonae group, these indicators turned much better than model group (P < 0.05). As for pathological changes in lungs, airway inflammation in the model group was aggravated. In the Radix Stemonae group, inflammation and emphysema were much milder. The concentrations of TNF-α, IL-8 and LTB4 in both model group and Radix Stemonae group were increased significantly (P < 0.05). But the levels in Radix Stemonae group were decreased significantly than model group (P < 0.05).. Radix Stemonae concentrated decoction may mitigate and improve airway rebuilding in the lungs of COPD rats by inhibiting the release of inflammatory mediators.

Topics: Animals; Drugs, Chinese Herbal; Humans; Interleukin-8; Lung; Male; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

COPD is a leading cause of dead worldwide and tobacco smoking is its major risk factor. IL8 is a proinflammatory chemokine mainly involved in the acute inflammatory reaction. The aim of this study was to test the association of IL-8, CXCR1 and CXCR2 gene variants and COPD susceptibility as part of a replication study and explore the effect of these variations in disease progression.. 9 tagSNPs were genotyped in 728 Caucasian individuals (196 COPD patients, 80 smokers and 452 non-smoking controls). Pulmonary compromise was evaluated using spirometry and clinical parameters at baseline and annually over a 2 years period. We also determined plasma levels of TNF-α, IL-6, IL-8 and IL-16 in COPD patients.. There was a lack of association between gene variants or haplotypes with predisposition to COPD. No correlation was observed between the polymorphisms and cytokines levels. Interestingly, significant associations were found between carriers of the rs4073A (OR = 3.53, CI 1.34-9.35, p = 0.01), rs2227306C (OR = 5.65, CI 1.75-18.88, p = 0.004) and rs2227307T (OR = 4.52, CI = 1.49-12.82, p = 0.007) alleles in the IL-8 gene and patients who scored higher in the BODE index and showed an important decrease in their FEV1 and FVC during the 2 years follow-up period (p < 0.05).. Despite no association was found between the studied genes and COPD susceptibility, three polymorphisms in the IL-8 gene appear to be involved in a worse progression of the disease, with an affectation beyond the pulmonary function and importantly, a reduction in lung function along the follow-up years.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Female; Follow-Up Studies; Genetic Markers; Genetic Predisposition to Disease; Genotyping Techniques; Humans; Interleukin-8; Logistic Models; Lung; Male; Middle Aged; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Respiratory Function Tests; Severity of Illness Index; Spirometry

Interleukin 8 (IL-8) is used to evaluate the severity of inflammation in the airways. The aim of this study was to evaluate patients with chronic obstructive pulmonary disease (COPD) for the presence of upper respiratory tract involvement by questioning patients regarding nasal symptoms and by measuring levels of IL-8 in nasal lavage material. A total of 47 COPD patients and 23 healthy controls were enrolled in this study. Pulmonary function tests were performed for all participants who were asked to complete a Sinonasal Outcome Test-20 (SNOT-20) questionnaire on the same day, as a measure of quality of life. Median IL-8 level in nasal lavage specimens of COPD patients with stable disease was higher than that of healthy controls. An increase in cigarette pack-years was significantly associated with an increase in nasal IL-8 levels. Similarly, IL-8 levels correlated positively with stage of COPD. A significant link between number of visits to the emergency department and stage of disease was observed. Patients with COPD had a significantly higher mean SNOT-20 severity score compared to healthy controls. Proper management of sinonasal disease may help to decrease the number of COPD attacks and consequently improve quality of life.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Nasal Lavage; Nasal Lavage Fluid; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Smoking; Surveys and Questionnaires

The role of exhaled H2S as a marker of airway inflammation and its relationship with COPD severity remain to be determined.. Airway inflammation was classified in 77 COPD subjects based on the presence of inflammatory cells in induced sputum. We investigated the association between disease phenotype and exhaled H2S, lung function, and plasma levels of several inflammatory factors, including tumor necrosis factor alpha, interleukin-8, and leukotriene B4.. In total, 33.77% of enrolled COPD subjects were diagnosed with eosinophilia. These subjects had a longer disease course, smoked fewer cigarettes, and experienced more frequent exacerbation events before study enrollment. However, they also had worse lung function and larger residual volume, they demonstrated greater changes in FEV1 following bronchodilator inhalation. Although levels of plasma inflammatory factors did not significantly differ between subjects with and without eosinophilia, subjects without eosinophilia had significantly higher levels of exhaled H2S (9.19±2.74 vs 7.24±1.68 parts per billion, P=.01). Furthermore, exhaled H2S levels were negatively correlated with induced sputum eosinophils (r=-0.45, P=.05), and positively correlated with inspiratory capacity in COPD subjects (r=0.51, P=.026), but did not correlate significantly with plasma inflammatory factors. A cut-off value of 7.10 parts per billion of exhaled H2S predicted a non-eosinophilic phenotype with 68.6% sensitivity and 77.9% specificity.. Exhaled levels of H2S were lower in subjects with eosinophilia. Increased levels of exhaled H2S predicted a non-eosinophilic phenotype in our study population.

Topics: Aged; Area Under Curve; Biomarkers; Breath Tests; Eosinophilia; Eosinophils; Exhalation; Female; Forced Expiratory Volume; Humans; Hydrogen Sulfide; Inflammation; Inspiratory Capacity; Interleukin-8; Leukotriene B4; Male; Middle Aged; Phenotype; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Residual Volume; ROC Curve; Sputum; Tumor Necrosis Factor-alpha

Club cell secretory protein (CCSP) is a protective biomarker associated with annual decline in lung function. COPD progression results from an imbalance between injury and repair initially triggered by cigarette smoking.. We investigated the effect of CCSP as a therapeutic strategy to restore the balance between injury and repair in COPD simultaneously, validating an ex vivo air-liquid interface (ALI) culture of human bronchial epithelial cells.. Endobronchial biopsy specimens (EBBs) were obtained from 13 patients with COPD, eight smokers, and eight control subjects. Morphometric analysis of the initial EBBs was performed. ALI cultures derived from the same EBBs were exposed to cigarette smoke extract (CSE) with or without exogenous recombinant human CCSP (rhCCSP) supplementation. CCSP and IL-8 concentrations were assessed at steady state and after CSE exposure.. Morphometric analysis of the initial EBBs showed increased cell density but decreased immunostaining of CCSP+ cells in EBBs of patients with COPD (P = .03 vs control subjects). At steady state, lower CCSP (P = .04) and higher IL-8 levels (P < .0001) were found in COPD ALI epithelium. Exogenous rhCCSP supplementation dampened CSE-induced IL-8-release in patients with COPD and returned to levels similar to those of smokers and control subjects (P = .0001). A negative correlation was found between IL-8-release in ALI and CCSP+ cell density in initial biopsy specimens (P = .0073).. In vitro, rhCCSP exogenous supplementation can reverse CSE-induced IL-8 release in biopsy specimens from patients with COPD, indicating a potential use of this strategy in vivo.

Topics: Adult; Aged; Case-Control Studies; Cells, Cultured; Epithelial Cells; Female; Humans; In Vitro Techniques; Interleukin-8; Male; Middle Aged; Nicotine; Pneumonia; Pulmonary Disease, Chronic Obstructive; Recombinant Proteins; Smoking; Uteroglobin

Chronic obstructive pulmonary disease (COPD) is a epidemic disease which is mainly due to cigarette smoking. The effect of carvacrol on systemic inflammation in guinea pig model of COPD was examined in the present study.. Guinea pigs of both sexes were divided into 6 groups, including: control, COPD, COPD+drinking water containing three concentrations of carvacrol and COPD+dexamethasone. Animals were exposed to cigarette smoke for 3 months in order to induce animal model of COPD. Weight changes, serum levels of IL-8 and malondialdehyde (MDA) as well as total and differential white blood cell (WBC) were measured (n=5 for control and COPD groups and n=6 for other groups).. Serum levels of IL-8 and MDA, total WBC (p<0.01 for all cases) and eosinophil counts (p<0.05) were increased and weight changes were decreased (p<0.05) in COPD group compared to controls. Serum MDA level and total WBC in treated groups with two higher carvacrol concentrations, eosinophil, neutrophil and lymphocyte percentage in those treated with its high concentration as well as IL-8 level and weight change in treated groups with its all concentrations and in dexamethasone treated group were significantly improved compared to COPD group (p<0.05 to p<0.001).. These results showed a preventive effect of the carvacrol on all measured parameter in COPD guinea pigs which was comparable to the effect of dexamethasone at used concentrations.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Cymenes; Dexamethasone; Eosinophils; Female; Guinea Pigs; Inflammation; Interleukin-8; Leukocyte Count; Male; Malondialdehyde; Monoterpenes; Pulmonary Disease, Chronic Obstructive; Tobacco Smoke Pollution

β2-Agonist inhibitors can relieve chronic obstructive pulmonary disease (COPD) symptoms by stimulating cyclic AMP (cAMP) signaling. A-kinase-anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the β2-agonist fenoterol, direct activation of protein kinase A (PKA), and exchange factor directly activated by cAMP decrease cigarette smoke extract (CSE)-induced release of neutrophil attractant interleukin-8 (IL-8) from human airway smooth muscle (ASM) cells. In the present study, we tested the role of AKAPs in CSE-induced IL-8 release from ASM cells and assessed the effect of CSE on the expression levels of different AKAPs. We also studied mRNA and protein expression of AKAPs in lung tissue from patients with COPD. Our data show that CSE exposure of ASM cells decreases AKAP5 and AKAP12, both capable of interacting with β2-adrenoceptors. In lung tissue of patients with COPD, mRNA levels of AKAP5 and AKAP12 were decreased compared with lung tissue from controls. Using immunohistochemistry, we detected less AKAP5 protein in ASM of patients with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II compared with control subjects. St-Ht31, which disrupts AKAP-PKA interactions, augmented CSE-induced IL-8 release from ASM cells and diminished its suppression by fenoterol, an effect mediated by disturbed ERK signaling. The modulatory role of AKAP-PKA interactions in the anti-inflammatory effects of fenoterol in ASM cells and the decrease in expression of AKAP5 and AKAP12 in response to cigarette smoke and in lungs of patients with COPD suggest that cigarette smoke-induced changes in AKAP5 and AKAP12 in patients with COPD may affect efficacy of pharmacotherapy.

Topics: A Kinase Anchor Proteins; Aged; Aged, 80 and over; Cell Cycle Proteins; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Female; Gene Expression; Humans; Interleukin-8; Male; Middle Aged; Myocytes, Smooth Muscle; Pulmonary Disease, Chronic Obstructive; Smoking

Chronic obstructive pulmonary disease (COPD) is characterised by chronic pulmonary inflammation punctuated by periods of viral exacerbations. Recent evidence suggests that the combination of roflumilast with corticosteroids may improve the compromised anti-inflammatory properties of corticosteroids in COPD. We analyzed differential and combination anti-inflammatory effects of dexamethasone and roflumilast N-oxide in human bronchial epithelial cells (HBECs) stimulated with viral toll like receptor (TLR) agonists.. Lung tissue and HBECs were isolated from healthy (n = 15), smokers (n = 12) and smokers with COPD (15). TLR3 expression was measured in lung tissue and in HBECs. IL-8 secretion was measured in cell cultures after TLR3 stimulation with poly I:C 10 μg/mL.. We found that TLR3 expression was increased by 1.95 fold (protein) and 2.5 fold (mRNA) in lung tissues from smokers with COPD and inversely correlated with lung function. The TLR3 agonist poly I:C 10 μg/mL increased the IL-8 release in HBECs that was poorly inhibited by dexamethasone in smokers (24.5%) and smokers with COPD (21.6%). In contrast, roflumilast showed similar inhibitory effects on IL-8 release in healthy (58.8%), smokers (56.6%) and smokers with COPD (50.5%). The combination of roflumilast N-oxide and dexamethasone showed additive inhibitory effects. Mechanistically, roflumilast N-oxide when combined with dexamethasone increased the expression of MKP1, and enhanced the inhibitory effects on phospho-p38, AP1 and NFκB activities which may explain the additive anti-inflammatory effects.. Altogether, our data provide in vitro evidence for a possible clinical utility to add roflumilast on top of inhaled corticosteroid in COPD.

Topics: Adrenal Cortex Hormones; Aged; Aminopyridines; Anti-Inflammatory Agents; Benzamides; Bronchi; Case-Control Studies; Cells, Cultured; Cyclopropanes; Dexamethasone; Drug Resistance; Drug Therapy, Combination; Epithelial Cells; Female; Humans; Interleukin-8; Male; Middle Aged; Poly I-C; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Smoking; Toll-Like Receptor 3

Corticosteroids (CS) have limited efficacy in the treatment of chronic obstructive pulmonary disease (COPD). p38 mitogen-activated protein kinase (MAPK) activation is increased in lung macrophages of COPD. We investigated whether p38 MAPK inhibition can modulate CS insensitivity of peripheral blood mononuclear cells (PBMCs) from patients with COPD.. PBMCs from patients with COPD (n=8) or healthy smokers (n=8) were exposed to lipopolysaccharide (LPS) with a selective p38 MAPK inhibitor (GW856553; 10(-10)-10(-6) M), with dexamethasone (10(-10)-10(-6) M), or with both. Phosphorylated glucocorticoid receptor (GR) was measured by Western blot.. Baseline (P<0.01) and LPS-induced (P<0.05) CXCL8 release was greater in PBMCs from COPD compared to healthy smokers. Inhibition of LPS-induced CXCL8 release by dexamethasone (10(-6) M) was reduced, and baseline and LPS-induced p38 MAPK activation increased in PBMCs of COPD. GW856553 (10(-9) and 10(-10) M) synergistically increased the inhibitory effect of dexamethasone (10(-8) and 10(-6) M) on LPS-induced CXCL8 release in COPD. Similar results were obtained for IL-6 release. GW856553 inhibited dexamethasone- and LPS-activated phosphorylation of serine 211 on GR. CS insensitivity in COPD PBMCs is reversed by inhibition of p38 MAPK activity, partly by preventing phosphorylation of GR at serine 211.. p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.

Topics: Adrenal Cortex Hormones; Aged; Case-Control Studies; Cells, Cultured; Cyclopropanes; Dexamethasone; Dose-Response Relationship, Drug; Drug Resistance; Female; Humans; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Middle Aged; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyridines; Receptors, Glucocorticoid; Serine

Body composition is an important prognostic factor in patients with COPD. The decrease in fat free mass (FFM), muscle mass (MM) and increase in visceral fat is associated with an elevated secretion of cytokines which promote systemic inflammation. The aim of the study was to evaluate body composition and the cytokine profile in patients with COPD in relation with the presence of hyperinflation.. The study group consisted of 149 patients (61F, 88M) with stable COPD in all stages of severity aged 68 ± 8.8 yrs. All the patients underwent spirometry and bodypletysmography with bronchial reversibility testing. Hyperinflation was defined as RV%TLC > 48% and > 126% predicted. Body composition was analyzed by bioimpedance. The following serum inflammatory markers were evaluated: C-reactive protein, IL-6, IL-8, TNF-a, CC16, adiponectin and resistin.. Hyperinflation was found in 96 patients (group A) and it was more frequent in women than men (49/61 vs. 47/88, p < 0.001). BMI and age in this group were comparable to those in patients without hyperinflation (group B). Patients with hyperinflation have lover FFM, FFM index, MM and MM index and total body water and higher fat mass and fat mass index. We found significantly higher serum concentrations of inflammatory markers in group A: IL-6 - 6.4 ± 10.9 vs. 3.6 ± 4.2 pg/ml, resistin - 9.3 ± 4.2 vs. 7.6 ± 2.4 ng/ml, CRP 4.1 ± 2.3 vs. 2.9±2.1 mg/l, respectively.. Patients with hyperinflation have a lower FFMI, TBW and MMI and a higher proportion of fat tissue. Hyperinflation is associated with elevated concentrations of inflammatory markers what may be associated with more severe disease. Body compositions abnormality and higher activity of systemic inflammation could therefore be a negative prognostic factor in COPD patients.

Topics: Adiponectin; Aged; Biomarkers; Body Composition; C-Reactive Protein; Cytokines; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Resistin; Tumor Necrosis Factor-alpha

The role of mitogen-activated protein kinases (MAPK) in regulating the inflammatory response in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthmatic patients is unclear.. To investigate the expression of activated MAPK in lungs of COPD patients and in bronchial biopsies of asthmatic patients and to study MAPK expression in bronchial epithelial cells in response to oxidative and inflammatory stimuli.. Immunohistochemical expression of phospho (p)-p38 MAPK, p-JNK1 and p-ERK1/2 was measured in bronchial mucosa in patients with mild/moderate (n = 17), severe/very severe (n = 16) stable COPD, control smokers (n = 16), control non-smokers (n = 9), in mild asthma (n = 9) and in peripheral airways from COPD patients (n = 15) and control smokers (n = 15). Interleukin (IL)-8 and MAPK mRNA was measured in stimulated 16HBE cells.. No significant differences in p-p38 MAPK, p-JNK or p-ERK1/2 expression were seen in bronchial biopsies and peripheral airways between COPD and control subjects. Asthmatics showed increased submucosal p-p38 MAPK expression compared to COPD patients (p < 0.003) and control non-smokers (p < 0.05). Hydrogen peroxide (H₂O₂), cytomix (tumour necrosis factor-α + IL-1β + interferon-γ) and lipopolysaccharide (LPS) upregulated IL-8 mRNA at 1 or 2 h. p38 MAPKα mRNA was significantly increased after H₂O₂ and LPS treatment. JNK1 and ERK1 mRNA were unchanged after H₂O₂, cytomix or LPS treatments.. p-p38 MAPK expression is similar in stable COPD and control subjects but increased in the bronchi of mild asthmatics compared to stable COPD patients. p38 MAPK mRNA is increased after bronchial epithelial challenges in vitro. These data together suggest a potential role for this MAPK in Th2 inflammation and possibly during COPD exacerbations.

Topics: Aged; Asthma; Blotting, Western; Bronchi; Case-Control Studies; Cell Line; Female; Humans; Immunohistochemistry; Interleukin-8; Lymphocyte Count; Male; Middle Aged; p38 Mitogen-Activated Protein Kinases; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Transcription Factor RelA

Although both chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) are characterised by chronic, systemic inflammation, their reciprocal interactions are poorly understood. The purpose of this study was to determine the concentrations of both inflammatory and oxidative stress biomarkers in the serum and exhaled breath condensate (EBC) of COPD patients, either with coexisting CVD or without cardio-vascular comorbidities.. Twenty-four COPD patients with CVD were allocated to group A, 20 COPD patients without CVD were assigned to group B and 16 healthy patients were included as a control. A medical history and physical examination were performed, and the following were measured: serum CRP concentration, glucose level, uraemic acid level and lipid profile. In addition 8-isoprostane, LTB4 and IL-8 concentrations were measured both in serum and EBC. Spirometry, six-minute walk test and echocardiography were performed in all subjects.. EBC concentrations of 8-isoprostane and LTB4, and serum levels of CRP, 8-soprostane, LTB4, IL-8 were significantly higher in COPD patients than in healthy controls. COPD patients with CVD were not found to have higher concentrations of the assessed markers than those without CVD, neither in the serum nor EBC. CRP, 8-isoprostane and LTB4 levels in serum, and IL-8 concentration in EBC correlated negatively with the value of forced expiratory volume in one second.. Although systemic inflammation coexists with COPD, it is not elevated in COPD patients with CVD. Since this phenomenon may result from treatment with statins, future studies should state whether COPD patients could benefit from the additional statin therapy.

Topics: Aged; Biomarkers; Breath Tests; Cardiovascular Diseases; Comorbidity; Dinoprost; Female; Humans; Inflammation Mediators; Interleukin-8; Leukotriene B4; Male; Middle Aged; Oxidative Stress; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is an epidemic and progressive health problem which is mainly a consequence of cigarette smoking, and associated with lung inflammation. Anti-inflammatory property of Zataria multiflora (Z. multiflora) and its constituent, carvacrol was shown in various inflammatory disorders previously. Therefore, in the present study, the effects of the plant and its constituent, carvacrol, on lung inflammation changes and oxidative stress, in guinea pigs model of COPD were evaluated.. Nine groups of animals including control, COPD, COPD + drinking water containing three concentrations of extract of Z. multiflora (0.4, 0.8, and 1.6 mg/mL), COPD + drinking water containing three concentrations of carvacrol (60, 120, and 240 μg/mL), and COPD + dexamethasone (50 μg/mL) were studied. For inducing COPD, animals were exposed to cigarette smoke for 3 months. Thiol groups, IL-8, total and differential WBC were measured in broncho-alveolar lavage fluid (BALF) (n = 6 for each group).. Total WBC, eosinophils, and neutrophils counts as well as the levels of IL-8 in BALF were significantly increased but thiol group was decreased in COPD compared to the control group (p < 0.05 to p < 0.001). Total WBC and IL-8 in all treated COPD groups, thiol group, eosinophils and neutrophils counts in treated groups with dexamethasone and two higher concentrations of the Z. multiflora and carvacrol were significantly improved compared to non-treated COPD group (p < 0.05 to p < 0.001). Lymphocyte count in treated groups with dexamethasone, highest concentration of Z. multiflora, and two higher concentration of carvacrol was also significantly higher than non-treated group (p < 0.05 to p < 0.001).. A preventive effect of Z. multiflora extract and its constituent carvacrol on lung inflammation changes and oxidative stress in animal model of COPD was suggested.

Topics: Animals; Anti-Inflammatory Agents; Cymenes; Dexamethasone; Eosinophils; Female; Guinea Pigs; Interleukin-8; Lamiaceae; Leukocyte Count; Lung; Male; Monoterpenes; Neutrophils; Oxidative Stress; Phytotherapy; Plant Extracts; Pneumonia; Pulmonary Disease, Chronic Obstructive; Smoking; Tobacco Products; Tobacco Smoke Pollution

Theophylline (TP) is a bronchodilator used orally to treat chronic obstructive pulmonary disease (COPD) that has been associated with multiple side effects, tempering its present use. This study aims to improve COPD treatment by creating a low-dose pressurized metered dose inhaler (pMDI) inhalable formulation of TP.. Aerosol performance was assessed using Andersen Cascade Impaction (ACI). Solubility of TP in HFA 134/ethanol mixture was measured and morphology of the particles analyzed with a scanning electron microscope (SEM). Calu-3 cell viability, epithelial cell transport and inflammatory-response assays were conducted to study the impact of the formulation on lung epithelial cells.. The mass deposition profile of the formulation showed an emitted dose of 250.04±14.48μg per 5 actuations, achieving the designed nominal dose (50μg/dose). SEM showed that the emitted particles were hollow with spherical morphology. Approximately 98% of TP was transported across Calu-3 epithelial cells and the concentration of interleukin-8 secreted from Calu-3 cells following stimulation with tissue necrosis factor-α (TNF-α) resulted in significantly lower level of interleukin-8 released from the cells pre-treated with TP (1.92±0.77ng·ml(-1) TP treated vs. 8.83±2.05ng·ml(-1) TNF-α stimulated, respectively).. The solution pMDI formulation of TP developed in present study was shown to be suitable for inhalation and demonstrated anti-inflammatory effects at low doses in Calu-3 cell model.

Topics: Administration, Inhalation; Aerosol Propellants; Aerosols; Anti-Inflammatory Agents; Bronchodilator Agents; Cell Line; Chemistry, Pharmaceutical; Drug Delivery Systems; Epithelial Cells; Equipment Design; Ethanol; Humans; Hydrocarbons, Fluorinated; Inflammation Mediators; Interleukin-8; Metered Dose Inhalers; Microscopy, Electron, Scanning; Particle Size; Pressure; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Solubility; Technology, Pharmaceutical; Theophylline; Tumor Necrosis Factor-alpha

Corticosteroid insensitivity, which is induced by cigarette smoke extract (CSE), is a significant barrier when treating chronic obstructive pulmonary disease (COPD). Erythromycin (EM) has been shown to have an anti-inflammatory role in some chronic airway inflammatory diseases, particularly diffuse panbronchiolitis and cystic fibrosis. Here, we explored whether the combination therapy of EM and dexamethasone (Dex) reverses corticosteroid insensitivity and investigated the molecular mechanism by which this occurs. We demonstrated that the combination of EM and Dex restored corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from COPD patients and U937 cells after CSE exposure. Moreover, pretreatment with 10, 50, or 100 μg/ml EM reversed the HDAC2 protein reduction induced by CSE exposure in a dose-dependent manner. U937 cells exposed to CSE show a reduction in histone deacetylase (HDAC) activity, which was potently reversed by EM or combination treatment. Although 10 and 17.5% CSE increased phosphorylated Akt (PAkt) expression in a concentration-dependent manner, preapplication of EM and the combination treatment in particular blocked this PAkt increase. Total Akt levels were unaffected by CSE or EM treatments. Furthermore, the combination treatment enhanced glucocorticoid receptor (GR)α expression. Our results demonstrate that the combination therapy of EM and Dex can restore corticosteroid sensitivity through inhibition of the PI3K-δ/Akt pathway and enhancing GRα expression.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Blotting, Western; Case-Control Studies; Dexamethasone; Drug Therapy, Combination; Erythromycin; Gastrointestinal Agents; Histone Deacetylase 2; Humans; Interleukin-8; Leukocytes, Mononuclear; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Receptors, Glucocorticoid; Smoking; U937 Cells

Chronic Obstructive Pulmonary Disease (COPD) is a common lung disease characterized by breathing difficulty as a consequence of narrowed airways. Previous studies have shown that COPD is correlated with neutrophil infiltration into the airways through chemotactic migration. However, whether neutrophil chemotaxis can be used to characterize and diagnose COPD is not well established. In the present study, we developed a microfluidic platform for evaluating neutrophil chemotaxis to sputum samples from COPD patients. Our results show increased neutrophil chemotaxis to COPD sputum compared to control sputum from healthy individuals. The level of COPD sputum induced neutrophil chemotaxis was correlated with the patient's spirometry data. The cell morphology of neutrophils in a COPD sputum gradient is similar to the morphology displayed by neutrophils exposed to an IL-8 gradient, but not a fMLP gradient. In competing gradients of COPD sputum and fMLP, neutrophils chemotaxis and cell morphology are dominated by fMLP.

Topics: Adult; Aged; Chemotaxis, Leukocyte; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Sputum; Young Adult

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. Exacerbation episodes impair lung function leading to disease progression. Levels of inflammation markers correlate with disease severity. Bacterial immunomodulators have shown a beneficial effect in COPD, improving symptoms and reducing the rate of exacerbations. This is an observational prospective study on 30 patients diagnosed with bronchiectasis and COPD, who received bacterial autogenous vaccine for 12 months. The rate of exacerbation, severity of symptoms and lung function were studied at baseline and after treatment. In addition, plasma levels CRP, IL6, IL8, and TNFα were measured. After treatment we found a reduction in mean acute respiratory infections and signs of lung disease. Acute phase proteins IL6 and CRP increased in blood and IL8 decreased. These changes may be related to the repeated injection of inactivated bacteria. Given the implication of these factors in the pathogenesis of COPD, particularly the production of IL8, the causes and consequences of cytokine modulation by bacterial vaccines should be investigated. Vaccination with autogenous vaccines for 1 year can produce a significant clinical improvement in COPD patients, reducing the frequency of exacerbations associated to changes in the profile of markers of inflammation.

Topics: Bacterial Vaccines; Biomarkers; Bronchiectasis; C-Reactive Protein; Disease Progression; Female; Humans; Immunotherapy; Interleukin-6; Interleukin-8; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Treatment Outcome; Tumor Necrosis Factor-alpha

IL-10 is well known for its ability to block the expression and production of numerous proinflammatory cytokines, in this manner preventing the development of excessive or chronic immune activation. IL-10-induced transcriptional repression of CXCL8 and TNFA genes consists of 2 distinct phases: an early phase, occurring rapidly and in a protein synthesis-independent manner, followed by a second phase that is more delayed and dependent on protein synthesis.. We sought to identify the mechanisms through which IL-10 rapidly and directly suppresses LPS-induced CXCL8 and TNF-α transcription, which might be defective under pathologic conditions.. The molecular events triggered by IL-10 in LPS-activated monocytes at the CXCL8 and TNFA loci were investigated by using the chromatin immunoprecipitation assay.. Inhibition of LPS-induced CXCL8 and TNF-α expression by IL-10 proceeds through a common mechanism targeting LPS-induced phosphorylation of the nuclear factor κB p65 serine 276 residue (pS276p65). As a result, all the pS276p65-dependent events occurring at the CXCL8 and TNFA loci are consistently reduced, ultimately leading to a reduction in transcript elongation. Additionally, IL-10 selectively controls CXCL8 transcript elongation through histone deacetylase (HDAC) 2-dependent covalent chromatin modifications, disrupting the assembly of the transcriptional machinery. Remarkably, PBMCs from patients with acute-phase chronic obstructive pulmonary disease, which express negligible HDAC2 levels, are scarcely affected by IL-10 in terms of inhibition of CXCL8 expression.. This study provides mechanistic evidence that IL-10 creates a chromatin environment that decreases the transcriptional rate of CXCL8 and TNF-α to Toll-like receptor 4-activating signals. Data identify novel molecular targets for therapeutic strategies aimed at dampening inflammation in pathologies such as chronic obstructive pulmonary disease, in which reduced intracellular HDAC2 levels have been described.

Topics: Adult; Aged; Binding Sites; Case-Control Studies; Cell Cycle Proteins; Female; Gene Expression Regulation; Histone Deacetylase 2; Humans; Interleukin-10; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Monocytes; Nuclear Proteins; Primary Cell Culture; Protein Binding; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA; Transcription Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha

The aim of the study was to prepare inhalable resveratrol by spray drying for the treatment of chronic obstructive pulmonary disease (COPD). Resveratrol, with a spherical morphology and particle diameter less than 5 μm, was successfully manufactured. Fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of spray-dried resveratrol was 39.9 ± 1.1% and 3.7 ± 0.1 μm, respectively, when assessed with an Andersen cascade impactor (ACI) at 60 l/min. The cytotoxicity results of resveratrol on Calu-3 revealed that the cells could tolerate high concentration of resveratrol (up to 160 μM). In addition, in transport experiments using Snapwells, it was observed that more than 80% of the deposited dry powder was transported across the Calu-3 cells to the basal chamber within four hours. The expression of interleukin-8 (IL-8) from Calu-3 induced with tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β1) and lipopolysaccharide (LPS) were significantly reduced after treatment with spray-dried resveratrol. The antioxidant assay (radical scavenging activity and nitric oxide production) showed spray-dried resveratrol to possess an equivalent antioxidant property as compared to vitamin C. Results presented in this investigation suggested that resveratrol could potentially be developed as a dry powder for inhalation for the treatment of inflammatory lung diseases like COPD.

Topics: Administration, Inhalation; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cell Line; Cell Survival; Chemistry, Pharmaceutical; Desiccation; Dry Powder Inhalers; Epithelial Cells; Free Radical Scavengers; Humans; Interleukin-8; Lipopolysaccharides; Particle Size; Pulmonary Disease, Chronic Obstructive; Resveratrol; Stilbenes; Stress, Physiological; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) concomitant with obstructive sleep apnea (OSA) is known as overlap syndrome. It has an increased rate of hospitalization due to COPD exacerbation which is believed to indicate a worsening of the underlying chronic airway inflammation. Therefore, the aim of this prospective study was to explore whether OSA exacerbates airway inflammation in subjects with COPD by examining the bronchoalveolar lavage (BAL) fluid.. This prospective study included 47 patients with overlap syndrome and 28 patients with moderate-to-severe stage stable COPD. Twenty-five patients with overlap syndrome adhered to the continuous positive airway pressure (CPAP) treatment; the remaining patients either refused CPAP treatment or discontinued it within two weeks owing to adverse effects or other reasons. BAL fluid was collected from all subjects for the evaluation of cell numbers and tumor necrosis factor alpha (TNFα) and interleukin-8 (IL-8) levels.. The BAL fluid of patients with overlap syndrome showed a significantly increased proportion of neutrophils and higher TNFα concentration and IL-8 levels than that of COPD patients; however, the serum CRP levels were not significantly different. An association was found between the percentage of neutrophils and the TNFα concentration and IL-8 levels. Moreover, the TNFα concentration was significantly correlated with the percentage of nighttime spent with oxygen saturation less than 90%. After CPAP treatment, airway inflammation was found to decrease significantly.. OSA exacerbates airway inflammation in COPD patients. CPAP treatment can improve nocturnal hypoxemia and decrease airway inflammation.

Topics: Aged; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Continuous Positive Airway Pressure; Female; Humans; Interleukin-8; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Sleep Apnea, Obstructive; Tumor Necrosis Factor-alpha

Dysfunctional innate responses of alveolar macrophages to nontypeable Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae contribute to morbidity in chronic obstructive pulmonary disease (COPD). Our earlier studies discovered impaired COPD alveolar macrophage responses to Toll-like receptor (TLR) ligands of nontypeable H. influenzae and provide rationale for further evaluation of TLR signaling. While the role of TLR single nucleotide polymorphisms is increasingly recognized in inflammatory diseases, TLR single nucleotide polymorphisms in COPD have only recently been explored. We hypothesized that specific TLR polymorphisms are associated with dysfunctional innate immune COPD alveolar macrophage responses and investigated polymorphisms of TLR2(Arg753Gln), TLR4(Thr399Ile; Asp299Gly), and TLR9(T1486C; T1237C).. DNA was purified from cells of 1) healthy nonsmokers (n = 20); 2) COPD ex-smokers (n = 83); 3) COPD active smokers (n = 93). DNA amplifications (polymerase chain reaction) were performed for each SNP. Alveolar macrophages from each group were incubated with nontypeable H. influenzae, M. catarrhalis and S. pneumoniae. Cytokine induction of macrophage supernatants was measured and the association with TLR single nucleotide polymorphism expression was determined.. No significant inter-group differences in frequency of any TLR SNP existed. However both TLR9 single nucleotide polymorphisms were expressed in high frequency. Among COPD ex-smokers, diminished IL-8 responsiveness to nontypeable H. influenzae, M. catarrhalis and S. pneumoniae was strongly associated with carriage of TLR9(T1237C) (p = 0.02; p = 0.008; p = 0.02), but not TLR9(T1486C). Carriage of TLR9(T1237C), but not TLR9(T1486C), correlated with diminished FEV1%predicted (p = 0.037).. Our results demonstrate a notable association of TLR9(T1237C) expression with dysfunctional innate alveolar macrophage responses to respiratory pathogens and with severity of COPD.

Topics: Alleles; Amino Acid Substitution; Case-Control Studies; Female; Gene Frequency; Humans; Immunity, Innate; Interleukin-8; Macrophages, Alveolar; Male; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Toll-Like Receptor 9

Chronic Obstructive Pulmonary Disease (COPD) is characterized by lung and systemic inflammation as well as airway goblet cell hyperplasia (GCH). Mucin production is activated in part by stimulation of the epidermal growth factor (EGF) receptor pathway through neutrophils and macrophages. How circulating cytokine levels relate to GCH is not clear.. We performed phlebotomy and bronchoscopy on 25 subjects (six nonsmokers, 11 healthy smokers, and eight COPD subjects FEV1 30-60 %). Six endobronchial biopsies per subject were performed. GCH was measured by measuring mucin volume density (MVD) using stereological techniques on periodic acid fast-Schiff stained samples. We measured the levels of chemokines CXCL8/IL-8, CCL2/MCP-1, CCL7/MCP-3, CCL22/MCD, CCL3/MIP-1α, and CCL4/MIP-1β, and the cytokines IL-1, IL-4, IL-6, IL-9, IL-17, EGF, and vascular endothelial growth factor (VEGF). Differences between groups were assessed using one-way ANOVA, t test, or Chi squared test. Post hoc tests after ANOVA were performed using Bonferroni correction.. MVD was highest in healthy smokers (27.78 ± 10.24 μL/mm(2)) compared to COPD subjects (16.82 ± 16.29 μL/mm(2), p = 0.216) and nonsmokers (3.42 ± 3.07 μL/mm(2), p < 0.0001). Plasma CXCL8 was highest in healthy smokers (11.05 ± 8.92 pg/mL) compared to nonsmokers (1.20 ± 21.92 pg/mL, p = 0.047) and COPD subjects (6.01 ± 5.90 pg/mL, p = 0.366). CCL22 and CCL4 followed the same trends. There were no significant differences in the other cytokines measured. When the subjects were divided into current smokers (healthy smokers and COPD current smokers) and non/ex-smokers (nonsmokers and COPD ex-smokers), plasma CXCL8, CCL22, CCL4, and MVD were greater in current smokers. No differences in other cytokines were seen. Plasma CXCL8 moderately correlated with MVD (r = 0.552, p = 0.003).. In this small cohort, circulating levels of the chemokines CXCL8, CCL4, and CCL22, as well as MVD, attain the highest levels in healthy smokers compared to nonsmokers and COPD subjects. These findings seem to be driven by current smoking and are independent of airflow obstruction.. These data suggest that smoking upregulates a systemic pattern of neutrophil and macrophage chemoattractant expression, and this correlates significantly with the development of goblet cell hyperplasia.

Topics: Adult; Aged; Case-Control Studies; Chemokine CCL2; Chemokine CCL22; Chemokine CCL3; Chemokine CCL4; Chemokine CCL7; Chemokines; Cytokines; Epidermal Growth Factor; Female; Goblet Cells; Humans; Hyperplasia; Interleukin-1; Interleukin-17; Interleukin-4; Interleukin-6; Interleukin-8; Interleukin-9; Lung; Male; Middle Aged; Mucins; Pulmonary Disease, Chronic Obstructive; Smoking; Vascular Endothelial Growth Factor A

Oxidative stress and inflammation play crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Most patients with COPD show a poor response to corticosteroids. Hydrogen sulfide (H2S ) has been implicated in the pathogenesis of COPD, but its expression and effects in lung tissue from COPD patients are not clear. In peripheral lung tissue samples from 24 patients, we found that compared with nonsmokers, the protein level of cystathionine-γ-lyase (CSE) was decreased in smokers and COPD patients. CSE mRNA increased but cystathionine-β-synthase (CBS) mRNA decreased in COPD patients. H2S donors increased glutathione and superoxide dismutase in CS exposed U937 cells and inhibited CS-induced TNF-α and IL-8 secretion. Dexamethasone alone had no effect on lipopolysaccharide (LPS) induced TNF-α release by alveolar macrophages from CS exposed rats, however the combination of dexamethasone and H2S donor significantly inhibited TNF-α release. Thus, H2S metabolism is altered in lung tissue of smokers and COPD patients. Supplementation of H2S protects against CS-induced oxidative stress and inflammation in macrophages and H2S on steroid sensitivity deserves further investigation.

Topics: Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Dexamethasone; Gene Expression Regulation; Glutathione; Humans; Hydrogen Sulfide; Inflammation; Interleukin-8; Lipopolysaccharides; Lung; Macrophages; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Smoking; Sulfides; Superoxide Dismutase; Tumor Necrosis Factor-alpha

On the model of chronic obstructive pulmonary disease, the effect of therapy with low-molecular-weight peptides on restructuring and functional activity of bronchial epithelium for restoring the immune and barrier function of the lungs and prevention of inflammatory process progression was studied. Chronic obstructive pulmonary disease was modeled in rats by 60-day intermittent exposure to NO2. Administration of tetrapeptide Bronchogen for 1 month eliminates symptoms of remodeling of the bronchial epithelium and lung tissue typical of chronic obstructive pulmonary disease (goblet cell hyperplasia, squamous metaplasia, lymphocytic infiltration and emphysema, and restoration of ciliated cells). Enhanced production of secretory IgA, a local immunity marker, attested to normalization of functional activity of bronchial epithelium, while normalization of cell composition and profile of proinflammatory cytokines in the bronchoalveolar space reflected reduction of neutrophilic inflammation.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cilia; Goblet Cells; Hyperplasia; Immunoglobulin A; Interleukin-8; Leukocyte Elastase; Lung; Male; Neutrophil Infiltration; Nitrogen Dioxide; Oligopeptides; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Rats; Rats, Wistar; Respiratory Mucosa; Respiratory System Agents; Tumor Necrosis Factor-alpha

To observe preventive and therapeutic effect of Yifei Jianpi Recipe (YJR) on chronic obstructive pulmonary disease (COPD) model rats and to explore its mechanism from the way of airway inflammation and airway mucus hypersecretion.. The COPD rat model was established by using cigarette smoking combined with intratracheal injection of lipopolysaccharide (LPS). Male SD rats were randomly divided into the blank control group (control group), the model group, the YJR group, 6 in each group. Forced vital capacity (FVC), forced expiratory volume in 0. 1 second (FEV0. 1), FEVO. 1/FVC, peak expiratory flow (PEF) was tested by lung function device. Pathological changes of bronchi and lung tissues were observed by HE staining. Airway Goblet cells were observed using AB-PAS staining. Contents of IL-8, IL-17, and TNF-α in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). Protein expressions of intercellular cell adhesion molecule-1 (ICAM-1), nuclear factor KB (NF-KB), mucin 5AC (Muc5AC), and Toll-like receptor 4 (TLR4) in rat airway were detected by immunohistochemical assay. mRNA expressions of TLR4 and Muc5AC in bronchi and lung tissues were detected by real-time quantitative PCR (RT qPCR).. Changes of bronchi and lung tissues in the model group rats were consistent with typical pathological manifestations of COPD. Compared with the model group, the degree of lung injury was significantly alleviated in the YJR group. Compared with the control group, FVC, FEV0. 1, FEVO. I/FVC, and PEF were decreased (P <0. 01), contents of IL-8, IL-17, and TNF-α in BALF were significantly increased (P <0. 01), protein expressions of ICAM-1, NF-KB, Muc5AC, and TLR4, mRNA expression levels of Muc5AC and TLR4 in bronchi and lung tissues were also significantly increased in the model group (P <0. 01). Compared with the model group, FVC, FEV0. 1, FEV0. 1/FVC, and PEF were significantly increased in the YJR group (P <0. 01, P <0. 05), but the rest indices were significantly lowered (P <0. 01, P <0. 05).. YJR could decrease contents of IL-8, IL-17, and TNF-α in BALF of COPD model rats, inhibit protein expression levels of ICAM-1, NF-κB, Muc5AC, and TLR4.in airway and lung tissues, thus playing preventive and therapeutic roles by reducing airway inflammation and airway mucus hypersecretion.

Topics: Animals; Bronchi; Bronchoalveolar Lavage Fluid; Drugs, Chinese Herbal; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-17; Interleukin-8; Lipopolysaccharides; Lung; Male; Models, Animal; Mucin 5AC; Mucus; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Random Allocation; Rats; Rats, Sprague-Dawley; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

The aim of this study is to investigate the anti-inflammatory effect of the adenosine derivative N6-(3-hydroxylaniline) adenosine (WS070117M1) on cigarette smoke plus LPS (lipopolysaccharide)-induced chronic obstructive pulmonary disease (COPD) in mice and its mechanism. COPD model was established by exposing male BALB/c mice to cigarette smoke and challenged with LPS inhalation. Supernatants of bronchoalveolar lavage fluid (BALF) were harvested and IL-1β, IL-6, IL-8 and TGF-β1 levels were measured by ELISA (enzyme-linked immunesorbent assay). The number of total white blood cells and neutrophils in bronchoalveolar lavage fluid was counted separately. Lung tissue was stained with Mayer 's hematoxylin and eosin for histopathologic examination. pAMPKa protein expression and distribution of lung tissue were analyzed by immunohistochemistry method. In vitro, levels of AMPKα phosphorylation in phorbol-12- myristate-13-acetate (PMA) differentiated THP-1 cells was detected by immunohistochemistry, IL-8 level in supernatants of cigarette smoke condensate stimulating PMA differentiated THP-1 cells was measured by ELISA. The results showed that WS070117M1 treatment significantly activated AMPKa in the lung tissue. It also resulted in down regulation of IL-1β, IL-6, IL-8 and TGF-β1 levels in bronchoalveolar lavage fluid and IL-8 level in cigarette smoke condensate stimulating PMA differentiated THP-1 cells. In addition, WS070117M1 could inhibit the recruitment of total white blood cells and neutrophils. These results suggest that WS070117M1 may alleviate the airway inflammation by activating AMPK in the lung tissue.

Topics: Adenosine; AMP-Activated Protein Kinases; Animals; Bronchoalveolar Lavage Fluid; Cell Line, Tumor; Disease Models, Animal; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukocyte Count; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Neutrophils; Nicotiana; Pulmonary Disease, Chronic Obstructive; Smoke; Transforming Growth Factor beta1

Topics: Bacterial Infections; Chronic Disease; Humans; Infections; Interleukin-17; Interleukin-8; Lung; Lung Diseases, Obstructive; Neutrophils; Pulmonary Disease, Chronic Obstructive; Smoking; Sputum

Peroxisome proliferator-activated receptor (PPAR)-γ is expressed in alveolar macrophages. The anti-inflammatory potential of the PPAR-γ ligands rosiglitazone and pioglitazone were investigated using in vitro alveolar macrophage models and in vivo animal models relevant to chronic obstructive pulmonary disease (COPD). PPAR-γ protein and gene expression in COPD alveolar macrophages was compared with control smokers and never-smokers. COPD macrophages were used to investigate the effects of PPAR-γ ligands and corticosteroids on lipopolysaccharide-induced cytokine production, alternative macrophage activation (M2) gene expression and efferocytosis. The effects of PPAR-γ ligands in a subchronic tobacco smoke model in mice were investigated. PPAR-γ protein expression was similar in COPD patients compared to controls, although increased gene expression levels were observed in COPD patients and control smokers compared to never-smokers. PPAR-γ ligands reduced tumour necrosis factor-α and CC chemokine ligand-5, but not CXC chemokine ligand-8, in COPD alveolar macrophages; these effects were generally less than those of the corticosteroid dexamethasone. Rosiglitazone increased M2 gene expression and enhanced efferocytosis of apoptotic neutrophils. Rosiglitazone and pioglitazone attenuated airway neutrophilia in a corticosteroid-resistant mouse model of pulmonary inflammation. We show biological actions of PPAR-γ agonists on corticosteroid-resistant disease, tobacco smoke-induced pulmonary inflammation, skewing of macrophage phenotype and clearance of apoptotic neutrophils.

Topics: Adrenal Cortex Hormones; Aged; Animals; Apoptosis; Chemokine CCL5; Dexamethasone; Female; Gene Expression Regulation; Humans; Hypoglycemic Agents; Inflammation; Interleukin-8; Ligands; Lipopolysaccharides; Macrophages; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Middle Aged; Neutrophils; Pioglitazone; PPAR gamma; Pulmonary Disease, Chronic Obstructive; Rosiglitazone; Smoking; Thiazolidinediones; Tumor Necrosis Factor-alpha

We hypothesised that increased oxidative stress, as present in the airways of asthma and chronic obstructive pulmonary disease (COPD) patients, induces epithelial damage and reduces epithelial responsiveness to suppressive effects of corticosteroids on proinflammatory cytokine production and barrier function.. We induced oxidative stress by H2O2 and/or cigarette smoke extract (CSE) in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBEC) derived by brushings from asthma patients, COPD patients, and smoking and non-smoking control individuals. We investigated effects of budesonide on barrier function (electrical resistance) and TNF-α-induced proinflammatory cytokine production (IL-8/CXCL8, granulocyte macrophage-colony stimulating factor (GM-CSF)).. We observed that H2O2 and CSE reduce epithelial resistance. Budesonide significantly counteracted this effect, likely by protection against epidermal growth factor receptor-dependent cell-cell contact disruption. Furthermore, budesonide suppressed proinflammatory cytokine production. H2O2 pretreatment reduced this effect of budesonide on cytokine production in both 16HBE cells and PBECs. Importantly, PBECs from asthma and COPD patients were less sensitive to budesonide with respect to cytokine production and barrier function than PBECs from control subjects.. Together, our data indicate that budesonide suppresses epithelial proinflammatory responses and barrier dysfunction and that oxidative stress reduces these effects in airway epithelium from asthma and COPD patients. Therefore, restoration of corticosteroid responsiveness in asthma and COPD may act to improve the airway epithelial barrier.

Topics: Adult; Asthma; Bronchi; Budesonide; Cells, Cultured; Epithelial Cells; Female; Glucocorticoids; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Male; Middle Aged; Oxidative Stress; Phosphorylation; Pulmonary Disease, Chronic Obstructive; Smoking

During bacterial infections, pathogen-associated molecular patterns (PAMPs) induce cytokine/chemokine release in immunoactive cells. This increases corticosteroid-resistant airway inflammation in chronic obstructive pulmonary disease (COPD) and leads to exacerbations. Anti-inflammatory therapies other than corticosteroids are required and resveratrol is currently under discussion. Resveratrol is an activator of sirtuins, which are class III histone deacetylases (HDACs). We suggested that human airway smooth muscle cells (HASMCs) release COPD-associated cytokines/chemokines in response to lipoteichoic acid (LTA), a major PAMP of gram-positive bacteria and that resveratrol is superior to the corticosteroid dexamethasone in suppressing these cytokines/chemokines. Cultivated HASMCs of patients with COPD were pre-incubated with resveratrol or dexamethasone before stimulation with LTA. CCL2, GM-CSF, IL-6 and IL-8 were analysed in culture supernatants by enzyme-linked immunosorbent assay. Drug effects were investigated in the absence and presence of trichostatin A (TSA), an inhibitor of class I/II HDACs, and EX527, an inhibitor of the sirtuin SIRT1. LTA induced robust cytokine/chemokine release. Resveratrol was superior to dexamethasone in reducing CCL-2, IL-6 and IL-8 in LTA-exposed HASMCs of patients with COPD. Both drugs were equally effective in reducing GM-CSF. Resveratrol effects were partially reversed by EX527 but not by TSA. Dexamethasone effects were partially reversed by TSA but not by EX527. We conclude that HASMCs contribute to the increase in airway inflammation in COPD exacerbations caused by gram-positive bacterial infections. Our data suggest resveratrol as an alternative anti-inflammatory therapy in infection-induced COPD exacerbations. Resveratrol and corticosteroids suppress cytokine/chemokine expression through activation of SIRT1 or interaction with class I/II HDACs, respectively, in HASMCs.

Topics: Adrenal Cortex Hormones; Aged; Anti-Inflammatory Agents; Carbazoles; Chemokine CCL2; Cytokines; Dexamethasone; Female; Gram-Positive Bacteria; Granulocyte-Macrophage Colony-Stimulating Factor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Myocytes, Smooth Muscle; Pulmonary Disease, Chronic Obstructive; Respiratory System; Resveratrol; Sirtuin 1; Stilbenes; Teichoic Acids

In a recent study, we demonstrated that transient receptor potential melastatin 8 (TRPM8), a calcium-permeable cation channel that is activated by cold temperatures, is localized in the bronchial epithelium and is upregulated in subjects with chronic obstructive pulmonary disease, which causes them to be more sensitive to cold air. In the present study, we found that exposure to cold temperatures induced ciliary ultrastructural anomalies and mucus accumulation on the epithelial surface. Male Sprague-Dawley rats were exposed to cold temperatures to determine the effects of cold air on ultrastructural changes in cilia and the airway epithelial surface. The rats were also exposed to cigarette smoke and/or cold temperatures to determine the effects of smoke and cold air on TRPM8 expression and the role of cold air in cigarette smoke-induced mucus hypersecretion. Following real-time RT-PCR and western blot analysis, we observed a high expression of TRPM8 mRNA and protein in the bronchial tissue following cigarette smoke inhalation. As shown by ELISA, concurrent cold air enhanced the levels of mucin 5AC (MUC5AC) protein, as well as those of inflammatory factors [tumor necrosis factor (TNF)-α and interleukin (IL)-8] that were induced by cigarette smoke inhalation to a greater extent than stimulation with separate stimuli (cold air and cigarette smoke separately). The results suggest that cold air stimuli are responsible for the ultrastructural abnormalities of bronchial cilia, which contribute to abnormal mucus clearance. In addition, cold air synergistically amplifies cigarette smoke-induced mucus hypersecretion and the production of inflammatory factors through the elevated expression of the TRPM8 channel that is initiated by cigarette smoke inhalation.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cold Temperature; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Interleukin-8; Male; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Mucin 5AC; Mucus; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Respiratory Mucosa; Smoking; TRPM Cation Channels; Tumor Necrosis Factor-alpha

In patients with chronic obstructive pulmonary disease (COPD), pulmonary macrophages increase in number, release increased levels of inflammatory mediators, and respond poorly to glucocorticosteroids. Whether this is due to a change in macrophage phenotype or localized activation is unknown.. We sought to investigate whether macrophages from patients with COPD are a distinct phenotype.. Macrophage populations were isolated from human lung tissue from nonsmokers, smokers, and patients with COPD by using Percoll density gradients. Five macrophage populations were isolated on the basis of density (1.011-1.023, 1.023-1.036, 1.036-1.048, 1.048-1.061, and 1.061-1.073 g/mL), and cell-surface expression of CD14, CD16, CD163, CD40, and CD206 was assessed by using flow cytometry. Release of active matrix metalloproteinase 9, TNF-α, CXCL8, and IL-10 was measured by using ELISA.. The 2 least dense fractions were more than 90% apoptotic/necrotic, with the remaining fractions greater than 70% viable. Macrophages from nonsmokers and smokers were CD163(+), CD206(+), CD14(+), and CD40(-), whereas macrophages from patients with COPD were less defined, showing significantly lower expression of all receptors. There were no differences in receptor expression associated with density. Macrophages from patients with COPD of a density of 1.036 to 1.048 g/mL released higher levels of active matrix metalloproteinase 9 compared with cells from nonsmokers, with no difference between the remaining fractions. This population of macrophages from patients with COPD was less responsive to budesonide compared with those from nonsmokers and smokers when stimulated with LPS. Glucocorticosteroid insensitivity was selective for proinflammatory cytokines because budesonide inhibition of LPS-stimulated IL-10 release was similar for all macrophages.. This study identifies a specific macrophage phenotype in the lungs of patients with COPD who are glucocorticosteroid insensitive with a density of 1.036 to 1.048 g/mL but do not correspond to the current concept of macrophage phenotypes.

Topics: Antigens, CD; Budesonide; Cell Separation; Drug Resistance; Female; Flow Cytometry; Humans; Immunophenotyping; Interleukin-10; Interleukin-8; Macrophages, Alveolar; Male; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Respiratory pathogens are frequently isolated from the airways of patients with chronic obstructive pulmonary disease (COPD) in the absence of an exacerbation. This bacterial "colonization" by potential pathogens is associated with host inflammatory and immune responses, which could increase respiratory symptoms.. To study whether bacterial colonization impacts daily respiratory symptoms in COPD.. In a longitudinal prospective observational study of COPD, patients recorded daily symptoms electronically on the Breathlessness, Cough, and Sputum Scale (BCSS). Sputum cultures and quantitative polymerase chain reaction (PCR) were performed every 2 weeks. The relationship of BCSS and bacterial colonization was analyzed with generalized linear mixed effects models, after controlling for exacerbations, weather conditions, lung function, and demographic variables.. A total of 41 patients recorded daily symptoms for 12,527 days. The average BCSS score was higher during the periods of colonization, determined by sputum culture with one or more of the following pathogens: nontypeable Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Pseudomonas aeruginosa, compared to periods without colonization (5.28 vs. 4.46; P = 0.008) after controlling for confounding variables. The finding did not change when colonization was defined by quantitative PCR (average BCSS, 4.77 vs. 4.25; P = 0.006). Sputum IL-8 levels were elevated with bacterial colonization.. Even in the absence of clinical exacerbation, colonization by bacterial pathogens in COPD was associated with a clinically significant moderate increase in daily symptoms, likely mediated by increased airway inflammation. Novel therapies that decrease bacterial colonization in COPD could improve daily symptoms and quality of life.

Topics: Aged; Cough; Dyspnea; Female; Haemophilus influenzae; Humans; Interleukin-8; Longitudinal Studies; Male; Middle Aged; Moraxella catarrhalis; Prospective Studies; Pseudomonas aeruginosa; Pulmonary Disease, Chronic Obstructive; Sputum; Streptococcus pneumoniae

Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal innate immune response. We have investigated the changes in the innate immune response of COPD alveolar macrophages exposed to both cigarette smoke and Toll-like receptor (TLR) stimulation. COPD and control alveolar macrophages were exposed to cigarette smoke extract (CSE) followed by TLR-2, -4 and -5 ligands [Pam3CSK4, lipopolysaccharide (LPS) and phase I flagellin (FliC), respectively] or non-typeable Haemophilus influenzae (NTHi). CSE exposure suppressed TLR-induced tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and regulated on activation, normal T cell expressed and secreted (RANTES) production in both COPD and control alveolar macrophages, but had no effect on interleukin 8 (CXCL8) production. Similarly, CSE suppressed NTHi-induced TNF-α but not NTHi-induced CXCL8 production in COPD alveolar macrophages. Gene expression analysis showed that CSE suppressed LPS-induced TNF-α transcription but not CXCL8 transcription in COPD alveolar macrophages. The dampening effect of CSE on LPS-induced cytokine production was associated with a reduction in p38, extracellular signal regulated kinase (ERK) and p65 activation. In conclusion, CSE caused a reduced innate immune response in COPD alveolar macrophages, with the exception of persistent CXCL8 production. This could be a mechanism by which alveolar macrophages promote neutrophil chemotaxis under conditions of oxidative stress and bacterial exposure.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Cytokines; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression; Gene Expression Regulation; Haemophilus Infections; Humans; Interleukin-8; Macrophage Activation; Macrophages; Macrophages, Alveolar; Male; Middle Aged; p38 Mitogen-Activated Protein Kinases; Pulmonary Disease, Chronic Obstructive; Smoking; Toll-Like Receptors; Transcription Factor RelA; Tumor Necrosis Factor-alpha

It is unclear whether cell culture methodology affects the corticosteroid sensitivity of chronic obstructive pulmonary disease (COPD) alveolar macrophages. We compared the effect of a short and a long isolation procedure on corticosteroid inhibition of lipopolysaccharide (LPS) stimulated cytokine release from COPD alveolar macrophages. We also investigated signalling pathways associated with macrophage activation during cell isolation. Macrophages cultured using a short isolation protocol released higher unstimulated levels of tumour necrosis factor (TNF)-α and chemokine C-X-C motif ligand (CXCL) 8; these macrophages were less sensitive to corticosteroid inhibition of LPS stimulated TNF-α and CXCL8 release when compared to a long isolation procedure. This was associated with increased p38 mitogen activated kinase (MAPK) activation. The p38 MAPK inhibitor, BIRB-796, significantly reduced unstimulated cytokine release. A key finding of this study was that both cell culture methods showed no difference in the corticosteroid sensitivity between COPD and control macrophages. We conclude that the culture of alveolar macrophages using a short isolation procedure alters cytokine production through p38 MAPK activation; this is associated with a change in corticosteroid sensitivity.

Topics: Aged; Blotting, Western; Cell Culture Techniques; Cells, Cultured; Culture Media, Conditioned; Cytokines; Dexamethasone; Enzyme-Linked Immunosorbent Assay; Female; Glucocorticoids; Humans; Interleukin-8; Lipopolysaccharides; Macrophages, Alveolar; Male; Middle Aged; Naphthalenes; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Transcription Factor RelA; Tumor Necrosis Factor-alpha

The origin(s) of systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) is unclear. We investigated the impact of exposure to ambient air pollution on systemic biomarkers of inflammation (C-reactive protein (CRP), tumour necrosis factor-α, interleukin (IL)-6, IL-8 and fibrinogen) and tissue repair (hepatocyte growth factor (HGF)) in 242 clinically stable COPD patients (mean age 67.8 years and forced expiratory volume in 1 s 71.3% predicted) in Barcelona, Spain, in 2004-2006. A spatiotemporal exposure assessment framework was applied to predict ambient nitrogen dioxide (NO2) and levels of particles with a 50% cut-off aerodynamic diameter of 2.5 μm (PM2.5) at each participant's home address during 10 periods of 24 h (lags 1-10) and 1 year prior to the blood sampling date. We used linear regression models to estimate associations between biomarkers and exposure levels. An interquartile range (IQR) increase in NO2 exposure in lag 5 was associated with 51%, 10% and 9% increases in CRP, fibrinogen and HGF levels respectively. We also observed 12% and 8% increases in IL-8 associated with an IQR increase in NO2 exposure in lag 3 and over the year before sampling, respectively. These increases were larger in former smokers. The results for PM2.5 were not conclusive. These results show that exposure to ambient NO2 increases systemic inflammation in COPD patients, especially in former smokers.

Topics: Aged; Air Movements; Air Pollutants; Air Pollution; Biomarkers; C-Reactive Protein; Cohort Studies; Female; Fibrinogen; Forced Expiratory Volume; Hepatocyte Growth Factor; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged; Nitrogen Dioxide; Obesity; Particulate Matter; Pulmonary Disease, Chronic Obstructive; Research Design; Smoking; Tumor Necrosis Factor-alpha

Airway inflammation and remodeling are major features of chronic obstructive pulmonary disease (COPD), whereas pulmonary hypertension is a common comorbidity associated with a poor disease prognosis. Recent studies in animal models have indicated that increased arginase activity contributes to features of asthma, including allergen-induced airway eosinophilia and mucus hypersecretion. Although cigarette smoke and lipopolysaccharide (LPS), major risk factors for COPD, may increase arginase expression, the role of arginase in COPD is unknown. This study aimed to investigate the role of arginase in pulmonary inflammation and remodeling using an animal model of COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pretreated by inhalation of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or vehicle. Repeated LPS exposure increased lung arginase activity, resulting in increased l-ornithine/l-arginine and l-ornithine/l-citrulline ratios. Both ratios were reversed by ABH. ABH inhibited the LPS-induced increases in pulmonary IL-8, neutrophils, and goblet cells as well as airway fibrosis. Remarkably, LPS-induced right ventricular hypertrophy, indicative of pulmonary hypertension, was prevented by ABH. Strong correlations were found between arginase activity and inflammation, airway remodeling, and right ventricular hypertrophy. Increased arginase activity contributes to pulmonary inflammation, airway remodeling, and right ventricular hypertrophy in a guinea pig model of COPD, indicating therapeutic potential for arginase inhibitors in this disease.

Topics: Airway Remodeling; Animals; Arginase; Fibrosis; Guinea Pigs; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Interleukin-8; Lipopolysaccharides; Lung; Mucin 5AC; Neutrophils; Pneumonia; Pulmonary Disease, Chronic Obstructive

Glucocorticoid functions are markedly impaired in patients with chronic obstructive pulmonary disease (COPD). The phosphodiesterase 4 inhibitor roflumilast N-oxide (RNO) is the active metabolite of roflumilast approved as a treatment to reduce the risk of exacerbations in patients with severe COPD.. We sought to characterize the differential effects of RNO versus corticosteroids and their potential additive/synergistic effect in neutrophils from patients with COPD, thus providing scientific rationale for the combination of roflumilast with corticosteroids in the clinic.. Peripheral blood neutrophils were isolated from patients with COPD (n = 32), smokers (n = 7), and healthy nonsmokers (n = 25). Levels of IL-8, matrix metallopeptidase 9 (MMP-9), and biomarkers of glucocorticoid resistance were determined by using ELISA and RT-PCR. Neutrophils were incubated with dexamethasone (0.1 nmol/L to 1 μmol/L), RNO (0.1 nmol/L to 1 μmol/L), or the combination of 1 nmol/L RNO plus 10 nmol/L DEX and stimulated with LPS (1 μg/mL) or cigarette smoke extract 5%; levels of IL-8, MMP-9, and other biomarkers were measured at the end of the incubation period.. Peripheral neutrophils from patients with COPD showed a primed phenotype with an increased basal release of IL-8 and MMP-9 and expressed a corticosteroid resistance molecular profile characterized by an increase in phosphoinositide 3-kinase δ, macrophage migration inhibitory factor, and glucocorticoid receptor β expression and a decrease in HDAC activity and mitogen-activated protein kinase phosphatase 1 expression. RNO demonstrated robust anti-inflammatory effects on neutrophils from patients with COPD, reversing their resistance to corticosteroids. The combination of RNO and dexamethasone showed additive/synergistic effects, which were consistent with the reversal of corticosteroid-resistant molecular markers by RNO.. RNO reverses corticosteroid resistance and shows strong anti-inflammatory effects alone or in combination with corticosteroids on neutrophils from patients with COPD.

Topics: Adrenal Cortex Hormones; Aged; Aminopyridines; Benzamides; Biomarkers; Complex Mixtures; Cyclopropanes; Dexamethasone; Drug Resistance; Drug Synergism; Female; Gene Expression; Histone Deacetylases; Humans; Interleukin-8; Intramolecular Oxidoreductases; Lipopolysaccharides; Macrophage Migration-Inhibitory Factors; Male; Matrix Metalloproteinase 9; Middle Aged; Mitogen-Activated Protein Kinase Phosphatases; Neutrophils; Nicotiana; Phosphatidylinositol 3-Kinases; Phosphodiesterase 4 Inhibitors; Primary Cell Culture; Pulmonary Disease, Chronic Obstructive

Alveolar macrophages (AM) in COPD have fundamentally impaired responsiveness to Toll-like receptor 2 (TLR2) and TLR4 ligands of non-typeable Haemophilus influenzae (NTHI). However, the contribution of innate immune dysfunction to exacerbations of COPD is unexplored. We hypothesised that impaired innate AM responses in COPD extend beyond NTHI to other pathogens and are linked with COPD exacerbations and severity.. AMs, obtained by bronchoalveolar lavage from 88 volunteers with stable-to-moderate COPD, were incubated with respiratory pathogens (NTHI, Moraxella catarrhalis (MC), Streptococcus pneumoniae (SP) and TLR ligands lipopolysaccharide, Pam3Cys) and elicited IL-8 and TNF-α were measured by microsphere flow cytometry. NF-κB nuclear translocation was measured by colorimetric assay. AM TLR2 and TLR4 expression was determined by immunolabeling and quantitation of mean fluorescent indices. Participants were monitored prospectively for occurrence of COPD exacerbations for 1 year following bronchoscopy. Non-parametric analyses were used to compare exacerbation-prone and non-exacerbation-prone individuals.. 29 subjects had at least one exacerbation in the follow-up period (exacerbation-prone) and 59 remained exacerbation-free (non-exacerbation-prone). AMs of exacerbation-prone COPD donors were more refractory to cytokine induction by NTHI (p=0.02), MC (p=0.045) and SP (p=0.046), and to TLR2 (p=0.07) and TLR4 (p=0.028) ligands, and had diminished NF-κB nuclear activation, compared with non-exacerbation-prone counterparts. AMs of exacerbation-prone subjects were more refractory to TLR2 upregulation by MC and SP (p=0.04 each).. Our results support a paradigm of impaired innate responses of COPD AMs to respiratory pathogens, mediated by impaired TLR responses, underlying a propensity for exacerbations in COPD.

Topics: Cells, Cultured; Coculture Techniques; Disease Progression; Female; Haemophilus influenzae; Humans; Immunity, Innate; Interleukin-8; Ligands; Lipopolysaccharides; Lipoproteins; Macrophages, Alveolar; Male; Middle Aged; Moraxella catarrhalis; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Signal Transduction; Streptococcus pneumoniae; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Up-Regulation

 Inflammation and oxidative stress play an essential role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD)..  The aim of the study was to evaluate the echocardiographic parameters of the left and right ventricular functions in patients with COPD with or without CVD and in healthy controls, and to establish their relationships with biomarkers of inflammation and oxidative stress..  The study included 24 patients with COPD and CVD, 20 patients with COPD, and 16 healthy controls. Physical examination, spirometry, and echocardiography were performed in all participants, and blood samples were collected. The levels of 8‑isoprostane, leukotriene B4, and interleukin 8 were determined in the blood and exhaled breath condensate (EBC)..  In patients with COPD, the left ventricular ejection fraction was lower than in healthy controls (58.84% ±9.57% vs. 65.50% ±3.35%, P <0.01); moreover, it was lower in patients with COPD and CVD than in those without comorbidities (54.29% ±10.58% vs. 64.30% ±3.74%, P <0.01). The systolic and diastolic functions of the right ventricle were lower in patients with COPD than in the control group, while systolic pulmonary arterial pressure was significantly higher in patients with COPD than in the control group (37.04 ±7.6 mmHg vs. 28.12 ±4.44 mmHg, P = 0.01). Some echocardiographic parameters of the left and right ventricular functions correlated with the concentrations of inflammatory markers both in serum and EBC..  The echocardiographic parameters of cardiac function correlate with the markers of inflammation in patients with COPD, which emphasizes the inflammatory background of CVD.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Diastole; Dinoprost; Echocardiography; Female; Heart Ventricles; Humans; Inflammation; Interleukin-8; Leukotriene B4; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Systole; Ventricular Function, Left; Ventricular Function, Right

Interleukin-33 is a newly described member of the interleukin-1 family. Recent research suggests that IL-33 is increased in lungs and plays a critical role in chronic airway inflammation in cigarette smoke-induced chronic obstructive pulmonary disease (COPD) mice. To determine the role of IL-33 in systemic inflammation, we induced COPD mice models by passive cigarette smoking and identified the IL-33 expression in bronchial endothelial cells and peripheral blood mononuclear cells (PBMCs) of them. After isolation, PBMCs were cultured and stimulated in vitro. We measured expressions of interleukin-6 and interleukin-8 in PBMCs in different groups. The expression of IL-33 in bronchial endothelial cells and PBMCs of COPD mice were highly expressed. Stimulated by cigarette smoke extract (CSE), the expression of IL-6 and IL-8 were induced and enhanced by IL-33. PBMCs of COPD mice produced more IL-6 and IL-8 stimulated by CSE and IL-33. Expression of IL-6 and IL-8 were decreased when stimulated by IL-33 together with soluble ST2. The mRNA production of ST2 in IL-33 stimulated PBMCs was increased. Being pretreated with several kinds of MAPK inhibitors, the secretions of IL-6 and IL-8 in PBMCs did not decrease except for the p38 MAPK inhibitor. We found that IL-33 could induce and enhance the expression of IL-6 and IL-8 in PBMCs of COPD mice via p38 MAPK pathway, and it is a promoter of the IL-6 and IL-8 production in systemic inflammation in COPD mice.

Topics: Animals; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukin-6; Interleukin-8; Interleukins; Male; Mice; Mice, Inbred C57BL; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin; Systemic Inflammatory Response Syndrome; Tobacco Smoke Pollution

Osteopontin (OPN) is a phosphorylated acidic glycoprotein that can function as both an extracellular matrix molecule and a cytokine. Published data support that OPN is upregulated in surgical lung tissue samples of patients with COPD. The aim of this study was to determine the levels of OPN in sputum supernatants of patients with COPD and to investigate possible associations with mediators and cells involved in the inflammatory and remodeling process as well as with the extent of emphysema.. Seventy-seven patients with COPD and 40 healthy subjects (20 smokers) were studied. All subjects underwent lung function tests, sputum induction for cell count identification, and OPN, transforming growth factor-β1, matrix metalloproteinase (MMP)-2, IL-8, and leukotriene-4 measurement in sputum supernatants. High-resolution CT (HRCT) scan of the chest was performed for quantification of emphysema.. OPN levels (pg/mL) were significantly higher in patients with COPD compared with healthy smokers and nonsmokers (median [interquartile range], 1,340 [601, 6,227] vs 101 [77, 110] vs 68 [50, 89], respectively; P < .001). Regression analysis showed a significant association between OPN and sputum neutrophils, IL-8, MMP-2, and the extent of emphysema. The associations previously listed were not observed in healthy subjects.. OPN levels are higher in patients with COPD compared with healthy subjects. OPN may play a role in the neutrophilic inflammation and in the pathogenesis of emphysema.

Topics: Aged; Emphysema; Female; Humans; Interleukin-8; Leukotriene B4; Male; Matrix Metalloproteinase 2; Middle Aged; Osteopontin; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum; Transforming Growth Factor beta1

Found in inflammatory zone 1 (FIZZ1) protein increased in pulmonary epithelial cells and in limited amounts of other lung cells. FIZZ1 increased in murine model of smoke induced chronic obstructive pulmonary disease. However, the direct role of FIZZ1 produced by pulmonary epithelium stimulated with cigarette smoke extraction has not been determined. We examined the expression and function of FIZZ1 in rat lung epithelial L2 cells.. The rat lung epithelial L2 cells (CCL 149) were exposed to cigarette smoke extraction, expression of FIZZ1 mRNA was investigated by RT-PCR. Levels of FIZZ1 protein were detected by Western blotting and laser confocal microscope. CCL 149 cells were treated with different concentrations and for different time of recombinant protein FIZZ1. After treatment, the expression levels of interleukin 8 (IL-8) were detected by enzyme-linked immunosorbent assay (ELISA).. When CCL 149 cells were exposed to cigarette smoke extraction, FIZZ1 mRNA and protein levels expressed significantly higher than control group. Recombinant protein FIZZ1 promoted the expression of IL-8 in a dose and time dependent manner in a certain range.. Cigarette smoke extraction activates FIZZ1 at mRNA and protein levels in CCL 149 cells. Recombinant protein FIZZ1 induces the expression of IL-8 and may thus participate in the process of chronic obstructive pulmonary disease airway inflammation and airflow obstruction. Generally, immune cells such as macrophages, neutrophils and lymphocytes are unavoidably involved in airway inflammatory and immune responses to cigarette smoke, but it is still unclear whether their involvement in the pathogenesis of chronic obstructive pulmonary disease is based on the specific expression in lung epithelial cells of FIZZ1.

Topics: Animals; Cell Line; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Interleukin-8; Nerve Growth Factor; Pulmonary Disease, Chronic Obstructive; Rats; RNA, Messenger; Smoking

The effects of Zataria multiflora (Z. multiflora) on systemic inflammation in guinea pigs model of COPD were examined. Control animals, COPD (induced by exposing animals to cigarette smoke), COPD+drinking water containing three concentrations of the extract of Z. multiflora, and COPD+dexamethasone were studied (n=6 for each group). Serum levels of IL-8 and malondialdehyde (MDA), total blood WBC (P<0.01 for all cases), and eosinophil counts (P<0.05) were higher and weight changes (P<0.05) were lower in the COPD group compared to controls. IL-8 level (P<0.001) and weight changes (P<0.01 to P<0.001) in all treated groups with Z. multiflora and total WBC number and MDA level in treated groups with two higher concentrations of the extract and lymphocytes percentage (P<0.05) in the highest concentration of Z. multiflora and dexamethasone (P<0.05 to P<0.001) were significantly improved compared to the COPD group. Results showed a preventive effect of hydroethanolic extract from Z. multiflora on all measured parameters in animals model of COPD which was comparable or even higher (in the highest concentration) compared to the effect of dexamethasone at the concentration used.

Topics: Animals; Dexamethasone; Disease Models, Animal; Guinea Pigs; Inflammation; Interleukin-8; Lamiaceae; Leukocyte Count; Male; Malondialdehyde; Phytotherapy; Plant Extracts; Pulmonary Disease, Chronic Obstructive; Smoking

Inhaled corticosteroids are anti-inflammatory medications that can down-regulate the immunologic response in patients with COPD; however, their role at onset of COPD exacerbation is still not understood. The aim of this study was to assess the early inflammatory response and clinical presentation of patients with COPD exacerbation mediated by inhaled corticosteroids.. Prospective data were collected on 123 hospitalized subjects with COPD exacerbation over a 30-month period at 2 Spanish university hospitals. Based on domiciliary use, comparative analyses were performed between subjects who did not use inhaled corticosteroids (n = 58) and subjects who did (n = 65). Measurements of serum biomarkers were recorded on admission to the hospital (day 1) and on day 3; clinical, physiological, microbiological, and severity data and mortality/readmission rates were also recorded.. At days 1 and 3, both groups showed a similar inflammatory response; fluticasone produced lower levels of interleukin-8 compared with budesonide (P < .01). All clinical features considered were similar in the 2 groups; multivariate analysis predicting clinical complications on hospitalization showed air-flow obstruction severity as the only predictive factor (odds ratio 3.13, 95% CI 1.13-8.63, P = .02).. Our study demonstrates a lack of inhaled corticosteroid influence in the early systemic inflammatory response to and clinical presentation of COPD exacerbation.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Androstadienes; Biomarkers; Budesonide; Comorbidity; Female; Fluticasone; Hospitalization; Humans; Interleukin-8; Male; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Spain

The role of interleukins in the severity and clinical profile of chronic obstructive pulmonary disease (COPD) is not known, but evidence supports the contribution of systemic inflammation to disease pathophysiology. This study evaluated the relationship of serum biomarkers to the severity and clinical parameters of COPD.. Serum levels of high-sensitivity C-reactive protein, interleukin-6 (IL-6), and interleukin-8 (IL-8) were measured in 50 patients with stable COPD and in 16 controls. The levels of these biomarkers were compared with parameters of severity, such as the grading of flow obstruction using the recommendations of the Global initiative for chronic Obstructive Lung Disease, the BMI (body mass index), obstruction, dyspnea, exercise capacity (health index) index, the number of exacerbations within the last year, and peripheral oxygen saturation after the six-minute walk test, and with clinical parameters, such as bronchitis and non-bronchitis phenotypes, the number of associated comorbidities, and the smoking burden. COPD patients exhibited higher levels of IL-6 and IL-8 compared to the control group. Higher levels of IL-6 occurred in COPD groups with body mass index <21 kg/m(2), with more than two exacerbations in the past year, with a higher smoking burden, and with bronchitis. The increase in serum IL-8 was found only in the group with the highest number of exacerbations within the previous year.. Increased IL-6 was mainly associated with smoking burden, in patients who had smoked for more than 30 pack-years and exhibited a bronchitis phenotype. No direct association was observed for both IL-6 and IL-8 blood levels with the severity of COPD in ex-smokers.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Case-Control Studies; Cross-Sectional Studies; Exercise Test; Female; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Lung; Male; Middle Aged; Predictive Value of Tests; Prognosis; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Risk Factors; Severity of Illness Index; Smoking; Smoking Cessation; Smoking Prevention

The effects of adipose derived stromal cells (ASCs) were evaluated on tracheal responsiveness and biochemical parameters in guinea pigs model of chronic obstructive pulmonary disease (COPD). Thirty six guinea pigs were divided into 6 groups including: Control, COPD, COPD+intratracheal delivery of PBS (COPD+ITPBS), COPD+intravenous delivery of PBS (COPD+IVPBS), COPD+intratracheal delivery of ASCs (COPD+ITASC) and COPD+intravenous injection of ASCs (COPD+IVASC). COPD was induced by exposing animals to cigarette smoke for 3 months. Cell therapy was then performed and after 14 days, tracheal responsiveness, concentration of interleukin-8 (IL-8) in serum and broncho-alveolar lavage fluid (BALF), as well as total and differential white blood cells (WBC) counts were evaluated. Tracheal responsiveness, total WBC counts, neutrophil and eosinophil percentage in BALF as well as concentration of IL-8 in serum and BALF significantly increased but lymphocyte percentage decreased in COPD compared to the control group (P<0.05 to p<0.001). Cell therapy was able to restore the tracheal hyper-responsiveness and the increased IL-8 concentration in serum and BALF of COPD-ITASC but not COPD-IVASC animals (P<0.05 for all cases). Total WBC in BALF also showed a significant decrease in both treated groups and the percentages of eosinophils, neutrophils and lymphocytes in BALF were reversed in COPD-ITASC compared to COPD-ITPBS animals (P<0.05 to P<0.001). Therefore, intratracheal cell therapy with ASC can decrease tracheal hyperresponsiveness and lung inflammation in cigarette smoke induced-COPD which may be helpful in attenuation of the severity of disease in patients suffering from COPD.

Topics: Adipose Tissue; Animals; Bronchoalveolar Lavage Fluid; Cell- and Tissue-Based Therapy; Guinea Pigs; Interleukin-8; Leukocyte Count; Pneumonia; Pulmonary Disease, Chronic Obstructive; Stromal Cells; Trachea; Treatment Outcome

Genetic factors play a role in the development and severity of chronic obstructive pulmonary disease (COPD). The pathogenesis of COPD is a multifactorial process including an inflammatory cell profile. Recent studies revealed that single nucleotide polymorphisms (SNPs) within ADAM33 increased the susceptibility to COPD through changing the airway inflammatory process and lung function.. In this paper, we investigated associations of four polymorphisms (T1, T2, S2 and Q-1) of ADAM33 as well as their haplotypes with pulmonary function and airway inflammatory process in an East Asian population of patients with COPD.. We found that T1, T2 and Q-1 were significantly associated with the changes of pulmonary function and components of cells in sputum of COPD, and T1 and Q-1 were significantly associated with cytokines and mediators of inflammation in airway of COPD in recessive models. 10 haplotypes were significantly associated with transfer factor of the lung for carbon monoxide in the disease state, 4 haplotypes were significantly associated with forced expiratory volume in one second, and other haplotypes were associated with airway inflammation.. We confirmed for the first time that ADAM33 was involved in the pathogenesis of COPD by affecting airway inflammation and immune response in an East Asian population. Our results made the genetic background of COPD, a common and disabling disease, more apparent, which would supply genetic support for the study of the mechanism, classification and treatment for this disease.

Topics: ADAM Proteins; Aged; Asia, Eastern; Asian People; Female; Forced Expiratory Volume; Haplotypes; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Lymphocyte Count; Macrophages; Male; Middle Aged; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Sputum; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

IL-17 is a pro-inflammatory mediator that is believed to play a critical role in regulating tissue inflammation during asthma, COPD, as well as other inflammatory disorders. The level of expression of IL-17 has been shown to be upregulated in lung bronchial tissue of asthmatic patients. Several reports have provided further evidence that this cytokine could play a key role in enhancing the migration of inflammatory as well as structural cells of the bronchial lung tissue during asthma and COPD. B cell infiltration to sites of inflammation during inflammatory disorders such as bowel disease, asthma and COPD has been reported. Accordingly, in this study we hypothesized that IL-17 may exert a chemotactic effect on primary B cells during asthma. We observed that B cells from asthmatic patients expressed significantly higher levels of IL-17RA and IL-17RC, compared to those of healthy subjects. Using an in-vitro migration assay, B cells were shown to migrate towards both IL-17A and IL-17F. Interestingly, blocking IL-17A and IL-17F signaling using either anti-IL-17R antibodies or MAP kinase inhibitors prevented in vitro migration of B cell towards IL-17. These observations indicate a direct chemotactic effect of IL-17 cytokines on primary peripheral blood B cells with higher effect being on asthmatic B cells. These findings revealed a key role for IL-17 in enhancing the migration of B cells to the lung tissue during asthma or COPD.

Topics: Adult; Asthma; B-Lymphocytes; Bronchi; Chemokine CXCL13; Chemotaxis; Enzyme Activation; Female; Humans; Imidazoles; Inflammation; Interleukin-17; Interleukin-8; Male; p38 Mitogen-Activated Protein Kinases; Pulmonary Disease, Chronic Obstructive; Pyridines; Receptors, Interleukin; Receptors, Interleukin-17; Th17 Cells

The collection of exhaled breath condensate (EBC) is a noninvasive method that can be used to monitor the inflammatory status of patients with chronic airway diseases. We aimed to study differences in cytokine expression between patients with exacerbations of chronic obstructive pulmonary disease (COPD) and patients with asthma attacks.. Using a custom-made device and methods based on American Thoracic Society (ATS)/European Respiratory Society (ERS) recommendations, EBC samples were collected from nine COPD patients, 12 asthma patients and 10 healthy individuals. Cytokine concentrations in serum and EBC were measured via commercial ELISA kits.. Of four cytokines measured in EBC [interleukin-8 (IL-8), IL-17, IL-4 and tumor necrosis factor-α (TNF-α)], only IL-8 was significantly higher in COPD than in asthma patients (5.27 ± 0.18 vs. 4.36 ± 0.34 pg/mL, p = 0.001). Moreover, COPD patients had higher serum IL-8 than asthma patients (10.57 ± 0.55 vs. 5.15 ± 0.24 pg/mL, p < 0.001). No significant correlation between serum and EBC cytokine concentrations was observed in each subgroup of patients.. Compared with patients with asthma attacks, patients with exacerbated COPD had increased IL-8 expression in both serum and EBC. These results suggest that IL-8 may be more important in airway and systemic inflammation in COPD exacerbations than in asthma attacks.

Topics: Adult; Aged; Asthma; Breath Tests; Disease Progression; Female; Humans; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is associated with persistent inflammation and oxidative stress in susceptible individuals. Using microarray analysis of bronchial biopsy samples from patients with COPD and controls, we identified Wnt4 as being up-regulated in COPD. Analysis of bronchial biopsy samples showed a very strong correlation between Wnt4 and IL8 gene expression, suggesting that Wnt4 plays a role in chronic lung inflammation. In vitro, Wnt4 induced proliferation and inflammation in human epithelial cells (BEAS-2B) and normal primary human bronchial epithelial cells in a concentration-dependent manner. This effect was enhanced in the presence of interleukin-1β (IL-1β) as a result of activation of the p38 and c-Jun NH2-terminal kinase mitogen-activated protein kinase pathways. Hydrogen peroxide, but not proinflammatory stimuli, up-regulated Wnt4 expression in epithelial cells. In monocytic THP-1 and primary airway smooth muscle cells, Wnt4 induced inflammation and enhanced the inflammatory response to lipopolysaccharide and IL-1β but did not induce proliferation. In addition, these other cell types did not have enhanced Wnt4 expression in response to hydrogen peroxide. Our results indicate that airway epithelial activation, due to oxidative stress, may lead to Wnt4 induction. Wnt4, in turn, acts through the noncanonical pathway to activate epithelial cell remodeling and IL8 gene expression, leading to neutrophil infiltration and inflammation.

Topics: Adult; Aged; Animals; Bronchi; Case-Control Studies; Cell Line; Cells, Cultured; Disease Models, Animal; Female; Humans; Inflammation Mediators; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Middle Aged; Pulmonary Disease, Chronic Obstructive; Up-Regulation; Wnt4 Protein

Cigarette smoke is the principal cause of chronic obstructive pulmonary disease (COPD), a disorder characterized by airway inflammation. As epithelial cells are the first line of defense against foreign material, the response of normal epithelial cells to smoke has been extensively studied. However, little is known about how epithelial cells derived from COPD patients respond to ongoing smoke exposure. This study was aimed at comparing the intracellular response of normal human bronchial/tracheal epithelial cells (NHBE) and COPD-diseased human bronchial/tracheal epithelial cells (DHBE) to cigarette smoke. NHBE and DHBE cells were treated with cigarette smoke condensate (CSC) for 24 h. IL-8 production was measured by ELISA and western blot was used to measure TLR4 expression. Cells were pretreated with CLI-095, a TLR4 inhibitor, or the signaling pathway inhibitors PD184352, Helenalin, or PI-103, which inhibit the ERK1/2, NF-κB and PI3K pathways, respectively. NHBE cells increased IL-8 production in a dose-dependent manner in response to CSC while DHBE cells did not show any significant difference and had a much lower production of IL-8 in response to CSC compared to NHBE cells. There was no change in TLR4 expression with CSC exposure. CLI-095 and PD184352 attenuated IL-8 secretion, indicating that CSC-induced inflammation is both TLR4- and ERK1/2-dependent. These results demonstrate that NHBE and DHBE cells differentially respond to cigarette smoke. DHBE cells exhibit a dampened IL-8 release, indicating that COPD is associated with a reduced capacity of airway epithelial cells to respond to foreign material.

Topics: Blotting, Western; Bronchi; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Inflammation; Interleukin-8; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Pulmonary Disease, Chronic Obstructive; Smoke; Toll-Like Receptor 4; Trachea

Chronic bronchitis (CB) is a risk factor in chronic obstructive pulmonary disease (COPD) for accelerated lung function decline and increased mortality. The lung and systemic inflammatory and immunological profile of COPD patients with CB which acutely experience respiratory failure upon a disease exacerbation is unknown.. In this study, we explored the expression of Foxp3 by western blot analysis, TLR4 by immunocytochemistry and the concentrations of IP-10 and IL-8 by ELISA in the mini-bronchoalveolar lavages (mini-BAL) and in the peripheral blood of patients with respiratory failure requiring intubation and mechanical ventilation. The recruited subjects were separated into three different groups: smokers with CB and COPD (COPD, n = 18), smokers with CB but without COPD (S, n = 8) and patients without CB and without COPD (C, n = 10).. In mini-BAL of COPD group, Foxp3 and IP-10 were significantly reduced while TLR4 was significantly increased in comparison to C. TLR4 was also increased in mini-BAL of S. In COPD peripheral blood, Foxp3 was reduced in comparison to C but no significant differences were observed for TLR4 and for IP-10. No significant differences were observed for IL-8 concentrations in the mini-BAL and in the blood of the recruited patients. The mini-BAL TLR4 expression correlated with the Clinical Infective Pulmonary Score.. In exacerbated COPD patients with respiratory failure, lung and systemic reduced immune regulatory events (low Foxp3 expression) and lung increased innate immunity responses (high TLR4 expression) occur. These events may contribute to the increased inflammatory events leading to respiratory failure.

Topics: Aged; Aged, 80 and over; Bronchitis, Chronic; Bronchoalveolar Lavage Fluid; Chemokine CXCL10; Female; Forkhead Transcription Factors; Humans; Interleukin-8; Leukocyte Count; Male; Neutrophils; Pulmonary Disease, Chronic Obstructive; Respiration, Artificial; Smoking; Statistics, Nonparametric; Toll-Like Receptor 4; Up-Regulation

A total of 98 patients with chronic obstructive pulmonary disease, arterial hypertension and combined flow of both chronic obstructive pulmonary disease and arterial hypertension were examined. The patients were divided into 3 groups. The first group included patients with arterial hypertension, the second consisted of patients with COPD, the third of patients with combined flow of COPD and AH. ELISA method was used to determine serum concentrations of interleukin-6 and tumor necrosis factor-α. Immunoturbidimetric method was used to measure the concentration of C-reactive protein. Spectrophotometrically markers of oxidative stress, the levels of oxidative protein modifications were measured. It was found that there was a significant increase in levels of interleukin-6, tumor necrosis factor-α and C-reactive protein in patients with combined flow of chronic obstructive pulmonary disease and arterial hypertension while comparing with other groups. In patients with comorbid disorders COPD and AH an increase in products of oxidative modification of proteins, spontaneous and iron induced aldehydephenylhydrazone's and ketondinitrophenylhydrazone's were also observed. Significant correlations between biomarkers of systemic inflammation and oxidative stress were found.

Topics: Adult; Aged; Biomarkers; C-Reactive Protein; Case-Control Studies; Comorbidity; Female; Humans; Hypertension; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged; Oxidative Stress; Pneumonia; Proteins; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Hydrogen peroxide (H(2)O(2)) is a highly reactive oxygen species involved in lung and bronchial epithelium injury. Increased H(2)O(2) levels have been reported in expired breath condensates of patients with inflammatory airway diseases such as chronic obstructive pulmonary disease. Protecting airway epithelial cells from oxidative stress is an important task in the prevention and management of airway diseases. Previous studies demonstrate that yam (Dioscorea batatas Decne) has antioxidant and anti-trypsin activities. This study evaluated the validity of dioscorin in vitro. The results showed that dioscorin attenuated the alteration of H(2)O(2) on G2/M cell cycle arrest. This might be associated with the activation of IκB and subsequent inactivation of NF-κB. Furthermore, dioscorin suppressed IL-8 secretion and reduced changes of adhesion molecule expressions in H(2)O(2)-injured A549 cells. These results help in understanding the potential of traditional Chinese herbal medicine as treatment for airway inflammatory diseases.

Topics: Antioxidants; Cell Adhesion Molecules; Cell Line; Enzyme Activation; Humans; Hyaluronan Receptors; Hydrogen Peroxide; I-kappa B Kinase; Integrin alpha2; Integrin alpha6; Integrin beta1; Interleukin-8; M Phase Cell Cycle Checkpoints; Medicine, Chinese Traditional; NF-kappa B; Oxidative Stress; Plant Proteins; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Respiratory Mucosa

Bacterial or viral infection of the airway plays a critical role in the pathogenesis and exacerbation of chronic obstructive pulmonary disease (COPD) which is expected to be the 3rd leading cause of death by 2020. The induction of inflammatory responses in immune cells as well as airway epithelial cells is observed in the disease process. There is thus a pressing need for the development of new therapeutics. Keratan sulfate (KS) is the major glycosaminoglycans (GAGs) of airway secretions, and is synthesized by epithelial cells on the airway surface. Here we report that a KS disaccharide, [SO3(-)-6]Galβ1-4[SO3(-)-6]GlcNAc, designated as L4, suppressed the production of Interleukin-8 (IL-8) stimulated by flagellin, a Toll-like receptor (TLR) 5 agonist, in normal human bronchial epithelial (NHBE) cells. Such suppressions were not observed by other L4 analogues, N-acetyllactosamine or chondroitin-6-sulfate disaccharide. Moreover, treatment of NHBE cells with L4 inhibited the flagellin-stimulated phosphorylation of epidermal growth factor receptor (EGFR), the down stream signaling pathway of TLRs in NHBE cells. These results suggest that L4 specifically blocks the interaction of flagellin with TLR5 and subsequently suppresses IL-8 production in NHBE cells. Taken together, L4 represents a potential molecule for prevention and treatment of airway inflammatory responses to bacteria infections, which play a critical role in exacerbation of COPD.

Topics: Bacterial Infections; Bronchi; Cells, Cultured; ErbB Receptors; Flagellin; Humans; Interleukin-8; Keratan Sulfate; Phosphorylation; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Toll-Like Receptor 5

Exacerbations in chronic obstructive pulmonary disease (COPD) reduce quality of life and are associated with a more rapid deterioration of the disease. It is desirable to predict an oncoming exacerbation before it occurs. The aim of the present study was to identify biomarkers that may predict a forthcoming exacerbation.. Forty-three patients with COPD in their stable state were included and followed up monthly until exacerbation, or for a maximum of 6 months. The patients come for an extra visit (prior to a scheduled visit) when exacerbated. The patients completed the questionnaires CCQ and MRC. Exhaled breath condensate (EBC) was collected followed by spirometry, impulse oscillometry, and sputum induction.. Twenty-five patients had an exacerbation within the 6-month period. Leukotriene B4 in sputum was the only biomarker that was increased at the visit prior to exacerbation compared to at the stable phase (p = 0.05). There also was a tendency for a similar but not significant increase in the sputum levels of 8-isoprostane, myeloperoxidase activity, and interleukin-8, as well as additional increases during exacerbation. Sputum purulence was not increased until exacerbation (p = 0.02). In contrast, none of the inflammatory biomarkers in EBC, the quality-of-life questionnaire score, CRP, spirometric parameters, or impulse oscillometry parameters were increased at the visit prior to exacerbation compared to the values at the stable phase.. Sputum biomarkers, especially leukotriene B4, could be used as predictors of a forthcoming exacerbation and worsening of COPD. This would be of great value for the patient, who may be a subject for early treatment and thereby avoid a progression of the disease.

Topics: Aged; Biomarkers; Dinoprost; Disease Progression; Female; Humans; Inflammation Mediators; Interleukin-8; Leukotriene B4; Lung; Male; Middle Aged; Oscillometry; Peroxidase; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Quality of Life; Spirometry; Sputum; Surveys and Questionnaires; Time Factors

Corticosteroid insensitivity is a major therapeutic problem for some inflammatory diseases including chronic obstructive pulmonary disease (COPD), and it is known to be induced by reduced histone deacetylase (HDAC)-2 activities via activation of the phosphoinositide 3-kinase (PI3K) pathway. The aim of this study is to evaluate effects of a novel macrolide/fluoroketolide, solithromycin (SOL, CEM-101), on corticosteroid sensitivity induced by oxidative stress.. Corticosteroid sensitivity was determined by IC50/EC50 of dexamethasone (Dex) on TNF-α-induced CXCL8 production in U937 monocytic cell line and peripheral blood mononuclear cells (PBMC) from COPD patients. Activities of HDAC and protein phosphatase 2A (PP2A) were measured by fluorescence-based assay in cells exposed to hydrogen peroxide (H2O2). We also investigated steroid insensitive airway neutrophilia in cigarette smoke exposed mice in vivo.. SOL (10 μM) restored Dex sensitivity in PBMC from COPD patients, H2O2-treated U937 cells and phorbol 12-myristate 13-acetate-differentiated U937 cells. In addition, SOL restored HDAC activity with concomitant inhibition of Akt phosphorylation as surrogate marker of PI3K activation. The inhibition of Akt phosphorylation by SOL was due to increased PP2A phosphatase activity, which was reduced in COPD and oxidative stress model. Other known macrolides, such as eryhthromycin, clarithromycin and azithromycin, were significantly less effective in these responses. In cigarette smoke-exposed mice, SOL (100 mg kg(-1), po) showed significant but weak inhibition of neutrophilia, whereas Dex (10 mg kg(-1), p.o.) showed no such effect. However, a combination of SOL and Dex inhibited neutrophilia by over 50%.. SOL has potential as novel therapy for corticosteroid-insensitive diseases such as COPD.

Topics: Adrenal Cortex Hormones; Animals; Anti-Bacterial Agents; Cells, Cultured; Dexamethasone; Drug Resistance; Histone Deacetylase 2; Humans; Hydrogen Peroxide; Interleukin-8; Leukocytes, Mononuclear; Macrolides; Male; Mice, Inbred C57BL; Neutrophils; Nicotiana; Oxidative Stress; Phosphoinositide-3 Kinase Inhibitors; Protein Phosphatase 2; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Smoke; Triazoles; Tumor Necrosis Factor-alpha; U937 Cells

The potential therapeutic effects of Costa Rican guava (Psidium friedrichsthalianum) extracts for chronic obstructive pulmonary disease were examined. The ethyl acetate fraction displayed the highest antioxidant activity, as compared to the hexane, chloroform, and n-butanol fractions, as well as the crude extract. This fraction was evaluated for its anti-inflammatory activity response relationship against interleukin-8 (IL-8) and inhibition of matrix metalloproteinase-1 (MMP-1) expression before and after treatment with cigarette smoke. The ethyl acetate fraction exhibited inhibitory activity against IL-8 production and MMP-1 expression, showing the most potent inhibitory activities in both assays at 100μg/mL, and nine compounds (1-9) were found. Phenolic compounds 1-O-trans-cinnamoyl-β-d-glucopyranose (2), ellagic acid (3), myricetin (4), quercitrin (7), and quercetin (9) were identified using standard compounds or literature reports from related species. Compounds 1, 5, 6, and 8 were tentatively identified as 1,5-dimethyl citrate (1), sinapic aldehyde 4-O-β-d-glucopyranose (5), 3,3',4-tri-O-methylellagic acid-4'-O-d-glucopyranoside (6), and 1,3-O-diferuloylglycerol (8), All nine compounds are reported for the first time in Costa Rican guava.

Topics: Anti-Inflammatory Agents; Antioxidants; Cell Line; Fruit; Humans; Interleukin-8; Matrix Metalloproteinase 1; Phenols; Plant Extracts; Psidium; Pulmonary Disease, Chronic Obstructive; Waste Products

Chronic airway inflammation can be mediated by an enhanced neutrophil oxidative burst. However, the role of bacteria in the pathogenesis of chronic obstructive pulmonary disease (COPD) exacerbations is highly controversial. The aim of this study was to evaluate the production of reactive oxygen species (ROS) in peripheral blood and sputum neutrophils during bacterial and nonbacterial acute exacerbations of COPD (AECOPD). A total of 40 patients with AECOPD, 10 healthy nonsmokers, and 10 "healthy" smokers were enrolled into the study. Peripheral blood and sputum samples were obtained during exacerbation and after recovery. Neutrophils were isolated by high-density gradient centrifugation and magnetic separation. ROS production by neutrophils was investigated after stimulation with phorbol-myristate-acetate and Staphylococcus aureus bacteria. ROS production by neutrophils was assessed as the mean fluorescent intensity using a flow cytometer. IL-8 levels in serum and induced sputum were determinant by ELISA. Spontaneous ROS production was significantly higher in neutrophils from the patients with bacterial AECOPD as compared with nonbacterial AECOPD and stable COPD (P <0.05). ROS production stimulated with PMA and with Staphylococcus aureus was significantly higher in neutrophils isolated from the patients with bacterial AECOPD as compared with nonbacterial and stable COPD (P <0.05). The serum and induced sputum IL-8 levels were significantly increased in the patients with bacterial AECOPD than nonbacterial AECOPD, stable COPS, and "healthy" smokers and nonsmokers (P <0.05) and higher in the induced sputum as the compared with serum in all studied groups (P <0.05). Enlarge CRP level was documented during AECOPD than in all other groups (P <0.05). A markedly increased ROS production in sputum neutrophils during bacterial AECOPD shows an inflammatory response reflecting enhanced local inflammation, which can be mediated by bacterial colonization.

Topics: Aged; Anemia, Refractory, with Excess of Blasts; Female; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Neutrophils; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Respiratory Burst; Respiratory Function Tests; Smoking; Sputum; Staphylococcus aureus; Tetradecanoylphorbol Acetate

Early preclinical diagnosis of COPD is urgent. We proposed that fatty acid composition of red blood cells may serve as a prognostic test for the complications in the chronic respiratory diseases. Fatty acid composition of the erythrocyte membranes in patients with chronic respiratory diseases (chronic bronchitis, CB, and stable chronic obstructive pulmonary disease, COPD) was studied. It was established that modification of the fatty acid composition in the erythrocyte membranes was unidirectional in both groups of patients.. Patients with CB and stable COPD (group A, GOLD 1) (15 subjects in each group) were studied in clinic. The activity of the inflammatory process was evaluated by the phagocytic activity of neutrophils, cytokine levels and cytokine receptors in the blood serum (TNFα, sTNF-RI, bFGF, TGF-β, IL-8). Fatty acid (FA) composition of the erythrocyte membranes was analyzed by gas liquid chromatography. Statistical data processing was performed by the methods of descriptive statistics with Statistica 6.0.. In both groups (CB and COPD), a significant accumulation of the saturated FAs (14:0, 15:0, 18:0) was established. The amount of the arachidonic acid (20:4n-6) was increased by 13% (р < 0.05) in CB patients and by 41% (р < 0.001) in COPD patients, as compared with healthy persons. The elevated level of the PUFA n-6 in the erythrocytes membranes in patients with chronic respiratory diseases confirms that proinflammatory (leukotriene B4) and bronchospasm (prostaglandin D2) mediator substrates is increased. The level of the eicosapentaenoic acid (20:5n-3) was decreased by 32% (р < 0.05) in CB patients and 2-fold (р < 0.001) in COPD patients. The observed increase in the 20:4n-6/20:5n-3 ratio--1.5-fold (р < 0.001) in CB patients and 3-fold in COPD patients--can be a specific marker of the adverse course of the respiratory pathology and the chronic inflammatory development.. Chronic respiratory disease development is associated with the disturbance of the fatty acid composition in erythrocyte membranes and disbalance of the ratio between precursor of pro- and antiinflammatory eicosanoids.

Topics: Adult; Bronchitis, Chronic; Eicosapentaenoic Acid; Erythrocyte Membrane; Fatty Acids, Unsaturated; Female; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Transforming Growth Factor beta

Alveolar macrophages produce neutrophil chemoattractants; this cellular cross-talk contributes to neutrophilic airway inflammation in chronic obstructive pulmonary disease (COPD). We have investigated the chemotaxis cross-talk mechanisms between these cells using COPD alveolar macrophages. Using conditioned media from stimulated COPD alveolar macrophages, we investigated the relative contributions of growth-related oncogene (CXCL1), interleukin-8 (CXCL8), and regulated on activation normal T cell expressed and secreted (CCL5) to neutrophil chemotaxis and evaluated the effect of blocking the chemokine receptors CXCR1 and CXCR2 on chemotaxis caused by macrophage-conditioned media. Furthermore, we evaluated whether corticosteroid treatment of stimulated alveolar macrophages inhibited the chemotaxis ability of conditioned media. Alveolar macrophages isolated from COPD (n = 8) and smoker (S) (n = 8) lungs were treated with ultra-pure lipopolysaccharide in the presence and absence of dexamethasone (1 μM). Supernatants were used for neutrophil chemotaxis assays. SB656933 (2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide) (CXCR2 antagonist) and Sch527123 [1-(2-chloro-3-fluorophenyl)-3-(4-chloro-2-hydroxy-3-piperazin-1-ylsulfonylphenyl)urea, 3-(2-chloro-3-fluoro-phenyl)-1-(4-chloro-2-hydroxy-3-piperazin-1-ylsulfonyl-phenyl)urea] (dual CXCR1 and CXCR2 antagonist) and blocking antibodies for CXCL8, CXCL1, and CCL5 were assessed. Conditioned media caused neutrophil chemotaxis in COPD and smokers (60.5 and 79.9% of total cells, respectively). Dexamethasone did not significantly reduce neutrophil chemotaxis in COPD or S. SB656933 and Sch527123 inhibited chemotaxis in a concentration-dependent manner, with the dual antagonist Sch527123 causing greater inhibition of chemotaxis. CXCL8 antibody inhibited neutrophil chemotaxis to basal levels, although there was no significant effect of blocking either CXCL1 or CCL5 (P > 0.05). CXCL8 plays a major role in neutrophil chemotaxis caused by alveolar macrophage-derived conditioned media, and this is most effectively inhibited by dual antagonism of CXCR1 and CXCR2. Corticosteroids do not inhibit chemotaxis caused by macrophage-derived chemokines.

Topics: Aged; Cells, Cultured; Chemotaxis; Female; Humans; Interleukin-8; Macrophages, Alveolar; Male; Middle Aged; Neutrophils; Phenylurea Compounds; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Sulfonamides

Patients with chronic obstructive pulmonary disease (COPD) have elevated cardiovascular risk, and myocardial injury is common during severe exacerbations. Little is known about the prevalence, magnitude, and underlying mechanisms of cardiovascular risk in community-treated exacerbations.. To investigate how COPD exacerbations and exacerbation frequency impact cardiovascular risk and myocardial injury, and whether this is related to airway infection and inflammation.. We prospectively measured arterial stiffness (aortic pulse wave velocity [aPWV]) and cardiac biomarkers in 98 patients with stable COPD. Fifty-five patients had paired stable and exacerbation assessments, repeated at Days 3, 7, 14, and 35 during recovery. Airway infection was identified using polymerase chain reaction.. COPD exacerbation frequency was related to stable-state arterial stiffness (rho = 0.209; P = 0.040). Frequent exacerbators had greater aPWV than infrequent exacerbators (mean ± SD aPWV, 11.4 ± 2.1 vs. 10.3 ± 2.0 ms(-1); P = 0.025). Arterial stiffness rose by an average of 1.2 ms(-1) (11.1%) from stable state to exacerbation (n = 55) and fell slowly during recovery. In those with airway infection at exacerbation (n = 24) this rise was greater (1.4 ± 1.6 vs. 0.7 ± 1.3 ms(-1); P = 0.048); prolonged; and related to sputum IL-6 (rho = 0.753; P < 0.001). Increases in cardiac biomarkers at exacerbation were higher in those with ischemic heart disease (n = 12) than those without (n = 43) (mean ± SD increase in troponin T, 0.011 ± 0.009 vs. 0.003 ± 0.006 μg/L, P = 0.003; N-terminal pro-brain natriuretic peptide, 38.1 ± 37.7 vs. 5.9 ± 12.3 pg/ml, P < 0.001).. Frequent COPD exacerbators have greater arterial stiffness than infrequent exacerbators. Arterial stiffness rises acutely during COPD exacerbations, particularly with airway infection. Increases in arterial stiffness are related to inflammation, and are slow to recover. Myocardial injury is common and clinically significant during COPD exacerbations, particularly in those with underlying ischemic heart disease.

Topics: Aged; Aged, 80 and over; Aorta; Blood Pressure; C-Reactive Protein; Cardiomyopathies; Cardiovascular Diseases; Cohort Studies; Disease Progression; Female; Fibrinogen; Heart Rate; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Pulse Wave Analysis; Risk Factors; Spirometry; Sputum; Troponin T; Vascular Stiffness

Combination inhaled therapy with long-acting β2 agonists (LABAs) and corticosteroids is beneficial in treating asthma and chronic obstructive pulmonary disease (COPD).. In asthma, LABAs enhance glucocorticoid receptor (GR) nuclear translocation in the presence of corticosteroids. Whether this biological mechanism occurs in COPD, a relatively corticosteroid-resistant disease, is uncertain.. Eight patients with mild/moderate COPD participated in a double-blind, placebo-controlled, crossover study and inhaled single doses of fluticasone propionate (FP) 100 μg, FP 500 μg, salmeterol xinafoate (SLM) 50 μg, and combination FP 100 μg + SLM 50 μg. One hour postinhalation, sputum was induced, nuclear proteins isolated from purified macrophages, and levels of activated nuclear GR quantified by using a GR-glucocorticoid response element ELISA-based assay.. Nuclear GR significantly increased after the inhalation of FP 500 μg (P < .01), but not after the inhalation of FP 100 μg or SLM 50 μg, compared with placebo. Interestingly, SLM in combination with FP 100 μg increased nuclear GR levels equivalent to those of FP 500 μg alone. This was significantly greater than either FP 100 μg (P < .05) or SLM 50 μg (P < .01) alone. In vitro in a human macrophage cell line, SLM (10(-8) mol/L) enhanced FP (10(-9) mol/L)-induced mitogen-activated protein kinase phosphatase-1 mRNA (5.8 ± 0.6 vs 8.4 ± 1.1 × 10(-6) copies, P < .05) and 2 × glucocorticoid response element-luciferase reporter gene activity (250.1 ± 15.6 vs 103.1 ± 23.6-fold induction, P < .001). Addition of SLM (10(-9) mol/L) to FP (10(-11) mol/L) significantly enhanced FP-mediated suppression of IL-1β-induced CXCL8 (P < .05).. Addition of SLM 50 μg to FP 100 μg enhanced GR nuclear translocation equivalent to that seen with a 5-fold higher dose of FP in sputum macrophages from patients with COPD. This may account for the superior clinical effects of combination LABA/corticosteroid treatment compared with either as monotherapy observed in COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Cell Line; Cell Nucleus; Dual Specificity Phosphatase 1; Female; Gene Expression; Genes, Reporter; Humans; Interleukin-1beta; Interleukin-8; Leukocytes, Mononuclear; Macrophages; Male; Middle Aged; Protein Binding; Protein Transport; Pulmonary Disease, Chronic Obstructive; Receptors, Glucocorticoid; Response Elements; Sputum; U937 Cells

Cigarette smoke represents the major risk factor for chronic obstructive pulmonary disease (COPD). Cigarette smoke extracts (CSE) alter TLR4 expression and activation in bronchial epithelial cells. Carbocysteine, an anti-oxidant and mucolytic agent, is effective in reducing the severity and the rate of exacerbations in COPD patients. The effects of carbocysteine on TLR4 expression and on the TLR4 activation downstream events are largely unknown. This study was aimed to explore whether carbocysteine, in a human bronchial epithelial cell line (16-HBE), counteracted some pro-inflammatory CSE-mediated effects. In particular, TLR4 expression, LPS binding, p21 (a senescence marker), IL-8 mRNA and release in CSE-stimulated 16-HBE as well as actin reorganization in neutrophils cultured with supernatants from bronchial epithelial cells which were stimulated with CSE and/or carbocysteine were assessed. TLR4 expression, LPS binding, and p21 expression were assessed by flow cytometry, IL-8 mRNA by Real Time PCR and IL-8 release by ELISA. Actin reorganization, a prerequisite for cell migration, was determined using Atto 488 phalloidin in neutrophils by flow cytometry and fluorescence microscopy. CSE increased: (1) TLR4, LPS binding and p21 expression; (2) IL-8 mRNA and IL-8 release due to IL-1 stimulation; (3) neutrophil migration. Carbocysteine in CSE stimulated bronchial epithelial cells, reduced: (1) TLR4, LPS binding and p21; (2) IL-8 mRNA and IL-8 release due to IL-1 stimulation; (3) neutrophil chemotactic migration. In conclusion, the present study provides compelling evidences that carbocysteine may contribute to control the inflammatory and senescence processes present in smokers.

Topics: Aging; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Bronchi; Carbocysteine; Cyclin-Dependent Kinase Inhibitor p21; Epithelial Cells; Flow Cytometry; Humans; Immunity, Innate; Interleukin-1; Interleukin-8; Neutrophils; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; Signal Transduction; Smoking; Toll-Like Receptor 4

Heat shock protein 70 (HSP70) plays a critical role in the process of inflammation and innate immunity response under environmental stress.. This study was to investigate HSP70 expression in the peripheral lung tissues of chronic obstructive pulmonary disease (COPD) patients and in human bronchial epithelial cells (16-HBE) exposed to cigarette smoke extract (CSE).. Peripheral lung tissues were collected after lung cancer resection from 26 patients without COPD, 20 with mild COPD and 15 with advanced COPD, classified by lung function criteria. Among these cases, 37 were smokers and 24 non-smokers. Lung tissues were examined for histopathological changes and levels of HSP70 and IL-8. Cultured 16-HBE cells were stimulated with CSE in the absence or presence of HSP70 neutralizing antibody and the expressions of IL-8 and phospho-EGFR protein were determined.. Compared to patients without COPD, the levels of HSP70 and IL-8 were significantly increased in the lung tissues of COPD patients and positively correlated with the severity of the disease. The HSP70 expression was significantly higher in current smokers than that in non-smokers. Moreover, CSE-induced HSP70 significantly enhanced IL-8 production and EGFR phosphorylation in 16-HBE cells. The increases in IL-8 and phospho-EGFR were blocked by anti-HSP70 antibody.. Our study clarified that increased expression of HSP70 is closely related to COPD disease severity and smoking status. Extracellular HSP70 regulated chemokine productions and EGFR phosphorylation and plays an important role in the CSE-induced inflammatory and innate immunity responses in bronchial epithelia cells.

Topics: Aged; Cell Line; Female; HSP70 Heat-Shock Proteins; Humans; Interleukin-8; Lung; Male; Middle Aged; Nicotiana; Pulmonary Disease, Chronic Obstructive; Smoke

Inflammation and remodeling of the small airways are major determinants of the progression and severity of COPD. The present study explored the correlation between sputum p38 mitogen-activated protein kinase (MAPK) activity and airway inflammation and reduction of lung function in the patients with chronic obstructive pulmonary disease (COPD).. Sputum samples were collected from 48 COPD patients and 12 healthy persons. Sputum p38 MAPK activity was measured by Western blotting and sputum levels of CXCL8 and neutrophil, and lung function was measured. The correlation between p38MAPK activity and airway inflammation and reduction of lung function was analyzed.. Our results showed the significantly increased expression of phospho-p38 MAPK and CXCL8 in the sputum samples of the COPD patients. The p38 MAPK activity was remarkably correlated with the CXCL8 level and neutrophils infiltration in the airway, and the decline of lung function in the COPD patients.. These findings suggest the pivotal role of p38 MAPK in the airway inflammation of COPD patients. We propose p38 MAPK as a potential target for the treatment of COPD.

Topics: Blotting, Western; Forced Expiratory Volume; Humans; Inflammation; Interleukin-8; Neutrophils; p38 Mitogen-Activated Protein Kinases; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum

We hypothesised that primary bronchial epithelial cells (PBECs) from subjects with chronic obstructive pulmonary disease (COPD) respond differently to Pseudomonas aeruginosa lipopolysaccharide (LPS) after cigarette smoke extract (CSE) exposure than PBECs obtained from smokers without airflow obstruction and nonsmokers. PBECs from 16 COPD subjects, 10 smokers without airflow obstruction and nine nonsmokers were cultured at air-liquid interface. Cultures were incubated with CSE prior to stimulation with P. aeruginosa LPS. Interleukin (IL)-6 and IL-8 were measured by ELISA and Toll-like receptor (TLR)-4 expression by fluorescence-activated cell sorter. Activation of nuclear factor (NF)-κB was determined by Western blotting and ELISA, and MAPK and caspase-3 activity by Western blotting. Apoptosis was evaluated using Annexin-V staining and the terminal transferase-mediated dUTP nick end-labelling methods. Constitutive release of IL-8 and IL-6 was greatest from the COPD cultures. However, CSE pretreatment followed by P. aeruginosa LPS stimulation reduced IL-8 release from COPD PBECs, but increased it from cells of smokers without airflow obstruction and nonsmokers. TLR-4 expression, MAPK and NF-κB activation in COPD cultures were reduced after CSE treatment, but not in the smokers without airflow obstruction or nonsmoker groups, which was associated with increased apoptosis. CSE attenuates inflammatory responses to LPS in cells from people with COPD but not those from nonsmoking individuals and those who smoke without airflow obstruction.

Topics: Adult; Aged; Apoptosis; Bronchi; Caspase 3; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; MAP Kinase Signaling System; Middle Aged; NF-kappa B; Pseudomonas aeruginosa; Pulmonary Disease, Chronic Obstructive; Smoke; Smoking; Toll-Like Receptor 4

Decreased activity of forkhead transcription factor class O (FoxO)3A, a negative regulator of NF-κB-mediated chemokine expression, is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Previously, we showed that quercetin reduces lung inflammation in a murine model of COPD. Here, we examined the mechanisms underlying decreased FoxO3A activation and its modulation by quercetin in COPD human airway epithelial cells and in a COPD mouse model.. Primary COPD and normal human airway epithelial cells were treated with quercetin, LY294002 or erlotinib for 2 weeks. IL-8 was measured by ELISA. FoxO3A, Akt, and epidermal growth factor (EGF) receptor (EGFR) phosphorylation and nuclear FoxO3A levels were determined by Western blot analysis. Effects of quercetin on lung chemokine expression, nuclear FoxO3A levels and phosphorylation of EGFR and Akt were determined in COPD mouse model.. Compared with normal, COPD cells showed significantly increased IL-8, which negatively correlated with nuclear FoxO3A levels. COPD bronchial biopsies also showed reduced nuclear FoxO3A. Decreased FoxO3A in COPD cells was associated with increased phosphorylation of EGFR, Akt and FoxO3A and treatment with quercetin, LY294002 or erlotinib increased nuclear FoxO3A and decreased IL-8 and phosphorylation of Akt, EGFR and FoxO3A, Compared with control, elastase/LPS-exposed mice showed decreased nuclear FoxO3A, increased chemokines and phosphorylation of EGFR and Akt. Treatment with quercetin partially reversed these changes.. In COPD airways, aberrant EGFR activity increases PI 3-kinase/Akt-mediated phosphorylation of FoxO3A, thereby decreasing nuclear FoxO3A and increasing chemokine expression. Quercetin restores nuclear FoxO3A and reduces chemokine expression partly by modulating EGFR/PI 3-kinase/Akt activity.

Topics: Animals; Antioxidants; Bronchi; Cell Nucleus; Disease Models, Animal; Enzyme Inhibitors; ErbB Receptors; Forkhead Box Protein O3; Forkhead Transcription Factors; Humans; Immunohistochemistry; Interleukin-8; Mice; Mice, Inbred C57BL; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Phosphorylation; Pulmonary Disease, Chronic Obstructive; Quercetin; Respiratory Mucosa

Indoleamine 2,3-dioxygenase (IDO) induces generation of regulatory T cells but suppresses Th17 cells and therefore might attenuate neutrophilic inflammation. The role of IDO in neutrophilic airway diseases such as chronic obstructive pulmonary disease (COPD) remains unknown. We evaluated IDO activity and expression and interleukin (IL)-10 and IL-17A levels in sputum from patients with COPD.. IDO activity and cytokine concentrations in sputum supernatants from patients with COPD of varying severity and in smoking and non-smoking control subjects were determined by high-performance liquid chromatography and ELISA, respectively.. Patients with COPD had reduced sputum IDO activity and expression and IL-10 levels, with increased IL-17A, IL-6 and CXCL8 concentrations and sputum neutrophils. These changes were significantly correlated with disease severity. IDO activity was decreased, but to a lesser extent, in normal smokers compared with non-smoking controls.. Patients with COPD have a progressive reduction in IDO activity with reversal of the balance between IL-10 and IL-17A, resulting in chronic airway neutrophilic inflammation.

Topics: Disease Progression; Female; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interleukin-10; Interleukin-17; Interleukin-6; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Sputum

Macrolides are reported to reduce exacerbation of chronic inflammatory respiratory disease, such as chronic obstructive pulmonary disease (COPD), and also show anti-inflammatory effects in vitro and in vivo. However the anti-inflammatory efficacies of current macrolides are relatively weak. Here we found that a novel macrolide/fluoroketolide solithromycin (CEM-101) showed superior anti-inflammatory effects to macrolides in current clinical use. The effects of solithromycin (SOL) on lipopolysaccharide-induced TNFα (tumor necrosis factor α) and/or CXCL8 (C-X-C motif chemokine ligand 8; interleukin-8) release, phorbol 12-myristate 13-acetate-induced MMP9 (matrix metalloproteinase 9) activity and NF-κB (nuclear factor-κB) activity under conditions of oxidative stress have been evaluated and compared with the effects of erythromycin, clarithromycin, azithromycin, and telithromycin in macrophage-like PMA-differentiated U937 cells and peripheral blood mononuclear cells (PBMC) obtained from COPD patients. We also examined effect of SOL on cigarette smoke-induced airway inflammation in mice. SOL exerted superior inhibitory effects on TNFα/CXCL8 production and MMP9 activity in monocytic U937 cells. In addition, SOL suppressed TNFα release and MMP9 activity in PBMC from COPD patients at 10 µM, which is 10 times more potent than the other macrolides tested. Activated NF-κB by oxidative stress was completely reversed by SOL. SOL also inhibited cigarette smoke-induced neutrophilia and pro-MMP9 production in vivo, although erythromycin did not inhibit them. Thus, SOL showed better anti-inflammatory profiles compared with macrolides currently used in the clinic and may be a promising anti-inflammatory and antimicrobial macrolide for the treatment of COPD in future.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-8; Macrolides; Macrophages, Alveolar; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; NF-kappa B; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Tobacco Smoke Pollution; Triazoles; Tumor Necrosis Factor-alpha; U937 Cells

Cigarette smoking induces inflammatory responses in all smokers and is the major risk factor for lung disease such as chronic obstructive pulmonary disease (COPD). In this progressive disease, chronic inflammation in the lung contributes to lung tissue destruction leading to the formation of chemotactic collagen fragments such as N-acetylated Proline-Glycine-Proline (N-ac-PGP). The generation of this tripeptide is mediated by a multistep pathway involving matrix metalloproteases (MMPs) 8 and 9 and prolyl endopeptidase (PE). Here we investigated whether cigarette smoke extract (CSE) stimulates human PMNs to breakdown whole matrix collagen leading to the generation of the chemotactic collagen fragment N-ac-PGP.. Incubating PMNs with CSE led to the release of chemo-attractant CXCL8 and proteases MMP8 and MMP9. PMNs constitutively expressed PE activity as well as PE protein. Incubating CSE-primed PMNs with collagen resulted in collagen breakdown and in N-ac-PGP generation. Incubation of PMNs with the tripeptide N-ac-PGP resulted in the release of CXCL8, MMP8 and MMP9. Moreover, we tested whether PMNs from COPD patients are different from PMNs from healthy donors. Here we show that the intracellular basal PE activity of PMNs from COPD patients increased 25-fold compared to PMNs from healthy donors. Immunohistological staining of human lung tissue for PE showed that besides neutrophils, macrophages and epithelial cells express PE.. This study indicates that neutrophils activated by cigarette smoke extract can breakdown collagen into N-ac-PGP and that this collagen fragment itself can activate neutrophils, which may lead in vivo to a self-propagating cycle of neutrophil infiltration, chronic inflammation and lung emphysema. MMP-, PE- or PGP-inhibitors can serve as an attractive therapeutic target and may open new avenues towards effective treatment of COPD.

Topics: Aged; Case-Control Studies; Cell Survival; Collagen; Collagen Type I; Female; Humans; Inflammation; Interleukin-8; Leukocytes, Mononuclear; Lung; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Middle Aged; Neutrophils; Oligopeptides; Proline; Prolyl Oligopeptidases; Pulmonary Disease, Chronic Obstructive; Serine Endopeptidases; Smoking; Tobacco Products

Nine anthocyanins (1-9) from the edible fruits of Eugenia brasiliensis were identified by HPLC-PDA and LC-MS, and seven of these are described for the first time in this Brazilian fruit. Two of the major anthocyanins, delphinidin (8) and cyanidin (9), were studied for their inhibitory activity against chemokine interleukin-8 (IL-8) production before and after cigarette smoke extract (CSE) treatment of cells. In non-treated cells the amount of IL-8 was unchanged following treatment with cyanidin and delphinidin in concentrations 0.1-10 μM. Both delphinidin (8) and cyanidin (9) decreased the production of IL-8 in treated cells, at 1 and 10 μM, respectively. Delphinidin (8) demonstrated IL-8 inhibition in the CSE treated cells in a dose-dependent manner.

Topics: Anthocyanins; Brazil; Cells, Cultured; Chromatography, High Pressure Liquid; Epithelial Cells; Eugenia; Fruit; Humans; Interleukin-8; Mass Spectrometry; Plant Extracts; Pulmonary Disease, Chronic Obstructive; Respiratory System; Smoke

Macrophages increase in number and are highly activated in chronic obstructive pulmonary disease (COPD). Muscarinic receptor antagonists inhibit acetylcholine-stimulated release of neutrophilic chemoattractants, suggesting that acetylcholine may regulate macrophage responses. Therefore, expression and function of components of the non-neuronal cholinergic system in monocyte-macrophage cells was investigated. RNA was isolated from monocytes, monocyte-derived macrophages (MDMs), lung and alveolar macrophages from nonsmokers, smokers and COPD patients, and expression of the high-affinity choline transporter, choline acetyltransferase, vesicular acetylcholine transporter and muscarinic receptors (M(1)-M(5)) ascertained using real-time PCR. M(2) and M(3) receptor expression was confirmed using immunocytochemistry. Release of interleukin (IL)-8, IL-6 and leukotriene (LT)B(4) were measured by ELISA or EIA. All monocyte-macrophage cells expressed mRNA for components of the non-neuronal cholinergic system. Lung macrophages expressed significantly more M(1) mRNA compared with monocytes, and both lung macrophages and alveolar macrophages expressed the highest levels of M(3) mRNA. Expression of M(2) and M(3) protein was confirmed in MDMs and lung macrophages. Carbachol stimulated release of LTB(4) from lung macrophages (buffer 222.3 ± 75.1 versus carbachol 1,118 ± 622.4 pg · mL(-1); n = 15, p<0.05) but not IL-6 or IL-8. LTB(4) release was attenuated by the M(3) antagonist, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP; half maximal effective concentration 5.2 ± 2.2 nM; n = 9). Stimulation of macrophage M(3) receptors promotes release of LTB(4), suggesting that anti-muscarinic agents may be anti-inflammatory.

Topics: Carbachol; Cells, Cultured; Choline O-Acetyltransferase; Humans; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Leukotriene B4; Macrophages; Membrane Transport Proteins; Muscarinic Agonists; Muscarinic Antagonists; Piperidines; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; RNA; Smoking; Vesicular Acetylcholine Transport Proteins

Dietary intake of polyunsaturated fatty acids, including omega-3 and omega-6, could modulate chronic obstructive pulmonary disease (COPD) persistent inflammation. We aimed to assess the relationship between dietary intake of omega-3 and omega-6 fatty acids and serum inflammatory markers in COPD. A total of 250 clinically stable COPD patients were included. Dietary data of the last 2 years were assessed using a validated food frequency questionnaire (122 items), which provided levels of three omega-3 fatty acids: docosahexaenoic acid, eicosapentaenoic acid and α-linolenic acid (ALA); and two omega-6 fatty acids: linoleic acid and arachidonic acid (AA). Inflammatory markers [C-reactive protein (CRP), interleukin (IL)-6, IL-8 and tumor necrosis factor alpha (TNFα)] were measured in serum. Fatty acids and inflammatory markers were dichotomised according to their median values, and their association was assessed using multivariate logistic regression. Higher intake of ALA (an anti-inflammatory omega-3 fatty acid) was associated with lower TNFα concentrations [adjusted odds ratio (OR)=0.46; P=.049]. Higher AA intake (a proinflammatory omega-6 fatty acid) was related to higher IL-6 (OR=1.96; P=.034) and CRP (OR=1.95; P=.039) concentrations. Therefore, this study provides the first evidence of an association between dietary intake of omega-3 and omega-6 fatty acids and serum inflammatory markers in COPD patients.

Topics: Aged; alpha-Linolenic Acid; Arachidonic Acid; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Dietary Fats; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Linoleic Acid; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Surveys and Questionnaires; Tumor Necrosis Factor-alpha

Angiogenesis is a prominent feature of structural tissue remodelling that occurs in chronic airway diseases, including chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the airway levels of VEGF, angiogenin, IL-8 and TNF-α in patients with COPD during the stable phase and during acute exacerbation of the disease. We analysed induced sputum samples from 28 patients with COPD. Thirteen of these patients were followed up and second samples of sputum were obtained during acute exacerbation of the disease. The two control groups consisted of 12 healthy smokers and seven healthy non-smokers, all with normal lung function tests. Concentrations of VEGF, angiogenin, IL-8, TNF-α and bFGF were measured by cytometric bead array. In the induced sputum of patients with stable COPD, concentrations of VEGF (P < 0.001, P = 0.02), angiogenin (P < 0.0001, P < 0.0001), IL-8 (P < 0.0001, P = 0.0021) and TNF-α (P < 0.001, P = 0.03) were significantly elevated in comparison with healthy smokers and non-smokers. No additional elevation of angiogenic factors was demonstrated at the time of exacerbation. There was a significant negative correlation between FEV1 and VEGF (P < 0.05, r = -0.38), angiogenin (P < 0.0001, r = -0.68) and IL-8 (P < 0.001, r = -0.54) among smokers (smoking COPD patients and healthy smokers). No significant differences were observed between groups of healthy smokers and non-smokers. These results showed increased airway angiogenesis in patients with COPD. Moreover, VEGF, IL-8 and angiogenin negatively correlated with pulmonary function, which suggests their important role in COPD airway remodelling. However, no additional angiogenic activation was found during exacerbation of COPD.

Topics: Adult; Aged; Female; Fibroblast Growth Factor 2; Flow Cytometry; Humans; Interleukin-8; Lung; Male; Middle Aged; Neovascularization, Pathologic; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Ribonuclease, Pancreatic; Sputum; Statistics, Nonparametric; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Young Adult

It has been known that high-mobility group box 1 (HMGB1) plays an important role in the pathogenesis of various inflammatory disorders in the lung. We attempted to determine the validity of measurement of HMGB1 levels in epithelial lining fluid (ELF) from patients with chronic obstructive pulmonary disease (COPD).. We measured HMGB1 levels in ELF separately obtained from central or peripheral airways using a bronchoscopic microsampling technique in 14 non-smokers, 13 smokers without COPD and 30 smokers with COPD. We also evaluated whether those levels were correlated with the indexes of pulmonary function and grade of low-attenuation area (LAA) on high-resolution computed tomographic scans.. HMGB1 levels in ELF from central airways did not significantly differ among the three groups. However, HMGB1 levels in peripheral airways were significantly higher in COPD patients than in non-smokers and smokers without COPD. Both the concentrations of interleukin-8 and human polymorphonuclear elastase in peripheral airways were also significantly higher in COPD patients. Moreover, those levels were significantly correlated with HMGB1 level. In addition, HMGB1 level in peripheral airways was closely correlated with the degree of airflow obstruction and grade of LAA in COPD patients.. HMGB1 levels in peripheral airways were elevated in smokers without COPD, as compared with non-smokers, and those levels were further augmented in COPD patients. Those levels were associated with the severity of COPD. Therefore, HMGB1 in peripheral airways may be a potentially interesting target for new pharmacological treatments in COPD patients.

Topics: Aged; Biomarkers; Bronchoalveolar Lavage Fluid; Bronchoscopy; Enzyme-Linked Immunosorbent Assay; Female; HMGB1 Protein; Humans; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Respiratory Function Tests; Respiratory Mucosa; Smoking; Statistics as Topic; Tomography, X-Ray Computed

Chronic Obstructive Pulmonary Disease (COPD) is a glucocorticoid resistant condition characterised by airway neutrophilia. Reduced glucocorticoid receptor (GR) expression in COPD airway neutrophils may be a mechanism that contributes to glucocorticoid resistance. Our objective was to investigate the expression and function of GR within COPD airway neutrophils. Dual-label immunofluorescence was used to analyse airway neutrophil expression of GR within peripheral lung tissue samples (11 COPD patients, 7 healthy non-smokers [NS]) and induced sputum (7 COPD patients, 7 NS). TNFα and CXCL8 release were measured in neutrophils isolated from induced sputum and peripheral blood (7 COPD patients) in the presence of dexamethasone. In lung tissue, GR was abundantly expressed in macrophages and lymphocytes, but very low expression was observed in neutrophils (means 6.8% and 4.3% in COPD patients and NS respectively). Similarly low expression was observed in sputum neutrophils (means 3.8% and 6.9% in COPD patients and NS respectively). In contrast, GR was expressed by 100% of blood neutrophils. Dexamethasone had less suppressive effect on TNFα and CXCL8 production in vitro by neutrophils from induced sputum compared to neutrophils from paired blood samples. Airway neutrophils have low expression of GR in both COPD patients and controls. The effects of glucocorticoids on cytokine production from airway neutrophils are reduced. Increased numbers of airway neutrophils lacking GR may contribute to glucocorticoid resistance in COPD patients.

Topics: Adult; Aged; Cells, Cultured; Dexamethasone; Glucocorticoids; Humans; Interleukin-8; Leukocyte Count; Lung; Macrophages, Alveolar; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Receptors, Glucocorticoid; Sputum; T-Lymphocytes; Tumor Necrosis Factor-alpha; Young Adult

Neutrophils and oxidative stress have been implicated in the pathogenesis of COPD. Severe, early-onset COPD is characterized by a rapid decline in the lung function at an early age; however, nothing is known about neutrophil activation in COPD patients.. The aim of this study was to evaluate peripheral blood neutrophil activation in severe, early-onset COPD patients versus healthy non-smokers and the effect of N-acetyl-L-cysteine (NAC) on neutrophil activation in vitro.. Neutrophils were isolated from 15 severe, early-onset COPD patients and 15 age-matched healthy subjects and stimulated with N-formyl-Met-Leu-Phe (fMLP) in the presence or absence of NAC (10 μM to 10 mM). Neutrophil chemotaxis, elastase release, reactive oxygen species (ROS), intracellular thiols and apoptosis were measured by Boyden chamber, spectrofluorometry, CMFDA and H2DCF-DA dyes and by annexin V-FITC, respectively.. Chemotaxis of peripheral blood neutrophils from COPD patients in response to fMLP was 30% more increased than that observed in healthy subjects. Elastase release in response to fMLP was 2-fold higher in neutrophils from COPD patients versus healthy subjects. Intracellular thiol levels were 30% lower in COPD and ROS was approximately 30% higher in COPD versus healthy neutrophils. Spontaneous apoptosis showed no differences in both groups of patients and fMLP-induced apoptosis was higher in COPD. Pre-treatment with the antioxidant NAC effectively attenuated neutrophil chemotaxis, elastase release and ROS as well as effectively increased thiol levels in COPD.. Neutrophils in severe, early-onset COPD patients are highly activated and this is alleviated by NAC in vitro.

Topics: Acetylcysteine; Apoptosis; Case-Control Studies; Chemotaxis; Female; Free Radical Scavengers; Humans; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophil Activation; Neutrophils; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Sulfhydryl Compounds

Chronic obstructive pulmonary disease (COPD) is characterized by loss of elastic fibres from small airways and alveolar walls, with the decrease in elastin increasing with disease severity. It is unclear why there is a lack of repair of elastic fibres. We have examined fibroblasts cultured from lung tissue from subjects with or without COPD to determine if the secretory profile explains lack of tissue repair. In this study, fibroblasts were cultured from lung parenchyma of patients with mild COPD [Global initiative for chronic Obstructive Lung Disease (GOLD) 1, n= 5], moderate to severe COPD (GOLD 2-3, n= 12) and controls (non-COPD, n= 5). Measurements were made of proliferation, senescence-associated β-galactosidase-1, mRNA expression of IL-6, IL-8, MMP-1, tropoelastin and versican, and protein levels for IL-6, IL-8, PGE(2,) tropoelastin, insoluble elastin, and versican. GOLD 2-3 fibroblasts proliferated more slowly (P < 0.01), had higher levels of senescence-associated β-galactosidase-1 (P < 0.001) than controls and showed significant increases in mRNA and/or protein for IL-6 (P < 0.05), IL-8 (P < 0.01), MMP-1 (P < 0.05), PGE(2) (P < 0.05), versican (P < 0.05) and tropoelastin (P < 0.05). mRNA expression and/or protein levels of tropoelastin (P < 0.01), versican (P < 0.05), IL-6 (P < 0.05) and IL-8 (P < 0.05) were negatively correlated with FEV1% of predicted. Insoluble elastin was not increased. In summary, fibroblasts from moderate to severe COPD subjects display a secretory phenotype with up-regulation of inflammatory molecules including the matrix proteoglycan versican, and increased soluble, but not insoluble, elastin. Versican inhibits assembly of tropoelastin into insoluble elastin and we conclude that the pro-inflammatory phenotype of COPD fibroblasts is not compatible with repair of elastic fibres.

Topics: Aged; beta-Galactosidase; Cell Proliferation; Female; Fibroblasts; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Male; Middle Aged; Phenotype; Pulmonary Disease, Chronic Obstructive; Real-Time Polymerase Chain Reaction; Tropoelastin; Up-Regulation; Versicans; Wound Healing

Chronic obstructive pulmonary disease (COPD) will soon be the third most common cause of death globally. Despite smoking cessation, neutrophilic mucosal inflammation persistently damages the airways and fails to protect from recurrent infections. This maladaptive and excess inflammation is also refractory to glucocorticosteroids (GC). Here, we identify serum amyloid A (SAA) as a candidate mediator of GC refractory inflammation in COPD. Extrahepatic SAA was detected locally in COPD bronchoalveolar lavage fluid, which correlated with IL-8 and neutrophil elastase, consistent with neutrophil recruitment and activation. Immunohistochemistry detected SAA was in close proximity to airway epithelium, and in vitro SAA triggered release of IL-8 and other proinflammatory mediators by airway epithelial cells in an ALX/FPR2 (formyl peptide receptor 2) receptor-dependent manner. Lipoxin A(4) (LXA(4)) can also interact with ALX/FPR2 receptors and lead to allosteric inhibition of SAA-initiated epithelial responses (pA(2) 13 nM). During acute exacerbation, peripheral blood SAA levels increased dramatically and were disproportionately increased relative to LXA(4). Human lung macrophages (CD68(+)) colocalized with SAA and GCs markedly increased SAA in vitro (THP-1, pEC(50) 43 nM). To determine its direct actions, SAA was administered into murine lung, leading to induction of CXC chemokine ligand 1/2 and a neutrophilic response that was inhibited by 15-epi-LXA(4) but not dexamethasone. Taken together, these findings identify SAA as a therapeutic target for inhibition and implicate SAA as a mediator of GC-resistant lung inflammation that can overwhelm organ protective signaling by lipoxins at ALX/FPR2 receptors.

Topics: Animals; Bronchoalveolar Lavage Fluid; Epithelial Cells; Epithelium; Glucocorticoids; Humans; Interleukin-8; Lipoxins; Lung; Macrophages; Mice; Mucous Membrane; Neutrophil Activation; Neutrophils; Pneumonia; Pulmonary Disease, Chronic Obstructive; Receptors, Formyl Peptide; Receptors, Lipoxin; Serum Amyloid A Protein

Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids, which has been linked to oxidative stress. Here we show that the long-acting β(2) -agonist formoterol (FM) reversed corticosteroid insensitivity under oxidative stress via inhibition of phosphoinositide-3-kinase (PI3K) signalling.. Responsiveness to corticosteroids dexamethasone (Dex), budesonide (Bud) and fluticasone propionate (FP) was determined, as IC(50) values on TNF-α-induced interleukin 8 release, in U937 monocytic cell line treated with hydrogen peroxide (H(2) O(2) ) or peripheral blood mononuclear cells (PBMCs) from patients with COPD or severe asthma.. PBMCs from severe asthma and COPD were less sensitive to Dex compared with those from healthy subjects. Both FM (10(-9)  M) and salmeterol (SM, 10(-8)  M) reversed Dex insensitivity in severe asthma, but only FM restored Dex sensitivity in COPD. Although H(2) O(2) exposure decreased steroid sensitivity in U937 cells, FM restored responsiveness to Bud and FP while the effects of SM were weaker. Additionally, FM, but not SM, partially inhibited H(2) O(2) -induced PI3Kδ-dependent (PKB) phosphorylation. H(2) O(2) decreased SM-induced cAMP production in U937 cells, but did not significantly affect the response to FM. The reduction of SM effects by H(2) O(2) was reversed by pretreatment with LY294002, a PI3K inhibitor, or IC87114, a PI3Kδ inhibitor.. FM reversed oxidative stress-induced corticosteroid insensitivity and decreased β(2) adrenoceptor-dependent cAMP production via inhibition of PI3Kδ signalling. FM will be more effective than SM, when combined with corticosteroids, for the treatment of respiratory diseases under conditions of high oxidative stress, such as in COPD.

Topics: 1-Phosphatidylinositol 4-Kinase; Adenine; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Albuterol; Androstadienes; Asthma; Budesonide; Chromones; Dexamethasone; Drug Resistance; Ethanolamines; Female; Fluticasone; Formoterol Fumarate; Humans; Hydrogen Peroxide; Interleukin-8; Leukocytes, Mononuclear; Male; Middle Aged; Morpholines; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Quinazolines; Receptors, Adrenergic, beta-2; Salmeterol Xinafoate; U937 Cells; Young Adult

25-Hydroxycholesterol (25-HC) is produced from cholesterol by the enzyme cholesterol 25-hydroxylase and is associated with atherosclerosis of vessels. Recently, 25-HC was reported to cause inflammation in various types of tissues. The aim of this study was to assess the production of 25-HC in the airways and to elucidate the role of 25-HC in neutrophil infiltration in the airways of patients with chronic obstructive pulmonary disease (COPD).. Eleven control never-smokers, six control ex-smokers without COPD and 13 COPD patients participated in the lung tissue study. The expression of cholesterol 25-hydroxylase in the lung was investigated. Twelve control subjects and 17 patients with COPD also participated in the sputum study. The concentrations of 25-HC in sputum were quantified by liquid chromatography/mass spectrometry/mass spectrometry analysis. To elucidate the role of 25-HC in neutrophilic inflammation of the airways, the correlation between 25-HC levels and neutrophil counts in sputum was investigated.. The expression of cholesterol 25-hydroxylase was significantly enhanced in lung tissue from COPD patients compared with that from control subjects. Cholesterol 25-hydroxylase was localized in alveolar macrophages and pneumocytes of COPD patients. The concentration of 25-HC in sputum was significantly increased in COPD patients and was inversely correlated with percent of predicted forced vital capacity, forced expiratory volume in 1 s and diffusing capacity of carbon monoxide. The concentrations of 25-HC in sputum were significantly correlated with sputum interleukin-8 levels and neutrophil counts.. 25-HC production was enhanced in the airways of COPD patients and may play a role in neutrophilic inflammation.

Topics: Aged; Alveolar Epithelial Cells; Female; Humans; Hydroxycholesterols; Interleukin-8; Leukocyte Count; Lung; Macrophages, Alveolar; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Smoking; Sputum; Steroid Hydroxylases

Chronic obstructive pulmonary disease (COPD) is characterized by the abnormal and chronic lung inflammation. We hypothesized that lung fibroblasts could contribute to the local inflammation and investigated whether low dose theophylline had a beneficial effect on fibroblasts inflammation. Subjects undergoing lobectomy for bronchial carcinoma were enrolled and divided into COPD and control groups according to spirometry. Primary human lung fibroblasts were cultured from peripheral lung tissue distant to tumor tissue. There was a significant increase in both the mRNA expressions and protein levels for IL-6 and IL-8 in fibroblasts in COPD group, and the values were negatively correlated with lung function (P < 0.05). For COPD fibroblasts, the protein levels of IL-6 and IL-8 decreased from 993.0 ± 738.9 pg/mL to 650.1 ± 421.9 pg/mL (P = 0.014) and from 703.1 ± 278.0 pg/mL to 492.0 ± 214.9 pg/mL (P = 0.001), respectively, with 5 μg/mL theophylline treatment. In addition, theophylline at the dose of 5 μg/mL reduced the increased production of IL-6 and IL-8 induced by 1 μg/mL LPS in primary human lung fibroblasts. Our data suggest that lung fibroblasts participate in the chronic inflammation in COPD by releasing IL-6 and IL-8, and low dose theophylline can alleviate the proinflammatory mediators' production by fibroblasts.

Topics: Aged; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Humans; Interleukin-6; Interleukin-8; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Real-Time Polymerase Chain Reaction; Theophylline

Cigarette smoke-induced release of pro-inflammatory cytokines including interleukin-8 (IL-8) from inflammatory as well as structural cells in the airways, including airway smooth muscle (ASM) cells, may contribute to the development of chronic obstructive pulmonary disease (COPD). Despite the wide use of pharmacological treatment aimed at increasing intracellular levels of the endogenous suppressor cyclic AMP (cAMP), little is known about its exact mechanism of action. We report here that next to the β(2)-agonist fenoterol, direct and specific activation of either exchange protein directly activated by cAMP (Epac) or protein kinase A (PKA) reduced cigarette smoke extract (CSE)-induced IL-8 mRNA expression and protein release by human ASM cells. CSE-induced IκBα-degradation and p65 nuclear translocation, processes that were primarily reversed by Epac activation. Further, CSE increased extracellular signal-regulated kinase (ERK) phosphorylation, which was selectively reduced by PKA activation. CSE decreased Epac1 expression, but did not affect Epac2 and PKA expression. Importantly, Epac1 expression was also reduced in lung tissue from COPD patients. In conclusion, Epac and PKA decrease CSE-induced IL-8 release by human ASM cells via inhibition of NF-κB and ERK, respectively, pointing at these cAMP effectors as potential targets for anti-inflammatory therapy in COPD. However, cigarette smoke exposure may reduce anti-inflammatory effects of cAMP elevating agents via down-regulation of Epac1.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents; Bronchi; Cell Nucleus; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Extracellular Signal-Regulated MAP Kinases; Female; Fenoterol; Gene Knockdown Techniques; Guanine Nucleotide Exchange Factors; Humans; I-kappa B Proteins; Interleukin-8; Male; Middle Aged; Myocytes, Smooth Muscle; NF-KappaB Inhibitor alpha; Phosphorylation; Protein Transport; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Smoking; Transcription Factor RelA

Chronic systemic inflammation is implicated in the systemic manifestations and, probably, the excess mortality risk of chronic obstructive pulmonary disease (COPD). The role of nuclear factor (NF)-κB repressing factor (NRF), a DNA-binding, protein-inhibiting NF-κB response gene, in human diseases has not been explored. We hypothesised that the NRF-negative regulatory mechanism is impaired in COPD peripheral blood mononuclear cells (PBMCs) leading to excessive interleukin (IL)-8/CXCL8 production. NRF expression, NF-κB activation, IL-8/CXCL8 release and intracellular oxidative stress were assessed in PBMCs of normal subjects and stable COPD patients. Primary PBMCs with NRF overexpression, NRF knockdown and exposure to H(2)O(2) were used to elucidate the mechanisms. Stable COPD patients, especially those with severe COPD, showed decreased NRF expression, enhanced NF-κB activation and increased IL-8/CXCL8 release in PBMCs compared with normal subjects. This was associated with reduced NRF and increased RNA polymerase II occupancy at the IL-8/CXCL8 promoter. NRF knockdown enhanced IL-8/CXCL8 production in normal PBMCs, whilst NRF overexpression attenuated IL-8/CXCL8 production. Intracellular oxidative stress was increased in COPD PBMCs. H(2)O(2)-decreased NRF expression and -enhanced IL-8/CXCL8 production was augmented in COPD PBMCs. NRF expression is reduced in PBMCs of stable COPD patients, probably through oxidative stress, leading to increased production of IL-8/CXCL8 and potentially chronic systemic inflammation.

Topics: Aged; Blotting, Western; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Interleukin-8; Leukocytes, Mononuclear; Male; Middle Aged; NF-kappa B; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Real-Time Polymerase Chain Reaction; Repressor Proteins; RNA Polymerase II; Transcriptome

The recovery of potentially pathogenic microorganisms (PPMs) from bronchial secretions is associated with a local inflammatory response in COPD patients. The objective of this study was to determine the relationships between bronchial colonisation and both bronchial and systemic inflammation in stable COPD. In COPD patients recruited on first admission for an exacerbation, bacterial sputum cultures, interleukin (IL)-1β, IL-6 and IL-8 levels, and blood C-reactive protein (CRP) were measured in stable condition. Bronchial colonisation was found in 39 of the 133 (29%) patients and was significantly related to higher sputum IL-1β (median [percentile 25-75]; 462 [121-993] vs. 154 [41-477] pg/ml, p = 0.002), IL-6 (147 [71-424] vs. 109 [50-197] pg/ml, p = 0.047) and IL-8 values (15 [9-19] vs. 8 [3-15] (×10³) pg/ml, p = 0.002). Patients with positive cultures also showed significantly elevated levels of serum CRP (6.5 [2.5-8.5] vs. 3.5 [1.7-5.4] mg/l, p = 0.016). Bronchial colonisation by Haemophilus influenzae was associated with higher levels of IL-1β and IL-8 and clinically significant worse scores on the activity and impact domains of the St. George's Respiratory Questionnaire. In conclusion, bronchial colonisation is associated with bronchial inflammation and high blood CRP levels in stable COPD patients, being Haemophilus influenzae related to a more severe inflammatory response and impairment in health-related quality of life.

Topics: Aged; Bronchi; C-Reactive Protein; Cross-Sectional Studies; Female; Haemophilus influenzae; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Interleukins; Male; Multivariate Analysis; Pulmonary Disease, Chronic Obstructive; Quality of Life; Spirometry; Sputum; Surveys and Questionnaires

Although chronic obstructive pulmonary disease (COPD) is amongst the leading causes of morbidity and mortality, no biomarkers for its early detection are known. We have recently demonstrated that COPD is accompanied by elevated serum heat shock protein (HSP) 27 levels as compared to a control population.. In an open prospective study, we investigated whether elevated HSP27 levels are associated with the early radiological signs of COPD, i.e., air trapping (AT), emphysema (E) and impaired lung function.. In total, 120 apparently healthy smokers underwent lung function testing and serum sampling. Serum levels of HSP27, phospho-HSP27, CXCR2 chemokines and proteins related to inflammation, tissue remodeling and apoptosis were evaluated by ELISA. Of these 120 subjects, 94 voluntarily underwent a high-resolution computed tomography scan.. AT or AT and E were detected in 57.45%. Subjects with AT and E (n = 23) showed significantly higher HSP27 levels than those without any pathology [i.e., nothing abnormal detected (NAD)] (4,618 +/- 1,677 vs. 3,282 +/- 1,607 pg/ml; p = 0.0081). In a univariate logistic regression model including NAD and AT and E, the area under the curve of HSP27 in the receiver-operating-characteristic curve was 0.724, (0.594–0.854, 95% CI; p = 0.0033). Interestingly, proinflammatory IL-8 was elevated in those subjects with evidence of AT and E compared to those with AT and NAD. Lung function did not correlate with increased HSP27 levels or pathological radiological findings.. HSP27 serum levels correlated with the early radiological signs of COPD, whereas lung function did not match with radiological findings or HSP27 serum levels. Serum HSP27 levels may serve as a potential marker to identify the early signs of COPD independent of lung function in young smokers.

Topics: Adult; Biomarkers; Early Diagnosis; Female; HSP27 Heat-Shock Proteins; Humans; Interleukin-8; Lung; Male; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; ROC Curve; Sensitivity and Specificity; Smoking; Tomography, X-Ray Computed

The number of airway neutrophils is increased in chronic obstructive pulmonary disease (COPD), and this may have a central pathophysiological role in the disease. In addition, activation of neutrophils increases their migration into sites of injury. We hypothesize that circulating neutrophils are activated in smokers.. Peripheral blood neutrophils were isolated from healthy non-smokers (n = 15), and smokers with (n = 15) or without COPD (n = 15), who were matched with regard to cumulative tobacco exposure, and chemotactic responses to N-formyl-methionyl-leucyl-phenylalanine (fMLP), interleukin-8 (IL-8, CXCL8) and leukotriene B(4) (LTB(4)) were assessed using the ChemoTx System (Neuro Probe Inc., Gaithersburg, MD, USA). Serum tumour necrosis factor-α (TNF-α) concentrations were measured by ELISA. Surface expression of the neutrophil activation marker, CD11b, was measured by flow cytometry.. The chemotactic response to CXCL8 was increased in smokers with or without COPD (P < 0.05). Migration towards LTB(4) was increased in smokers without COPD compared with non-smokers (P < 0.05), whereas there was no difference in fMLP-induced chemotaxis between the groups. There was a correlation between serum TNF-α levels and migration induced by IL-8 (Rho = 0.442; P = 0.038) and LTB(4) (Rho = 0.428; P = 0.044) in the smokers. Furthermore, there was a tendency towards higher CD11b expression in the COPD group (P = 0.057).. Chemotaxis of circulating neutrophils towards CXCL8, and partly towards LTB(4), is increased in smokers, indicating a systemic influence of smoking on cell activation, irrespective of the presence of airflow limitation. The relationship between TNF-α and chemotactic response suggests that TNF-α is involved in neutrophil activation, resulting in enhanced migration.

Topics: Aged; Case-Control Studies; Cell Movement; Chemotaxis, Leukocyte; Female; Humans; Interleukin-8; Leukotriene B4; Male; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pulmonary Disease, Chronic Obstructive; Smoking; Tumor Necrosis Factor-alpha

Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD). Recently, toll-like receptor 3 (TLR3) was shown to recognize pathogen-associated molecular patterns, especially viral-derived double-stranded RNA, and to be involved in immune responses. However, the effects of cigarette smoke on TLR3 remain unclear. In this study, it was examined whether cigarette smoke affects the expression and responses of TLR3 in human macrophages.. The expression of TLR3 in alveolar macrophages from human lung tissues was analysed by immunohistochemistry, and the correlation of TLR3 expression with smoking history and lung function was evaluated. In addition, the effect of cigarette smoke on the expression and responses of TLR3 in macrophage lineage cells was investigated.. TLR3-positive alveolar macrophage numbers were significantly increased in smokers and COPD patients compared with non-smoking control subjects, but there was no difference between smokers and COPD patients. TLR3-positive macrophage numbers were positively correlated with smoking history and inversely correlated with corrected carbon monoxide diffusing capacity, but were not correlated with % predicted forced expiratory volume in 1 s. Furthermore, cigarette smoke extract potentiated the expression of TLR3 in monocyte-derived macrophages and significantly augmented the release of interleukin-8, as well as total matrix metalloproteinase-9 activity, in cells treated with TLR3 ligand.. These data suggest that cigarette smoke augments the expression and responses of TLR3 in human macrophages, and this may contribute to neutrophilic airway inflammation and parenchymal destruction in the lungs of smokers and patients with COPD.

Topics: Aged; Cells, Cultured; Female; Humans; Interleukin-8; Lung; Macrophages, Alveolar; Male; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Smoking; Tobacco Smoke Pollution; Toll-Like Receptor 3

There is inherent daily variability of sputum inflammatory mediators in stable-state patients with usual chronic obstructive pulmonary disease (COPD). The variability of pulmonary inflammation in patients with α(1)-antitrypsin deficiency (A1ATD) is unknown. Our study aimed to quantify this variability, in comparison to patients with usual COPD, in order to facilitate power calculations for proof of concept trials of putative specific anti-inflammatory agents in both groups. Sputum interleukin (IL)-8, myeloperoxidase (MPO), leukotriene B(4) (LTB(4)) and differential cell counts were measured in 12 usual COPD patients and 12 A1ATD patients on nine occasions over a 1-month period. All samples were obtained in the stable clinical state. There was significant daily variability in all mediators in all patients. A1ATD patients had higher sputum concentrations of IL-8 and LTB(4) compared with usual COPD, but lower levels of MPO and absolute neutrophil counts. Patients with usual COPD had more intra-patient variability, A1ATD patients demonstrated greater inter-patient variability. There are increased concentrations of pulmonary inflammatory mediators but fewer sputum neutrophils in A1ATD compared with usual COPD. The daily variability of inflammatory mediators and cell counts was significantly reduced in both groups by averaging sequential samples. This can be utilised to perform power calculations for future proof of concept studies; averaging three sequential samples appears optimum.

Topics: Adult; Aged; alpha 1-Antitrypsin Deficiency; Cell Count; Female; Humans; Inflammation Mediators; Interleukin-8; Leukotriene B4; Male; Middle Aged; Peroxidase; Pulmonary Disease, Chronic Obstructive; Sputum

To examine changes in body weight and the lung inflammation factors interleukin-1beta (IL-1beta), interleukin-8 (IL-8), IL-10 and tumor necrosis factor-alpha (TNF-alpha) in a rat model of cold-dryness syndrome in Northwest (Xinjiang) China to provide a reference for treating chronic obstructive pulmonary disease (COPD) with local peculiarities.. The rat COPD model was established by intratracheal instillation of porcine pancreatic elastase (PPE) in combination with cigarette smoking (CS). The rat model of cold-dryness syndrome of COPD in the northwest of China was set up by intratracheal instillation of PPE in combination with CS and environmental cold-dryness stress. The level of IL-1beta, IL-8, IL-10 and TNF-alpha in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). The data were analyzed using the software SPSS 11.5.. (1) Body weight was less in the two model groups than that of control group (P < 0.01), PPE plus CS cold-dryness group was less than that of PPE plus CS group (P < 0.01). (2) IL-1beta in BALF significantly increased in PPE plus CS and cold-dryness group than that of control group (P < 0.01). (3) IL-8 and TNF-alpha in BALF significantly increased in PPE plus CS and cold-dryness group and PPE plus CS group than that of control group (P < 0.01).. Body weight in COPD model rats was reduced compared with controls. Cold-dryness may aggravate such a condition lung inflammation in the model was mainly manifested by an increase in IL-1beta, IL-8 and TNF-alpha levels, with no change in IL-10 levels. Cold-dryness may aggravate lung inflammation of COPD.

Topics: Animals; Body Weight; China; Cold Temperature; Interleukin-10; Interleukin-1beta; Interleukin-8; Male; Nicotiana; Pneumonia; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Smoke; Syndrome; Tumor Necrosis Factor-alpha

The relationship between serum biomarkers and clinical expressions of COPD is limited. We planned to further describe this association using markers of inflammation and injury and repair.. We studied lung function, comorbidities, exercise tolerance, BODE index, and quality of life in 253 COPD patients and recorded mortality over three years. Serum levels of Interleukins 6,8 and16, tumor necrosis factor alpha (TNF α) [inflammatory panel], vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) [injury and repair panel] and pulmonary and activation-regulated chemokine (PARC/CCL-18) and monocyte chemotactic protein 1 (MCP-1/CCL2) [chemoattractant panel] were measured. We related the pattern of the biomarker levels to minimal clinically important differences (MCID) using a novel visualization method [ObServed Clinical Association Results (OSCAR) plot].. Levels of the inflammatory markers IL-6, TNF α were higher and those of injury and repair lower (p < 0.01) with more advanced disease (GOLD 1 vs. 4). Using the OSCAR plot, we found that patients in the highest quartile of inflammatory and lowest quartile of injury and repair biomarkers level were more clinically compromised and had higher mortality (p < 0.05).. In COPD, serum biomarkers of inflammation and repair are distinctly associated with important clinical parameters and survival.

Topics: Aged; Biomarkers; Chemokine CCL2; Chemokines, CC; Cohort Studies; Cytokines; Exercise Tolerance; Female; Humans; Interleukin-16; Interleukin-6; Interleukin-8; Lung; Male; Matrix Metalloproteinase 9; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Severity of Illness Index; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease‑altering therapies currently exist. Airway remodeling is one of the most important mechanisms in the pathogenesis of COPD and is triggered by chronic inflammation mediated by angiopoietin-1 (Ang-1), interleukin-8 (IL-8) and transforming growth factor-β1 (TGF-β1). The aim of this study was to investigate the effects of Ang-1, IL-8 and TGF-β1 on the pathogenesis of COPD. Forty-two COPD patients and 10 healthy adults (group A) were included in this study. We divided the 42 patients into 4 groups (groups B-E) according to the severity of the disease. We investigated the levels of Ang-1, IL-8 and TGF-β1 and the levels of pulmonary function (PF) in the stable and acute phases of COPD by enzyme-linked immunosorbent assay. We found statistically significant differences in the expression levels of Ang-1, IL-8 and TGF-β1 between the stable and acute phases in groups B-E. We found statistically significant differences in the expression levels of Ang-1 among all groups in the stable phase. In addition, there were statistically significant differences in the expression levels of TGF-β1 among all groups. There were statistically significant differences in the expression levels of IL-8 between group A and the other groups in the stable phase. Furthermore, in groups C-E we found higher correlations between Ang-1 and the forced expiratory volume in one second of forced vital capacity (FVC) [FEV1(%)] and FEV1/FVC(%) than between TGF-β1 and FEV1(%) and FEV1/FVC(%). We conclude that the blood vessel factor is more closely related to the pathogenesis of COPD.

Topics: Acute Disease; Angiopoietin-1; Forced Expiratory Volume; Humans; Interleukin-8; Male; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Transforming Growth Factor beta1; Vital Capacity

To evaluate the influence and long-term effects on systemic and local inflammation responses in rat with stable chronic obstructive pulmonary disease (COPD) treated with traditional Chinese medicine (TCM) for regulating and invigorating the lung and kidney, including invigorating the lung and spleen (Bufei Jianpi) therapy, supplementing the lung and kidney (Bufei Yishen) therapy, and nourishing qi and kidney (Yiqi Zishen) therapy.. Rats were randomly divided into six groups: control, model, aminophyline, Bufei Jianpi, Bufei Yishen and Yiqi Zishen groups. The stable COPD model of rat was duplicated by cigarette smoke inhalations and bacterial infection. From the ninth week, the rats with stable COPD were treated with Bufei Jianpi, Bufei Yishen, Yiqi Zishen granules or aminophyline respectively until the 20th week. Half of the animals were sacrificed at the 20th or 32nd week respectively. The leukocyte count and neutrophil percentage in peripheral blood and bronchoalveolar lavage fluid (BALF) were measured; levels of interleukin (IL)-8, IL-10 and tumor necrosis factor-α (TNF-α) in BALF, and levels of IL-1β, IL-6, IL-8, IL-10 and TNF-α and soluble tumor necrosis factor receptor II (sTNFR2) in serum and lungs were detected by enzyme-linked immunosorbent assay or immunohistochemical method.. There were no statistical differences in leukocyte count and neutrophil percentage in peripheral blood among six groups (P>0.05). At the 20th week, leukocyte count in BALF was higher in the model group than in the control group (P<0.01), and was lower in the three TCM groups and the aminophyline group than in the model group (P<0.05, P<0.01), and that of the Bufei Jianpi group was lower than the aminophyline group (P<0.01); while at the 32nd week, leukocyte count in BALF of the three TCM groups decreased and was lower than that of the aminophyline group (P<0.05, P<0.01). At the 20th and 32nd weeks, levels of IL-1β, IL-6, IL-8, IL-10, TNF-α and sTNFR2 in serum and lungs, and IL-8, IL-10 and TNF-α in BALF of the model group increased, which were higher than those in the control group (P<0.05, P<0.01); the mentioned cytokines were decreased in the three TCM groups compared with the model group (P<0.05, P<0.01), and were also lower in serum and BALF of the three TCM groups than those of the aminophyline group (P<0.05, P<0.01). Expressions of cytokines in lung tissues were depressed in the three TCM groups as compared to those in the aminophyline group. There was no statistical difference on expressions of the mentioned cytokines either in serum and BALF or in the lungs between week 32 and week 20.. The Bufei Jianpi, Bufei Yishen and Yiqi Zishen therapies can significantly reduce the systemic and local inflammation responses in rats with stable COPD, and have evident long-term effects.

Topics: Animals; Bronchoalveolar Lavage Fluid; Drugs, Chinese Herbal; Female; Inflammation; Interleukin-1; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Lung; Male; Phytotherapy; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Previous research has shown that innate immune system was more important than the acquired immune system in the pathogenesis of COPD. LL-37 is the only human cathelicidin identified so far. As an integral part of the innate immune system, besides antibacterial activity, its chemotactic activity, damage repairing, influencing apoptosis and its cytotoxicity are attracting people's attention. The aim of the present study was to evaluate role of LL-37 in the pathogenesis of COPD.. ELISA and immunohistochemistry were applied to investigate the expression of LL-37 in induced sputum and lung tissue of COPD patients. Bronchial epithelial cell (BEP2D) and alveolar epithelial cell (A549) were treated with LL-37 synthesis polypeptide in vitro to assess the role of LL-37 in inflammation and apoptosis.. We found that increased induced sputum levels of LL-37 in COPD patients were associated with airflow limitation, health status and exercise tolerance and the expressing intensity of LL-37 in both airway district and pulmonary alveoli area in COPD group significantly increased compared with control group. Through stimulation by CSE and LPS, the expression of LL-37 was increased in bronchial epithelial cell and alveolar epithelial cell. LL-37 synthesis polypeptide can promote the releasing of inflammatory factor IL-8 and induce apoptosis of bronchial epithelial cell and alveolar epithelial cell.. This study suggested that LL-37 may play important role in the pathogenesis of COPD and may be a possible novel therapeutic target in COPD.

Topics: Antimicrobial Cationic Peptides; Apoptosis; Bronchi; Case-Control Studies; Cathelicidins; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Forced Expiratory Volume; Humans; Immunity, Innate; Immunohistochemistry; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Smoke; Sputum; Tobacco Products; Tumor Necrosis Factor-alpha; Vital Capacity

Naringin, a well-known flavanone glycoside of grapefruit and citrus fruits, was found to be as an effective anti-inflammatory compound in our previous lipopolysaccharide-induced acute lung injury mouse model via blockading activity of nuclear factor κB. The current study sought to explore the anti-inflammatory effects of naringin on chronic pulmonary neutrophilic inflammation in cigarette smoke (CS)-induced rats. Seventy Sprague-Dawley rats were randomly divided into seven groups to study the effects of CS with or without various concentrations of naringin or saline for 8 weeks. The results revealed that naringin supplementation at 20, 40, and 80 mg/kg significantly increased body weight of CS-induced rats as compared to that in the CS group. Moreover, naringin of 20, 40, and 80 mg/kg prevented CS-induced infiltration of neutrophils and activation of myeloperoxidase and matrix metalloproteinase-9, in parallel with suppression of the release of cytokines, such as tumor necrosis factor-α and interleukin-8 (IL-8). IL-10 in bronchoalveolar lavage fluid was significantly suppressed after CS exposure, but dose dependently elevated by naringin. The results from hematoxylin and eosin staining revealed that naringin dose dependently reduced CS-induced infiltration of inflammatory cells, thickening of the bronchial wall, and expansion of average alveolar airspace. In conclusion, our data suggest that naringin is an effective anti-inflammatory compound for attenuating chronic pulmonary neutrophilic inflammation in CS-induced rats.

Topics: Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Female; Flavanones; Interleukin-10; Interleukin-8; Male; Matrix Metalloproteinase 9; Neutrophils; Peroxidase; Pneumonia; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Smoking; Tumor Necrosis Factor-alpha

Human β-defensin 2 (hBD-2) has antimicrobial activity and may play a role in airway mucosal defense, but studies have not yet examined its expression in lung tissue of patients with chronic obstructive pulmonary disease (COPD). Here we investigated hBD-2 levels in lung tissues of COPD patients and analyzed their correlations with IL-8, IL-1β, cigarette smoking and lung function in order to see whether the protein may be involved in pathogenesis of the disease. Peripheral lung tissue specimens were obtained from 51 patients who underwent lung resection for peripheral lung cancer: healthy non-smokers (n=8), healthy current smokers (n=7), non-smokers with COPD (n=11), and current smokers with COPD (n=25). RT-PCR and immunohistochemical staining were used to detect expression levels of hBD-2, IL-8 and IL-1β. Expression of hBD-2 mRNA was significantly higher in COPD patients than in healthy controls, and significantly higher in current smokers than in non-smokers (p<0.05). Among healthy controls, hBD-2 mRNA levels were similar between current smokers and non-smokers. Immunohistochemistry showed hBD-2 protein to be expressed mainly in epithelia of distal bronchioles and its expression pattern among our patient groups mirrored that of the mRNA. IL-8 mRNA levels were significantly higher in COPD patients than in healthy controls (p<0.05), while IL-1β mRNA levels did not differ significantly among the groups. Levels of hBD-2 mRNA positively correlated with levels of IL-8 mRNA (r=0.545, p=0.002), and negatively correlated with FEV1/FVC ratios and with predicted FEV1% values (r=-0.406, p=0.011). Our results indicate that hBD-2 expression is elevated in distal airways of COPD patients and that it may be involved in pathogenesis of the disease. Our data implicate cigarette smoking as a factor that may elevate hBD-2 levels in lung tissues of COPD patients.

Topics: beta-Defensins; Humans; Immunohistochemistry; Interleukin-1beta; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Activation of Toll-like receptors (TLR) seems to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Upon TLR activation the release of defensins, including human beta defensin 2 (HBD-2), may occur. In this study, we explored the innate responses in patients with respiratory failure, with and without COPD, requiring intubation and mechanical ventilation. Mini-bronchoalveolar lavage (mini-BAL) samples were collected from nonsmoker subjects without COPD (n = 10), smokers without COPD (n = 6), and smokers with COPD (n = 15). TLR4, TLR2, and HBD-2 expression was evaluated by immunocytochemistry; interleukin (IL)-8, IP-10, and HBD-2 concentrations were evaluated by enzyme-linked immunosorbent assay; chemotactic activity toward neutrophils and lymphocytes; and cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL] and by flow cytometry with anti-TLR4 and with HBD-2 depleted and not depleted mini-BAL). COPD mini-BAL showed increased neutrophil numbers, reduced neutrophil apoptosis, increased TLR4 and HBD-2 expression, increased neutrophil chemotactic activity, reduced IP-10 concentrations, and reduced lymphocyte chemotactic activity compared with those in nonsmoker subjects without COPD. In the smokers without COPD the mini-BAL showed reduced TLR4 and HBD-2 expression, higher IP-10 concentrations, and higher chemotactic activity than in patients with COPD. The blocking of TLR4 activation and HBD-2 depletion increased neutrophil apoptosis. No differences were observed for TLR2 expression and IL-8 concentrations. This study strengthens the contribution of TLR4 to promoting airway neutrophilia in COPD.

Topics: Acute Disease; Aged; Aged, 80 and over; Apoptosis; beta-Defensins; Bronchoalveolar Lavage Fluid; Chemotaxis; Female; Humans; Interleukin-8; Leukocytosis; Male; Neutrophils; Pulmonary Disease, Chronic Obstructive; Respiratory Insufficiency; Smoking; Toll-Like Receptor 2; Toll-Like Receptor 4

There are increased neutrophils in the lungs of patients with chronic obstructive pulmonary disease (COPD), but it is unclear if this is due to increased inflammatory signal or related to the inherent behavior of the neutrophils. This is critical, because inaccurate or excessive neutrophil chemotaxis could drive pathological accumulation and tissue damage.. To assess migratory dynamics of neutrophils isolated from patients with COPD compared with healthy smoking and nonsmoking control subjects and patients with α(1)-antitryspin deficiency.. Migratory dynamics and structure were assessed in circulating neutrophils, using phase and differential interference contrast microscopy and time-lapse photography. The effect of COPD severity was studied. Surface expression of receptors was measured using flow cytometry. The in vitro effects of a phosphoinositide 3-kinase inhibitor (LY294002) were studied.. COPD neutrophils moved with greater speed than cells from either control group but with reduced migratory accuracy, in the presence of IL-8, growth-related oncogene α, formyl-methionyl-leucyl-phenylalanine, and sputum. This was present across all stages of COPD. Structurally, COPD neutrophils formed fewer pseudopods during migration. There were no differences in surface expression of the receptors CXCR1, CXCR2, or FPR1. LY294002 reduced COPD neutrophil migratory speed while increasing chemotactic accuracy, returning values to normal. The inhibitor did not have these effects in healthy control subjects or patients with a similar degree of lung disease.. COPD neutrophils are intrinsically different than cells from other studied populations in their chemotactic behavior and migratory structure. Differences are not due to surface expression of chemoattractant receptors but instead appear to be due to differences in cell signaling.

Topics: Adult; Aged; Chemokine CXCL1; Chemotaxis; Chromones; Female; Flow Cytometry; Humans; Interleukin-8; Lung; Male; Middle Aged; Morpholines; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Smoking; Sputum

Little is known about gender differences in plasma biomarker levels in patients with chronic obstructive pulmonary disease (COPD).. There are differences in serum biomarker levels between women and men with COPD.. Explore gender differences in plasma biomarker levels in patients with COPD and smokers without COPD.. We measured plasma levels of IL-6, IL-8, IL-16, MCP-1, MMP-9, PARC and VEGF in 80 smokers without COPD (40 males, 40 females) and 152 stable COPD patients (76 males, 76 females) with similar airflow obstruction. We determined anthropometrics, smoking history, lung function, exercise tolerance, body composition, BODE index, co-morbidities and quality of life. We then explored associations between plasma biomarkers levels and the clinical characteristics of the patients and also with the clinical and physiological variables known to predict outcome in COPD.. The plasma biomarkers level explored were similar in men and women without COPD. In contrast, in patients with COPD the median value in pg/mL of IL-6 (6.26 vs 8.0, p = 0.03), IL-16 (390 vs 321, p = 0.009) and VEGF (50 vs 87, p = 0.02) differed between women and men. Adjusted for smoking history, gender was independently associated with IL-16, PARC and VEGF levels. There were also gender differences in the associations between IL-6, IL-16 and VEGF and physiologic variables that predict outcomes.. In stable COPD patients with similar airflow obstruction, there are gender differences in plasma biomarker levels and in the association between biomarker levels and important clinical or physiological variables. Further studies should confirm our findings.

Topics: Biomarkers; Chemokine CCL2; Chemokines, CC; Cohort Studies; Female; Humans; Interleukin-16; Interleukin-6; Interleukin-8; Male; Matrix Metalloproteinase 9; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Sex Characteristics; Sex Factors; Smoking; Vascular Endothelial Growth Factor A

Corticosteroid insensitivity represents a major barrier to the treatment of chronic obstructive pulmonary disease (COPD) and severe asthma. It is caused by oxidative stress, leading to reduced histone deacetylase-2 (HDAC2) function through activation of phosphoinositide-3-kinase-δ (PI3Kδ). The tricyclic antidepressant nortriptyline has been identified in high-throughput screens as an agent that increases corticosteroid responsiveness. The aim of this study was to identify the molecular mechanism whereby nortriptyline increases corticosteroid sensitivity. Phosphorylation of Akt, a footprint of PI3K activation, and HDAC activity were evaluated by Western blotting and fluorescent activity assay in U937 monocytic cells. Corticosteroid sensitivity was evaluated by the inhibition of tumor necrosis factor α (TNFα)-induced interleukin 8 (IL-8) production by budesonide. Hydrogen peroxide (H(2)O(2)) or cigarette smoke extract (CSE) increased the level of phosphorylated Akt (pAkt) and reduced HDAC activity. Pretreatment with nortriptyline inhibited pAkt induced by CSE and H(2)O(2) as well as restored HDAC activity that had been decreased by H(2)O(2) and CSE. In addition, nortriptyline inhibited PI3Kδ activity, but had no effect on the PI3Kα and PI3Kγ isoforms. Although CSE reduced the effects of budesonide on TNFα-induced IL-8 production in U937 cells, nortriptyline reversed CSE-induced corticosteroid insensitivity. Nortriptyline restores corticosteroid sensitivity induced by oxidative stress via direct inhibition of PI3Kδ and is a potential treatment for corticosteroid-insensitive diseases such as COPD and severe asthma.

Topics: Adrenal Cortex Hormones; Adrenergic Uptake Inhibitors; Anti-Inflammatory Agents; Budesonide; Cells, Cultured; Chromones; Class I Phosphatidylinositol 3-Kinases; Drug Synergism; Enzyme Inhibitors; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Hydrogen Peroxide; Interleukin-8; Morpholines; Nortriptyline; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Smoking; Tumor Necrosis Factor-alpha; U937 Cells

Chronic obstructive pulmonary disease (COPD) is currently the fifth leading cause of death worldwide. Exposure to cigarette smoke (CS) is the primary factor associated with the COPD development. CS activates epithelial cells to secrete chemokines such as interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) that recruit neutrophils and macrophages to the lung. These inflammatory cells then release additional chemokines and cytokines leading to chronic inflammation that initiates apoptosis in epithelial and endothelial cells and destruction of alveolar structure. Pulmonary epithelium responds to oxidative stress mediated by CS through activating NRF2-dependent pathways, leading to an increased expression of antioxidant and cytoprotective enzymes thereby providing a protective response against CS-induced lung injury. We hypothesized that activating NRF2-dependent cytoprotective gene expression with sulforaphane (SFN) affords protection against CS-induced lung damage by inhibiting chemokine production. Results indicate that in the human BEAS-2B epithelial cell line, 5 μM SFN activated NRF2-dependent gene expression by triggering the translocation of NRF2 to the nucleus and significantly increased the expression of NRF2-dependent genes such as NADPH quinone oxidoreductase-1, heme oxygenase-1, and glutamate cysteine ligase modulatory subunit. Cigarette smoke extract (CSE) exposure of BEAS-2B cells significantly increased production of both IL-8 and MCP-1. Production of both chemokines was significantly reduced with SFN given prior to CSE; SFN inhibited IL-8 and MCP-1 gene expression at the transcription level. Our results indicate that activating NRF2 pathways with SFN inhibits CSE-induced chemokine production in human epithelial cells. However, the mechanism by which the production of chemokines is inhibited through SFN still remains to be elucidated. SFN may enhance NRF2 transcriptional activity resulting in the inhibition of proinflammatory pathways such as NF-κB.

Topics: Anticarcinogenic Agents; Cell Line; Chemokine CCL2; Epithelial Cells; Gene Expression Regulation; Glutamate-Cysteine Ligase; Heme Oxygenase-1; Humans; Interleukin-8; Isothiocyanates; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; NF-kappa B; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive; Smoke; Smoking; Sulfoxides; Thiocyanates

Through the consideration of decreased proliferation of lung fibroblasts from subjects with chronic obstructive pulmonary disease (COPD) and the proinflammatory role of lipopolysaccharide (LPS) in the COPD development, we hypothesized that LPS might inhibit proliferation in lung fibroblasts and the possible mechanism was investigated. Primary human lung fibroblasts were cultured from peripheral lung tissue and then treated with or without LPS. Proliferation was measured by AlamarBlue® assay. Levels of TNF-α, IL-6, IL-8, IL-12p70, IL-1β and IL-10 in the supernatants were measured by ELISA. The mRNA of histone deacetylases 2 (HDAC2) was analyzed using real-time PCR. LPS appeared to have a dose-dependent inhibitory effect on fibroblasts proliferation. The concentrations of IL-6 and IL-8 in the treatment culture media were significantly increased, accompanied by a reduced mRNA expression of HDAC2. IL-6 or IL-8 itself led to the reduction of fibroblasts proliferation. Treatment with 1 ng/ml TNF-α in fibroblasts also caused a significant decrease in proliferation and an increase in the production of IL-8 and IL-6. Our data suggest that LPS can inhibit the proliferation of in vitro human lung fibroblasts at least through a production of IL-6 and IL-8. The cytokine response is related to the decreased HDAC2 transcription.

Topics: Cell Proliferation; Fibroblasts; Gene Expression Regulation; Histone Deacetylase 2; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Macrophages; Pulmonary Disease, Chronic Obstructive; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha; U937 Cells

Airway inflammation in chronic obstructive pulmonary disease (COPD) is believed to be insensitive to corticosteroids. However, corticosteroids are recommended in COPD (GOLD stages III, IV) with frequent exacerbations. Resveratrol has anti-inflammatory properties and could be an alternative to corticosteroids in COPD therapy. We investigated the effect of dexamethasone versus resveratrol on the release of COPD-related inflammatory mediators (IL-6, IL-8, GM-CSF and MCP-1) and matrix-metalloprotease-9 (MMP-9) from alveolar macrophages exposed to gram-negative bacterial endotoxin (lipopolysaccharide, LPS). We compared never-smokers, current smokers without airway obstruction and current smokers with COPD. The cytokines and MMP-9 were measured in cell culture supernatants with ELISA. The release of IL-8 and MMP-9 from LPS-exposed alveolar macrophages was increased in COPD, the release of GM-CSF and IL-6 was decreased in COPD and the release of MCP-1 was without differences between the cohorts. Dexamethasone impaired the release of all cytokines and MMP-9 from LPS-exposed alveolar macrophages of all cohorts, but for IL-8 and GM-CSF this effect was reduced in COPD. In alveolar macrophages of COPD, there was an almost complete reduction in IL-6 release but only a partial reduction in IL-8, GM-CSF, MCP-1 and MMP-9 release demonstrating a partial corticosteroid-insensitivity. In contrast, resveratrol almost completely reduced the release of all cytokines and MMP-9 without significant differences between the cohorts. Our data provide evidence for a corticosteroid resistance of alveolar macrophage-dependent inflammatory responses induced by gram-negative bacteria in COPD and thus question the utility of corticosteroids in COPD therapy. Instead, resveratrol may prove an alternative.

Topics: Adrenal Cortex Hormones; Aged; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Macrophages, Alveolar; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Resveratrol; Stilbenes

Chronic obstructive pulmonary disease (COPD) is characterised by irreversible airflow obstruction, neutrophilic airway inflammation and chronic bacterial colonisation, however the role of the innate immune response in the pathogenesis of COPD remains unclear.. Induced sputum was obtained from adults with COPD (n=22), and healthy controls (n=29) and was processed for differential cell counts. The sputum supernatant was assayed for innate immune mediators using ELISA, whilst sputum gene expression was measured using real-time PCR. Peripheral blood neutrophils were isolated and their response to lipopolysaccaride (LPS) stimulation was assessed in a subgroup of participants with COPD (n=13) and healthy controls (n=21).. Participants with COPD had significantly higher protein levels of interleukin (IL)-8, and neutrophil elastase (NE) and detection of oncostatin M (OSM) compared to healthy controls. Gene expression for toll-like receptor (TLR) 2, IL-8 and OSM were also significantly higher in COPD participants. The level of IL-1β, surfactant protein (SP)-A, matrix metalloproteinase (MMP)-9 and TLR4 mRNA was not significantly different between groups. The level of innate immune response markers were highly associated with the presence of sputum neutrophils, each other and the degree of airflow limitation (FEV1/FVC). Peripheral blood neutrophils from participants with COPD had an increased response to stimulation by LPS; with a greater fold increase in the production of IL-8 and MMP-9 protein, and gene expression of IL-8, TLR2 and TLR4.. The innate immune response is increased in the airways and circulating neutrophils in COPD, and may be an important mechanism involved in disease pathogenesis.

Topics: Aged; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunity, Innate; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Toll-Like Receptor 2

Interleukin-8 (IL-8, CXCL8), chemokine produced by macrophages and epithelium cells, plays a major role in activating neutrophils and eosinophils in the airways of patients with COPD and might act as a stimulator of inflammatory process. The aim of the research was to assess whether pulmonary physiotherapy influences the concentration of IL-8 in the induced sputum of patients with COPD.. The study included 44 patients (21 males, 23 females, average age 56.47 ± 9.52) with COPD treated in Physiotherapy Department of MSWiA Hospital in Glucholazy, with unchanged pharmacological treatment for the duration of the therapy. Before treatment, efficiency treadmill test by Bruce modified protocol and dyspnea assessment with the modified 20-point Borg scale was given to qualify each patient for physiotherapy. All patients participated in a 3-week multi-treatment pulmonary physiotherapy programme based on efficiency training on a cycloergometer. The physical workload was determined individually for each patient based on the assessment of individual exercise tolerance. Standard physiotherapy programme also included respiratory muscles' training with particular emphasis on training of abdominal muscles and diaphragm, inhalations with isotonic saline, drainage, chest clapping, relaxations and walking. IL-8 concentration in each patient's induced sputum was collected prior to complex physiotherapy, and after it has been completed. IL-8 concentration was determined with the use of the ELISA test.. It was found that the concentration of IL-8 was significantly lower in patients with COPD after a 3-week physiotherapy programme. It fell from 18.91 ± 25.2 to 9.69 ± 14.06 ng/ml (p = 0.0215). The most significant IL-8 concentration decrease was observed in patients with the highest initial level of IL-8.. The study shows that multi-treatment pulmonary physiotherapy causes decrease of IL-8 level in the induced sputum in patients with COPD, what can suggest decrease activity of neutrophils, which may be one of the factors leading to the improvement in patients' clinical condition.

Topics: Female; Humans; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Sputum; Treatment Outcome

Nuclear factor-κB (NF-κB) is a transcriptional factor of different inflammatory patterns involved in asthma and chronic obstructive pulmonary disease (COPD) that is tightly controlled by IκB kinase (IKK) complex.. We investigated the dysregulation of IKK-driven NF-κB activation in patients with asthma and COPD.. We assessed IKKα and IKKβ expression and activation, their regulation by glucocorticosteroids, and their involvement in IL-8 synthesis in PBMCs isolated from asthmatic patients, healthy smokers (HSs), patients with COPD, and control subjects. PBMCs from control subjects were stimulated with TNF-α and cigarette smoke extract in the presence or absence of fluticasone propionate (FP), L-glutathione reduced, or both, and IKK activation and IL-8 release were evaluated.. IKKα activity was higher in patients with COPD and HSs than in asthmatic patients and control subjects. IKKβ activity was higher in asthmatic patients, HSs, and patients with COPD than in control subjects. In vitro FP treatment induced inhibition of both IKKα and IKKβ activity in PBMCs from asthmatic patients, patients with COPD, and HSs, although IKKβ activity was more sensitive to FP than that of IKKα. FP reduced the IL-8 released from PBMCs of asthmatic patients, patients with COPD, and HSs, although IL-8 inhibition was higher in asthmatic patients than in patients with COPD and HSs. FP reduced IKKα and IKKβ activities in TNF-α and cigarette smoke extract-treated PBMCs, with higher levels of inhibition for IKKβ than IKKα activity. L-glutathione reduced improved the downregulatory effects of FP on IKKα and IL-8 levels.. Based on differential activation of IKKα and IKKβ, our findings suggest a different profile in the upstream regulation of the IKK-driven NF-κB system in asthmatic patients and patients with COPD. These differences in the regulation of the inflammatory process may explain, at least in part, the different pharmacologic responses in these patients.

Topics: Adult; Asthma; Bronchodilator Agents; Enzyme Activation; Female; Gene Expression Regulation; Glucocorticoids; Humans; I-kappa B Kinase; Interleukin-8; Leukocytes, Mononuclear; Male; Middle Aged; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Smoking

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways and progressive destruction of lung parenchyma. Apoptosis is critical for the maintenance of normal tissue homeostasis and is in equilibrium with proliferation and differentiation. This study was undertaken to investigate relationship between apoptosis of peripheral blood lymphocytes during exacerbation of COPD and inflammatory response that characterizes this condition.. Seventeen patients with COPD exacerbation, 21 stable COPD, and 12 control subjects were included. T lymphocytes were isolated from peripheral blood using MACS. Apoptosis of T lymphocytes was assessed with FACS using annexin V and 7-aminoactinomycin. Serum levels of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α were determined by an immunoassay technique.. There was significantly increased percentage of apoptotic lymphocytes, CD 4+, and CD 8+ T cells in the peripheral blood of patients with exacerbation of COPD compared with stable COPD. Serum levels of IL-6, IL-8, and TNF-α were significantly increased in patients with exacerbation of COPD compared with stable COPD. Only TNF-α presented a positive correlation with apoptotic lymphocytes in patients with exacerbation of COPD.. Increased apoptotic lymphocytes may be associated with upregulation of TNF-α in the peripheral blood of patients with acute exacerbation of COPD.

Topics: Apoptosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Flow Cytometry; Humans; Interleukin-6; Interleukin-8; Pulmonary Disease, Chronic Obstructive; T-Lymphocytes; Tumor Necrosis Factor-alpha

The pivotal role of neutrophils and macrophages in smoking-related lung inflammation and COPD development is well-established. We aimed to assess whether sputum concentrations of Human Neutrophil Peptides (HNP), Neutrophil Elastase (NE), Interleukin-8 (IL-8), and Metalloproteinase-9 (MMP-9), major products of neutrophils and macrophages, could be used to trace airway inflammation and progression towards pulmonary functional impairment characteristic of COPD. Forty-two symptomatic smokers and 42 COPD patients underwent pulmonary function tests; sputum samples were collected at enrolment, and 6 months after smoking cessation. HNP, NE, IL-8, MMP-9 levels were increased in individuals with COPD (p < 0.0001). HNP and NE concentrations were higher in patients with severe airways obstruction, as compared to patients with mild-to-moderate COPD (p =0.002). A negative correlation was observed between FEV_{1} and HNP, NE and IL-8 levels (p < 0.01), between FEV_{1}/FVC and HNP, NE and IL-8 levels (p< 0.01), and between NE enrolment levels and FEV_{1} decline after 2 years (p =0.04). ROC analysis, to discriminate symptomatic smokers and COPD patients, showed the following AUCs: for HNP 0.92; for NE 0.81; for IL-8 0.89; for MMP-9 0.81; for HNP, IL-8 and MMP-9 considered together 0.981. The data suggest that the measurement of sputum markers may have an important role in clinical practice for monitoring COPD.

Topics: Adult; alpha-Defensins; Biomarkers; Female; Humans; Interleukin-8; Leukocyte Elastase; Male; Matrix Metalloproteinase 9; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Smoking; Smoking Cessation; Sputum

Recently, involvement of IL-17 in development of COPD has been noticed. Unlike IL-8, the role of IL-17 in COPD remains controversial. In order to further understand mechanisms in cigarette smoke (CS) induced COPD, we investigated IL-17 and IL-8 levels in different stages of COPD patients, and time courses of IL-17 and IL-8 release in CS induced COPD rats. A total of 73 elderly patients with COPD and 31 healthy volunteers were recruited in the study. IL-17 and IL-8 levels in the sputum and plasma were measured, and number of differential cells was counted. A newly developed CS induced rat COPD model was employed to study time courses of IL-17 and IL-8 release and nucleated cell accumulation. The results showed that IL-8 levels in the sputum of severe COPD patients were elevated by 16.5-fold, but IL-17 levels were reduced by 4.8-fold. While IL-8 correlated with neutrophils, IL-17 correlated with monocytes and lymphocytes. Similarly, level of IL-8 was increased, but IL-17 was decreased in the bronchoalveolar lavage fluid (BALF) of CS rats. Time course study showed that increased IL-8 production in the BALF initiated at 6 weeks, but decreased IL-17 production started at 10 weeks following CS exposure. In conclusion, increased IL-8 level in COPD patients appears mainly secreted from neutrophils and macrophages, whereas decreased IL-17 level seems resulted from reduced number of monocytes or damaged epithelial cells. Increased IL-8 (a proinflammatory cytokine) secretion and decreased IL-17 (a protective cytokine of airways) release can both contribute to development of COPD.

Topics: Aged; Aged, 80 and over; Animals; Blood Cell Count; Bronchoalveolar Lavage Fluid; Cell Nucleus; Humans; Inflammation; Interleukin-17; Interleukin-8; Lung; Macrophages; Male; Patient Admission; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Smoking; Sputum; Time Factors

Long-term cigarette smoking is associated with pulmonary inflammation, but the acute effects of smoking have been less well studied. Analysis of the exhaled breath condensate (EBC) can provide noninvasive markers that might be indicative of inflammation.. The aim of the study was to determine whether the pH , electrical conductivity and the levels of ammonium and interleukin 8 (IL-8) of EBC were altered in smokers and whether they changed after smoking a single cigarette.. We included 19 healthy nonsmokers (controls), 29 asymptomatic smokers, 10 patients with stable chronic obstructive pulmonary disease (COPD) [Global Initiative for Chronic Obstructive Lung Disease stages (GOLD) stages II-III], and 10 patients with exacerbated COPD. In 13 smokers, EBC was also analyzed before and after smoking. EBC was obtained during 10 min tidal breathing with a cooled RTube. pH was determined after deaeration with argon.. Acute smoking did not alter the pH or ammonium and IL-8 levels, but raised conductivity. As in COPD patients, the pH was significantly decreased in chronic smokers with a history of at least 10 pack-years compared to controls.. EBC can be used to detect the acute and chronic effects of smoking. The increased conductivity of EBC after smoking suggests acute inflammatory effects. The reduced pH in chronic smokers shows cigarette-induced inflammation.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Breath Tests; Case-Control Studies; Electric Conductivity; Female; Humans; Hydrogen-Ion Concentration; Inflammation; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quaternary Ammonium Compounds; Smoking; Young Adult

Chronic obstructive pulmonary disease (COPD) is a smoking related inflammatory airway disease in which macrophages play a key role. Previously we have shown that cigarette smoke extract (CSE) causes suppression of macrophage inflammatory mediators, with the exception of IL-8. We now investigate the effects of dexamethasone on these gene expression changes. Monocyte derived macrophages (MDMs) were cultured with CSE and dexamethasone. Microarray analysis was used to assess inflammatory mediator regulation, with qPCR and ELISA also performed for selected cytokines. The major effect of CSE was down-regulation of inflammatory genes (11 probe sets). For CSE regulated genes (n=13), the median fold change with CSE alone was -2.84 and with dexamethasone alone was -2.97. Both treatments combined caused the greatest suppression of gene expression; -4.47. qPCR also showed that IL-1beta, GM-CSF and IL-6 mRNA levels were significantly reduced by CSE and further suppressed by dexamethasone. qPCR and ELISA showed that IL-8 levels were increased by CSE, with suppression by dexamethasone. We show that CSE suppressed the expression of some inflammatory genes whilst up-regulating IL-8. Dexamethasone further suppressed gene expression when combined with CSE. The combined effect of GC and CSE causes suppression of the macrophage innate immune response.

Topics: Aged; Anti-Inflammatory Agents; Cells, Cultured; Cytokines; Dexamethasone; Gene Expression Profiling; Gene Expression Regulation; Humans; Immunity, Innate; Inflammation Mediators; Interleukin-8; Macrophages; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Pulmonary Disease, Chronic Obstructive; Smoking

Chronic obstructive pulmonary disease (COPD) is a major health problem and cigarette smoke is the main risk factor for the development of COPD. The characteristic changes in airway morphology, inflammatory cell infiltration and mediator expression in COPD may result from direct effects of cigarette smoke on airway cells. Toll-like receptors (TLRs) are key elements in pathogen recognition by the host immune system. Although TLRs have been intensely studied in innate immunity and infection, their critical role in noninfectious challenges has only recently emerged. Here we investigate whether cigarette smoke induces TLR9 signalling in human neutrophils. Human neutrophils were isolated from buffy coat and exposed to cigarette smoke extract. The production of CXC chemokine ligand (CXCL)8 was measured as a functional readout and the role of TLR9 signalling was investigated. Cigarette smoke extract induced CXCL8 release via TLR9 activation in neutrophils, which was confirmed in TLR9 stably transfected human embryonic kidney 293 cells. Moreover, cigarette smoke extract upregulated the expression of TLR9 and the upregulated expression was suppressed by N-acetylcysteine. TLR9 mediates cigarette smoke-induced release of CXCL8 and this may contribute to the accumulation of neutrophils and inflammation within the airways of smokers.

Topics: HEK293 Cells; Humans; Interleukin-8; Neutrophils; NF-kappa B; Nitric Oxide; Pneumonia; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Risk Factors; Signal Transduction; Smoking; Toll-Like Receptor 9; Transfection

Vasoactive intestinal peptide (VIP) is one of the most abundant molecules found in the respiratory tract. Due to its anti-inflammatory and bronchodilatatory properties, it has been proposed as a novel treatment for chronic obstructive pulmonary disease (COPD). The actions of VIP are mediated via three different G-protein-coupled receptors (VPAC1, VPAC2 and PAC1) which are expressed in the respiratory tract and on immunocompetent cells including macrophages. Alveolar macrophages (AM) are key players in the pathogenesis of COPD and contribute to the severity and progression of the disease. While VPAC1 has been reported to be elevated in subepithelial cells in smokers with chronic bronchitis, little is known about VPAC expression of AM in COPD patients. AM from COPD patients show a strong VPAC1 expression which exceeds VPAC2. A similar receptor expression pattern was also observed in lipopolysaccharide (LPS)-activated monocyte-derived macrophages (MDM) from healthy volunteers and COPD patients. VIP has been shown to down-regulate interleukin 8 (IL-8) secretion significantly in MDM after LPS stimulation. The response to VIP was similar in MDM from COPD patients and healthy volunteers. Our results indicate that VPAC1 up-regulation in macrophages is a common mechanism in response to acute and chronic pro-inflammatory stimuli. Although VPAC1 up-regulation is dominant, both receptor subtypes are necessary for optimal anti-inflammatory signaling. The high VPAC1 expression in AM may reflect the chronic pro-inflammatory environment found in the lung of COPD patients. Treatment with VIP may help to decrease the chronic inflammation in the lung of COPD patients.

Topics: Aged; Animals; Female; Humans; Inflammation; Interleukin-8; Lipopolysaccharides; Lung; Macrophages; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Signal Transduction

Adenosine is generated in response to cellular stress and damage and is elevated in the lungs of patients with chronic lung disease. Adenosine signaling through its cell surface receptors serves as an amplifier of chronic lung disorders, suggesting adenosine-based therapeutics may be beneficial in the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Previous studies in mouse models of chronic lung disease demonstrate that the key components of adenosine metabolism and signaling are altered. Changes include an up-regulation of CD73, the major enzyme of adenosine production and down-regulation of adenosine deaminase (ADA), the major enzyme for adenosine metabolism. In addition, adenosine receptors are elevated.. The focus of this study was to utilize tissues from patients with COPD or IPF to examine whether changes in purinergic metabolism and signaling occur in human disease. Results demonstrate that the levels of CD73 and A(2B)R are elevated in surgical lung biopsies from severe COPD and IPF patients. Immunolocalization assays revealed abundant expression of CD73 and the A(2B)R in alternatively activated macrophages in both COPD and IPF samples. In addition, mediators that are regulated by the A(2B)R, such as IL-6, IL-8 and osteopontin were elevated in these samples and activation of the A(2B)R on cells isolated from the airways of COPD and IPF patients was shown to directly induce the production of these mediators.. These findings suggest that components of adenosine metabolism and signaling are altered in a manner that promotes adenosine production and signaling in the lungs of patients with COPD and IPF, and provide proof of concept information that these disorders may benefit from adenosine-based therapeutics. Furthermore, this study provides the first evidence that A(2B)R signaling can promote the production of inflammatory and fibrotic mediators in patients with these disorders.

Topics: 5'-Nucleotidase; Adenosine; Adult; Aged; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Humans; Idiopathic Pulmonary Fibrosis; Interleukin-6; Interleukin-8; Lung; Macrophages, Alveolar; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Purinergic P1 Receptor Antagonists; Purines; Pyrazoles; Receptors, Purinergic P1; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transcription, Genetic

It has been reported that small airway inflammation is closely associated with the severity of airflow limitation in COPD (chronic obstructive pulmonary disease). We tested a new method of measurement of biochemical constituents in ELF (epithelial lining fluid) obtained separately from the central or peripheral airways using a bronchoscopic microsampling technique. The present study was designed to determine the validity of measuring CML [N(epsilon)-(carboxymethyl)lysine] levels in ELF for the assessment of small airway inflammation in COPD. Ten non-smokers, ten current smokers and 16 COPD patients were included in the present study. Concentrations of CML, 8-isoprostane and IL-8 (interleukin-8) were measured in ELF separately from the central or peripheral airways. CML levels in central airways did not differ significantly, but were markedly higher in peripheral than in central airways in the three groups. However, CML levels in peripheral airways of COPD patients were significantly higher than those in non-smokers and current smokers. In COPD patients, the CML level in peripheral airways was significantly correlated with FEV1 (forced expiratory volume in 1 s) (r=-0.82, P=0.002) and FEV1/FVC (forced vital capacity) (r=-0.57, P=0.03). Moreover, CML levels in peripheral airways were significantly correlated with levels of both 8-isoprostane (r=0.76, P=0.003) and IL-8 (r=0.67, P=0.01). In conclusion, these findings suggest that elevated levels of CML in ELF from peripheral airways were observed in COPD patients, and this parameter was correlated with the severity of airflow limitation.

Topics: Aged; Bronchioles; Bronchoscopy; Dinoprost; Forced Expiratory Volume; Humans; Interleukin-8; Lysine; Middle Aged; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Smoking; Specimen Handling; Vital Capacity

Chronic obstructive pulmonary disease (COPD) has a genetic component, explaining susceptibility. Tumor necrosis factor (TNF)-alpha polymorphisms have been associated with COPD, but it is unclear if genotype influences clinical phenotype, protein expression, and bioactivity.. To determine if a functional polymorphism was important by assessing TNF-alpha expression and activity and its association with clinical severity over time.. Patients with COPD with rs361525 polymorphism were matched to patients with COPD without rs361525 polymorphism. TNF-alpha, its antagonists, and downstream mediators were measured in plasma and sputum. To determine TNF-alpha bioactivity, IL-8 secretion from primary bronchial epithelial cells (PBECs) was measured, and neutrophil migration was assessed using sputum from both subject groups in the presence and absence of TNF-alpha antibody. Subjects were followed annually and compared.. Patients with polymorphism had more chronic bronchitis, a lower body mass index, and a greater annual decline in FEV(1) than patients with COPD without rs361525 polymorphism. TNF-alpha concentrations were 100-fold higher in airway secretions from the patients with the rs361525 polymorphism, with no difference in TNF-alpha antagonists. Their lung secretions contained more IL-8 and myeloperoxidase, consistent with downstream inflammation. Sputum from patients with rs361525 polymorphism induced greater secretion of IL-8 from PBECs and increased neutrophil migration. These effects could be abrogated by TNF-alpha antibody, demonstrating the bioactivity of TNF-alpha in lung secretions from this group.. This TNF-alpha polymorphism is associated with clinical features of disease including progression. There is clear evidence of TNF-alpha overexpression and bioactivity with neutrophilic inflammation. The polymorphism is likely to be a factor that influences a COPD disease phenotype and its progression.

Topics: Adult; Aged; Body Mass Index; Bronchi; Bronchitis; Case-Control Studies; Cell Movement; Disease Progression; Epithelial Cells; Female; Forced Expiratory Volume; Genotype; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Peroxidase; Phenotype; Polymorphism, Genetic; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Sputum; Tumor Necrosis Factor-alpha

Plasmacytoid dendritic cells (pDCs) are professional antigen-presenting cells with antiviral and tolerogenic capabilities. Viral infections and autoimmunity are proposed to be important mechanisms in the pathogenesis of chronic obstructive pulmonary disease (COPD). The study aimed to quantify blood dendritic cell antigen 2-positive pDCs in lungs of subjects with or without COPD by immunohistochemistry and flow cytometry, combined with the investigation of the influence of cigarette smoke extract (CSE) on the function of pDCs in vitro. pDCs were mainly located in lymphoid follicles, a finding compatible with their expression of lymphoid homing chemokine receptors CXCR3 and CXCR4. pDC accumulated in the lymphoid follicles and in lung digests of patients with mild to moderate COPD, compared with smokers without airflow limitation and patients with COPD Global Initiative for Chronic Obstructive Lung disease (GOLD) stage III-IV. Exposing maturing pDC of healthy subjects to CSE in vitro revealed an attenuation of the expression of co-stimulatory molecules and impaired interferon-α production. Maturing pDC from patients with COPD produced higher levels of tumour necrosis factor (TNF)-α and interleukin (IL)-8 compared to pDC from healthy subjects. CSE significantly impairs the antiviral function of pDCs. In COPD, a GOLD stage dependent accumulation of pDC in lymphoid follicles is present, combined with an enhanced production of TNF-α and IL-8 by maturing pDCs.

Topics: Aged; Case-Control Studies; Dendritic Cells; Female; Flow Cytometry; Humans; Immunohistochemistry; Inflammation; Interleukin-8; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Smoking; Tumor Necrosis Factor-alpha

To explore the mechanism of Wenfei Huayin Recipe (WHR) in treating chronic obstructive pulmonary diseases (COPD).. The COPD model was induced by modified fumigating method and intra-tracheal instillation of lipopolysaccharide. Then reformed COPD model of cold-phlegm retention in Fei syndrome type. All the model rats were randomly divided into two groups, the model group and the treated group, treated respectively with WHR and saline for 14 successive days. Besides, a blank group without any intervention was set up for control. The general condition, weight growth rate, pathological changes of lung tissue under light microscope, ultrastructure under electron microscope, arterial blood gas analysis and levels of interleukin 4 (IL-4), interleukin 8 (IL-8), tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) in lung homogenate by radio-immunity assay were observed.. In the treated group, as compared with the control group, the symptoms of aversion to cold, swarming, wheezing, the degree of epithelial cell degeneration and necrosis, the inflammatory cell infiltration and the volume of cilia lodging, sloughing, and bullae of lung were lessened and weight growth rate was higher (P<0.01). Moreover, the treated group was superior to the control group in decreasing levels of PaCO2, IL-4, IL-8, TNF-alpha and increasing PaO2, IFN-gamma and IFN-gamma/IL-4 ratio (P<0.01 or P<0.05).. WHR can correct the Th1/Th2 imbalance and inhibit the inflammatory reaction, displaying an important role in improving the airway function and structure in COPD rats.

Topics: Animals; Disease Models, Animal; Drugs, Chinese Herbal; Interferon-gamma; Interleukin-4; Interleukin-8; Lung; Male; Phytotherapy; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Copy number variations of the cluster of beta-defensin genes have been associated with psoriasis and inflammatory bowel disease. Controversy still exists on whether the beta-defensins genes determine susceptibility for chronic obstructive pulmonary disease (COPD).. We investigated whether genomic copy number variations of the beta-defensin gene cluster have a functional role in airway epithelial cells and associate with the presence of COPD.. Baseline and inflammatory induced transcript expression of DEFB4 was studied in nasal epithelial cell cultures and its effect on Pseudomonas aeruginosa inhibition was assessed. Subsequently, relevant functional cut-offs for copy numbers were used to explore associations with COPD in two independent case-control studies.. Copy number variation in the beta-defensin encoding genes correlated with baseline mRNA DEFB4 expression levels (R(2) = 0.96; P = 0.02), with a plateau effect from five copies or more. Only when higher copy numbers of beta-defensin genes were present, transcription was significantly up-regulated by tumor necrosis factor-alpha (P < 0.0001), which resulted in better antimicrobial activity in vitro. When comparing healthy smokers with COPD patients, a copy number greater than or equal to 5 was associated with increased risk for COPD with an adjusted odds ratio of 1.8 (confidence interval, 1.1-2.8; P = 0.02), which was confirmed by a second independent case-control study.. Genomic copy number variation of beta-defensin encoding genes has a functional role in airway epithelial cells, which may contribute to the pathogenesis of COPD.

Topics: Aged; beta-Defensins; Case-Control Studies; Cells, Cultured; Diploidy; Epithelial Cells; Female; Gene Dosage; Genetic Predisposition to Disease; Genetic Variation; Humans; Interleukin-8; Male; Middle Aged; Nasal Mucosa; Polymerase Chain Reaction; Pseudomonas aeruginosa; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; Up-Regulation

Topics: Airway Remodeling; Biomarkers; Forced Expiratory Volume; Humans; Interleukin-8; Phenotype; Pulmonary Disease, Chronic Obstructive; Smoking; Uteroglobin

Smoking associated COPD progression is likely to be directly linked to differential injury and repair dynamics in small airways (SA). Although IL8 is a well-accepted marker for injured airway epithelium, Clara cells [the predominant proliferating cells in SA] and SCGB1A1 protein [their major secretory product] have only recently emerged as potential SA repair markers. We therefore postulate that the SCGB1A1/IL8 ratio in the airways of smokers would be inversely associated with physiological, radiological and clinical measures of COPD. A cross-sectional cohort of 28 smokers undergoing surgery for peripheral nodule was recruited (24M/4F, age 61 +/- 11 y, FEV1s 76 +/- 20%, smoking 40 +/- 12 p.y). SCGB1A1 and IL8 were measured by ELISA in the induced sputum (IS) 3 to 5 days prior to surgery as well as by immunohistochemistry from lung tissue (also assessed morphometrically) obtained distant to the cancer surgery site. COPD was assessed using standard clinical, functional and radiological parameters. Log-transformed IS-SCGB1A1 was linearly correlated with SCGB1A1-positive epithelial cells detected via immunohistochemistry (r = .533, p = .001), while IS-IL8 was positively related to SA infiltrating neutrophils (Elastase-positive cells). There was a striking negative correlation between IS-SCGB1A1/IL8 levels and whole airway thickness [SA < 2 mm] at morphometry (r = -0.83, p < 0.0001). IS-SCGB1A1/IL8 levels were also inversely associated with nitrogen slope [r = -0.52, p < 0.001] and HRCT SA score [r = -0.51, p < 0.001]. In a multivariate analysis the IS-SCGB1A1/IL8 ratio was a stronger predictor than both the physiological and radiological measures of SA disease assessed. The SCGB1A1/IL8 ratio measured in sputum is a potentially valuable biomarker for non-invasive assessment of SA remodelling in smokers.

Topics: Aged; Airway Remodeling; Cohort Studies; Female; Humans; Interleukin-8; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Smoking; Sputum; Uteroglobin

Nontypeable Haemophilus influenzae (NTHI) may play a role as an infectious trigger in the pathogenesis of chronic obstructive pulmonary disease (COPD). Few data are available regarding the influence of acute and persistent infection on tissue remodelling and repair factors such as transforming growth factor (TGF)-beta.. NTHI infection in lung tissues obtained from COPD patients and controls was studied in vivo and using an in vitro model. Infection experiments were performed with two different clinical isolates. Detection of NTHI was done using in situ hybridization (ISH) in unstimulated and in in vitro infected lung tissue. For characterization of TGF-beta signaling molecules a transcriptome array was performed. Expression of the TGF-pseudoreceptor BMP and Activin Membrane-bound Inhibitor (BAMBI) was analyzed using immunohistochemistry (IHC), ISH and PCR. CXC chemokine ligand (CXCL)-8, tumor necrosis factor (TNF)-alpha and TGF-beta expression were evaluated in lung tissue and cell culture using ELISA.. In 38% of COPD patients infection with NTHI was detected in vivo in contrast to 0% of controls (p < 0.05). Transcriptome arrays showed no significant changes of TGF-beta receptors 1 and 2 and Smad-3 expression, whereas a strong expression of BAMBI with upregulation after in vitro infection of COPD lung tissue was demonstrated. BAMBI was expressed ubiquitously on alveolar macrophages (AM) and to a lesser degree on alveolar epithelial cells (AEC). Measurement of cytokine concentrations in lung tissue supernatants revealed a decreased expression of TGF-beta (p < 0.05) in combination with a strong proinflammatory response (p < 0.01).. We show for the first time the expression of the TGF pseudoreceptor BAMBI in the human lung, which is upregulated in response to NTHI infection in COPD lung tissue in vivo and in vitro. The combination of NTHI-mediated induction of proinflammatory cytokines and inhibition of TGF-beta expression may influence inflammation induced tissue remodeling.

Topics: Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Profiling; Haemophilus influenzae; Humans; Immunohistochemistry; In Situ Hybridization; Inflammation Mediators; Interleukin-8; Lung; Male; Membrane Proteins; Middle Aged; Polymerase Chain Reaction; Pulmonary Disease, Chronic Obstructive; Receptors, Transforming Growth Factor beta; Smad3 Protein; Tissue Culture Techniques; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To compare phlegm-heat syndrome with phlegm-dampness syndrome of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in regard to inflammatory response, hormone level, lung pathological examination and lung function.. Fifty-six Wistar rats were randomly divided into four groups, including normal control group, AECOPD group, phlegm-heat syndrome of AECOPD group (PHs group), phlegm-dampness syndrome of AECOPD group (PDs group). The level of white blood cell (WBC) count, neutrophil ratio, free triiodothyronine (FT(3)), free thyroxine (FT(4)), epinephrine (E), norepinephrine (NE), cortisol (COR), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) in blood, and TNF-alpha, IL-8, intercellular adhesion molecule-1 (ICAM-1) in broncho-alveolar lavage fluid (BALF) were determined with radioimmunology. Lung function was tested by whole-body plethysmography.. (1)The count of WBC and neutrophil ratio in PDs group were higher than in PHs group, AECOPD group and normal group, there was significant difference in multiple comparison. The levels of inflammatory mediators in serum and BALF in three model groups were evidently higher than in normal group, and IL-8 [(4.13+/-1.28) microg/L] and CRP [(3.07+/-0.69) microg/L ] in serum in PDs group were higher than those in PHs group [(1.75+/-0.53) microg/L, (1.98+/-0.42) microg/L, both P<0.01]. (2)FT(3) level in blood in both AECOPD group and PHs group [(9.44+/-3.17) pmol/L , (9.95+/-3.68) pmol/L] was significantly higher than that in normal control group [(4.53+/-2.80) pmol/L], FT(3) in PDs group [(2.13+/-1.31) pmol/L] was evidently lower than that in normal group (P<0.05 or P<0.01). The level of FT(4) [(2.23+/-0.71) pmol/L], E [(87.27+/-29.32) nmol/L] and NE [(71.69+/-21.24) nmol/L] in PDs group were all obviously lower than those in normal group [FT(4): (4.64+/-1.49) pmol/L, E: (143.94+/-32.90) nmol/L, NE: (100.32+/-27.73) nmol/L, P<0.05 or P<0.01]. There was no significant difference in the above three parameters between AECOPD group and normal group. Each parameter in PHs group was markedly higher than that in AECOPD group. The content of COR in PDs group was higher than in PHs group, in which COR was higher than in AECOPD group, which was equal to that in normal group. (3)The pathological changes in lung included inflammatory cell infiltration , exfoliation of cilia, dilatation of alveolar spaces of lung tissue in AECOPD group, which were more significant in PHs group and PD group. Inflammatory cells infiltration around the bronchi, thickening of interalveolar spaces, and vasodilatation were more pronounced in PHs group and PDs group than in AECOPD group. Inflammatory cell infiltration around the bronchi were about the same between PHs and PDs groups. (4)The levels of peak expiratory velocity (PEV), tidal volume (V(T)), minute ventilation (MV) were significantly lower in AECOPD group, PHs group and PDs group than in normal control group, but the levels of frequency (f) and inspiratory resistance (Rin) were evidently higher. Compared with AECOPD group, the levels of PEV, V(T), MV were significantly decreased, the level of respiratory f and Rin evidently increased in PDs group. Compared with PHs group, the levels of PEV, V(T), MV significantly decreased in PDs group, while the level of f and Rin evidently increased. There was no significant difference in the above fiv. The changes in local and systemic inflammatory response, lung histopathological injury in PHs group and PDs group were more evident than changes in AECOPD group. The changes in systemic inflammatory response, decrease in functional indicators of thyroid and adrenal medulla, and decline in lung function were more marked in PDs group than in PHs group.

Topics: Animals; C-Reactive Protein; Disease Models, Animal; Intercellular Adhesion Molecule-1; Interleukin-8; Lung; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

The percentage of neutrophils in sputum are increased in COPD patients, and may therefore be a biomarker of airway inflammation. We studied the relationships between sputum neutrophils and FEV1, health status, exacerbation rates, systemic inflammation and emphysema, and long term variability at 1 year.. Sputum samples were obtained from 488 COPD patients within the ECLIPSE cohort. 359 samples were obtained at baseline, and 297 after 1 year. 168 subjects provided samples at both visits. Serum interleukin-6 (IL-6), IL-8, surfactant protein D and C-reactive protein levels were measured by immunoassays. Low-dose CT scans evaluated emphysema.. Sputum neutrophil % increased with GOLD stage. There was a weak association between % sputum neutrophils and FEV1 % predicted (univariate r2 = 0.025 and 0.094 at baseline and year 1 respectively, p < 0.05 after multivariate regression). Similar weak but significant associations were observed between neutrophil % and health status measured using the St Georges Respiratory Questionairre. There were no associations between neutrophils and exacerbation rates or emphysema. Associations between sputum neutrophils and systemic biomarkers were non-significant or similarly weak. The mean change over 1 year in neutrophil % was an increase of 3.5%.. Sputum neutrophil measurements in COPD are associated weakly with FEV1 % predicted and health status. Sputum neutrophil measurements were dissociated from exacerbation rates, emphysema and systemic inflammation.

Topics: Aged; Biomarkers; C-Reactive Protein; Canada; Europe; Female; Forced Expiratory Volume; Humans; Immunoassay; Interleukin-6; Interleukin-8; Linear Models; Longitudinal Studies; Lymphocyte Count; Male; Middle Aged; Multivariate Analysis; Neutrophils; New Zealand; Prognosis; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Pulmonary Surfactant-Associated Protein D; Risk Assessment; Risk Factors; Severity of Illness Index; Sputum; Surveys and Questionnaires; Time Factors; Tomography, X-Ray Computed; United States

Chronic obstructive pulmonary disease (COPD) predisposes for the acquisition of community-acquired pneumonia (CAP).. To assess clinically and scientifically suggested disorders in innate immune response during acute phrase and resolution CAP (T2), we evaluated peripheral and pulmonary polymorphnuclear neutrophils (PMN), recovered by induced sputum, from CAP patients with and without COPD with regard to cell activation, interleukin-8 (CXCL-8) and CXCL-8 receptor expression, and apoptosis rate.. At T1, COPD patients displayed significantly lower pulmonary PMN apoptosis rates, while total cell count, the amount of macrophages, and vital and necrotic neutrophils in sputum samples were similar between study groups. At T2, there were no differences between study groups or between pulmonary and peripheral compartment. While under systemic steroid treatment apoptosis rates of peripheral and pulmonary PMN at T1 were slightly decreased, there were no significant differences in intrapulmonary CXCL-8 levels. Regarding cell activation, no significant differences could be seen, neither in comparing study groups nor in pulmonary to peripheral PMN.. Elucidating the pathology of suspected disorder in innate immune response, we found decreased apoptosis rates of pulmonary neutrophils in COPD at the peak of CAP indicating an increased inflammatory response, which is independent from anti-apoptotic cytokines such as CXCL-8, severity of disease and isolation of bacteria from sputum cultures.

Topics: Aged; Aged, 80 and over; Apoptosis; Case-Control Studies; Community-Acquired Infections; Female; Humans; Immunity, Innate; Interleukin-8; Male; Middle Aged; Neutrophils; Pneumonia, Bacterial; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8A; Sputum

The aim of study was to investigate a chemotactic effect of induced sputum and bronchoalveolar lavage fluid on blood neutrophils in patients with chronic obstructive pulmonary disease (COPD) and healthy individuals.. Forty-three smokers with COPD, 19 ex-smokers with COPD, 13 healthy smokers, and 17 healthy nonsmokers were recruited to the study. Neutrophils were isolated from peripheral blood of study individuals. For the same experimental conditions, pooled induced sputum and bronchoalveolar lavage fluid of 20 COPD patients were used. Neutrophil chemotaxis in vitro was performed in cell-transmigration chamber. Substances tested for chemoattraction (interleukin-8, induced sputum, bronchoalveolar lavage fluid directly or in addition to interleukin-8) were added to lower wells. Upper wells were filled with 2.5 x 10(6)/mL of neutrophil culture and incubated for 2 hours. Migration was analyzed by flow cytometry.. Interleukin-8 (10-100 ng/mL) induced a dose-dependant neutrophil migration in all the groups. Only 100 ng/L of interleukin-8 induced more intensive chemotaxis of neutrophils from COPD smokers as compared to ex-smokers (P<0.05). Such difference between healthy individuals was obtained using 30 ng/mL of interleukin-8 (P<0.05). Induced sputum/interleukin-8 (10-100 ng/mL), as well as induced sputum directly, induced neutrophil migration (P<0.05). Chemotaxis of neutrophils isolated from COPD patients and healthy nonsmokers did not depend on additional interleukin-8 concentration. Bronchoalveolar lavage fluid/interleukin-8 (30-100 ng/mL) induced more intensive migration of neutrophils from COPD patients than bronchoalveolar lavage fluid (P<0.05) alone.. Migration of neutrophils isolated from patients with COPD was more intensive compared to healthy individuals. Induced sputum and bronchoalveolar lavage fluid directly and with addition of interleukin-8 stimulated chemotaxis, and it was higher in neutrophils from COPD patients. Migration of neutrophils did not depend on smoking status.

Topics: Aged; Bronchoalveolar Lavage Fluid; Data Interpretation, Statistical; Female; Forced Expiratory Volume; Humans; Interleukin-8; Male; Middle Aged; Neutrophil Activation; Patient Selection; Pulmonary Disease, Chronic Obstructive; Smoking; Smoking Cessation; Spirometry; Sputum; Statistics, Nonparametric; Vital Capacity

The objective of this investigation was to verify the hypothesis that the presence of lower airway bacterial colonization (LABC) can be a stimulating factor of airway inflammation, more frequent exacerbation, and impact on pulmonary function, independent of current tobacco smoking in the stable phase of chronic obstructive pulmonary disease (COPD). A total of 46 ex-smokers with moderate to severe COPD, 19 healthy non-smokers, and 17 ex-smokers without COPD were included in this study. Their sputum specimens were collected at the first baseline visit and at the second visit after a follow-up of one year. The samples were analyzed for bacterial growth by culture, and the levels of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α) were measured by enzyme-linked immunosorbent assay (ELISA). The frequencies of exacerbations and pulmonary function were compared at visit 2. At visit 1, 37.0% (17/46) were found to have LABC with bacterial loads ≥10⁶ CFU/ml in their sputum specimens. Haemophilus influenzae was the predominant pathogenic organism isolated. IL-8, IL-6, and TNF-α in these patients' sputum were significantly higher than those without LABC (p < 0.05). It was the presence of LABC that contributed to the significantly elevated IL-8 and IL-6 at the 1-year period (p < 0.05). LABC was also associated with significantly increased frequencies of exacerbations and declined forced expiratory volume in 1 s (FEV₁) (p < 0.05). LABC was documented in a subpopulation of stable COPD patients; it may be responsible for the deterioration of pulmonary function of COPD patients by promoting airway inflammation and/or increased frequency of exacerbations independently of tobacco smoking.

Topics: Aged; Bacterial Load; Female; Haemophilus influenzae; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) therapy is complicated by corticosteroid resistance of the interleukin 8 (IL-8)-dependent and granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent chronic airway inflammation, for whose establishment human airway smooth muscle cells (HASMCs) might be crucial. It is unclear whether the release of inflammatory mediators from HASMCs is modulated by cigarette smoking and is refractory to corticosteroids in COPD. Resveratrol, an antiaging drug with protective effects against lung cancer, might be an alternative to corticosteroids in COPD therapy. Vascular endothelial growth factor (VEGF) might offer protection from developing emphysema. We tested the following hypotheses for HASMCs: 1) smoking with or without airway obstruction modulates IL-8, GM-CSF, and VEGF release; and 2) corticosteroids, but not resveratrol, fail to inhibit cytokine release in COPD. Cytokine release from HASMCs exposed to tumor necrosis factor α (TNFα), dexamethasone, and/or resveratrol was measured via enzyme-linked immunosorbent assay and compared between nonsmokers (NS), smokers without COPD (S), and smokers with COPD (all n = 10). In response to TNFα, IL-8 release was increased, but GM-CSF and VEGF release was decreased in S and COPD compared with NS. Dexamethasone and resveratrol inhibited concentration-dependently TNFα-induced IL-8, GM-CSF, and VEGF release. For IL-8 and GM-CSF efficiency of dexamethasone was NS > S > COPD. That of resveratrol was NS = S = COPD for IL-8 and NS = S < COPD for GM-CSF. For VEGF the efficiency of dexamethasone was NS = S = COPD, and that of resveratrol was NS = S > COPD. All resveratrol effects were partially based on p38 mitogen-activated protein kinase blockade. In conclusion, smoking modulates cytokine release from HASMCs. Corticosteroid refractoriness of HASMCs in COPD is cytokine-dependent. Resveratrol might be superior to corticosteroids in COPD therapy, because it more efficiently reduces the release of inflammatory mediators and has limited effects on VEGF in COPD.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Bronchi; Cells, Cultured; Cytokines; Dexamethasone; Female; Gene Expression; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Male; Middle Aged; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Respiratory System; Resveratrol; Smoking; Stilbenes; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Adiponectin is an anti-inflammatory adipokine that may play a role in chronic obstructive pulmonary disease (COPD) pathogenesis.. To investigate the relationship between adiponectin, interleukin (IL) 6, IL-8 and C-reactive protein (CRP) and COPD by evaluating these biomarkers in ever-smokers with or without the disease.. Plasma levels of adiponectin, IL-6, IL-8 and CRP were measured using commercially available kits in COPD patients (n = 71), healthy ever-smokers (n = 62) and non-smokers (n = 51).. There were significant increases in plasma adiponectin, IL-6 and CRP in COPD patients (median [IQR] 4.39 microg/ml [2.68-6.98], 4.19 pg/ml [<2.40-6.40], 8.75 mg/l [4.26-40.63], respectively) compared to healthy ever-smokers (1.90 microg/ml [0.86-2.86], <2.40 pg/ml [<2.40-2.77], 3.71 mg/l [1.97-10.37 mg/l], respectively, P < 0.001) and non-smokers (1.76 microg/ml [1.34-2.52], <2.40 pg/ml [<2.40-2.78], 3.12 mg/l [2.11-5.71], respectively, P < 0.001). COPD patients had lower plasma IL-8 levels than healthy ever-smokers. Among ever-smokers with or without COPD, plasma adiponectin, IL-6 and CRP levels were inversely correlated with forced expiratory volume in 1 second (% predicted) after adjustment for age, body mass index, smoking status and pack-years.. Our findings suggest that in COPD patients, adiponectin might be associated with COPD pathogenesis.

Topics: Adiponectin; Adult; Aged; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Databases, Factual; Forced Expiratory Volume; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Smoking

despite a number of important differences in the pathogenesis, course, and prognosis, asthma and chronic obstructive pulmonary disease (COPD) have many features in common. Furthermore, smoking induces considerable overlap in pathogenesis and clinical features between these conditions. This study aimed to reveal what inflammatory patterns prevail in clinically established diagnosis groups, including overlap phenotypes of asthma and COPD, and to evaluate the correlation with airway reversibility and hyperreactivity in these overlapping conditions.. a total of 110 patients (17 healthy subjects; 16 "healthy" smokers; 46 asthma patients: 24 smokers and 22 non-smokers; and 31 COPD patients: 10 COPD patients with reversibility and 21 without) participated in the study. Induced sputum, reversibility testing, methacholine and adenosine 5'monophosphate (AMP) provocation challenges, and skin prick testing were performed. Airways inflammation was assessed by differential cell counts, and cytokines (interleukin-8 [IL-8] and tumor necrosis factor-alpha [TNF-α]) were measured in induced sputum by enzyme-linked immunosorbent assay (ELISA).. COPD patients with reversibility had increased sputum neutrophils, IL-8, and TNF-α levels compared to smoking asthmatics. No difference was found in inflammatory cells and cytokines between COPD subgroups. Sputum neutrophilia was inversely correlated with the change in forced expiratory volume in one second (ΔFEV(1)) in smoking asthmatic patients (r = -0.563, P = 0.036). No correlation was found between airway hyperresponsiveness (AHR), either with methacholine or AMP, and inflammation in asthmatic patients, regardless of smoking. Reversibility was not correlated with inflammation in COPD patients. However, the response to AMP challenge was correlated with sputum neutrophils (r = 0.844, P = 0.001).. although overlaps exist in the disease characteristics of asthma and COPD, the combination of lung function testing, sputum induction, and AHR reveals information that facilitates the distinction between these diseases, allowing clinicians to better tailor their therapy.

Topics: Adult; Asthma; Bronchial Hyperreactivity; Cytokines; Diagnosis, Differential; Diagnostic Tests, Routine; Humans; Interleukin-8; Middle Aged; Phenotype; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Smoking; Spirometry; Sputum; Tumor Necrosis Factor-alpha

Smoking effects on physiological and gross pathology in chronic obstructive pulmonary disease (COPD) are relatively well described. However, there is little known in COPD about the detailed interrelationships between lung function and inflammatory profiles in different airway compartments from the same individual and whether airway inflammation in these different compartments differs in ex- and current smokers with established COPD.. We compared sputum, bronchoalveolar (BAL), and airway wall inflammatory profiles in current versus ex-smokers and related this to smoking intensity and lung function in 17 current and 17 ex-smokers with mild to moderate COPD.. Current smokers had more sputum mast cells (% differential and absolute numbers), whereas ex-smokers had increased sputum neutrophils. In BAL, there was a significant increase in eosinophils in current smokers, but ex-smokers had significantly increased neutrophils, lymphocytes, and epithelial cells. There were no cell profile differences observed in airway biopsies between current and ex-smokers and there were no correlations between the individual inflammatory cell populations in any of the airway compartments. In current smokers only, smoking intensity was negatively correlated with lung function, and associated with a reduction in overall cellularity of both sputum and BAL.. Airway inflammation persists in ex-smokers with COPD, but differs from COPD current smokers. The impact of smoking appears to vary in different airway compartments and any direct relationships between cellularity and lung function tended to be negative, ie, worse lung function indicated the presence of fewer cells.

Topics: Aged; Biopsy; Bronchi; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cross-Sectional Studies; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation Mediators; Interleukin-8; Lymphocytes; Male; Mast Cells; Maximal Midexpiratory Flow Rate; Middle Aged; Neutrophils; Pneumonia; Pulmonary Disease, Chronic Obstructive; Smoking; Smoking Cessation; Sputum; Tasmania; Vital Capacity

We screened bronchoalveolar lavage (BAL) fluids from COPD-E (chronic obstructive pulmonary disease-Emphysema) and control subjects using a 120 Ab cytokine array and demonstrated that adiponectin was highly expressed in BAL in COPD-E. An adiponectin ELISA confirmed that adiponectin was highly expressed in BAL in COPD-E compared with smokers and healthy control subjects. Immunohistochemistry studies of lung sections from subjects with COPD-E demonstrated that airway epithelial cells expressed significant levels of adiponectin and adiponectin receptor (AdipoR) 1 but not AdipoR2. In vitro studies with purified populations of human lung A549 epithelial cells demonstrated that they expressed both adiponectin and AdipoR1 (but not AdipoR2) as assessed by RT-PCR, Western blot, and immunohistochemistry. Lung A549 epithelial AdipoR1were functional as incubation with adiponectin induced release of IL-8, which was inhibited by small interfering RNA to AdipoR1. Using a mouse model of COPD, tobacco smoke exposure induced both evidence of COPD as well as increased levels of adiponectin in BAL fluid and increased adiponectin expression by airway epithelial cells. As adiponectin expression in adipocytes is dependent upon NF-kappaB we determined levels of adiponectin in tobacco smoke exposed CC10-Cre(tg)/Ikkbeta(Delta/Delta) mice (deficient in the ability to activate NF-kappaB in airway epithelium). These studies demonstrated that CC10-Cre(tg)/Ikkbeta(Delta/Delta) and wild-type mice had similar levels of BAL adiponectin and airway epithelial adiponectin immunostaining. Overall, these studies demonstrate the novel observation that adiponectin and functional AdipoR1are expressed by lung epithelial cells, suggesting a potential autocrine and/or paracrine pathway for adiponectin to activate epithelial cells in COPD-E.

Topics: Adiponectin; Animals; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Interleukin-8; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Receptors, Adiponectin; Respiratory Mucosa; Signal Transduction

Peroxynitrite (PN) formed by the reaction of nitric oxide and superoxide is a powerful oxidant/nitrosant. Nitrative stress is implicated in COPD pathogenesis, but PN has not been detected due to a short half-life (< 1 s) at physiologic condition. Instead, 3-nitrotyrosine has been measured as a footprint of PN release.. PN was measured using oxidation of 2',7'-dichlorofluorescein (DCDHF) in exhaled breath condensate (EBC) collected in high pH and sputum cells. The PN scavenging effect was also evaluated by the same system as PN-induced bovine serum albumin (BSA) nitration.. The mean (+/- SD) PN levels in EBC of COPD patients (7.9 +/- 3.0 nmol/L; n = 10) were significantly higher than those of healthy volunteers (2.0 +/- 1.1 nmol/L; p < 0.0001; n = 8) and smokers (2.8 +/- 0.9 nmol/L; p = 0.0017; n = 6). There was a good correlation between PN level and disease severity (FEV(1)) in COPD (p = 0.0016). Fudosteine (FDS), a unique mucolytic antioxidant, showed a stronger scavenging effect of PN than N-acetyl-cysteine on DCDHF oxidation in vitro and in sputum macrophages, and also on PN-induced BSA nitration. FDS (0.1 mmol/L) reduced PN-enhanced interleukin (IL)-1beta-induced IL-8 release and restored corticosteroid sensitivity defected by PN more potently than those induced by H(2)O(2) in A549 airway epithelial cells.. This noninvasive PN measurement in EBC may be useful for monitoring airway nitrative stress in COPD. Furthermore, FDS has the potential to inhibit PN-induced events in lung by its scavenging effect.

Topics: Adult; Aged; Breath Tests; Case-Control Studies; Cystine; Enzyme-Linked Immunosorbent Assay; Female; Half-Life; Humans; Inflammation Mediators; Interleukin-8; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Peroxynitrous Acid; Pilot Projects; Probability; Pulmonary Disease, Chronic Obstructive; Reference Values; Respiratory Function Tests; Sensitivity and Specificity; Severity of Illness Index; Sputum

It has been shown that interleukin (IL)-18 levels in induced sputum are reduced in asthmatic and healthy smokers. However, in chronic obstructive pulmonary disease (COPD) patients, recent data show an overproduction in the lungs and increased serum levels of IL-18, suggesting that IL-18 may be involved in the pathogenesis of COPD.. In order to assess the relation of IL-18 with pulmonary function and airway inflammation in COPD, IL-18, tumour necrosis factor-alpha, and IL-8 levels were measured by ELISA in sputum supernatants obtained from patients with bronchitis type COPD (n=28), and healthy subjects (18 smokers and 17 non-smokers). Cellular localization of IL-18 was assessed by immunocytochemistry.. The levels of IL-18 were significantly higher in sputum supernatants of COPD patients compared to healthy smokers and non-smokers (p<0.05). IL-18 production was localized to sputum macrophages. IL-18 levels were inversely correlated with FEV(1) (% predicted) (r=-0.572, p=0.002) and FEV(1)/FVC ratio in COPD smokers (r=-0.608, p=0.001). No correlations were found between IL-18 levels and inflammatory markers studied in induced sputum obtained from COPD patients, healthy smokers and non-smokers.. In patients with COPD, increased levels of IL-18 in induced sputum were associated with airflow limitation, suggesting that IL-18 may be implicated in the pathogenesis of COPD.

Topics: Biomarkers; Female; Humans; Immunohistochemistry; Interleukin-18; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum; Tumor Necrosis Factor-alpha

Topics: Cholesterol, LDL; Humans; Inflammation; Interleukin-8; Oxidative Stress; Oxygen; Oxygen Inhalation Therapy; Peroxidase; Pulmonary Disease, Chronic Obstructive; Transforming Growth Factor beta; Treatment Outcome

Markers of airway inflammation and oxidative stress have been mainly investigated in moderate/severe chronic obstructive pulmonary disease (COPD) or during its exacerbation. They have not been compared in noninvasive specimens such as exhaled breath condensate (EBC) and induced sputum in healthy nonsymptomatic smokers or in those who have symptoms and are at risk for COPD development.. To compare the relative proportions of 2 potential COPD biomarkers, 8-isoprostane and interleukin- 8 (IL-8) in the induced sputum and EBC sampled from the same subjects: nonsmokers (n = 14), healthy smokers (n = 17) and symptomatic smokers (n = 9) who are considered to be at risk for COPD. COPD patients with acute exacerbation (n = 10) were employed as positive controls.. The levels of the aforementioned biomarkers in induced sputum and EBC were investigated using commercial biochemical techniques.. In induced sputum, the levels of 8-isoprostane and IL-8 were at least 10-fold higher compared to EBC levels in all groups. Healthy nonsmokers had the lowest levels, and patients with exacerbation of COPD the highest levels of 8-isoprostane in induced sputum and EBC. The same observation held true for IL-8 in induced sputum. Inverse correlations with lung function parameters were observed for both mediators.. The levels of both potential markers were clearly higher in the induced sputum than in EBC. The results point to an advantage of induced sputum over EBC for assessing the degree of airway oxidative stress and inflammation in smokers with a potential risk for COPD development.

Topics: Adult; Aged; Biomarkers; Breath Tests; Dinoprost; Female; Humans; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Smoking; Sputum

Recently, we identified several flavonoids as inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 in vitro and in vivo. PARP-1 is recognized as coactivator of nuclear factor-kappaB and plays a role in the pathophysiology of diseases with low-grade systemic inflammation, such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D). In this study, we assessed the antiinflammatory effects of flavonoids with varying PARP-1-inhibiting effects in whole blood from male patients with COPD or T2D and healthy men. A total of 10 COPD, 10 T2D patients, and 10 healthy volunteers matched for age and BMI were recruited. Blood from each participant was exposed to 1 microg/L lipopolysaccharide (LPS) over 16 h with or without preincubation with 10 micromol/L of flavone, fisetin, morin, or tricetin. Concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, -8, and -10 were measured in the supernatant. Preincubation with fisetin and tricetin strongly attenuated LPS-induced increases in concentrations of TNFalpha in blood from COPD patients [mean (+/- SEM): -41 +/- 4% (fisetin) and -31 +/- 4% (tricetin); P < 0.001] and IL-6 in blood from T2D patients [-31 +/- 5% (fisetin) and -29 +/- 6% (tricetin); P < or = 0.001]. Moreover, LPS-induced changes in TNFalpha and IL-6 concentrations were positively correlated with the extent of reduction by fisetin and tricetin. The PARP-1-inhibiting flavonoids fisetin and tricetin were able to attenuate LPS-induced cytokine release from leukocytes of patients with chronic systemic inflammation, indicating a potential application as nutraceutical agents for these patient groups.

Topics: Aged; Chromones; Cytokines; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Flavonoids; Flavonols; Humans; Interleukin-1; Interleukin-10; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

The Gly80Ser polymorphism in phospholipase A2-IID (PLA2G2D, NCBI SNP reference: rs584367) is associated with a loss in body weight in patients with chronic obstructive pulmonary disease (COPD). The T allele missense mutation results in the 80th amino acid of the PLA2G2D protein changing from a glycine (Gly; C allele) to a serine (Ser; T allele). COPD patients carrying Ser lose a significant amount of weight compared with those carrying Gly. The mechanism for this weight loss following carriage of this Ser allele has not been clarified.. We aimed to evaluate whether this allelic change alters PLA2 enzymatic activity and/or pro-inflammatory cytokine inducibility.. A549 cells (a human pulmonary epithelial cell line) were transfected with PLA2G2D-Gly or PLA2G2D-Ser. We evaluated PLA2 activity and cytokine expressions in these cells.. The enzymatic activity of sPLA2 in A549-PLA2G2D-Ser cells did not differ from the A549-PLA2G2D-Gly cells. A549-PLA2G2D-Ser cells spontaneously produced higher levels of interleukin (IL)-6 and IL-8 than A549-PLA2G2D-Gly cells. Upon tumor necrosis factor-alpha stimulation, IL-6 and IL-8 mRNA and protein levels in A549-PLA2G2D-Ser cells were elevated compared with those of A549-PLA2G2D-Gly cells. Upon hydrogen peroxide stimulation, IL-8 mRNA and protein levels in A549-PLA2G2D-Ser cells were higher than those of A549-PLA2G2D-Gly cells.. PLA2G2D-Ser enhances the expression of IL-6 and IL-8 compared with PLA2G2D-Gly. This enhanced cytokine expression observed with the allelic change in PLA2G2D may be associated with the body weight loss seen in COPD patients.

Topics: Cell Line; Emaciation; Extracellular Signal-Regulated MAP Kinases; Group II Phospholipases A2; Humans; Interleukin-6; Interleukin-8; Mutation, Missense; p38 Mitogen-Activated Protein Kinases; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Several chronic respiratory diseases exhibit hyperactive immune responses in the lung: abundant inflammatory mediators; infiltrating neutrophils, macrophages, lymphocytes and other immune cells; and increased level of proteases. Such diseases include cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and severe/neutrophilic asthma. Paradoxically, patients with these diseases are also susceptible to detrimental bacterial infection and colonization. In this paper, we seek to explain how a positive feedback mechanism via IL-8 could lead to desensitization of epithelial cells to pathogen recognition thus perpetuating bacterial colonization and chronic disease states in the lung. Such insight was obtained from mathematical modeling of the IRAK/TRAF6 signaling module, and is consistent with existing clinical evidence. The potential implications for targeted treatment regimes for these persistent respiratory diseases are explored.

Topics: Asthma; Epithelial Cells; Humans; Interleukin-1 Receptor-Associated Kinases; Interleukin-8; Lung; Models, Biological; Pulmonary Disease, Chronic Obstructive; Respiration Disorders; Signal Transduction; TNF Receptor-Associated Factor 6

Assessment of airway inflammation in the clinical course of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) may advance our understanding of the pathogenesis and treatment.. To assess airway inflammation in patients during the course of AECOPD by serial analyses of their exhaled breath condensates (EBC).. Twenty-six patients with AECOPD (22 males, mean[SD] percentage predicted forced expiratory volume in one second (FEV(1)) 44.8 [14.3]), 11 with stable COPD, and 14 age and sex-matched healthy controls were studied. Patients with AECOPD were treated with systemic steroid and antibiotic for 7 days. EBC was collected from each patient with AECOPD on Day 5, 14, 30, and 60 post-hospitalization using EcoScreen (VIASYS Healthcare, USA) during tidal breathing over 10 minutes. Concentrations of tumor necrosis factor-alpha (TNF-alpha), leukotriene B4 (LTB4), and interleukin-8 (IL-8) were measured by enzyme-linked immunosorbent assay.. The median (IQR) of TNF-alpha level on Day 5 was 5.08 (3.80-6.32) pg/ml, which was lower than on Day 14 (5.84 [4.91-9.14] pg/ml, p = 0.017), Day 30 (6.14 [3.82-7.67] pg/ml, p = 0.045), and Day 60 (5.60 [4.53-8.80] pg/ml, p = 0.009). On Day 60, subjects receiving inhaled corticosteroid (ICS) had a lower level of TNF-alpha than those who were not (4.82 [4.06-5.65] vs 7.66 [5.48-10.9] pg/ml, p = 0.02). EBC LTB4 level did not change significantly during recovery from AECOPD whereas IL-8 was mostly undetectable.. EBC TNF-alpha level was low in patients receiving systemic steroid and antibiotic therapy for AECOPD. These findings suggest a potential role for serial EBC TNF-alpha for non-invasive monitoring of disease activity.

Topics: Adrenal Cortex Hormones; Aged; Aged, 80 and over; Anti-Bacterial Agents; Breath Tests; Case-Control Studies; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Exhalation; Female; Forced Expiratory Volume; Humans; Inflammation Mediators; Interleukin-8; Leukotriene B4; Lung; Male; Pulmonary Disease, Chronic Obstructive; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Acetylcholine is the primary parasympathetic neurotransmitter in the airways and is known to cause bronchoconstriction and mucus secretion. Recent findings suggest that acetylcholine also regulates aspects of remodelling and inflammation through its action on muscarinic receptors. In the present study, we aimed to determine the effects of muscarinic receptor stimulation on cytokine production by human airway smooth muscle cells (primary and immortalised cell lines). The muscarinic receptor agonists carbachol and methacholine both induced modest effects on basal interleukin (IL)-8 and -6 secretion, whereas the secretion of RANTES, eotaxin, vascular endothelial growth factor-A and monocyte chemoattractant protein-1 was not affected. Secretion of IL-8 and -6 was only observed in immortalised airway smooth muscle cells that express muscarinic M3 receptors. In these cells, methacholine also significantly augmented IL-8 secretion in combination with cigarette smoke extract in a synergistic manner, whereas synergistic effects on IL-6 secretion were not significant. Muscarinic M3 receptors were the primary subtype involved in augmenting cigarette smoke extract-induced IL-8 secretion, as only tiotropium bromide and muscarinic M3 receptor subtype selective antagonists abrogated the effects of methacholine. Collectively, these results indicate that muscarinic M3 receptor stimulation augments cigarette smoke extract-induced cytokine production by airway smooth muscle. This interaction could be of importance in patients with chronic obstructive pulmonary disease.

Topics: Acetylcholine; Bronchi; Cells, Cultured; Chemokine CCL5; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation; Interleukin-6; Interleukin-8; Methacholine Chloride; Myocytes, Smooth Muscle; Neurotransmitter Agents; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Smoking

Airway inflammation in COPD can be measured using biomarkers such as induced sputum and Fe(NO). This study set out to explore the heterogeneity of COPD using biomarkers of airway and systemic inflammation and pulmonary function by principal components analysis (PCA).. In 127 COPD patients (mean FEV1 61%), pulmonary function, Fe(NO), plasma CRP and TNF-alpha, sputum differential cell counts and sputum IL8 (pg/ml) were measured. Principal components analysis as well as multivariate analysis was performed.. PCA identified four main components (% variance): (1) sputum neutrophil cell count and supernatant IL8 and plasma TNF-alpha (20.2%), (2) Sputum eosinophils % and Fe(NO) (18.2%), (3) Bronchodilator reversibility, FEV1 and IC (15.1%) and (4) CRP (11.4%). These results were confirmed by linear regression multivariate analyses which showed strong associations between the variables within components 1 and 2.. COPD is a multi dimensional disease. Unrelated components of disease were identified, including neutrophilic airway inflammation which was associated with systemic inflammation, and sputum eosinophils which were related to increased Fe(NO). We confirm dissociation between airway inflammation and lung function in this cohort of patients.

Topics: Aged; Body Mass Index; C-Reactive Protein; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Multivariate Analysis; Phenotype; Pulmonary Disease, Chronic Obstructive; Smoking; Sputum; Tumor Necrosis Factor-alpha

It has been reported that alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD) display glucocorticoid (Gc) resistance. The Gc sensitivity of inflammatory mediators released by COPD macrophages may vary. The objective of this study was to identify Gc-insensitive inflammatory mediators produced by lipopolysaccharide (LPS)-stimulated alveolar macrophages from COPD patients. LPS-stimulated alveolar macrophages from 15 COPD patients, nine smokers (S) and nine healthy non-smokers (HNS) were stimulated with LPS with or without dexamethasone (100 and 1000 nM). Luminex and enzyme-linked immunosorbent assay were used to measure 23 inflammatory mediators. After LPS stimulation there were lower levels of inflammatory mediators in COPD patients and S compared to HNS. There was no difference between groups for the effects of dexamethasone at either concentration (P > 0.05 for all comparisons). Tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and growth-related oncogene (GRO)-alpha displayed the greatest sensitivity to dexamethasone in COPD patients, while IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) were the least sensitive. COPD macrophages have a reduced response to LPS. Gc sensitivity was similar in COPD macrophages compared to controls. We identify some Gc-insensitive cytokines, including GM-CSF, G-CSF and IL-8, that may be involved in the progression of airway inflammation in COPD patients.

Topics: Adaptor Proteins, Signal Transducing; Aged; Analysis of Variance; Bronchoalveolar Lavage Fluid; Cells, Cultured; Chemokine CXCL1; Cytokines; Dexamethasone; Dose-Response Relationship, Drug; Drug Resistance; Enzyme-Linked Immunosorbent Assay; Female; Glucocorticoids; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Macrophages, Alveolar; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Smoking; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

The BODE index, based on BMI, obstructive ventilatory impairment, dyspnoea scale and exercise capacity, has been used to evaluate the severity of patients with COPD. However, the correlations between serum biomarkers and the BODE index in patients with stable COPD are not widely studied. This study evaluated potential serum biomarkers for their ability to identify smokers with COPD and reflect disease severity.. A comparative study was conducted of 100 clinically stable COPD patients and 50 matched healthy smokers and the difference in levels of biomarkers between the COPD patients and healthy smokers was measured. Serum inflammatory mediators measured were growth-related oncogene-alpha (GRO-alpha), IL-8, tumour necrosis factor-alpha (TNF-alpha), matrix metalloproteinase-9 (MMP-9) and monocyte chemoattractant protein-1 (MCP-1). Variables included age, pack-years, current or ex-smoker status, inhaler or oral steroid use and BODE index components, including airflow obstruction, the distance walked in 6MWD, modified Medical Research Council (MMRC) dyspnoea scale and BMI. The association between serum biomarkers and the components of the BODE index was assessed in the COPD patients.. The level of serum MCP-1 was significantly different between the COPD group and the healthy smoker group (P = 0.003). Significant results in univariate and multivariate analysis of the association between biomarkers and BODE components were: serum MCP-1 correlated with FEV(1)% and 6MWD; serum IL-8 and GRO-alpha correlated with steroid use; serum TNF-alpha correlated with steroid use and FEV(1)%; and serum MMP-9 correlated with MMRC dyspnoea scale.. No single specific serum inflammatory mediator was completely correlated with BODE variable parameters in patients with stable COPD. Serum MCP-1 may be an important biomarker for identifying COPD subjects from healthy smokers and classifying COPD severity.

Topics: Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Case-Control Studies; Chemokine CCL2; Chemokine CXCL1; Dyspnea; Exercise Tolerance; Forced Expiratory Volume; Humans; Interleukin-8; Lung; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Smoking; Tumor Necrosis Factor-alpha

Sulfur mustard (SM) is a blistering chemical agent which has short and long term toxicity against many organs. The respiratory tract is one of the main targets, and is the most disabling long term complication of SM. Inflammatory mediators especially IL-8 and IL-6 play the primary role in the various chronic pulmonary diseases. Sardasht-Iran Cohort Study (SICS) was designed to evaluate immunological and molecular parameters in SM exposed people 20 years after exposure. In the present study, the association of the serum levels of IL-8, IL-6, C reactive protein (CRP) and rheumatoid factor (RF) with long term pulmonary involvement was evaluated. There were 348 exposed and 120 control participants. The clinical evaluations were done for all subjects and Spirometry was performed according to American Thoracic Society Criteria. Severity of pulmonary involvement was assessed by Global Initiative for chronic Obstructive Lung Disease (GOLD) classification. The serum levels of IL-8, IL-6 and RF were assessed by ELISA assay. CRP was assessed by photometric method. The serum levels of IL-8 and IL-6 significantly decreased in the SM exposed participants compared to the control group. There were no significant associations between the serum levels of IL-8 and pulmonary symptoms (chronic cough, sputum, hemoptysis, and dyspnea), pulmonary findings (crackles, rales, and wheezing) as well as spirometry parameters. IL-6 was associated with wheezing and CRP was associated with wheezing and rales in SM exposed group. We concluded the serum levels of these inflammatory mediators probably do not have any major role in pathogenesis and persistence of pulmonary complications and do not reflect the degree of severity of pulmonary involvement following SM exposure.

Topics: C-Reactive Protein; Chemical Warfare Agents; Cohort Studies; Cough; Dyspnea; Humans; Interleukin-6; Interleukin-8; Iran; Mustard Gas; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Respiratory Sounds; Rheumatoid Factor; Time Factors

To observe the airway inflammatory change in asthmatic rats complicated with chronic obstructive pulmonary disease (COPD) and to assess the intervention effects of Chinese herbs for reinforcing Shen and supplementing qi (CH) on it.. Eighty-four Norway rats were randomized into 7 groups, the normal control group (A), the COPD model group (B), the asthma model group (C), the combined COPD and the asthma model group (D), and the three CH treated groups (E, F and G, combined model rats administered by low-, moderate- and high- dose CH, respectively), 12 rats in each group. Changes of symptoms, pathologic changes of the lung tissue, airway reactivity, and serum levels of interleukin-4, interleukin-6, interleukin-8 (IL-4, IL-6, and IL-8) and interferon-gamma (IFN-gamma) in rats were observed.. Symptoms were alleviated in the three CH treated groups. Similar pathological features were shown in group B and D, showing inflammatory cell, mainly lymphocyte, infiltration in bronchial and lung tissues, with cilia denudation, partial alveolar wall rupture, alveolar cavity expansion, and accompanied with evident eosinophilic infiltration. These inflammatory exudation in group E-G was alleviated, while in group C, it developed showing a trend similar to that in group D. Airway resistance raised along with the concentration of Mch used. In group D, the serum level of IL-4 was higher than that in group B, and level of INF-gamma was lower than that in group A, B and C (all P <0.05). CH showed a lowering effect on serum levels of IL-4 and -8, and a dose-dependent rising effect on IFN-gamma.. IL- 4 significantly increased and INF-gamma decreased in rat model of combined COPD and asthma, its mechanism is similar to that of Th1/Th2 imbalance in asthma. Chinese herbs for reinforcing Shen and supplementing qi could improve the symptoms and inhibit the airway inflammation in the combined COPD and asthma model rats, its mechanism might be related with the alleviation of TH1/TH2 imbalance.

Topics: Animals; Asthma; Drugs, Chinese Herbal; Inflammation; Interferon-gamma; Interleukin-4; Interleukin-6; Interleukin-8; Male; Phytotherapy; Pulmonary Disease, Chronic Obstructive; Qi; Rats; Rats, Inbred BN

Moraxella catarrhalis causes approximately 10% of exacerbations in chronic obstructive pulmonary disease (COPD) and also colonizes the lower airway in stable patients. Little is known about the effects of colonization by M. catarrhalis on airway inflammation and protease-antiprotease balance, and how these changes compare to those seen during exacerbations. Since COPD is a progressive inflammatory disease, elucidating the effects of bacterial colonization and exacerbation on airway inflammation is relevant to understanding disease progression in COPD. Our aims were (1) Analyze changes in airway inflammation in colonization and exacerbation of COPD due to M. catarrhalis; (2) Explore protease-antiprotease balance in colonization and exacerbation due to M. catarrhalis. Our hypothesis were (1) Acquisition of a new strain of M. catarrhalis in COPD increases airway inflammation from baseline and alters the protease-antiprotease balance towards a more proteolytic environment; (2) These changes are greater during exacerbations associated with M. catarrhalis as compared to colonization.. Thirty-nine consecutive COPD patients with 76 acquisitions of a new strain of M. catarrhalis over a 6-year period were identified in a prospective study. Seventy-six pre-acquisition sputum supernatant samples, obtained just before acquisition of M catarrhalis, and 76 acquisition samples (34 were associated with exacerbation, 42 with colonization) were analyzed for IL-8, TNF-alpha, Neutrophil Elastase (NE) and Secretory leukocyte protease inhibitor (SLPI). Changes were compared in paired samples from each patient.. IL-8, TNF-alpha and NE were significantly elevated after acquisition of M. catarrhalis, compared to pre-acquisition samples (p =< 0.001 for all three). These changes were present in colonization (p = 0.015 for IL-8; p =< 0.001 for TNF-alpha and NE) as well as in exacerbation (p =< 0.001 for all three), compared to pre-acquisition levels. SLPI was significantly lower after acquisition (p =< 0.001), in colonization (p =< 0.001) as well as in exacerbation (p = 0.004), compared to pre-acquisition levels. SLPI levels correlated negatively with NE levels (R2 = 0.07; p = 0.001).. Acquisition of M. catarrhalis in COPD causes increased airway inflammation and worsening protease-antiprotease imbalance during exacerbations and also in colonization, even in the absence of increased symptoms. These effects could contribute to progression of airway disease in COPD.

Topics: Adult; Aged; Female; Humans; Inflammation; Interleukin-8; Leukocyte Elastase; Linear Models; Male; Middle Aged; Moraxella catarrhalis; Moraxellaceae Infections; Prospective Studies; Protease Inhibitors; Pulmonary Disease, Chronic Obstructive; Secretory Leukocyte Peptidase Inhibitor; Sputum; Tumor Necrosis Factor-alpha

To investigate the expression of interleukin (IL)-8 in lung tissues from patients with chronic obstructive pulmonary disease (COPD) and its association with stages of COPD.. The levels of mRNA and protein of IL-8 were measured with semi-quantitative polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) in patients with mild COPD (n=21), patients with advanced COPD (n=15), and controls (n=15). The correlations between IL-8 levels and stages of COPD, lung function (FEV1/ FVC%, FEV1% pred) and cigarette smoking were analyzed with Pearson correlation analysis.. The levels of IL-8 mRNA and protein in the lung tissues of COPD patients were significantly higher than those in the control group (P<0.05). The patients with advanced COPD had higher levels of IL-8 mRNA and protein than the patients with mild COPD (P<0.05). The COPD patients who smoked had higher levels of IL-8 mRNA and protein than those who did not smoke (P<0.05). But no significant differences in the levels of IL-8 mRNA and protein were found between smokers and and nonsmokers who did not have COPD (P>0.05). Increased expression of IL-8 in patients with COPD was positively correlated with stages of COPD (r=0.81, P<0.05); negatively correlated with lung function (FEV1/FVC%, FEV1% pred) (r=-0.62, -0.56, P<0.05), and positively correlated with volumes of cigarette smoking (r=0.53, P<0.05).. IL-8 is associated with stages of COPD, which may serve as an indication for clinical progress. Cigarette smoking increases IL-8 expression in the lung tissues of COPD patients.

Topics: Aged; Biomarkers; Female; Humans; Interleukin-8; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; Smoking

Myrtol standardized is established in the treatment of acute and chronic bronchitis and sinusitis. It increases mucociliar clearance and has muco-secretolytic effects. Additional anti-inflammatory and antioxidative properties have been confirmed for Myrtol standardized, eucalyptus oil, and orange oil in several in vitro studies.. The aim of this study was to prove the ability of essential oils to reduce cytokines release and reactive oxygen species (ROS) production derived from ex vivo cultured alveolar macrophages.. Alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD, n=26, GOLD III-IV) were pre-cultured with essential oils (10(3)-10(-8)%) for 1 h and then stimulated with LPS (1 microg/ml). After 4 h and 20 h respectively a) cellular reactive oxygen species (ROS) using 2',7'-dichlorofluorescein (DCF), and b) TNF-alpha, IL-8, and GM-CSF secretion were quantified.. In comparison with negative controls, pre-cultured Myrtol, eucalyptus oil and orange oil (10-4%) reduced in the LPS-activated alveolar macrophages ROS release significantly after 1+20 h as follows: Myrtol -17.7% (P=0.05), eucalyptus oil -21.8% (P<0.01) and orange oil -23.6% (P<0.01). Anti-oxidative efficacy was comparable to NAC (1 mmol/l). Essential oils also induced a TNF-alpha reduction: Myrtol (-37.3%, P<0.001), eucalyptus oil (-26.8%, P<0.01) and orange oil (-26.6%, P<0.01). TNF-a reduction at 1+4 h and 1+20 h did not vary (Myrtol: -31.9% and -37.3% respectively, P= 0.372) indicating that this effect occurs early and cannot be further stimulated. Myrtol reduced the release of GM-CSF by -35.7% and that of IL-8 only inconsiderably.. All essential oils tested have effective antioxidative properties in ex vivo cultured and LPS-stimulated alveolar macrophages. Additionally, Myrtol inhibited TNF-a and GM-CSF release best indicating additional potent anti-inflammatory activity.

Topics: Adult; Aged; Anti-Inflammatory Agents; Drug Combinations; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Macrophages, Alveolar; Male; Middle Aged; Monoterpenes; Oils, Volatile; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

The combination of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists is increasingly used in chronic obstructive pulmonary disease (COPD). Recently, we have demonstrated that combination of salmeterol and fluticasone propionate (FP) additionally suppress the production of IL-8 by human monocyte. In this study, the molecular mechanism behind the effectiveness of this combination therapy is investigated in human neutrophils. Human neutrophils were preincubated with salmeterol or FP or the combination. The amount of interleukin-8 (IL-8), elastase and matrix metalloproteinases (MMP)-2 and -9 releases, and reactive oxygen species (ROS) generation and expression of MAP kinase phosphatase (MKP-1) and glucocorticoid receptor (GR) were determined. Cigarette smoke medium (CSM) induces an increased expression of CXC receptors and the production of ROS that may explain the strong production of IL-8 by neutrophils. The expression of CXC receptors, the production of ROS, and the release of elastase and MMP-2 and -9 were not influenced by salmeterol, FP, or the combination. Interestingly, the combination therapy had an additive suppressive effect on the CSM-induced production of IL-8. The latter could be explained by an increased mRNA expression of MKP-1, the GR and an increased translocation of the GR to the nucleus. This leads eventually to suppression of both the NF-kappaB and MAPK pathways and, hence, to less IL-8 production by the neutrophil. These data are in support for the use of a combination therapy in COPD patients.

Topics: Adrenergic beta-Agonists; Albuterol; Androstadienes; Animals; Bronchodilator Agents; Dual Specificity Phosphatase 1; Fluticasone; Humans; Interleukin-8; Matrix Metalloproteinases; Mitogen-Activated Protein Kinases; Neutrophils; NF-kappa B; Nicotiana; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Receptors, Glucocorticoid; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Salmeterol Xinafoate; Signal Transduction; Smoke

To investigate the role of anaphylatoxin C5a in the pathogenesis of chronic obstructive pulmonary disease (COPD).. A total of 64 elderly patients with COPD (31 acute exacerbation of COPD, 34 stable COPD) and 15 healthy subjects were recruited into the study. Lung function, the levels of serum C5a and high sensitivity CRP (hs-CRP), and the levels of C5a, IL-8 and cell differentials in induced sputum were determined. For nonnormally distributed variables, differences between two groups were analysed using a Mann-Whitney u test, and comparison of three groups was performed using analysis of Kruskal-Wallis test. For normally distributed variables, differences between two groups were analyzed using unpaired t test, and comparison of three groups was performed using analysis of one-way ANOVA. Comparisons of the groups were performed using Chi-squared test for enumeration data. The association between variables was assessed by Spearman rank-order method.. The levels of serum C5a in acute exacerbation of COPD [215 (109 - 376) microg/L] were higher than those in stable COPD [91 (53 - 365) microg/L, z = -2.123, P < 0.05], and were positively correlated with the level of serum hs-CRP (r = 0.574, P < 0.05), and negatively correlated with FEV1% predicted (r = -0.562, P < 0.05). The levels of C5a in induced sputum in acute exacerbation of COPD [1.8 (1.0 - 3.2) microg/L] were significantly higher than those in stable COPD [0.9 (0.2 - 2.4) microg/L, z = - 2.079, P < 0.05] and were positively correlated with the level of IL-8 in induced sputum (r = 0.518, P < 0.05). The levels of C5a in induced sputum in stable COPD were significantly higher than those in healthy subjects [0.3 (0.1 - 0.7) microg/L, z = -2.044, P < 0.05]. The level of C5a in induced sputum was positively correlated with the number of total cells count (r = 0.441, P < 0.05), the percentage of neutrophils (r = 0.439, P < 0.05) and macrophages (r = 0.449, P < 0.05) in acute exacerbation of COPD.. Anaphylatoxin (C5a) may be involved in the pathogenesis of COPD.

Topics: Aged; Anaphylatoxins; C-Reactive Protein; Complement C5a; Female; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Sputum

To measure the levels of human alpha-defensin 1-3 (HNP1-3) in the serum and induced sputum in patients with chronic obstructive pulmonary disease (COPD) and therefore to investigate the possible roles of HNP1-3 in COPD.. Thirty patients with acute exacerbation of COPD, 21 patients with stable COPD, and 22 healthy subjects were recruited. The concentrations of HNP1-3 and interleukin-8 (IL-8) in serum and induced sputum were measured by enzyme-linked immunosorbent assay (ELISA). The correlations among HNP1-3, neutrophils, IL-8, and lung functions were investigated. The data were analyzed using a statistical software package (SPSS 11.5). Variables were compared with One-Way ANOVA or Chi-square test. The correlations between variables were analyzed using Pearson's correlation coefficient or Spearman correlation coefficient.. The sputum HNP1-3 level was significantly higher in AECOPD patients [9,652(4,272 -12,576) ng/L] than in healthy subjects [4,194 (700 -10,505) ng/L, chi2 =7.53, P <0.01] and in stable COPD patients [7,011(6,658 -7,319) ng/L, chi2 = 10.24, P <0.01]. There was significant difference among the three groups (chi2 =7.31, P <0.05). There was no significant difference in the serum HNP1-3 level among the three groups: AECOPD group [51(39 - 173) ng/L], stable COPD group [135(113 - 241) ng/L], healthy subjects group [130(13 - 160) ng/ L], chi2 = 5.75, P > 0.05. The sputum HNP1-3 level was positively correlated with the number, percentage of sputum neutrophils, and sputum IL-8 level (r = 0.29 to 0.53, respectively P <0.01). The sputum HNP1-3 level was negatively correlated with FEV1/predicted values, FEV1/FVC, and PaO2 (r= -0.33 to -0.44, respectively P <0.01).. HNP1-3 may be involved in the pathogenesis of airway inflammation in COPD. Sputum HNP1-3 may be a noninvasive marker of severity of COPD.

Topics: Aged; alpha-Defensins; Case-Control Studies; Female; Humans; Interleukin-8; Leukocyte Count; Pulmonary Disease, Chronic Obstructive; Smoking; Sputum

Although the clinical pictures of asthma and chronic obstructive pulmonary disease (COPD) may be similar, the pathogenesis differs in many aspects. The aim of the present study was to compare the cellular and biochemical features of airway inflammation in patients with asthma and COPD. The study was conducted in 22 patients with asthma (M/F 12/10, mean age 36 +/-14 years) and 17 patients with COPD (M/F 10/7, mean age 57 +/-11 years). Each patient underwent sputum induction followed by bronchoscopy, and bronchoalveolar lavage. Total and differential cell counts and the concentration of interleukin-8 (IL-8) and myeloperoxidase (MPO) were measured in induced sputum (IS) and BALF. We found no significant differences in the total and differential cell counts in IS between asthma and COPD patients. However, COPD patients showed an increased total macrophage count in BALF compared with asthma patients. The relative eosinophil count in BALF was significantly higher in patients with asthma vs. COPD. The concentration of IL-8 in IS and BALF was significantly higher in patients with COPD vs. asthma patients. The BALF concentration of MPO was significantly higher in patients with COPD compared with asthma patients. We conclude that the comparison of cellular composition and the concentration of inflammatory mediators in IS does not differentiate between asthma and COPD. The evaluation of BALF reveals more differences in the cellular and biochemical features of airways inflammation in patients with asthma and COPD than that of IS.

Topics: Adult; Aged; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Bronchoscopy; Female; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Peroxidase; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum

Inflammation is an important constituent of the pathology of chronic obstructive pulmonary disease (COPD), leading to alveolar destruction and airway remodelling.. The aim of this study was to assess the difference in plasma biomarkers of inflammation between asymptomatic smokers and patients with COPD.. We used commercially available enzyme-linked immunosorbent assay kits to measure the plasma levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9), monocyte chemotactic protein-1 (MCP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and tissue inhibitor of metalloproteinase-2 (TIMP-2) on two occasions with a 2-week interval in patients with COPD (n = 20), asymptomatic smokers (n = 10) and healthy lifelong non-smokers (n = 10). The participants were characterised clinically, physiologically and by quantitative computed tomography by measuring the relative area of emphysema below -910 Hounsfield units (RA-910).. The results of the biomarker measurements on the two occasions were highly reproducible. Patients with COPD had significantly higher plasma levels of IL-8 (P = 0.004) and significantly lower levels of TIMP-1 (P = 0.02) than smokers and non-smokers. There was no statistically significant difference between the three groups in the level of TNF-alpha, MMP-9, MCP-1 and TIMP-2. The IL-8/TIMP-1 ratio correlated significantly with the degree of airway obstruction measured as forced expiratory volume in 1 second (FEV(1)) % predicted (r = -0.47, P < 0.01); with the diffusion capacity (r = -0.41, P < 0.01); and with the grade of emphysema measured as RA-910 (r = 0.39, P = 0.01).. These findings suggest that the measurement of plasma biomarkers, such as IL-8/TIMP-1, may aid to discriminate patients with COPD from smokers at lower risk of developing COPD.

Topics: Aged; Biomarkers; Case-Control Studies; Female; Forced Expiratory Volume; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Pulmonary Diffusing Capacity; Pulmonary Disease, Chronic Obstructive; Smoking; Tissue Inhibitor of Metalloproteinase-1; Tomography, X-Ray Computed

Indoor air pollution has been documented as an important risk factor for chronic obstructive pulmonary disease (COPD), and inflammation is central to the development and progression of COPD. Single nucleotide polymorphisms (SNP) in some cytokine genes have been reported to be associated with COPD. We examined the association between 18 SNPs in 10 cytokine genes and COPD risk in a case-control study conducted in a population with high exposure to indoor smoky coal emissions. The study included 53 COPD cases and 122 healthy community controls. Carriers of the CSF2 117Ile allele had a 2.4-fold higher risk of COPD than the wild type (Thr/Thr) carriers (OR: 2.44; 95% CI: 1.10-5.41), and the AA genotype at IL8 -351 was associated with an increased risk of COPD (OR: 2.71; 95% CI: 1.04-7.04). When the combined effects of CSF2 117Ile and IL8 -351A were examined, individuals carrying at least one variant in both genes had a five-fold increased risk of COPD (OR: 5.14, 95% CI: 1.32-29.86). This study suggests that polymorphisms in both CSF2 and IL8 may play a role in the pathogenesis of COPD, at least in highly exposed populations. However, in view of our relatively small sample size, this study should be replicated in other populations with substantial exposure to indoor air pollutants such as polycyclic aromatic hydrocarbons (PAH) and particulate matter.

Topics: Air Pollutants; Air Pollution, Indoor; Alleles; Case-Control Studies; China; Coal; Cytokines; Female; Genotype; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Logistic Models; Male; Middle Aged; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Risk Factors

Whether the airway and systemic inflammatory profile in bacterial exacerbations of chronic obstructive pulmonary disease (COPD) is distinct from nonbacterial exacerbations is unclear. Previous studies have not used molecular typing of bacterial pathogens, which is required to accurately define bacterial infection in COPD. The relationship between clinical severity and course of exacerbation and inflammation is also not fully understood.. To determine if (1) systemic and airway inflammation is distinct in new bacterial strain exacerbations and (2) clinical severity and resolution of exacerbations is related to airway and systemic inflammation.. In a prospective longitudinal cohort study in COPD, sputum and serum samples obtained before, at, and following exacerbations during a 2-year period were studied.. Clinical information, molecular typing of bacterial pathogens, sputum IL-8, tumor necrosis factor (TNF)-alpha and neutrophil elastase, and serum C-reactive protein. From 46 patients, 177 exacerbations were grouped as new strain, preexisting strain, other pathogen, and pathogen negative. New strain exacerbations were associated with significantly greater increases from baseline in sputum TNF-alpha and neutrophil elastase, and in serum C-reactive protein compared with the other three groups. Increases in inflammatory markers were similar among the other three groups. Clinical resolution was accompanied by resolution of inflammation to preexacerbation levels, whereas persistent symptoms were paralleled by persistently elevated inflammation. Clinical exacerbation severity was significantly correlated with levels of all four markers.. Neutrophilic airway inflammation and systemic inflammation are more intense with well-defined bacterial exacerbations than with nonbacterial exacerbations. Clinical course of exacerbation and inflammation are closely linked.

Topics: Aged; Aged, 80 and over; Bacterial Infections; C-Reactive Protein; Female; Humans; Inflammation; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; ROC Curve; Severity of Illness Index; Sputum; Tumor Necrosis Factor-alpha

Inducible cyclooxygenase (COX-2) and inflammatory cytokines play important roles in inflammatory processes of chronic obstructive pulmonary disease (COPD). Endothelin-1 (ET-1) might be also involved in the pathophysilogical processes in COPD. In the present study, we determined whether ET-1 could regulate the expression of COX-2 and alter the production of interleukin-8 (IL-8) in human pulmonary epithelial cells (A549). Induced sputum samples were collected from 13 stable COPD patients and 14 healthy subjects. The COX-2 protein, ET-1, PGE(2) and IL-8 in these sputum samples were analyzed. A549 cells were incubated with ET-1 in the presence or absence of celecoxib, a selective COX-2 inhibitor. The expression of COX-2 protein in the cell and the amounts of PGE(2) and IL-8 in the medium were measured. The levels of COX-2 protein, ET-1, PGE(2) and IL-8 were significantly increased in induced sputum from COPD patients when compared to healthy subjects. ET-1 increased the expression of COX-2 protein, as well as the production of PGE(2) in A549 cells. Increased production of PGE(2) was inhibited by celecoxib. ET-1 also increased the production of IL-8. Interestingly, ET-1-induced production of IL-8 was also inhibited by celecoxib. These findings indicate that ET-1 plays important roles in regulating COX-2 expression and production of IL-8 in A549 cells. ET-1 mediated production of IL-8 is likely through a COX-2-dependent mechanism.

Topics: Aged; Cell Line, Tumor; Cyclooxygenase 2; Dinoprostone; Endothelin-1; Epithelial Cells; Female; Humans; Interleukin-8; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Sputum

Vascular endothelial growth factor (VEGF) and its receptor may have an important role in the pathogenesis of emphysema. The effect of another angiogenic factor, placenta growth factor (PlGF), in chronic obstructive pulmonary disease (COPD) is unknown.. The serum levels of VEGF and PlGF in patients with COPD (n = 184), smokers (n = 212) and non-smokers (n = 159) and the bronchoalveolar lavage (BAL) fluid levels of VEGF and PlGF in another group (20 patients with COPD, 18 controls) were measured. In vitro cell culture experiments were performed to investigate the effect of PlGF on VEGF.. The mean (SE) serum levels of PlGF were significantly higher in patients with COPD than in controls (27.1 (7.4) pg/ml vs 12.3 (5.1) pg/ml in smokers and 10.8 (6.3) pg/ml in non-smokers, p = 0.005). The levels of PlGF in BAL fluid were also significantly higher in patients with COPD than in controls (45.7 (12.3) pg/ml vs 23.9 (7.6) pg/ml, p = 0.005), associated with an increase in the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8). In patients with COPD the levels of PlGF correlated inversely with forced expiratory volume in 1 s (FEV(1)) in serum (r = -0.59, p = 0.002) and in BAL fluid (r = -0.51, p = 0.001). While the serum levels of VEGF were the same in patients with COPD and controls, the BAL fluid levels were significantly lower in patients with COPD than in controls (127.5 (30.1) pg/ml vs 237.8 (36.1) pg/ml, p = 0.002). In cultured bronchial epithelial cells, proinflammatory cytokines induced an increase in the protein expression of both PlGF and VEGF. Continuous concomitant treatment with PlGF, TNF-alpha and IL-8 stimulation reduced VEGF expression and induced cell death. This phenomenon was suppressed by VEGF receptor inhibitor (CBO-P11).. The serum and BAL fluid levels of PlGF are increased in patients with COPD and are inversely correlated with FEV(1). Concomitant treatment with PlGF, TNF-alpha and IL-8 causes detrimental effects on airway epithelial cells. These data suggest that bronchial epithelial cells can express PlGF, which may contribute to the pathogenesis of COPD.

Topics: Aged; Bronchoalveolar Lavage Fluid; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Forced Expiratory Volume; Humans; Interleukin-8; Male; Placenta Growth Factor; Pregnancy Proteins; Pulmonary Disease, Chronic Obstructive; Smoking; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vital Capacity

Rhinovirus infection is the most common cause of acute exacerbations of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease, where it provokes steroid refractory and abnormally intense neutrophilic inflammation that can be life threatening. Epidermal growth factor receptor (EGFR) expression correlates with disease severity and neutrophil infiltration in these conditions. However, the role of EGFR signaling in rhinovirus infection is unknown. We measured the key determinants of neutrophilic inflammation interleukin (IL)-8 and ICAM-1 in rhinovirus (RV16 serotype)-infected bronchial epithelial cells, BEAS-2B. RV16 infection stimulated IL-8 and ICAM-1 expression, which was further elevated (2-fold) by transient up-regulation of EGFR levels. Detection of viral RNA by quantitative real time PCR confirmed that enhanced expression was not associated with increased viral replication. EGFR ligands (epiregulin, amphiregulin, and heparin-binding epidermal growth factor) were induced by RV16 infection, and inhibition of metalloproteases responsible for ligand shedding partially suppressed this response. The EGFR inhibitor AG1478, completely blocked IL-8 and ICAM-1 expression to basal levels, as did the specific Erk1/2 inhibitor U0126. The p38 mitogen-activated protein kinase inhibitor SB203580 blocked IL-8 secretion but not ICAM-1 expression, whereas the PI3K inhibitor wortmannin was ineffective in both responses. Kinase inactive K721R EGFR, which is selectively deficient in STAT signaling, reversed RV16 responses associated with EGFR overexpression. In conclusion, RV16 infection rapidly promotes induction of EGFR ligands and utilizes EGFR signaling to increase IL-8 and ICAM-1 levels. These results suggest that targeting EGFR may provide a selective therapy that dampens neutrophil-driven inflammation without compromising essential antiviral pathways mediated by pathogen recognition receptors such as TLR3.

Topics: Amino Acid Substitution; Asthma; Common Cold; Enzyme Inhibitors; ErbB Receptors; Gene Expression Regulation; HeLa Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Ligands; Matrix Metalloproteinases; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neutrophils; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Rhinovirus; RNA, Viral; Signal Transduction; STAT Transcription Factors; Toll-Like Receptor 3

Smokers who develop chronic obstructive pulmonary disease (COPD) have amplified inflammation within their lungs, involving selective tissue accumulation of neutrophils, macrophages and CD8+ T cells. CD11b (Mac-1, alphaMbeta(2)-integrin) is both a complement receptor (CR3) and a cell adhesion molecule present on the surface of peripheral blood leukocytes, and undergoes rapid surface upregulation from preformed cytoplasmic stores on activation. Cellular activation can also trigger chemotaxis and shape change, the activation itself being caused by the binding of chemokines to cell surface receptors.. We developed a method of whole blood flow cytometry to measure neutrophil and monocyte CD11b upregulation on CD16+ and CD14+ cells, employing staining with the nuclear dye LDS-751 immediately before flow cytometry. In addition we assessed neutrophil shape change by modified gated autofluorescence with forward scatter (GAFS), this being correlated with chemotactic responses.. In smokers with COPD there was a lower maximal shape change for neutrophils in response to CXCL8 (IL-8) in comparison to healthy smokers (p=0.025), and a trend for lower expression of CD11b and shape change in response to CXCL1 (GRO-alpha). Neutrophils were found to predominantly express chemokine receptors CXCR1 and CXCR2 and respond to CXCL8 with CD11b upregulation, while monocytes express more CCR2 and upregulate CD11b preferentially to CCL2 (MCP-1). A CXCR2 antagonist (SB-656933) was found to inhibit neutrophil CD11b upregulation (IC50=260.7nM) and shape change (IC50=310.5nM) in COPD patients.. Neutrophils and monocytes participate in inflammatory processes in a range of diseases. These whole blood assays can be employed to monitor activity in disease and perform in vitro and ex vivo assessment of chemokine receptor (CXCR) antagonists.

Topics: Antigens, CD; CD11b Antigen; Cell Shape; Chemokine CXCL11; Chemokines, CXC; Dose-Response Relationship, Drug; Flow Cytometry; GPI-Linked Proteins; Humans; Interleukin-8; Lipopolysaccharide Receptors; Monocytes; Neutrophils; Pulmonary Disease, Chronic Obstructive; Receptors, IgG; Receptors, Interleukin-8B; Reproducibility of Results; Up-Regulation

Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased airway and systemic inflammation, though relationships between exacerbation recovery, recurrent exacerbation and inflammation have not been previously reported. In the present study, inflammatory changes at COPD exacerbations were related to clinical nonrecovery and recurrent exacerbations within 50 days. Serum interleukin (IL)-6, C-reactive protein (CRP), sputum IL-6 and IL-8 were measured in 73 COPD patients when stable, at exacerbation and at 7, 14 and 35 days post-exacerbation. In 23% of patients, symptoms did not recover to baseline by day 35. These patients had persistently higher levels of serum CRP during the recovery period. A total of 22% of the patients who had recurrent exacerbations within 50 days had significantly higher levels of serum CRP at day 14, compared with those without recurrences: 8.8 mg.L(-1) versus 3.4 mg.L(-1). Frequent exacerbators had a smaller reduction in systemic inflammation between exacerbation onset and day 35 compared with infrequent exacerbators. Nonrecovery of symptoms at chronic obstructive pulmonary disease exacerbation is associated with persistently heightened systemic inflammation. The time course of systemic inflammation following exacerbation is different between frequent and infrequent exacerbators. A high serum C-reactive protein concentration 14 days after an index exacerbation may be used as a predictor of recurrent exacerbations within 50 days.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Albuterol; Biomarkers; C-Reactive Protein; Cohort Studies; Disease Progression; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; London; Male; Middle Aged; Peak Expiratory Flow Rate; Prognosis; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Recurrence; Sputum

Neutrophilic airway inflammation is considered to be a major factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), with sputum and bronchoalveolar lavage neutrophil counts broadly correlating with disease severity. The mechanisms responsible for neutrophil accumulation are poorly understood, but they could involve increased influx and/or survival of these cells.. To investigate whether neutrophil chemotactic responsiveness and/or chemotactic activity in airway secretions are increased in subjects with COPD.. Chemotaxis experiments were performed using induced sputum supernatants from subjects with and without COPD as a source of chemotactic activity, and neutrophils from healthy donors as responder cells. In addition, chemotactic responses to N-formyl-Met-Leu-Phe (fMLP) and interleukin-8 (IL-8/CXCL8) were studied using neutrophils from healthy subjects and subjects with COPD.. As reported in the literature, sputum neutrophil counts were significantly increased in subjects with COPD compared with healthy subjects. However, this was associated with reduced chemotactic activity in sputum in COPD, as judged by reduced chemotaxis to the fluid phase of sputum from subjects with COPD compared with healthy subjects. Furthermore, whereas neutrophils from subjects with stage I COPD had normal responses to fMLP and IL-8, subjects with more severe stage II-IV COPD showed reduced levels of spontaneous migration and chemotaxis to fMLP and IL-8.. Neither increased chemotactic activity in the airways nor increased chemotactic responsiveness of neutrophils explains the increased number of these cells in subjects with stable COPD. The implications of the observed reduction in neutrophil chemotactic activity remain to be established.

Topics: Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Female; Humans; Interleukin-8; Leukocyte Count; Male; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Sputum

Systemic inflammation in patients with COPD may worsen during exacerbations, but there is limited information relating levels of systemic inflammatory markers with symptoms and physiologic changes during an exacerbation. We measured dyspnea using the visual analog scale, pulmonary function tests, hemograms, and plasma levels for interleukin (IL)-6, IL-8, leukotriene B(4) (LTB4), tumor necrosis factor-alpha, and secretory leukocyte protease inhibitor (SLPI) in 20 patients on admission to a hospital for exacerbation of COPD (ECOPD), 48 h later (interim), and 8 weeks after hospital discharge (recovery).. Dyspnea was present in all patients. Inspiratory capacity improved faster than FEV(1). Compared to recovery, there was a significant increase in the mean (+/- SD) hospital admission plasma levels of IL-6 (6.38 +/- 0.72 to 2.80 +/- 0.79 pg/mL; p = 0.0001), IL-8 (8.18 +/- 0.85 to 3.72 +/- 0.85 pg/mL; p = 0.002), and LTB4 (8,675 +/- 1,652 to 2,534 +/- 1,813 pg/mL; p = 0.003), and the percentages of segmented neutrophils (79 to 69%; p < 0.02) and band forms (7.3 to 1.0%; p < 0.01) in peripheral blood, with no changes in TNF-alpha and SLPI. There were significant correlations between changes in IL-6 (r = 0.61; p = 0.01) and IL-8 (r = 0.56; p = 0.04) with changes in dyspnea and levels of IL-6 (r = -0.51; p = 0.04) and TNF-alpha (r = -0.71; p < 0.02) with changes in FEV(1.). Hospitalized patients with ECOPDs experience significant changes in systemic cytokine levels that correlate with symptoms and lung function. An ECOPD represents not only a worsening of airflow obstruction but also increased systemic demand in a host with limited ventilatory reserve.

Topics: Aged; Aged, 80 and over; Biomarkers; Cytokines; Female; Hospitalization; Humans; Interleukin-6; Interleukin-8; Leukotriene B4; Linear Models; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Secretory Leukocyte Peptidase Inhibitor; Severity of Illness Index; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Chlamydia pneumoniae (Cpn) infection may play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Few data are available comparing persistent and acute infection of this pathogen in the human respiratory tract.. To study Cpn-induced innate immune responses in lung tissue from patients with COPD and control subjects ex vivo and in vitro.. Cpn detection was done by nested polymerase chain reaction, in situ hybridization, and immunohistochemistry ex vivo in unstimulated tissue and in vitro using an acute Cpn infection model. As main endpoints for the assessment of early cellular responses, nuclear factor (NF)-kappaB activation and CXC chemokine ligand (CXCL)-8 expression were evaluated. The role of Toll-like receptors (TLRs) as recognition molecules in Cpn-induced innate responses was tested by blocking experiments.. Fifteen percent of patients with COPD were chronically infected with Cpn in contrast to 0% of control subjects (p < 0.05). There were no differences in CXCL-8 and NF-kappaB expression between infected and noninfected COPD tissue ex vivo. In contrast, acute in vitro infection induced an intense innate immune response including up-regulation of TLR2. Blocking experiments demonstrated the predominant role of TLR2 in induction of the early immune response, whereas no influence on chlamydial infection rates was observed.. Acute in vitro infection of human lung tissue with Cpn elicited a marked innate response via TLR2, whereas chronic chlamydial infection in patients with COPD was not associated with enhanced cellular activation. These findings suggest different roles of Cpn during acute and chronic stages of pulmonary infection.

Topics: Case-Control Studies; Chlamydophila Infections; Chlamydophila pneumoniae; Female; Humans; Immunity, Innate; Interleukin-8; Male; Middle Aged; NF-kappa B; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; Tissue Culture Techniques; Toll-Like Receptors

The airway epithelium is critical in the pathogenesis of chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease, and, by expressing numerous inflammatory genes, plays a prominent role in disease exacerbations. Since inflammatory gene expression often involves the transcription factor nuclear factor (NF)-kappaB, this signaling pathway represents a site for anti-inflammatory intervention. As the airway epithelium is targeted by inhaled therapeutic agents, for example corticosteroids, human A549 pulmonary cells and primary human bronchial epithelial (HBE) cells were selected to evaluate inhibitor of kappaB kinase (IKK) inhibitors. In A549 cells, interleukin (IL)-1beta and tumor necrosis factor (TNF) alpha increased phosphorylation of IkappaBalpha, and this was followed by loss of IkappaBalpha, induction of NF-kappaB DNA binding, and the induction of NF-kappaB-dependent transcription. These events were repressed by the IKK-selective inhibitors, PS-1145 [N-(6-chloro-9H-beta-carbolin-8-ly) nicotinamide] and ML120B [N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methyl-nicotinamide]. Inhibition of NF-kappaB-dependent transcription was concentration-dependent and correlated with loss of intercellular adhesion molecule (ICAM)-1 expression. Similarly, IL-1beta- and TNFalpha-induced expression of IL-6, IL-8, granulocyte macrophage-colony-stimulating factor (GM-CSF), regulated and activation normal T cell expressed and secreted (RANTES), growth-related oncogene alpha, and monocyte chemotactic protein-1 (MCP-1) was also significantly repressed. Likewise, PS-1145 and ML120B profoundly reduced NF-kappaB-dependent transcription induced by IL-1beta and TNFalpha in primary HBE cells. Parallel effects on ICAM-1 expression and a significant repression of IL-8 release were observed. In contrast, the corticosteroid, dexamethasone, was without effect on NF-kappaB-dependent transcription or the expression of ICAM-1. The above data provide strong support for an anti-inflammatory effect of IKK2 inhibitors acting on the pulmonary epithelium and suggest that such compounds may prove beneficial in situations where traditional corticosteroid therapies prove inadequate.

Topics: Carbolines; Cells, Cultured; Cytokines; Epithelial Cells; Gene Expression Regulation; Heterocyclic Compounds, 3-Ring; Humans; I-kappa B Kinase; Interleukin-1beta; Interleukin-6; Interleukin-8; Lung; NF-kappa B; Niacinamide; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyridines; Transcription, Genetic; Tumor Necrosis Factor-alpha

Noncapsulate Haemophilus influenzae is commonly found in the airways of patients with chronic obstructive pulmonary disease (COPD), both during stable disease and during exacerbations. Neutrophils are also found in large numbers in sputum from patients with COPD, which also contains released neutrophil products such as elastase. Why H. influenzae colonizes the lungs of patients with COPD in the presence of such large numbers of infiltrating neutrophils is not known. We set out to determine if abnormal interactions between H. influenzae and neutrophils could impact on COPD pathology. Noncapsulate H. influenzae clinical isolates were incubated in vitro with neutrophils from healthy volunteers, and respiratory burst activity, cytokine and chemokine production, phagocytosis and killing of bacteria, and neutrophil apoptosis and necrosis were measured. Neutrophil morphology was determined in sputum samples. H. influenzae were phagocytosed by neutrophils, thereby activating a respiratory burst and the secretion of the neutrophil chemoattractant IL-8. However, rather than kill the bacteria, the neutrophils themselves were killed (largely via necrosis) and released their granule contents into the extracellular environment. Neutrophil-derived IL-8, generated after the interaction of H. influenzae with neutrophils, may result in the further infiltration of neutrophils into the lungs, thereby amplifying the inflammatory response. However, the infiltrating neutrophils fail to kill the bacteria and instead release tissue-damaging products into the lung as they undergo necrosis. These results may help to explain the clinical picture in COPD.

Topics: Haemophilus Infections; Haemophilus influenzae; Humans; Interleukin-8; Leukocyte Elastase; Necrosis; Neutrophil Activation; Neutrophils; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Respiratory Burst; Sputum

Polymorphonuclear neutrophils (PMNs) play an important role in chronic obstructive pulmonary disease (COPD) pathogenesis. The tetraspanin CD63 is a membrane marker of azurophilic granules and is actively involved in the process of PMN endocytosis and azurophilic granule exocytosis. In this study, we investigated genetic polymorphisms of the CD63 gene, quantified CD63 expression and PMN myeloperoxidase (MPO) release in healthy individuals and COPD patients. We evaluated the potential correlations between genetic polymorphisms and gene expression and MPO release. COPD patients had significantly lower CD63 expression and released less MPO upon chemokine stimulation compared with the healthy individuals. Eleven putative polymorphisms in the CD63 gene were investigated but only three were polymorphic in our study subjects. None of the polymorphisms was associated with CD63 expression in either the healthy subjects or the COPD patients. However, the 8041C/G polymorphism, which is located 3' to the CD63 gene, was associated with MPO release in the healthy subjects. The CC genotype was associated with greater MPO release than the GG genotype (P=0.007). These results suggest that COPD patients have different patterns of CD63 expression and PMN mediator release than healthy individuals. It is likely that genetic variants have limited effect on CD63 expression and MPO release in the context of COPD but their role in other diseases has yet to be determined.

Topics: Adult; Antigens, CD; Case-Control Studies; Cell Degranulation; Exons; Female; Gene Expression Regulation; Genotype; Health; Humans; Interleukin-8; Male; Neutrophils; Peroxidase; Platelet Membrane Glycoproteins; Polymorphism, Genetic; Pulmonary Disease, Chronic Obstructive; Tetraspanin 30

To explore the role of IL-8 in the pathogenesis of chronic obstructive pulmonary disease (COPD) and the effect of glucocorticoid on COPD.. 24 health males of Wistar rats were randomly divided into three groups (group A: normal control group, group B: COPD model group, group C: group pretreated with prednisone), of which each got 8 rats for this study project. Rat COPD model was established by exposing rat to cigarette smoke daily for 120 days. The prednisone was, via stomachal injection, given to the rats of group C with a dose of 5 mg/kg on every other day just before rats exposed to cigarette smoke. After COPD model was set up, the bronchoalveolar lavage (BAL) was performed. The total cells and neutrophils in bronchoalveolar lavage fluid (BALF) were counted for examination, and the levels of IL-8 and TNF-alpha in supernatants of BALF and serum were detected by ELISA. The lung tissue section stained by HE was observed in order to study the alternation of morphology, and also measured in terms of mean lining interval (MLI), mean alveolus number (MAN) and percentage of alveolar area in total area (PAA).. MLI and PAA in group B were higher than those in group A (P < 0.01), and decreased after pretreatment with prednisone (P < 0.01), in which however MAN was just on the contrary. The statistic analysis showed that levels of IL-8 [(114.5 +/- 15.7) pg/mL vs (259.4 +/- 20.1) pg/mL, respectively, P < 0.01], TNF-alpha [(80.5 +/- 9.5) pg/mL vs (145.9 +/- 17.3) pg/ mL, P < 0.01], total cell counts [(1.64 +/- 0.12) x 10(8)/L vs (5.76 +/- 0.29) x 10(8)/L, P < 0.01], neutrophil counts [(0.099 +/- 0.065) x 10(8)/L vs (1.26 +/- 0.25) x 10(8)/L P < 0.01], neutrophil proportion [(5.9 +/- 3. 6)% vs (21.8 +/- 3.7)%, P < 0.05] in BALF of group B were higher than those of group A. After pretreatment with prednisone, the above measured values were significant reduction (P < 0.01 or 0.05). The level of IL-8 in serum of group B was higher than that of group A [(45.2 +/- 13.5) pg/mL vs (85.7 +/- 7.0) pg/mL, P < 0.01], but which, after pretreatment, there was reduction but no significance (P > 0.05). The positive correlation was demonstrated among the levels of IL-8, TNF-alpha and counted neutrophils in BALF of group B, but not between the level of IL-8 and TNF-alpha in serum.. There is a close correlation between IL-8 in BALF and airway inflammation with COPD. The IL-8 cooperating with TNF-alpha may be responsible for the persistence and amplification of airway inflammation with COPD. By modulating the expression of IL-8 gene, inhibiting granulocyte chemotaxis and degranulation, the prednisone may relieve airway inflammation, and relieve the lesion of airway resulting from inflammatory cytokines and cells, hence postpone the progress of COPD.

Topics: Animals; Bronchoalveolar Lavage Fluid; Gene Expression Regulation; Glucocorticoids; Interleukin-8; Lung; Male; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Several chemoattractants have been measured in exhaled breath condensate (EBC) from patients with COPD. The aim of this study was to compare the eosinophil and neutrophil chemotactic activity contained in EBC from healthy subjects and patients with COPD.. EBC collected using a commercially available condenser (EcoScreen; Erich Jaeger Viasys; Hoechberg, Germany) was compared in 45 COPD patients and 65 healthy subjects. EBC chemotactic activity for eosinophils and neutrophils was assessed using microchambers (Boyden; Neuro Probe; Cabin John, MD). Chemotactic index (CI) was used to evaluate cell migration.. EBC from patients with COPD (CI, 2.21 +/- 0.16 [mean +/- SEM]) and healthy subjects (CI, 1.67 +/- 0.11) displayed significant neutrophil chemotactic activity (p < 0.0001 for both), which was however higher in patients with COPD (p < 0.001). Healthy smokers had a significantly raised CI for neutrophils by comparison with healthy nonsmokers (p < 0.01) and ex-smokers (p < 0.05). Likewise, current COPD smokers tended to have greater neutrophil CI than COPD who stopped smoking (p = 0.08). COPD ex-smokers had raised chemotactic activity by comparison with healthy ex-smokers (p < 0.05). Anti-interleukin-8 (10(-6) g/mL) antibodies reduced neutrophil chemotactic activity by 35.2% (p < 0.05). EBC also contained significant eosinophil chemotactic activity in healthy subjects (CI, 1.68 +/- 0.09; p < 0.0001) and patients with COPD (CI, 1.23 +/- 0.07; p < 0.01), with a significantly lower CI in patients with COPD as compared to healthy subjects (p < 0.001). Smoking did not influence eosinophil chemotactic activity in healthy subjects or patients with COPD.. Current smoking favors neutrophil chemotactic activity. As compared to healthy subjects, EBC from patients with COPD displays a skewed chemotactic activity toward neutrophils vs eosinophils.

Topics: Adult; Aged; Breath Tests; Case-Control Studies; Chemotaxis, Leukocyte; Eosinophils; Female; Granulocytes; Heating; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Smoking

It has been shown that the beta2-integrin molecule is up-regulated in circulating neutrophils in COPD subjects. However, little has been reported about the expression of the cell surface molecules in such patients and their relationship with pulmonary function. The aim of the present study was to investigate the surface expression of molecules in circulating neutrophils and to clarify their possible role in the airflow limitation of COPD.. The surface expression of Mac-1 cells (ie, CD-11b and CD-18 cells) and CXC chemokine receptor (CXCR) 1 and CXCR2 of circulating neutrophils obtained from COPD patients and healthy subjects (HSs) was measured by flow cytometry analysis. The serum levels of interleukin (IL)-8 were measured by enzyme-linked immunosorbent assay.. Both CD-11b and CXCR1 expression were significantly higher in COPD patients than in HSs (mean [+/- SE] CD-11b concentration: HSs, 9.7 +/- 1.0; COPD patients, 14.2 +/- 1.8 [p < 0.05]; mean CXCR1 concentration: HSs, 9.6 +/- 0.5; COPD patients, 11.9 +/- 0.4 [p < 0.01]). Although aging was positively correlated with the expression of CXCR1 (r = 0.440; p < 0.01), none of the other background factors, including smoking and body mass index, showed a correlation with the expression of the molecules. Although serum IL-8 levels were higher in patients with COPD than in HSs, no significant correlation between serum IL-8 levels and the expression of any molecule was seen. The expression of CD-11b (r = -0.317) and CXCR1 (r = -0.383) showed a significant negative correlation with the severity of airflow limitation (both p < 0.05).. The overexpression of CD-11b and CXCR1 in circulating neutrophils may be associated with the development of airflow limitation in COPD patients.

Topics: Aged; Case-Control Studies; CD11b Antigen; CD18 Antigens; Female; Forced Expiratory Volume; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Total Lung Capacity

Airway inflammation is associated with an increased expression and release of inflammatory reactants that regulate processes of cell migration, activation and degranulation. The purpose of this study was to quantify bronchial lavage (BAL) fluid and serum levels of chemokine (IL-8), secretory leukocyte protease inhibitor (SLPI), soluble intracellular adhesion molecules-1 (sICAM-1) and sCD14, as surrogate markers of inflammatory and immune response in asthma and chronic obstructive pulmonary disease (COPD) patients with similar disease duration time.. Biomarkers in serum and BAL fluid from asthma (n=13) and COPD (n=25) patients were measured using commercially available ELISA kits.. We found that in asthma and COPD groups the concentrations of IL-8 and SLPI are significantly higher in BAL fluid than in serum, while levels of sICAM-1 and sCD14 in BAL fluid are significantly lower than in serum. Of these 4 measured biomarkers, only the BAL IL-8 was higher in COPD patients when compared to asthma (P<0.05). In both groups, BAL IL-8 correlated with SLPI (r=0.577, P<0.01 and r=0.589, P<0.05, respectively). In patients with COPD the BAL sICAM-1 correlated with sCD14 (r=0.576, P<0.01), while in asthma patients BAL sICAM-1 correlated with FEV(1)/FVC (r=0.418, P<0.01). Moreover, in asthma patients the serum SLPI correlated with sCD14 (r=0.688, P<0.01) and serum sICAM-1 negatively correlated with FEV(1)/FVC (r=-0.582, P<0.05).. Our findings point to the importance of selecting a correct biological fluid when analyzing specific biomarkers, and also show that of 4 measured biomarkers, only the BAL IL-8 was higher in COPD patients when compared to asthma.

Topics: Adult; Aged; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Bronchoscopy; Female; Forced Expiratory Volume; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-8; Lipopolysaccharide Receptors; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Secretory Leukocyte Peptidase Inhibitor; Vital Capacity

Smoking cigarettes is the major risk factor for chronic obstructive pulmonary disease (COPD). COPD is a condition associated with chronic pulmonary inflammation, characterized by macrophage activation, neutrophil recruitment, and cell injury. Many substances contained in cigarette smoke, including reactive oxygen species (ROS), have been proposed to be responsible for the inflammatory process of COPD. However, this issue remains unsettled. By gas chromatography/mass spectrometry (GC/MS) we show that acrolein and crotonaldehyde, two alpha,beta-unsaturated aldehydes, are contained in aqueous cigarette smoke extract (CSE) at micromolar concentrations and mimic CSE in evoking the release of the neutrophil chemoattractant IL-8 and of the pleiotropic inflammatory cytokine TNF-alpha from the human macrophagic cell line U937. In addition, acrolein (10-30 microM) released IL-8 also from cultured human alveolar macrophages and THP-1 macrophagic cells. 4-hydroxy-2-nonenal (30-100 microM), an endogenous alpha,beta-unsaturated aldehyde that is abundant in lungs of patients with COPD, stimulated the release of IL-8 from U937 cells, whereas the saturated aldehyde, acetaldehyde, was ineffective. CSE-evoked IL-8 release was remarkably (> 80%) inhibited by N-acetyl-cysteine (0.1-3 mM) or glutathione monoethyl ester (1-3 mM). Both compounds, by forming covalent adducts (Michael adducts), completely removed unsaturated aldehydes from CSE. Our data demonstrate that alpha,beta-unsaturated aldehydes are major mediators of cigarette smoke-induced macrophage activation, and suggest that they might contribute to pulmonary inflammation associated with cigarette smoke.

Topics: Aldehydes; Humans; Inflammation Mediators; Interleukin-8; Macrophages; Pulmonary Disease, Chronic Obstructive; Smoking; Tumor Necrosis Factor-alpha; U937 Cells

Topics: Bronchodilator Agents; C-Reactive Protein; Humans; Interleukin-6; Interleukin-8; Peroxidase; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Saliva; Scopolamine Derivatives; Tiotropium Bromide

Disuse and/or local inflammation in the muscle cannot be excluded as potential influences for the decreased muscle force in patients hospitalised due to an acute chronic obstructive pulmonary disease (COPD) exacerbation. This study aims to compare expression levels of markers of disuse (insulin-like growth factor-1 (IGF-I), MyoD and myogenin) and inflammation [interleukin-6 (IL-6), IL-8 and tumour necrosis factor-alpha (TNF-alpha)] in the muscle of hospitalised and stable COPD patients and healthy elderly.. Muscle biopsies (m. vastus lateralis) were taken in 14 hospitalised COPD patients (aged 68 +/- 8), 11 clinically stable COPD patients (aged 68 +/- 9) and seven healthy subjects (aged 70 +/- 7) to analyse local mRNA expression levels of IL-6, IL-8, TNF-alpha, IGF-I and protein expression levels of IGF-I, MyoD and myogenin. Relationships of these expression levels with lung and skeletal muscle function were investigated.. IGF-I mRNA and MyoD protein levels were significantly lower in hospitalised patients compared to healthy subjects. MyoD protein levels were positively related to quadriceps force. Muscle IL-6 and IL-8 expression in hospitalised patients was similar compared to stable patients and healthy subjects and was not related to expression levels of muscle markers of disuse or quadriceps force. Muscle TNF-alpha and myogenin were not detected.. Decreased expression levels of muscle IGF-I and MyoD in hospitalised patients suggest a potential influence of disuse in the increased muscle weakness during an acute COPD exacerbation. This study did not find any evidence supporting local inflammation via IL-6, IL-8 and/or TNF-alpha in the vastus lateralis muscle of COPD patients.

Topics: Adult; Aged; Biomarkers; Cross-Sectional Studies; Female; Humans; Insulin-Like Growth Factor I; Interleukin-6; Interleukin-8; Male; Middle Aged; Muscular Atrophy; MyoD Protein; Pulmonary Disease, Chronic Obstructive; Quadriceps Muscle; RNA, Messenger; Tumor Necrosis Factor-alpha

Limited information is available on repeatability of inflammatory parameters in whole induced sputum samples from patients with COPD.. To study short-term and long-term repeatability in induced sputum samples in 22 patients with moderate to severe, stable COPD (mean age 64 yr, mean FEV(1) 1.91 L=65% of predicted). Samples were collected on 71 occasions twice within 1 to 7 days (mean 3.8 days) and on 12 occasions twice with an interval of 3 months while clinically stable. Cell differentials, markers of neutrophilic and eosinophilic inflammation, respiratory membrane permeability and size-selective permeation were assessed.. Parameters of permeability and of size-selective permeation, % eosinophils and % neutrophils showed the best short-term repeatability with intra-class correlation coefficients (Ri) of 0.61 to 0.90, followed by total cell count (TCC) with Ri of 0.52. Repeatability of soluble cell activation markers was less satisfactory (Ri 0.34 to 0.52). Mean short-term within-patient variability for TCC and permeability was approximately 2-fold and for cell activation markers 3-fold; mean between-patients variability was twice as high. Inducing sputum slightly enhanced eosinophil numbers and % neutrophils and decreased % macrophages in successive IS samples. Long-term repeatability was comparable to short-term repeatability but variability increased.. Repeatability of parameters assessed in whole sputum is similar as reported previously for sputum plugs. In COPD an induced sputum procedure has a minor pro-inflammatory effect. The current data facilitates power calculations but also indicates that studies using inflammatory markers in sputum may easily be underpowered.

Topics: Adult; Aged; Biomarkers; Cell Count; Cell Membrane Permeability; Enzyme-Linked Immunosorbent Assay; Eosinophil Cationic Protein; Eosinophils; Female; Follow-Up Studies; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Neutrophils; Peroxidase; Prognosis; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Sputum

The toll-like receptors (TLRs) are a key component of host defense in the respiratory epithelium. Cigarette smoking is associated with increased susceptibility to infection, while COPD is characterised by bacterial colonisation and infective exacerbations. We found reduced TLR4 gene expression in the nasal epithelium of smokers compared with non-smoking controls, while TLR2 expression was unchanged. Severe COPD was associated with reduced TLR4 expression compared to less severe disease, with good correlation between nasal and tracheal expression. We went on to examine the effect of potential modulators of TLR4 expression in respiratory epithelium pertinent to airways disease. Using an airway epithelial cell line, we found a dose-dependent downregulation in TLR4 mRNA and protein expression by stimulation with cigarette smoke extracts. Treatment with the corticosteroids fluticasone and dexamethasone resulted in a dose-dependent reduction in TLR4 mRNA and protein. The functional significance of this effect was demonstrated by impaired IL-8 and HBD2 induction in response to LPS. Stimulation with salmeterol (10-6 M) caused upregulation of TLR4 membrane protein presentation with no upregulation of mRNA, suggesting a post-translational effect. The effect of dexamethasone and salmeterol in combination was additive, with downregulation of TLR4 gene expression, and no change in membrane receptor expression. Modulation of TLR4 in respiratory epithelium may have important implications for airway inflammation and infection in response to inhaled pathogens.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Aged; Albuterol; Androstadienes; beta-Defensins; Case-Control Studies; Cell Line; Dexamethasone; Dose-Response Relationship, Drug; Drug Interactions; Female; Fluticasone; Gene Expression Regulation; Humans; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Nasal Mucosa; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; RNA, Messenger; Salmeterol Xinafoate; Severity of Illness Index; Smoke; Smoking; Toll-Like Receptor 4

To explore the acute systemic inflammatory and anabolic effects of cycling in hospital admitted patients with chronic obstructive pulmonary disease (COPD) and in patients with clinically stable disease.. Cross-sectional comparative study.. University Hospital Gasthuisberg, a tertiary care setting.. 16 patients with clinically stable COPD (no acute exacerbation in the past 12 weeks; median age: 73 years (IQR: 60 to 75); median forced expiratory volume in the first second (FEV1): 45% predicted (IQR: 33 to 58)) and 14 patients who were admitted to a hospital due to an acute exacerbation of COPD (median age: 65 years (IQR: 59 to 74); median FEV1 on day 8 of hospital stay: 41% predicted (IQR: 33 to 54)).. None.. Circulating levels of C reactive protein, interleukin 6, interleukin 8 and insulin-like growth factor I were determined before, at the end and 2 and 30 minutes after a symptom-limited peak cycling test and before, at the end and 2 and 30 minutes after a symptom-limited constant-work-rate cycling test at 70% of the peak load. Non-significant changes in the circulating markers of inflammation and anabolism were found during or up to 30 minutes after ceasing the peak or constant-work-rate cycling exercise tests. The systemic responses of the hospitalized patients with COPD did not differ from those with clinically stable disease.. High-intensity cycling exercises did not increase the circulating levels of inflammatory markers in patients with chronic obstructive pulmonary disease, irrespective of their clinical stability.

Topics: Aged; Belgium; C-Reactive Protein; Cross-Sectional Studies; Exercise Tolerance; Female; Hospitals, University; Humans; Inpatients; Insulin-Like Growth Factor Binding Protein 1; Interleukin-6; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive

The study investigated the relationship between apoptosis of peripheral blood neutrophils during exacerbation of chronic obstructive pulmonary disease (COPD) and the inflammatory response that characterises this condition. Twenty-six hospitalised patients with COPD exacerbation and 13 controls were included. Three sequential blood and sputum samples were obtained from patients at admission, after 3 days and at discharge. Blood apoptotic neutrophils were measured by flow-cytometry and light microscopy. Serum and sputum levels of IL-6, IL-8 and TNF-alpha were determined by an immunoassay technique. We found a significantly reduced percentage of apoptotic neutrophils at the onset of COPD exacerbation which increased over time (1.1+/-0.4% at admission vs. 2.4+/-0.4% at discharge, P<0.0001). Patients presented no changes in serum cytokines neither during exacerbation nor in comparison to controls. In contrast, sputum levels of cytokines were significantly increased compared to serum levels. There was no significant correlation between the apoptotic neutrophils and the cytokine concentrations in serum or sputum. None of the clinical parameters, such as smoking, microbial infection, corticosteroids or hypoxemia showed a correlation with neutrophil apoptosis. No relationship could be found between the reduced percentage of apoptotic neutrophils in blood and serum concentration of IL-6, IL-8 and TNF-alpha or other clinical parameters in patients with COPD exacerbation.

Topics: Aged; Apoptosis; Female; Humans; Interleukin-6; Interleukin-8; Male; Neutrophils; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Sputum; Tumor Necrosis Factor-alpha

Cytokines are known to be increased in induced sputum in chronic obstructive pulmonary disease (COPD). In this study, the relationship between the levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumour necrosis factor-alpha (TNF-alpha) in induced sputum of patients with exacerbation of COPD, and the severity of the disease, pulmonary function tests (PFT), arterial blood gases (ABG) were studied. Twenty-four patients with exacerbation of COPD were included in the study. The patients were grouped according to their PFT into two as: Group 1 (FEV1 below 50% of the predicted value, severe-very severe COPD, n=12) and, Group 2 (FEV1 above 50% of the predicted value, mild-moderate COPD, n=12). The levels of IL-6, IL-8 and TNF-alpha in induced sputum of the subjects were measured. The mean levels of IL-6, IL-8 and TNF-alpha in induced sputum were found to be higher in Group 1 (severe-very severe COPD) than in Group 2 (mild-moderate COPD). The differences in IL-6 and IL-8 levels between groups were statistically significant (P<0.05). A significant correlation was observed between the IL-6 value and FEV(1) (r=-0.435, P=0.034), FEV1/FVC (r=-0.446, P=0.029), PaO2 (r=-0.711, P=0.000), SaO2 (r=-0.444, P=0.030) and disease duration (r=0.427, P=0.037), respectively. Also, the level of IL-8 in induced sputum was inversely correlated with FEV1 (r=-0.562, P=0.004), PaO2 (r=-0.540, P=0.006) and SaO2 (r=-0.435, P=0.034). However, all three cytokines were positively correlated with the smoking load (r=0.653, P=0.001; r=0.439, P=0.032; r=0.649, P=0.001). We conclude, therefore, that in exacerbated COPD cases with greater degrees of obstruction of the airways have higher levels of cytokines in induced sputum. This can be interpreted to mean that these cytokines are related to the clinical parameters like the ABG and PFT and seem to be the determinant of the severity of the disease.

Topics: Aged; Blood Gas Analysis; Forced Expiratory Volume; Humans; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Sputum; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) is a disease primarily caused by cigarette smoking, which in turn has been shown to affect the susceptibility to and progression of airway infections. The question addressed in this study was how components from cigarette smoke could affect the defence mechanisms of T-cells and epithelial cells, and thereby contribute to the development of the COPD pathology. T-cells and monocytes were isolated from buffycoats from healthy donors and T-cell responses studied in response to cigarette smoke extract (CSE). Activation level (CD25 expression), proliferation (BrdU incorporation) and intracellular expression of the cytotoxic markers granzyme-b and TIA-1 were determined using flowcytometry. Normal human bronchial epithelial cells were obtained from Cambrex and differentiated in air-liquid interface cultures. After exposure to CSE barrier function (trans-epithelial electric resistance, TEER), MUC5AC and interleukin-8 production were measured. T-cell activation, proliferation and expression of the cytotoxic proteins granzyme-b and TIA-1 were significantly reduced in response to 0.5-1% of CSE. The epithelial cells were more resistant to CSE and responded at doses 20 times higher than T-cells. The expression of interleukin-8 and MUC5AC was significantly increased after exposure to 15% and 30% CSE and TEER was largely unaffected at 30% CSE but clearly reduced at 40% CSE. This study shows that mechanisms, in both T-cells and airway epithelial cells, involved in the defence against infectious agents are modulated by CSE.

Topics: Bronchi; Cell Proliferation; Cells, Cultured; Epithelial Cells; Humans; Interleukin-8; Mucin 5AC; Mucins; Nicotiana; Pulmonary Disease, Chronic Obstructive; Smoke; Smoking; T-Lymphocytes

It is unclear how chronic expectoration influences airway inflammation in patients with chronic lung disease. The aim of this study was to investigate factors influencing inflammation in induced sputum samples, including, in particular, chronic sputum production. Myeloperoxidase, interleukin-8, leukotriene B4 (LTB4), neutrophil elastase, secretory leukoprotease inhibitor (SLPI) and protein leakage were compared in induced sputum samples from 48 patients (36 with chronic expectoration) with COPD (with and without alpha-1-antitrypsin deficiency; AATD), 9 individuals with AATD but without lung disease and 14 healthy controls. There were no differences in inflammation in induced sputum samples from healthy control subjects and from AATD deficient patients with normal lung function but without chronic expectoration (P>0.05). Inflammation in induced sputum from AATD patients with airflow obstruction and chronic sputum expectoration was significantly greater than for similar patients who did not expectorate: Interleukin-8 (P<0.01), elastase activity (P=0.01), and protein leakage (P<0.01). The presence of spontaneous sputum expectoration in AATD patients with airflow obstruction was associated with increased neutrophilic airway inflammation in induced sputum samples. The presence of chronic expectoration in some patients will clearly complicate interpretation of studies employing sputum induction where this feature has not been identified.

Topics: Adult; Aged; alpha 1-Antitrypsin Deficiency; Biomarkers; Bronchi; Case-Control Studies; Cough; Female; Humans; Inflammation; Interleukin-8; Leukotriene B4; Male; Middle Aged; Pancreatic Elastase; Peroxidase; Pulmonary Disease, Chronic Obstructive; Saline Solution, Hypertonic; Serum Albumin; Sputum

Cigarette smoke-mediated oxidative stress induces an inflammatory response in the lungs by stimulating the release of proinflammatory cytokines. Chromatin remodeling due to histone acetylation and deacetylation is known to play an important role in transcriptional regulation of proinflammatory genes. The aim of this study was to investigate the molecular mechanism(s) of inflammatory responses caused by cigarette smoke extract (CSE) in the human macrophage-like cell line MonoMac6 and whether the treatment of these cells with the antioxidant glutathione (GSH) monoethyl ester, or modulation of the thioredoxin redox system, can attenuate cigarette smoke-mediated IL-8 release. Exposure of MonoMac6 cells to CSE (1% and 2.5%) increased IL-8 and TNF-alpha production vs. control at 24 h and was associated with significant depletion of GSH levels associated with increased reactive oxygen species release in addition to activation of NF-kappaB. Inhibition of IKK ablated the CSE-mediated IL-8 release, suggesting that this process is dependent on the NF-kappaB pathway. CSE also reduced histone deacetylase (HDAC) activity and HDAC1, HDAC2, and HDAC3 protein levels. This was associated with posttranslational modification of HDAC1, HDAC2, and HDAC3 protein by nitrotyrosine and aldehyde-adduct formation. Pretreatment of cells with GSH monoethyl ester, but not thioredoxin/thioredoxin reductase, reversed cigarette smoke-induced reduction in HDAC levels and significantly inhibited IL-8 release. Thus cigarette smoke-induced release of IL-8 is associated with activation of NF-kappaB via IKK and reduction in HDAC levels/activity in macrophages. Moreover, cigarette smoke-mediated proinflammatory events are regulated by the redox status of the cells.

Topics: Cell Line, Tumor; Glutathione; Histone Deacetylases; Humans; I-kappa B Kinase; Interleukin-8; Leukemia, Monocytic, Acute; Macrophages; NF-kappa B; Oxidants; Oxidative Stress; Protein Processing, Post-Translational; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Smoking; Thioredoxin-Disulfide Reductase; Tumor Necrosis Factor-alpha

The inflammatory responses and associated clinical severity of COPD exacerbations are greatly variable, and the determinants of these factors are poorly understood. We examined the hypothesis that bacteria and viruses may modulate this heterogeneity and that interactions between bacterial and viral infection may affect changes in airway bacterial load and the clinical features and inflammatory responses of exacerbations in patients with COPD.. Prospective cohort study.. Outpatient Department, London Chest Hospital, London, UK.. Thirty-nine patients with COPD.. We prospectively studied 56 COPD exacerbations, obtaining clinical data and paired sputum and serum samples at baseline and exacerbation. Qualitative and quantitative microbiology, polymerase chain reaction detection for rhinovirus, and estimation of cytokine levels by enzyme-linked immunosorbent assay were performed.. A total of 69.6% of exacerbations were associated with a bacterial pathogen, most commonly Haemophilus influenzae. Rhinovirus was identified in 19.6% of exacerbations. The rise in bacterial load at exacerbation correlated with the rise in sputum interleukin (IL)-8 (r = 0.37, p = 0.022) and fall in FEV1 (r = 0.35, p = 0.048). Exacerbations with both rhinovirus and H. influenzae had higher bacterial loads (10(8.56) cfu/mL vs 10(8.05)cfu/mL, p = 0.018) and serum IL-6 (13.75 pg/mL vs 6.29 pg/mL, p = 0.028) than exacerbations without both pathogens. In exacerbations with both cold symptoms (a marker of putative viral infection) and a bacterial pathogen, the FEV1 fall was greater (20.3% vs 3.6%, p = 0.026) and symptom count was higher (p = 0.019) than those with a bacterial pathogen alone.. The clinical severity and inflammatory responses in COPD exacerbations are modulated by the nature of the infecting organism: bacterial and viral pathogens interact to cause additional rises in inflammatory markers and greater exacerbation severity.

Topics: Aged; Bacterial Infections; Common Cold; Female; Forced Expiratory Volume; Haemophilus Infections; Haemophilus influenzae; Humans; Interleukin-6; Interleukin-8; Male; Picornaviridae Infections; Pulmonary Disease, Chronic Obstructive; Respiratory System; Respiratory Tract Infections; Rhinovirus; Sputum

It has been suggested that patients with noneosinophilic asthma (NEA) show increased numbers of sputum neutrophils and a lack of response to therapy with corticosteroids, which are features that are commonly related to COPD. The aim of our study was to test the hypothesis that airway inflammation in NEA patients is different from that seen in patients with eosinophilic asthma (EA) and is similar to COPD.. Sputum cellular stress markers and neutrophilic and eosinophilic fluid-phase mediators were analyzed in asthma and COPD patients. NEA patients were identified based on a sputum eosinophil count of < or = 2.2% of the total nonsquamous cell count, and were compared to EA and COPD patients.. University Hospital of Heraklion, Department of Thoracic Medicine.. A total of 37 atopic asthmatic patients and 25 patients with COPD.. Sputum cell counts, cellular expression of heme oxygenase-1, inducible nitric oxide synthase, and nitrotyrosine, and sputum levels of eosinophilic cationic protein (ECP), myeloperoxidase (MPO), interleukin-8, and granulocyte macrophage colony-stimulating factor.. A total of 17 asthmatic patients (46%) belonged to the NEA group and 20 patients (54%) to the EA group. Patients with NEA showed no difference in neutrophil counts, fluid-phase mediators, or cellular stress markers compared to patients with EA. Compared to COPD patients, NEA patients showed the following significant differences: lower total cell counts (p < 0.03); lower neutrophil counts (p < 0.01); lower nitrotyrosine positive cell counts (p < 0.003); lower ECP levels (p < 0.005); lower MPO levels (p < 0.000); higher lymphocyte counts (p < 0.01); and higher macrophage counts (p < 0.03).. Despite low eosinophil counts, airway inflammation in NEA patients may share common features with that in EA patients but is distinct from COPD. Larger studies are needed to investigate further the clinical and inflammatory characteristics of NEA before we are able to categorize asthma patients into those with or without eosinophilic inflammation.

Topics: Aged; Asthma; Biomarkers; Cell Count; Eosinophil Cationic Protein; Eosinophils; Female; Forced Expiratory Volume; Humans; Immunohistochemistry; Inflammation; Interleukin-8; Male; Middle Aged; Oxidative Stress; Peroxidase; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Sputum

alpha(1)-Antitrypsin (AAT)-Z deficiency is a risk factor for the development of COPD. Compared to wild-type M, AAT-Z has an increased tendency to polymerize, rendering it inactive as a serine proteinase inhibitor. It has been demonstrated that wild-type M- and Z-deficiency AAT polymers are chemotactic for human neutrophils. However, our own studies dispute a proinflammatory role for polymerized AAT-M and AAT-Z, suggesting rather that they are predominantly antiinflammatory, exhibiting inhibitory effects on lipopolysaccharide-stimulated human monocyte activation. The discrepancies between these observations prompted us to re-examine the effects of AAT.. The effects of native and polymerized AAT-M and AAT-Z with varying levels of endotoxin contamination (0.08 to 2.55 endotoxin units [EU]/mg protein) on human neutrophil chemotaxis and interleukin (IL)-8 release, in vitro, were evaluated. Neither native nor polymerized (M- or Z-deficient) AAT contaminated with low levels of endotoxin (/= 0.88 EU/mg protein), and significant chemotaxis occurred when AAT was spiked with either endotoxin or zymosan. In support, native and polymeric AAT-M with low endotoxin contamination completely inhibited neutrophil IL-8 release triggered by the zymosan, while AATs with high endotoxin contamination strongly induced IL-8 release and did not inhibit zymosan-stimulated IL-8 release.. The proinflammatory effects of native and polymeric AAT may be critically dependent on the presence of other cell activators, bacterial or otherwise, while pure preparations of AAT appear to exert predominantly antiinflammatory activity.

Topics: Adult; Aged; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Biopolymers; Cell Culture Techniques; Chemotaxis; Humans; Interleukin-8; Lipopolysaccharides; Neutrophil Activation; Neutrophils; Pulmonary Disease, Chronic Obstructive; Saccharomyces cerevisiae; Zymosan

Topics: Aged; Biomarkers; C-Reactive Protein; Disease Progression; Forced Expiratory Volume; Humans; Inflammation; Interleukin-6; Interleukin-8; Leukocyte Count; Nasal Lavage Fluid; Peroxidase; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Sputum

Topics: Haemophilus influenzae; Humans; Inflammation; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Severity of Illness Index; Sputum

To study whether patients with chronic obstructive pulmonary disease (COPD) at the same level of flow limitation but with different clinical phenotypes present different degrees of systemic and/or pulmonary inflammation.. We studied 15 male smokers without COPD (control group) and 39 males with COPD in stable clinical condition. The COPD patients were assigned to 2 groups based on the ratio of carbon monoxide diffusing capacity (DLCO) to alveolar volume (DLCO/VA) expressed as a percentage as follows: a) mainly emphysema (n = 15) and b) mainly chronic bronchitis (n = 24). Classification was determined by comparing both clinical features and diagnostic images.. Mean (SD) concentrations of interleukin 8 (IL-8) and 8-isoprostane in exhaled breath condensate (EBC) were significantly lower in patients with mainly emphysema (IL-8, 0.34 [0.70] pg/mL; 8-isoprostane, 0.07 [0.26] pg/mL) than in patients with chronic bronchitis (IL-8, 2.32 [3.10] pg/mL; 8-isoprostane, 1.77 [2.98] pg/mL) or in the controls (IL-8, 3.14 [4.59] pg/mL; 8-isoprostane, 1.92 [2.84] pg/mL); P < .05 for IL-8 comparisons and P < .01 for 8-isoprostane. IL-8, leukotriene B4, and 8-isoprostano in EBC correlated significantly with DLCO/VA (% of predicted) (r = 0.30, P < .05; r = 0.29, P < or = .05; and r = 0.46, P < .01, respectively) but not with forced expiratory volume in 1 second. There was a negative correlation between EBC and serum levels of both IL-8 (r = -0.31; P < .05) and 8-isoprostane (r = -0.51; P < .001). The correlation between leukotriene B4 concentrations in EBC and serum was not significant, however. No significant differences were found between smokers' and ex-smokers' serum levels of IL-8, leukotriene B4, 8-isoprostane in serum or EBC.. The results indicate that COPD patients with an emphysematous phenotype have a less intense inflammatory response and less oxidative stress in the lung.

Topics: Carbon Monoxide; Diffusion; Dinoprost; Emphysema; Humans; Hydrogen-Ion Concentration; Interleukin-8; Leukotriene B4; Male; Middle Aged; Oxidative Stress; Phenotype; Pneumonia; Pulmonary Disease, Chronic Obstructive; Smoking

Lipoxins and 15-epi-lipoxins are lipid mediators that modulate leukocyte trafficking and promote the inflammation resolution. They are produced by different enzymatic pathways. Patients with severe asthma present ongoing airway inflammation despite chronic long-term treatment including oral glucocorticoids.. The aim of this study was to assess the presence of proinflammatory and anti-inflammatory mediators in the supernatants of induced sputum.. Induced sputum supernatants were collected from 10 normal subjects; 12 subjects with mild, 15 with moderate, and 24 with severe asthma; and 13 patients with chronic obstructive pulmonary disease. First, we validated the measurements of IL-8, leukotriene B 4 , lipoxin A 4 , and 15-epi-lipoxin A 4 in these samples. Then we measured these mediators by using immunoenzymatic methods.. IL-8 levels were highly increased in patients with severe asthma ( P < .0001), and leukotriene B 4 levels were significantly increased in patients with severe asthma and patients with chronic obstructive pulmonary disease. Lipoxin A 4 was significantly increased in the supernatant obtained from patients with mild asthma ( P < .0001), whereas 15-epi-lipoxin A 4 levels were higher in patients with severe asthma ( P = .05). More interestingly, we found a positive correlation between the level of lipoxin A 4 and IL-8 in patients with mild asthma.. These results indicate that induced sputum is a suitable method to assess lipoxin and 15-epi-lipoxin measurements in bronchi. The mechanisms involved in the synthesis of these 2 eicosanoid mediators would be helpful to understand better the imbalance between proinflammatory and anti-inflammatory mediators occurring in severe asthma. Lipoxin production involves interaction between lipoxygenases, whereas 15-epi-lipoxin production might involve CytP450 activity.

Topics: Adult; Asthma; Female; Humans; Interleukin-8; Leukotriene B4; Lipoxins; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Sputum

COPD is characterised by damage to small airways due to an inflammatory process as well as an imbalance between oxidants and antioxidants. Several cytokines and cell adhesion molecules enhancing a mainly neutrophilic inflammation have been associated with COPD. The aim of the study was to investigate whether inflammation or oxidative markers gave an indication of the course of COPD during an exacerbation. Fourteen patients with moderate to severe COPD admitted to the St. Antonius Hospital because of an exacerbation have been monitored during treatment with prednisolone 50 mg intravenously during 24 h at admission, reduced to 25 mg at day 3 and tapered off with oral prednisolone at day 7. On three separate occasions, day 1, 3 and 7, H2O2 in exhaled air, IL-8 and the soluble cell adhesion molecule sICAM and sE-selectin in serum were measured. We compared the patients at day 1 with healthy controls (in both non-smokers and smokers). Furthermore, we examined the changes from the study group in time during therapy. At admission all the markers were raised in comparison with the control groups. During treatment H2O2 concentrations in breath condensate declined significantly (P<0.001) as well as IL-8 and sICAM in serum (P=0.002, respectively, P<0.001). There was no significant change in sE-selectin (P=0.132). No significant improvement has been found in spirometry. These data suggest that the markers H2O2 in exhaled air, IL-8 and sICAM in serum are suitable markers in monitoring exacerbated COPD.

Topics: Aged; Anti-Inflammatory Agents; Breath Tests; Cell Adhesion Molecules; Drug Monitoring; Female; Humans; Hydrogen Peroxide; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Middle Aged; Oxidative Stress; Prednisolone; Pulmonary Disease, Chronic Obstructive

Anemia in patients with COPD and its pathophysiology is an understudied issue.. In a group of 101 COPD patients (FEV(1) percentage of predicted, 37 +/- 2% [mean +/- SEM]; mean age, 61 +/- 1 years; 35% female gender), the prevalence of anemia and its relationship to body mass and weight loss, inflammatory parameters, and erythropoietin levels was determined. Data were compared to a control group (healthy persons with matched age) in order to identify potential factors that may influence the development of anemia in patients with COPD.. Anemia was diagnosed in 13 patients (hemoglobin levels < 13.5 mg/dL in male patients and < 12.0 mg/dL in female patients), which represents a prevalence of 13%. Anemic COPD patients showed elevated erythropoietin levels (41.8 +/- 25.4 U/L vs 16.3 +/- 2.9 U/L) and an increased inflammatory response compared to nonanemic patients. A significant inverse correlation of hemoglobin vs erythropoietin (r = - 0.84, p < 0.01) was observed in anemic COPD patients, but not in the nonanemic group.. Anemic COPD patients show high erythropoietin levels, which may indicate presence of erythropoietin resistance. The latter may be mediated through inflammatory mechanisms, which is typical for anemia of chronic illness.

Topics: Anemia; Body Mass Index; Erythropoietin; Female; Forced Expiratory Volume; Hemoglobins; Humans; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Vital Capacity; Weight Loss

A study was undertaken to assess both oxidative stress and inflammation in the lungs of patients with chronic obstructive pulmonary disease (COPD) during severe and very severe exacerbations compared with those with stable COPD, healthy smokers, and non-smokers. Two sites within the lungs were compared: the large airways (in sputum) and the peripheral airways (by bronchoalveolar lavage (BAL)).. BAL fluid cell numbers and levels of tumour necrosis factor (TNFalpha) and interleukin (IL)-8 were measured as markers of airway inflammation and glutathione (GSH) levels as a marker of antioxidant status. Nuclear translocation of the pro-inflammatory transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) were also measured by electromobility shift assay in BAL fluid leucocytes and lung biopsy samples.. Influx of inflammatory cells into the peripheral airways during exacerbations of COPD was confirmed. Increased IL-8 levels were detected in BAL fluid from patients with stable COPD compared with non-smokers and healthy smokers, with no further increase during exacerbations. In contrast, IL-8 levels in the large airways increased during exacerbations. GSH levels were increased in the BAL fluid of smokers (444%) and patients with stable COPD (235%) compared with non-smokers and were reduced during exacerbations (severe 89.2%; very severe 52.3% compared with stable COPD). NF-kappaB DNA binding in BAL leucocytes was decreased in healthy smokers compared with non-smokers (41.3%, n = 9, p<0.001) but did not differ in COPD patients, whereas AP-1 DNA binding was significantly decreased during exacerbations of COPD.. There is evidence of increased oxidative stress in the airways of patients with COPD that is increased further in severe and very severe exacerbations of the disease. This is associated with increased neutrophil influx and IL-8 levels during exacerbations.

Topics: Bronchitis; Bronchoalveolar Lavage Fluid; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Male; Middle Aged; NF-kappa B; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Airway infection with Haemophilus influenzae causes airway inflammation, and isolation of new strains of this bacteria is associated with increased risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD).. To determine whether strains of H. influenzae associated with exacerbations cause more inflammation than strains that colonize the airways of patients with COPD.. Exacerbation strains of H. influenzae were isolated from patients during exacerbation of clinical symptoms with subsequent development of a homologous serum antibody response and were compared with colonization strains that were not associated with symptom worsening or an antibody response. Bacterial strains were compared using an in vivo mouse model of airway infection and in vitro cell culture model of bacterial adherence and defense gene and signaling pathway activation in primary human airway epithelial cells.. H. influenzae associated with exacerbations caused more airway neutrophil recruitment compared with colonization strains in the mouse model of airway bacterial infection. Furthermore, exacerbation strains adhered to epithelial cells in significantly higher numbers and induced more interleukin-8 release after interaction with airway epithelial cells. This effect was likely mediated by increased activation of the nuclear factor-kappaB and p38 mitogen-activated protein kinase signaling pathways.. The results indicate that H. influenzae strains isolated from patients during COPD exacerbations often induce more airway inflammation and likely have differences in virulence compared with colonizing strains. These findings support the concept that bacteria infecting the airway during COPD exacerbations mediate increased airway inflammation and contribute to decreased airway function.

Topics: Acute Disease; Aged; Animals; Bacterial Adhesion; Female; Haemophilus Infections; Haemophilus influenzae; Humans; In Vitro Techniques; Interleukin-8; Longitudinal Studies; Male; Mice; Middle Aged; Neutrophils; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Pneumonia; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa

The upper and lower airways are continuous. While upper airway symptoms are common in COPD patients, with accumulating evidence to suggest increased nasal inflammation, the relationships among upper airway, lower airway, and systemic inflammatory indexes have not been studied. We aimed to confirm that there is heightened nasal inflammation in COPD patients, to test the hypothesis that the degree of upper airway inflammation relates to the degree of lower airway inflammation, and to investigate the underlying associations with bacterial carriage and the systemic inflammatory response.. Prospective cohort study.. Outpatient Department, London Chest Hospital, London, UK.. Forty-seven patients with COPD and 12 control subjects of similar age, sex, and smoking status.. Serum, nasal wash fluid, and sputum samples were obtained from 47 stable patients with COPD for the analysis of inflammatory indexes and bacterial colonization. Nasal wash fluid specimens were obtained from 12 control subjects.. COPD patients had an increased nasal interleukin (IL)-8 concentration compared to control subjects (difference, 97.2 pg/mL; p = 0.009). The nasal IL-8 concentration in COPD patients correlated with that in sputum (r = 0.30; p = 0.039). In both the upper and lower airways of patients with COPD, the IL-8 concentration was associated with indexes of bacterial colonization. Patients colonized with a sputum potentially pathogenic microorganism had a higher total nasal bacterial load (difference, 1.5 log cfu/mL; p = 0.016). We did not find significant relationships between the degree of upper or lower airway inflammation, or bacterial carriage, and the systemic inflammatory response.. COPD is associated with an increased nasal concentration of the neutrophil chemoattractant protein IL-8, the degree of which reflects that present in the lower airway. A relationship between lower airway bacterial colonization, postnasal drip, and higher nasal bacterial load may suggest a mechanism underlying this finding. This study is the first to report a correlation between the degree of upper and lower airway inflammation in COPD.

Topics: Aged; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Nasal Lavage Fluid; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Sputum

To explore the inhibitory mechanism of phosphodiesterase(PDE) inhibitor on expression of IL-8 mRNA in peripheral blood mononuclear cells (PBMCs) from chronic obstructive pulmonary disease(COPD) patients.. PBMCs isolated from 20 COPD patients and 15 healthy subjects were co-cultured with non-selective inhibitor theophylline or PDE type IV inhibitor Rolipram. The expression of IL-8 mRNA was assayed by RT-PCR. The expression of NF-kappaB was determined by immunocytochemical staining. The content of I-kappaB protein was detected by Western blot.. The expression of IL-8 mRNA was elevated and the percentage of NF-kappaB nucleus positive cells was higher in COPD patients than in normal controls(P<0.01), while the expression of I-kappaB was lower in COPD patients (P<0.01). Theophylline of 1 mmol/L caused a decrease in the percentage of NF-kappaB nucleus positive cells (P<0.05). The expression of IL-8 mRNA and I-kappaB were not affected by theophylline at the dose of 100 micromol/L or 1 mmol/L. Rolipram inhibited the expression of IL-8 mRNA and the activation of NF-kappaB(P<0.05).. The results indicated that IL-8 mRNA may play a pathogenic role in the development of COPD and that selective PDE type IV inhibitor Rolipram inhibit the expression of IL-8 mRNA via NF-kappaB.

Topics: Adult; Aged; Female; Gene Expression Regulation; Humans; I-kappa B Proteins; Interleukin-8; Leukocytes, Mononuclear; Male; Middle Aged; NF-kappa B; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; RNA, Messenger

Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammation in the pulmonary tissue. The disease is associated with a switch from a self-limiting inflammatory response, mainly initiated by smoke inhalation, to a chronic persistent inflammatory response after prolonged interaction with cigarette smoke. The development and progression of chronic obstructive pulmonary disease have been associated with increased oxidative stress and reduced antioxidant resources. As a result, the antioxidant capacity decreases in COPD patients. Additionally, there is an imbalance between the release of proteases and of endogenous anti-protease enzymes that prevent elastin digestion. The inflammatory basis of COPD is now well established. In patients with COPD increased numbers of macrophages and neutrophils have been found in induced sputum, the former predominating in mild disease. Biopsy data confirm these observations but also demonstrate increased numbers of CD8-positive T- lymphocytes in the airway wall, which may have a role in the regulation of the inflammatory response to cigarette smoke. The extent of the inflammatory reaction is correlated with the severity of the disease. An imbalance between pro- and anti-inflammatory cytokines may favour this process. Several mediators are involved in COPD including leukotriene B4 (LTB4), tumor necrosis factor alpha (TNF-alpha), and interleukin8 (IL-8). They are selective attractants of neutrophils and regulate the ongoing inflammatory process. The whole process would be predicted to be self-perpetuating leading to a chronic inflammatory state with associated airway remodelling and progressive lung function decline.

Topics: Antioxidants; Bronchoalveolar Lavage Fluid; Cytokines; Humans; Inflammation; Inflammation Mediators; Interleukin-8; Leukotrienes; Oxidants; Oxidative Stress; Peptide Hydrolases; Pulmonary Disease, Chronic Obstructive; Smoking; Sputum; T-Lymphocytes; Tumor Necrosis Factor-alpha

Beta2-agonists and glucocorticosteroids are two common treatments for COPD and they are often used in combination. Glucocorticosteroids mediate the anti-inflammatory response through the glucocorticosteroid receptors (GRs). Beta2-agonists are potent bronchodilators but they can have some anti-inflammatory properties by elevating the level of intracellular cAMP. In this study we aimed to investigate the anti-inflammatory effect of combination therapy in vitro.. Neutrophils or the bilayer of endothelial and epithelial cells were preincubated with salbutamol, budesonide or budesonide followed by salbutamol. FMLP-induced IL-8, elastase release and neutrophil migration through the bilayer was measured.. Salbutamol at concentrations of 10(-4), 10(-5) and 10(-9) M inhibited IL-8, elastase release and migration of neutrophils in an inverse bell-shaped concentration-response manner. When given after budesonide (10(-9) and 10(-8)M), the inhibitory effect on migration was additive. This additive effect was not observed for elastase and IL-8 release.. Salbutamol inhibits neutrophil migration and IL-8 and elastase release in a concentration-dependent manner. Preincubation with low concentration of budesonide enhanced the inhibition of migration achieved by low concentrations of salbutamol.

Topics: Adrenergic beta-Agonists; Albuterol; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epithelial Cells; Humans; Interleukin-8; Neutrophil Infiltration; Neutrophils; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive

Pulmonary disease in cystic fibrosis (CF) is characterized by an exaggerated interleukin (IL)-8-driven, neutrophilic, inflammatory response to infection. Binding of IL-8 to heparan sulfate (HS)-containing proteoglycans (HSPG) facilitates binding of the chemokine to its specific receptor, stabilizes and prolongs IL-8 activity, and protects it from proteolysis. We hypothesized that increased expression of HSPG contributes to the sustained inflammatory response in CF bronchial tissue.. Our objectives were to analyze the distribution and abundance of IL-8 and HS, in intact and cleaved forms, in bronchial tissue from adult patients with CF or chronic obstructive pulmonary disease (COPD) and a control group without inflammatory airway disease.. Immunostaining and quantitative image analysis were applied to ethanol-fixed and paraffin-embedded tissue obtained at transplant in patients with CF or COPD, or postmortem in the control group.. Quantitative immunohistochemical analysis demonstrated significant disease-related differences. Intact HS was significantly more abundant in epithelial and endothelial basement membranes in CF than in COPD or the control group. Conversely, cleaved HS was significantly more abundant in COPD than the other groups. More IL-8-positive blood vessels were observed in CF and COPD compared with the control group, whereas more extensive IL-8 expression in the epithelium was observed in CF compared with COPD.. Sustained neutrophil recruitment in the CF airway may therefore be related not only to increased IL-8 expression but also to the increased stability and prolonged activity and retention of IL-8 when it is bound to HSPG in bronchial tissue.

Topics: Adult; Cystic Fibrosis; Endothelium, Vascular; Female; Heparan Sulfate Proteoglycans; Humans; Immunohistochemistry; Interleukin-8; Male; Middle Aged; Neutrophil Infiltration; Pulmonary Disease, Chronic Obstructive

Topics: Administration, Inhalation; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Dose-Response Relationship, Drug; Dyspnea; Humans; Interleukin-8; Neutrophil Activation; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8A; Respiratory Function Tests

Airway inflammation is the main pathophysiological feature of patients with chronic obstructive pulmonary disease (COPD). Interleukin-8 (IL-8) is a potent chemoattractant for neutrophils and eosinophils. Increased IL-8 levels were observed in bronchoalveolar lavage (BAL) and induced sputum in patients with COPD. To evaluate the role of the IL-8 gene, we genotyped blood samples of 122 COPD-patients and 385 healthy controls for a known polymorphism in the promoter region (-251 A/T) of the IL-8 gene. Additionally, we screened the coding region for further polymorphisms by SSCP analyses. Comparison of the allele and genotype frequencies among each group revealed no significant differences between patients and controls. Although IL-8 plays an important role in the chemotaxis of inflammatory cells, the polymorphisms investigated here do not seem to be involved in the genetic predisposition to COPD.

Topics: Adult; Aged; Aged, 80 and over; Bronchoalveolar Lavage Fluid; Female; Genetic Predisposition to Disease; Humans; Interleukin-8; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic; Pulmonary Disease, Chronic Obstructive; Sputum

Low-grade systemic inflammation may cause a chronic catabolic state that may affect trainability in patients with COPD as has been seen previously in healthy elderly. Therefore, the aim of the present study was to study the relationship between baseline circulating levels of inflammatory markers and the response to exercise training in clinically stable patients with COPD.. An open prospective intervention study.. Tertiary care setting, University Hospital Gasthuisberg, Leuven, Belgium.. Seventy-eight clinically stable outpatients with COPD.. A 12-week outpatient exercise-training program consisting of strengthening and endurance types of exercises.. Circulating levels of inflammatory markers were assessed at baseline. Moreover, lung function, quadriceps force (QF), peak and functional exercise capacity, and health-related quality of life were determined at baseline and after the intervention. Sixty-five of the 78 consecutive outpatients completed the study protocol. QF, peak and functional exercise capacity and health-related quality of life improved significantly compared to baseline. The absolute changes in health-related quality of life showed weak relationships with baseline circulating levels of interleukin-8 (CXCL8) in the whole group (n = 65; r= -0.26; p = 0.04). In addition, soluble tumor necrosis factor receptor p55 was strongly and positively related to the absolute changes in QF in the female patients only (n = 18; r = 0.81; p = 0.0001), while CXCL8 was inversely related to the absolute change in the total score of the Chronic Respiratory Disease Questionnaire (r= -0.65; p = 0.004).. Baseline markers of low-grade systemic inflammation did not clearly explain the variances in absolute changes in QF, the distance walked in 6 min, peak external load, or health-related quality of life following a 12-week exercise-training program. Hence, they seem not very constructive in the characterization of patients with advanced COPD who do or do not respond to exercise training.

Topics: Aged; Chemokines, CXC; Exercise Therapy; Female; Humans; Inflammation Mediators; Interleukin-8; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Sex Factors; Tumor Necrosis Factor-alpha

Exacerbations often complicate the progressive course of chronic obstructive pulmonary disease (COPD), mainly due to infectious agents. The precise role of bacterial infections in the course and the pathogenesis of COPD has been a source of controversy for decades. Also viruses and other non-infectious causes of exacerbation play a relevant role and also contribute to persisting airway inflammation. Usually, the etiologic identification of the infective causes of COPD require considerable time and costs. The development of more rapid, reliable, and widely applicable methods to promptly define the etiology of COPD exacerbations should represent a relevant issue in devising earlier and more specific strategies for their effective therapeutic control.. Of the study was to assess the predictive role of some pro-inflammatory cytokines measured in spontaneous bronchial secretions in discriminating the main infectious causes of COPD exacerbations.. 124 subjects with moderate COPD (51-79 y; mean basal FEV1 = 49.6% pred. +/- 4.6 sd; FEV1 reversibility +3.9% from baseline +/- 4.8 sd after salbutamol 200 mcg) were studied during acute exacerbation. Respiratory viruses were isolated from bronchial secretions in 21 cases; common bacteria (CFU > or = 10(6)/ml) in 28 cases; Pseudomonas Aeruginosa (Ps.Ae.; CFU > or = 10(6)/ml) in 20 cases. The cytokines IL1beta, IL8, and TNFalpha (pg/ml; Immulite; Diagnostic Product Corp, Los Angeles, CA, USA), and neutrophils (% total count) were measured in bronchial secretions of all patients.. A two-stage logistic model was chosen for discriminating the different causes of COPD exacerbations (such as: non-infectious, or viral, bacterial, or due to Ps.Ae.).. At the first decisional step, the two-stage logistic model proved that TNFalpha levels in bronchial secretions recognise clearly patients belonging to the Ps.Ae. group from those of all other groups (Area under ROC curve = 0.96; 95% CI = 0.91-0.99), and that, at the second decisional step, IL8 + IL10 levels discriminate patients with bacterial causes (such as all bacteria) from the non-infected ones and from those with a viral cause of exacerbation (Area under ROC curve = 0.87; 95% CI = 0.77-0.94). Neutrophil percent count did not support any contribution in discriminating the different subgroups of COPD subjects.. When exacerbated, COPD subjects express different patterns of pro-inflammatory mediators in bronchial secretions, which appear modulated according to the etiological cause of the exacerbation. In particular, TNFalpha concentration per se enables recognition of COPD exacerbations due to Ps.Ae., while IL8 + IL1beta levels prove helpful in discriminating those to common bacteria from those to viral agents and to non-infectious causes. When present data are further confirmed, the use of a decisional rule based on cytokine measurements might be regarded as a helpful predictive tool. As measures of pro-inflammatory cytokines are low-cost, simple, and faster to perform, they could support rapid clinical decision making at the bedside regarding therapeutic strategy for COPD exacerbations, in particular when they are needed for severe COPD patients.

Topics: Aged; Bacteria; Bronchi; Female; Humans; Interleukin-1beta; Interleukin-8; Logistic Models; Male; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Sputum; Tumor Necrosis Factor-alpha; Viruses

An early response to cigarette smoke is an influx of leukocytes into the lung. Alveolar epithelial type II (ATII) cells may contribute by releasing chemokines in response to cigarette smoke and neutrophil elastase (NE). Human ATII cells were purified from normal regions of lungs resected for carcinoma (n = 14). In vitro, these cells exhibited ATII cell characteristics: lamellar bodies, apical microvilli, tight junctions, and expressed surfactant apoprotein C. Basal ATII cell release of five chemokines ranked as follows: monocyte chemotactic protein (MCP)-1 > interleukin (IL)-8 > growth-related oncogene (GRO)-alpha > macrophage inflammatory protein (MIP)-1alpha > regulated on activation, normal T cell expressed and secreted (RANTES). MIP-1alpha and RANTES were often not detectable. After stimulation with a mixture of lipopolysaccharide/endotoxin (LPS), tumor necrosis factor-alpha, IL-1beta, and IFN-gamma, MCP-1 and IL-8 secretion rose 4-6-fold, whereas GRO-alpha rose 25-fold. NE stimulated IL-8 mRNA expression, and 10nM NE stimulated IL-8 secretion; however, 100 nM NE caused a decrease in extracellular IL-8, MCP-1, and GRO-alpha, attributed to proteolysis. Cigarette smoke extract (CSE) inhibited IL-8 mRNA expression and release of all chemokines. Glutathione protected against the effects of CSE, suggesting oxidative mechanisms. GRO-alpha, important in growth and repair, was sensitive to both stimulation, by LPS:cytokines, and inhibition, by CSE. Thus, contrary to the original hypothesis, high concentrations of NE and CSE resulted in reduced extracellular chemokine levels. We hypothesize that reduced ATII cell-derived chemokine levels compromise alveolar repair, contributing to cigarette smoke-induced alveolar damage and emphysema.

Topics: Aged; Cells, Cultured; Chemokines; Epithelial Cells; Female; Humans; Interleukin-8; Leukocyte Elastase; Lipopolysaccharides; Male; Middle Aged; Monocytes; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; Smoking; Up-Regulation

The inflammatory chemokines interleukin-8, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1, are reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Although bronchiolar epithelial cells and macrophages are known to be the cellular sources, the relative contribution of each cell type remains to be elucidated. In the present study, we first quantified cytokine mRNA in human bronchiolar epithelial cells and macrophages obtained using laser-capture microdissection and explored the relationship with early-stage COPD. Only in bronchiolar epithelial cells were interleukin-8, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1 mRNA levels higher in smokers with airflow limitation and/or emphysema than those in never-smokers or smokers without either airflow limitation or emphysema. No difference was observed in macrophages. Complementary DNA (cDNA) array further revealed the overexpression of CC chemokine receptor 2 in bronchiolar epithelial cells from smokers with airflow limitation and/or emphysema. This study supports the role of bronchiolar epithelium as the source of increased inflammatory chemokine levels in the early development of COPD and also demonstrates the potential use of laser-capture microdissection, combined with reverse transcriptase-polymerase chain reaction and cDNA microarrays, to investigate functional profiles of individual structural and inflammatory cells in human lungs.

Topics: Adult; Aged; Aged, 80 and over; Bronchi; Chemokine CCL2; Chemokine CCL4; Emphysema; Epithelial Cells; Female; Gene Expression Profiling; Humans; Interleukin-8; Lasers; Macrophage Inflammatory Proteins; Macrophages; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Pulmonary Disease, Chronic Obstructive; Reverse Transcriptase Polymerase Chain Reaction; Smoking; Surveys and Questionnaires

The management of stable patients with COPD depends on the severity of symptoms and airflow limitation. Regarding inflammation, corticosteroids are the only medications that are recommended for use, and only under restricted circumstances. Corticosteroids tend to undertreat or overtreat patients with COPD when only clinical manifestations and the findings of simple spirometry are considered. Accordingly, our aim was to survey the characteristics of airway inflammation in stable COPD patients, and to assess the interrelations among inflammatory cells, inflammatory mediators, bronchodilator reversibility, and pulmonary function. Factors related to airway inflammation and bronchodilator reversibility may be important in the management of stable COPD patients.. A total of 88 stable patients with smoking-related COPD were recruited into the study. All patients were steroid-free, and had been treated with theophylline, oral beta(2)-agonist agents, anticholinergic agents, and possibly mucolytic agents. Bronchodilator tests and sputum induction were performed to evaluate bronchodilator reversibility, and numbers of inflammatory cells and mediators (eg, interleukin [IL]-8, eotaxin, and regulated on activation, normal T cells expressed and secreted [RANTES]).. Thirty-one of 48 patients (64.6%) who had bronchodilator reversibility, and 19 of 40 patients (47.5%) without bronchodilator reversibility had sputum eosinophilia (median, 8.0% and 7.0%, respectively). FEV(1) showed a significant inverse correlation with the number of sputum neutrophils. The correlation coefficient for postbronchodilator FEV(1) vs the percentage of neutrophils in patients with nonreversible COPD was higher than that in those with reversible COPD. The levels of IL-8 were closely associated with the percentage of neutrophils. The sputum concentrations of IL-8 and albumin were significantly higher in patients with nonreversible COPD than in those with reversible COPD. A significant inverse correlation was found between bronchodilator response (ie, DeltaFEV(1) and DeltaFVC) and prebronchodilator FEV(1).. Eosinophilic inflammation may play a substantial role in COPD, while neutrophils and IL-8 may have a great influence on nonreversible obstructive airways. The assessment of airway inflammation and bronchodilator responses can help the selection of specific therapies and the prediction of clinical outcomes for COPD patients.

Topics: Aged; Albumins; Bronchodilator Agents; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Interleukin-8; Male; Neutrophils; Pulmonary Disease, Chronic Obstructive; Respiratory System; Sputum

Inhaled glucocorticoids may decrease exacerbations in some patients with COPD, and oral glucocorticoids may improve FEV(1) and shorten hospital stay during exacerbations. The mechanism of these improvements is unknown. This study examines the effect of oral glucocorticoids on markers of neutrophilic airway inflammation.. Eighteen patients with COPD received oral prednisone, 0.5 mg/kg/d for 2 weeks. Clinical status, lung function measurements, and sputum induction were performed before and after treatment with oral prednisone. Levels of the neutrophil chemoattractant (interleukin-8 [IL-8]) and neutrophil activation marker (myeloperoxidase [MPO]) were measured in the supernatant of induced sputum by enzyme-linked immunosorbent assay.. Levels of MPO decreased significantly after treatment with prednisone (p = 0.0004): before treatment median, 2.54 microg/mL (range, 1.49 to 12.58 microg/mL); after treatment median, 1.79 microg/mL (range, 1.32 to 3.57 microg/mL). Treatment with prednisone did not influence the levels of IL-8.. The treatment of patients with COPD with oral glucocorticoids decreases the activation of neutrophils, which may be partially responsible for clinical improvement in these patients.

Topics: Administration, Oral; Enzyme-Linked Immunosorbent Assay; Female; Glucocorticoids; Humans; Interleukin-8; Male; Neutrophil Activation; Peroxidase; Prednisone; Pulmonary Disease, Chronic Obstructive; Sputum

To study the role of interleukin-9 in the airway inflammation from patients with COPD.. Induced sputum was obtained from 30 COPD patients with stable disease(group A),31 asthmatics patients with stable disease(group B) and 15 healthy individuals(group C). IL-9,IL-5 and IL-8 in sputum supernatants were measured by sandwich enzyme-linked immunosorbent assay(ELISA) and IL-9 positive expression and quantitative analysis were conducted by Streptavidin peroxidase method and image analysis technology.. The levels of IL-9 in group A and B were all significantly higher than those in groups C. IL-9 positive expression mainly located in the cytoplasm of macrophages. The positive rates of IL-9 in group A and B were all significantly higher than that of group C (chi(2)=20.821, 19.908, P<0.001 . The percentage of neutrophil and the level of IL-8 in group A was significantly higher than those of groups B and C. The level of IL-9 was positively correlated with the number of macrophages in group A(r=0.407,P=0.039).. The level of IL-9 from the patients with COPD was significantly higher than that of healthy individuals and correlated with the number of macrophages and the level of IL-8. This suggests that IL-9 may be used as a new diagnostic marker in airway inflammation of COPD.

Topics: Adult; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Interleukin-9; Macrophages; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Sputum

Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lungs with little or no response to glucocorticoids and a high level of oxidative stress. Histone deacetylase (HDAC) activity is reduced in cells of cigarette smokers, and low concentrations of theophylline can increase HDAC activity. We measured the effect of theophylline on HDAC activity and inflammatory gene expression in alveolar macrophages (AM) from patients with COPD. AM from normal smokers showed a decrease in HDAC activity compared with normal control subjects, and this was further reduced in COPD patients (51% decrease, P < 0.01). COPD AMs also showed increased basal release of IL-8 and TNF-alpha, which was poorly suppressed by dexamethasone. Theophylline induced a sixfold increase in HDAC activity in COPD AM lysates and significantly enhanced dexamethasone suppression of induced IL-8 release, an effect that was blocked by the HDAC inhibitor trichostatin A. Therefore, theophylline might restore steroid responsiveness in COPD patients.

Topics: Aged; Blotting, Western; Bronchodilator Agents; Enzyme-Linked Immunosorbent Assay; Female; Glutathione; Histone Deacetylases; Humans; Hydroxamic Acids; Immunohistochemistry; Inflammation; Interleukin-8; Lipopolysaccharides; Macrophages; Male; Middle Aged; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Smoking; Steroids; Theophylline; Tumor Necrosis Factor-alpha; U937 Cells

Topics: Antibodies, Monoclonal; Clinical Trials as Topic; Humans; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8A; Treatment Outcome

Asthma is a chronic inflammatory disease of the airways in which many cell types play a role. Although the most important cells are eosinophils, there are suggestions that also neutrophils may play a role in asthma. The aim of the study was to measure and compare chemotactic activity of neutrophils in patients with severe asthma and with COPD. We examined 49 patients with severe asthma and 23 patients with COPD. The mean number of neutrophils in peripheral blood of 20 asthmatics with irreversible airflow obstruction was 3.96 x 10(6)/ml. The chemotactic activity of neutrophils to FMLP was 2.69 SEM +/- 0.4, to IL-8 in concentration 10-7 microg/ml - 1.64, SEM +/- 0.2, and to IL-8 in concentration 10-8 microg/ml - 1.17, SEM +/- 0.1. The mean number of neutrophils in 29 asthmatics with reversible airflow obstruction was 3.08 x 10(6)/ml. Their chemotactic activity to fMLP was 1.7, SEM +/- 0.1 to IL-8 in concentration 10-7 microg/ml - 1.51. SEM +/- 0.2, and to IL-8 in concentration 10-8 microg/ml - 1.08, SEM +/- 0.1. The mean number of neutrophils in COPD patients was 4.05 x 10(6)/ml and their chemotactic activity to FMLP was 1.9, SEM +/- 0.1 to IL-8 - 1.35, SEM +/- 0.1. All asthmatic patients were treated with inhaled corticosteroids and some of them with oral corticosteroids. Despite of that treatment the number of neutrophils isolated from patients with asthma with irreversible airflow obstruction was almost the same like in COPD patients and chemotactic activity of neutrophils in this group was the highest. We concluded that corticosteroids treatment did not diminished chemotactic activity of neutrophils isolated from patient suffering from asthma with irreversible airflow obstruction.

Topics: Adolescent; Adult; Asthma; Chemotaxis, Leukocyte; Child; Child, Preschool; Female; Humans; Interleukin-8; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index

To investigate the correlations between chymase activity, levels of tryptase, interleukin-8 (IL-8), eotaxin, neutrophil and eosinophil numbers in the sputum of elderly patients with chronic obstructive pulmonary disease (COPD) and their clinical implications.. A total of 73 elderly patients with COPD (21 severe, 21 moderate and 31 mild) were recruited into the study. IL-8 and eotaxin levels were detected with Sandwich enzyme-linked immunosorbent assay (ELISA) procedures and tryptase levels were measured with antibody against tryptase with Uni CAP system. Chymase activity was determined spectrophotometrically (410 nm) by the rate of hydrolysis of 0.7 mmol/L N-succinyl-L-Ala-L-Ala-L-Pro-L-Phe-p-nitroanilide (SAAPP) in NaCl 1.5 mol/L and Tris 0.3 mol/L The specific activity of chymase was expressed as mU/ml. Actions of protease inhibitors on chymase activities were also examined with enzyme assay.. (1) At acute attack stage, the sputum levels of tryptase of patients with severe, moderate and mild COPD were 284.0, 215.0 and 59.5 ng/L, respectively. The sputum levels of tryptase in the severe and moderate patients were greater than that in mild patients (P <0.01). The tryptase levels in the sputum of all patients were significantly decreased following treatment( 151.0, 92.0, 3.3 ng/L respectively; P <0. 01). At acute attack stage, the sputum levels of IL-8 and eotaxin were 1 299. 8,454. 9,78.7 ng/L; 22.7, 15.1, 7.4 ng/L, respectively. Severe and moderate-patients were greater than that of patients at mild stages. At convalescent stage,the sputum levels of IL-8 and eotaxin were 1 037. 5,326.6, 67.9 ng/L; 7.9, 6.3, 6.8 ng/L, respectively. The IL-8 and eotaxin levels in the sputum of severe and moderate patients were significantly decreased following treatment (P < 0.01). (2) The specific chymase activities of severe and moderate patients were higher than mild patients. Native protease inhibitors alpha1-antitrypsin (alpha1-AT) and soy bean trypsin inhibitor (SBTI) inhibited 83% and 89% enzymatic chymase activity, respectively. (3) The numbers of neutrophils and eosinophils in sputum were increased in patients with COPD at the acute stage compared with the mild convalescent stage. At all remission stages, the elevated numbers of cells were significantly reduced. (4) At acute attack stage of patients with COPD, there were correlations between the sputum levels of tryptase, IL-8, eotaxin, neutrophils and eosinophils; and there were correlations between the sputum levels of tryptase, chymase and neutrophils.. COPD is not merely a neutrophil associated disease, but mast cells, eosinophils and their released mediators also actively contribute to the pathogenesis of the disease.

Topics: Aged; Aged, 80 and over; Chemokine CCL11; Chymases; Eosinophils; Humans; Interleukin-8; Mast Cells; Neutrophils; Pulmonary Disease, Chronic Obstructive; Sputum; Tryptases

Neutrophilic inflammation is a major feature of COPD. Induced sputum is increasingly used to monitor inflammatory airway diseases. Although short-term repeatability of selected sputum markers has been extensively studied in several populations, data on the long-term repeatability of induced sputum markers in stable COPD are scant.. Sputum supernatant of 12 patients with stable COPD was analyzed on three separate occasions with 4-weekly intervals. Sputum cells and inflammatory markers interleukin (IL)-8 and soluble intercellular adhesion molecule (sICAM)-1 were measured in supernatant using enzyme-linked immunosorbent assay. Repeatability of sputum markers was expressed by intraclass correlation coefficients (Ri).. Sputum induction was safe in all patients. None of the sputum parameters analyzed changed significantly throughout the study. The repeatability for cell differential counts in stable COPD was as follows: total cells, Ri = 0.07; neutrophils, Ri = 0.66; macrophages, Ri = 0.47; eosinophils, Ri = 0.49; and lymphocytes, Ri = 0.58. The repeatability of soluble markers was as follows: IL-8, Ri = 0.50; and sICAM, Ri = 0.58. Sputum neutrophils were negatively correlated with lung function on each separate occasion, whereas soluble markers were not correlated with sputum cells (p > 0.16, all correlations) or lung function (p > 0.24, all correlations).. Clinically stable, moderate COPD is associated with equally stable sputum inflammatory markers. Repeatability of induced-sputum markers of neutrophilic inflammation in stable COPD is satisfactory, even over extended periods of time. These data support the usefulness of serial monitoring of induced-sputum inflammatory markers in COPD.

Topics: Analysis of Variance; Biomarkers; Forced Expiratory Volume; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Leukocyte Count; Linear Models; Neutrophils; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Spirometry; Sputum; Vital Capacity

Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function and progressive airway inflammation. Bacteria have been isolated from the lower airway of stable COPD patients, and airway inflammation has been related to bacterial load and type. The relationship between bacterial colonization, airway inflammation, and lung function decline remains uncertain. We studied 30 patients with COPD, mean (SD) FEV1 0.947 (0.329), 34.8% (13.6%) predicted, for 12 months. Sputum collected at recruitment and the end of the study was analyzed for cytokines and for quantitative bacteriology. The decline in FEV1 was 57.6 (137.6) ml year-1. Bacterial growth was identified in all subjects, with an initial count of 107.47(0.91) cfu ml-1 rising to 107.93(0.81) cfu ml-1 at the end of the study (p = 0.019). FEV1 decline was related to this increase in airway bacterial load (r = 0.59, p = 0.001). FEV1 decline was greater in subjects who exhibited a change in the colonizing bacterial type compared with those with persistence of a single bacterial species over the study period (p = 0.017). Higher sputum interleukin (IL-8) was associated with greater declines in FEV1 (p = 0.03). Rising airway bacterial load and species changes are associated with greater airway inflammation and accelerated decline in FEV1. Bacterial colonization in COPD is an important factor in disease progression.

Topics: Aged; Female; Forced Expiratory Volume; Humans; Interleukin-6; Interleukin-8; Male; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Sputum

Topics: Chemotactic Factors; Chemotaxis, Leukocyte; Humans; Interleukin-8; Leukotriene B4; Pulmonary Disease, Chronic Obstructive; Sputum

Neutrophilic inflammation is a major feature of COPD. Several factors in bronchial secretions have been identified as chemoattractants for neutrophils. The present study was designed to assess the contribution of interleukin (IL)-8 and leukotriene B(4) (LTB(4)) to neutrophil chemotaxis evoked by sputum obtained from patients with established COPD.. Sputum supernatant of 20 patients with COPD was used as chemoattractant in a 96-well chemotaxis chamber, with subsequent quantification of migrated cells by a luminescence assay. The contribution of IL-8 and LTB(4) to chemotaxis was determined by addition of a neutralizing antibody and a selective receptor antagonist, respectively.. COPD sputum caused neutrophil chemotaxis in a concentration-dependent manner, with a maximum response evoked with a 10-fold dilution of the original sample. Pretreatment of sputum or neutrophils with either an anti-IL-8 antibody or the LTB(4) antagonist, SB 201146, led to a concentration-dependent inhibition of sputum-induced neutrophil chemotaxis, with a maximum suppression (mean +/- SEM) of 29.2 +/- 4.9% (p < 0.001) from baseline by 100 ng/mL of anti-IL-8 antibody, and 45.6 +/- 7% (p < 0.02) by 10 micro mol/L of SB 201146. The combination of the anti-IL-8 antibody and SB 201146 inhibited neutrophil chemotaxis, but this was not significantly greater than the effect of SB 201146 or anti-IL-8 alone.. These data confirm the importance of IL-8 and LTB(4) as chemoattractants for neutrophils in bronchial secretions from patients with COPD, and suggest that specific inhibitors may have therapeutic potential in COPD.

Topics: Acrylates; Antibodies, Monoclonal; Chemotactic Factors; Chemotaxis, Leukocyte; Humans; Interleukin-8; Leukotriene B4; Neutrophils; Pulmonary Disease, Chronic Obstructive; Pyridines; Sputum

Chemokines and T-lymphocytes play an important role in lower respiratory tract inflammation. This study evaluated the concentration of IL-8 and count of T-lymphocytes expressing adhesion molecules LFA-1, Mac-1, Lsel and their correlation in patients with asthma and COPD in periods of exacerbation and clinical improvement (after seven days of anti-inflammatory treatment). In all subjects bronchoscopic examination with BAL procedure were done in exacerbation period and after seven days of treatment. The concentration of IL-8 was measured by ELISA, and the expression of adhesion molecules by biotin-streptavidin methods. The highest concentration of IL-8 was observed in asthma patients in clinical improvement period, and the highest count of T-lymphocytes was observed in patients with COPD in remission phase. Increased concentration of chemokines could have been influenced by type of treatment administered, especially beta 2-mimetics. The significant correlation observed in COPD patients between IL-8 concentration and counts of T-cells expressing LFA-1 (r = 0.44), Mac-1 (r = 0.49), Lsel (r = 0.42) in exacerbation period suggest a chemotactic influence of IL-8 on T-lymphocytes.

Topics: Acute Disease; Adult; Asthma; Bronchoalveolar Lavage Fluid; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; L-Selectin; Lymphocyte Function-Associated Antigen-1; Macrophage-1 Antigen; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; T-Lymphocytes; Time Factors

To study the correlation between the inflammatory mediators released by alveolar macrophages and the pulmonary ventilatory capacity in patients with chronic obstructive pulmonary disease (COPD).. Alveolar macrophages were collected by fiberoptic bronchoscopy from 8 patients with chronic bronchitis, 8 with COPD with a forced expiratory volume in one second (FEV(1)) < or = 70%, and 8 healthy nonsmokers. All patients were in the stable stage. The macrophages were cultured and stimulated with lipopolysaccharide (LPS, 10 microg/ml). IL-8, IL-1 beta, TNF-alpha and IL-6 in the supernatants were measured by ELISA. Pulmonary functions were tested in all three groups. The correlation between different cytokines was tested with Pearson's relevant analysis, and the correlation between lung functions and cytokines was tested with multiple reverse regression analysis.. (1) The concentrations of IL-8 released from macrophages in the COPD group were (43 +/- 27) microg/L and (57 +/- 41) microg/L (with LPS), higher than those from healthy controls [(13 +/- 10) microg/L and (20 +/- 13) microg/L] (P < 0.05), but not different from those in patients with chronic bronchitis [(29 +/- 21) microg/L and (32 +/- 23) microg/L] (P > 0.05). (2) The concentrations of IL-1 beta released from macrophages in the COPD group, the chronic bronchitis group and the control group were [(50 +/- 41) ng/L, (94 +/- 59) ng/L, (37 +/- 32) ng/L] before LPS, and [(225 +/- 108) ng/L, (153 +/- 175) ng/L, (70 +/- 37) ng/L] after LPS stimulation, which were positively correlated with the concentrations of IL-8 (P < 0.05). The concentrations of TNF-alpha released from macrophages in three groups were [(1,238 +/- 679) ng/L, (3,088 +/- 2,879) ng/L and (1,332 +/- 1,846)ng/L], which were positively correlated with the concentrations of IL-1 beta (P < 0.05). The concentrations of IL-6 released from macrophages in the three groups were [(7,959 +/- 8,458) ng/L, (5,317 +/- 10,112) ng/L and (6,480 +/- 4,982) ng/L, which were positively correlated with the concentrations of IL-8 (P < 0.05). (3) The values of FEV(1)/FVC, V(max50) and V(max25) measured in the COPD group were [(65.1 +/- 5.3)%, (43 +/- 8)% and (37 +/- 11)%, respectively, which were negatively correlated with the concentrations of IL-8 (P < 0.05), but negatively correlated with the concentrations of IL-1 beta only in the presence of LPS (P < 0.05).. IL-8 released by alveolar macrophages plays an important role in the process from chronic cough to chronic airflow obstruction. TNF-alpha, IL-1 beta and IL-6 released by alveolar macrophages are also involved in the airway inflammation in COPD.

Topics: Cytokines; Female; Humans; Inflammation; Interleukin-1; Interleukin-6; Interleukin-8; Lung Volume Measurements; Macrophages; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests

Inflammation in chronic obstructive pulmonary disease (COPD) is characterised by increased neutrophilic infiltration of the airways. Cilomilast, a novel selective phosphodiesterase 4 inhibitor in clinical development for COPD treatment, exerts anti-inflammatory effects. The ability of cilomilast to inhibit the release of neutrophil chemoattractants such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-8, and granulocyte-macrophage colony stimulating factor (GM-CSF) by bronchial epithelial cells and sputum cells isolated from 10 patients with COPD, 14 normal controls, and 10 smokers was investigated.. Bronchial epithelial cells obtained by bronchial brushing and sputum cells isolated from induced sputum samples were cultured for 24 hours in the presence or absence of cilomilast (1 micro M). After incubation the supernatants were harvested and the levels of mediators measured by ELISA. Chemotactic activity in supernatants was also measured using a Boyden chamber.. TNF-alpha and IL-8 release by bronchial epithelial cells and sputum cells was higher in patients with COPD than in controls (p<0.0001) and smokers (p<0.0001). GM-CSF was only detectable in sputum cell supernatants and its level was higher in patients with COPD than in controls and smokers (p<0.0001, respectively). Cilomilast significantly reduced TNF-alpha release by bronchial epithelial cells and sputum cells (p=0.005) and GM-CSF release by sputum cells (p=0.003), whereas IL-8 release was not statistically inhibited. Supernatants of sputum cells and bronchial epithelial cells treated with cilomilast significantly decreased neutrophil chemotaxis (p<0.006 and p<0.008, respectively).. Cilomilast inhibits the production of some neutrophil chemoattractants by airway cells. This drug may play a role in the resolution of neutrophilic inflammation associated with COPD and cigarette smoke.

Topics: Adult; Aged; Bronchodilator Agents; Carboxylic Acids; Cell Count; Cells, Cultured; Chemotaxis, Leukocyte; Cyclohexanecarboxylic Acids; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Male; Middle Aged; Nitriles; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Sputum; Tumor Necrosis Factor-alpha

We have applied immunohistology and in situ hybridization to bronchial biopsies of patients with chronic obstructive pulmonary disease (COPD) to examine neutrophil recruitment and to determine neutrophil chemoattractant and CXC receptor (CXCR) 1 and CXCR2 gene expression associated with acute severe exacerbations. Cells were counted in endobronchial biopsies of (1) patients with COPD intubated for exacerbations (E-COPD; n = 15), (2) those with COPD in a stable phase of their disease (S-COPD; n = 7), and (3) nonsmoker surgical control subjects intubated for a nonrespiratory surgical procedure (n = 15). In comparison with the nonrespiratory surgical procedure and S-COPD groups, neutrophilia and gene expression for epithelial-derived neutrophil attractant-78 (CXCL5), interleukin-8 (CXCL8), CXCR1, and CXCR2 were each upregulated in the E-COPD group (p < 0.01); compared with the S-COPD group, by 97-, 6-, 6-, 3-, and 7-fold, respectively (p < 0.01). In E-COPD, there was a significant positive association between the number of neutrophils and CXCR2 mRNA-positive cells (r = 0.79; p < 0.01) but not between the number of neutrophils and CXCR1 mRNA-positive cells. At the time of sampling of the mucosa, there was no association between neutrophil number and either the length of intubation or viral infection. Thus, in COPD, in addition to CXCL8 and CXCR1, CXCL5 and CXCR2 appear to play important roles in the airway neutrophilia characteristic of severe exacerbations.

Topics: Acute Disease; Aged; Biopsy; Bronchoscopy; Case-Control Studies; Chemokine CXCL5; Chemokines, CXC; Female; Forced Expiratory Volume; Gene Expression; Humans; Immunohistochemistry; In Situ Hybridization; Inflammation; Interleukin-8; Male; Middle Aged; Neutrophil Infiltration; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Respiratory Mucosa; Severity of Illness Index; Up-Regulation

This study examined inflammatory responses from primary cultured human bronchial epithelial cells in chronic obstructive pulmonary disease (COPD) and the clinical factors modulating them. Epithelial cells from bronchoscopic biopsies from 14 patients with COPD ((mean +/- SD) age 74.6 +/- 5.7 yrs, forced expiratory volume in one second (FEV1) 1.21 +/- 0.36 L, FEV1 %, predicted 51.1 +/- 15.8%, 51.5 +/- 24.0 pack-yrs of smoking, inhaled steroid dosage 1237.5 +/- 671.0 microg x day(-1), Medical Research Council (MRC) dyspnoea score 3.18 +/- 1.33) and eight current/exsmokers with normal pulmonary function (age 60.4 +/- 13.5 yrs, FEV1 2.66 +/- 1.27 L, FEV1 % pred 89.6 +/- 17.7%, 49 +/- 44 pack-yrs of smoking, MRC dyspnoea score 1 +/- 0) were grown in primary culture and exposed to 50 ng x mL(-1) tumour necrosis factor-alpha. Stimulated COPD cells produced significantly more interleukin (IL)-6 at 24 and 48 h, and IL-8 at 6 and 24 h than unstimulated COPD cells. This response was not seen in cells from current/exsmokers. IL-6 and IL-8 production was lower in COPD patients taking inhaled steroids. Following an inflammatory stimulus, bronchial epithelial cells in chronic obstructive pulmonary disease show a significant cytokine response not seen in smokers with normal pulmonary function and this may be modified by inhaled steroid therapy.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchi; Bronchoscopy; Cells, Cultured; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Smoking; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) is often associated with peripheral muscle weakness, which is caused by several factors. Acute exacerbations may contribute, but their impact on muscle force remains unclear. Correlations between peripheral muscle force and inflammatory and anabolic markers have never been studied in COPD. The effect of an acute exacerbation on quadriceps peak torque (QPT) was therefore studied in hospitalised patients, and the aforementioned correlations were examined in hospitalised and in stable patients.. Lung function, respiratory and peripheral muscle force, and inflammatory and anabolic markers were assessed in hospitalised patients on days 3 and 8 of the hospital admission and 90 days later. The results on day 3 (n=34) were compared with those in clinically stable outpatients (n=13) and sedentary healthy elderly subjects (n=10).. Hospitalised patients had lowest mean (SD) QPT (66 (22)% predicted) and highest median (IQR) levels of systemic interleukin-8 (CXCL8, 6.1 (4.5 to 8.3) pg/ml). Insulin-like growth factor I (IGF-I) tended to be higher in healthy elderly subjects (p=0.09). QPT declined between days 3 and 8 in hospital (mean -5% predicted (95% CI -22 to 8)) and partially recovered 90 days after admission to hospital (mean 6% predicted (95% CI -1 to 23)). QPT was negatively correlated with CXCL8 and positively correlated with IGF-I and lung transfer factor in hospitalised and in stable patients.. Peripheral muscle weakness is enhanced during an acute exacerbation of COPD. CXCL8 and IGF-I may be involved in the development of peripheral muscle weakness in hospitalised and in stable patients with COPD.

Topics: Acute Disease; Aged; Cross-Sectional Studies; Forced Expiratory Volume; Hospitalization; Humans; Insulin-Like Growth Factor I; Interleukin-8; Muscle Weakness; Pulmonary Disease, Chronic Obstructive; Vital Capacity

Balanced secretion of pro- and anti-inflammatory cytokines is essential in limiting pulmonary inflammation in respiratory infections. It was hypothesised that, in acute infection with Chlamydia pneumoniae, mononuclear cells from chronic obstructive pulmonary disease (COPD) patients lack the opportunity to compensate for the inflammatory immune response by secreting adequate amounts of anti-inflammatory cytokines. Alveolar macrophages (AMs) and peripheral blood mononuclear cells (PBMCs) from eight COPD patients and eight healthy controls were infected with C. pneumoniae in order to determine interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1RA) and IL-8 expression and messenger ribonucleic acid levels. Secretion of IL-1beta was significantly enhanced in AMs (six-fold) and PBMCs (four-fold) from COPD patients after infection with C. pneumoniae. Compared to the control group, release of its anti-inflammatory counterpart IL-1RA was diminished in COPD patients, resulting in a significantly higher IL-1beta/IL-1RA ratio in C. pneumoniae-infected AMs and PBMCs from COPD patients. Mononuclear cells from chronic obstructive pulmonary disease patients have less capacity for balancing the pro-inflammatory immune response caused by Chlamydia pneumoniae infection than those from healthy controls. These findings suggest that, during acute exacerbation with intracellular pathogens, chronic obstructive pulmonary disease patients are predisposed to inflammatory changes in the lungs.

Topics: Adult; Aged; Chlamydia Infections; Chlamydophila pneumoniae; Humans; In Vitro Techniques; Interleukin-1; Interleukin-8; Leukocytes, Mononuclear; Macrophages, Alveolar; Middle Aged; Pneumonia, Bacterial; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-1; RNA, Messenger

Nontypeable Haemophilus influenzae (NTHI) is an important etiological agent of otitis media (OM) and of exacerbated chronic obstructive pulmonary diseases (COPD). Inflammation is a hallmark of both diseases. Interleukin-8 (IL-8), one of the important inflammatory mediators, is induced by NTHI and may play a significant role in the pathogenesis of these diseases. Our studies demonstrated that a soluble cytoplasmic fraction (SCF) from NTHI induced much greater IL-8 expression by human epithelial cells than did NTHI lipooligosaccharides and envelope proteins. The IL-8-inducing activity was associated with molecules of < or =3 kDa from SCF and was peptidase and lipase sensitive, suggesting that small lipopeptides are responsible for the strong IL-8 induction. Moreover, multiple intracellular signaling pathways were activated in response to cytoplasmic molecules. The results indicated that the p38 mitogen-activated protein kinase (MAPK) and Src-dependent Raf-1-Mek1/2-extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) pathways are required for NTHI-induced IL-8 production. In contrast, the phosphatidylinositol 3-kinase (PI3K)-Akt pathway did not affect IL-8 expression, although this pathway was concomitantly activated upon exposure to NTHI SCF. The PI3K-Akt pathway was also directly activated by IL-8 and significantly inhibited by an antagonist of IL-8 receptors during NTHI stimulation. These results indicated that the PI3K-Akt pathway is activated in response to IL-8 that is induced by NTHI and may lead to other important epithelial cell responses. This work provides insight into essential molecular and cellular events that may impact on the pathogenesis of OM and COPD and identifies rational targets for anti-inflammatory intervention.

Topics: Base Sequence; Cell Line; DNA, Complementary; Haemophilus Infections; Haemophilus influenzae; HeLa Cells; Humans; Interleukin-8; Lipase; Lipopolysaccharides; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Models, Biological; NF-kappa B; Otitis Media; p38 Mitogen-Activated Protein Kinases; Peptide Hydrolases; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Up-Regulation

Chronic obstructive pulmonary disease (COPD) is characterized by incompletely reversible airflow obstruction associated with inflammation in which monocytes/macrophages are the predominant inflammatory cells. The only known genetic factor related to COPD is inherited PiZZ deficiency of alpha1-antitrypsin (AAT), an inhibitor of serine proteases.. We investigated the basal and LPS-stimulated release of pro-inflammatory molecules from blood monocytes isolated from age and gender matched healthy (n = 30) and COPD (n = 20) individuals with and without AAT deficiency.. After 18 h of cell culture the basal release of MMP-9 was 2.5-fold, p < 0.02 greater, whereas IL-8 was 1.8-fold (p < 0.01) lower from COPD patient monocytes than from controls. LPS-stimulated release of IL-6 and MCP-1 was greater from COPD patient's monocytes relative to controls, while activation of control cells resulted in enhanced secretion of ICAM-1 and MMP-9 compared to COPD patients. Independent of disease status, monocytes from PiZZ AAT carriers released less TNFalpha (by 2.3-fold, p < 0.03).. The basal and LPS-stimulated secretion of specific pro-inflammatory molecules from circulating monocytes differs between healthy and COPD subjects. These findings may be valuable for further studies on the mechanisms involved in recruitment and activation of inflammatory cells in COPD.

Topics: Adult; alpha 1-Antitrypsin Deficiency; Case-Control Studies; Cells, Cultured; Chemokine CCL2; Female; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Matrix Metalloproteinase 9; Middle Aged; Monocytes; NF-kappa B; Pulmonary Disease, Chronic Obstructive

Neutrophil recruitment to the airway is thought to be an important component of continuing inflammation and progression of chronic obstructive pulmonary disease (COPD), particularly in the presence of severe alpha(1)-antitrypsin (alpha(1)-AT) deficiency. However, the chemoattractant nature of secretions from these patients has yet to be clarified.. The chemotactic activity of spontaneous sputum from patients with stable COPD, with (n=11) and without (n=11) alpha(1)-AT deficiency (PiZ), was assessed using the under-agarose assay. The contribution of leukotriene B(4) (LTB(4)) and interleukin 8 (IL-8) to the chemotactic activity was examined using an LTB(4) receptor antagonist (BIIL 315 ZW) and an IL-8 monoclonal antibody, respectively.. Sputum neutrophil chemotactic activity (expressed as % n-formylmethionyl leucylphenylalanine (fMLP) control) was significantly higher in patients with alpha(1)-AT deficiency (mean (SE) 63.4 (8.9)% v 36.7 (5.5)%; mean difference 26.7% (95% CI 4.9 to 48.4), p<0.05). The mean (SE) contribution of both LTB(4) and IL-8 (expressed as % fMLP control) was also significantly higher in alpha(1)-AT deficient patients than in patients with COPD with normal levels of alpha(1)-AT (LTB(4): 31.9 (6.3)% v 18.0 (3.7)%; mean difference 13.9% (95% CI -1.4 to 29.1), p<0.05; IL-8: 24.1 (5.2)% v 8.1 (1.2)%; mean difference 15.9% (95% CI 4.7 to 27.2), p<0.05). When all the subjects were considered together the mean (SE) contribution of LTB(4) (expressed as % total chemotactic activity) was significantly higher than IL-8 (46.8 (3.5)% v 30.8 (4.6)%; mean difference 16.0% (95% CI 2.9 to 29.2), p<0.05). This difference was not significantly influenced by alpha(1)-AT phenotype (p=0.606).. These results suggest that the bronchial secretions of COPD patients with alpha(1)-AT deficiency have increased neutrophil chemotactic activity. This relates to the increased levels of IL-8 and, in particular LTB(4), which accounted most of the sputum chemotactic activity in the patients with COPD as a whole. Increased chemotactic activity, together with inhibitor deficiency, may contribute to the more rapid disease progression seen in alpha(1)-AT deficiency via increased neutrophil recruitment and release of neutrophil elastase.

Topics: alpha 1-Antitrypsin Deficiency; Chemotactic Factors; Chemotaxis; Female; Humans; Interleukin-8; Leukotriene B4; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Sputum

The peptide endothelin-1 (ET-1) plays an unknown role in the pathogenesis and progression of two important neonatal pulmonary disorders, chronic lung disease (CLD) of prematurity and persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (INO) is a proven vasodilator therapy in PPHN and is an experimental therapy in CLD. We sought to determine the effects, if any, of the interaction of inhaled INO with ET-1 in these two separate disorders. Infants (n=21) with PPHN (mean gestation age, 39.4 weeks; mean birth weight, 3470 g) were treated with INO. All infants were <72 h of age at baseline. Plasma obtained at baseline and after 24 h of INO therapy was assessed for ET-1. The change in ET-1 levels with INO was inversely correlated with change in arterial partial pressure of O(2) (r=-0.71, P=0.0003). A separate group of 33 patients with CLD (mean gestational age, 27 weeks; mean birth weight, 740 g; mean age, 19 days) had tracheal aspirate levels of ET-1 obtained before, during, and after 7 days' administration of INO. Values were normalized by soluble secretory component of IgA. Tracheal aspirate ET-1 levels were detectable before INO therapy. There was no significant change during or after treatment with INO. There was not a significant correlation between baseline fractional inspired O(2) and ET-1 levels. There was a non-significant trend in the correlation between the change in ET-1 and the change in interleukin-8 levels in tracheal aspirate. This report confirms the presence of ET-1 in tracheal aspirate of premature infants who are developing CLD and reaffirms the presence of ET-1 in plasma of infants with PPHN. Short-term INO therapy was associated with a decrease in plasma ET-1 levels in PPHN, but did not affect tracheal aspirate ET-1 in CLD. Given the vasconstrictive, profibrotic, and proinflammatory properties of ET-1, specific ET-1 receptor antagonists could be considered as candidates for trials as adjunct therapy in either or both of these disorders.

Topics: Administration, Inhalation; Biomarkers; Endothelin-1; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Interleukin-8; Nitric Oxide; Persistent Fetal Circulation Syndrome; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is characterized by significant chronic inflammation in the pulmonary compartment as well as in the circulation. This study aimed to elucidate the relationship between local and systemic inflammation in smoking-induced COPD by assessing levels of soluble (s) tumor necrosis factor (TNF) receptors, TNF-alpha, and interleukin-8 (IL-8) in induced sputum and in plasma. Sputum induction was performed in 18 subjects with COPD (FEV(1) 56% predicted) and 17 healthy smokers (FEV(1) 99% predicted). Patients with COPD showed significantly higher percentages of neutrophils and levels of sTNF-R55 and IL-8 in sputum as compared with control subjects, whereas sputum sTNF-R75 levels tended to be higher in COPD. Sputum TNF-alpha levels were similar in both groups. When comparing sTNF receptors in sputum and plasma, no direct correlations were found despite elevation of circulating sTNF-R75 levels in patients with COPD. In addition, sputum sTNF receptors were inversely related to the FEV(1) in patients with COPD, whereas circulating sTNF receptors were not, suggesting different regulation of inflammation in the pulmonary and systemic compartment. When subjects were divided according to their current smoking status, levels of sTNF-R55, sTNF-R75, and IL-8 in sputum were significantly elevated in ex-smoking versus currently smoking patients with COPD, suggesting ongoing inflammation in airways and circulation of patients with COPD after smoking cessation.

Topics: Aged; Antineoplastic Agents; Etanercept; Female; Humans; Immunoglobulin G; Immunologic Factors; Interleukin-8; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Receptors, Tumor Necrosis Factor; Smoking; Sputum; Tumor Necrosis Factor-alpha

Different forms of chronic airway inflammation may involve diverse pathogenic elements. In general, deficient defence response is a feature of chronic obstructive pulmonary disease (COPD), whereas distorted immunoregulatory mechanisms lead to development of asthmatic symptoms. In addition to diverse effector mechanisms, the cellular and humoral elements participating in the development of immune response may appear to be different in COPD and bronchial asthma (BA) patients.. To evaluate the immunoregulatory properties of T cells and monocytes in cultures of peripheral blood mononuclear cells (PBMC) and to determine the chosen cytokine profiles in COPD and BA patients.. The microcultures of PBMC from COPD and BA patients were assessed for the T-cell response to mitogens, saturation of interleukin (IL)-2 receptors, T-cell suppressive activity and monokine influence on lymphocyte proliferation. Concomitantly, the cytokine (IL-1beta, interleukin-1 receptor antagonist, tumour necrosis factor-alpha, IL-4, IL-6, IL-8) concentrations were determined in the serum, the broncho-alveolar lavage fluid and in the culture supernatants.. The T-lymphocyte reactions (response to phytohaemagglutinin, IL-2 receptor saturation, suppressive activity) were lower in BA patients than in COPD patients. Reversely, the immunogenic activity of monocytes (IL-1beta versus IL-1ra production) was higher in BA patients than in COPD patients. The highest values of cytokine concentrations were found in the culture supernatants. The concentrations of tumour necrosis factor-alpha, IL-4, IL-6 and IL-8 were significantly higher and the concentration of IL-1ra was lower in BA patients than in COPD patients.. The assessments of cellular immunoregulatory properties and cytokine profiles in the cultures of blood mononuclear cells may prove helpful for diagnostic and therapeutic discrimination between BA and COPD patients.

Topics: Adult; Asthma; Bronchoalveolar Lavage Fluid; Cells, Cultured; Cytokines; Diagnosis, Differential; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-4; Interleukin-6; Interleukin-8; Male; Middle Aged; Monocytes; Pulmonary Disease, Chronic Obstructive; Sialoglycoproteins; T-Lymphocytes; Tumor Necrosis Factor-alpha

The circulating blood levels of several inflammatory cytokines and acute phase proteins are higher in patients with stable chronic obstructive pulmonary disease (COPD). However, whether or not these inflammatory markers increase during COPD exacerbation or are modified by corticosteroid treatment has not been investigated. The objective of this study was therefore 1) to describe changes in several inflammatory markers in systemic circulation during COPD exacerbation, and 2) to assess the potential effects of corticosteroid treatment during exacerbation.. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP) were determined for 10 patients (65 2 years old) with severe COPD (FEV1 35 4% reference) who were hospitalized for acute respiratory failure (PaO2 57 2 mm Hg; PaCO2 48 3 mm Hg). Blood samples were obtained in the emergency room (before starting intravenous corticosteroid treatment), during the first 24 hours of admission, upon discharge and two months later. Eight healthy non-smokers of a similar age (54 3 years) were also studied as control subjects.. The COPD patients had higher concentrations of IL-6 (5.1 1.6 vs. 1.8 0.5 pg/mL, p < 0.05) and CRP (2.2 0.4 vs. 0.6 0.2 mg/dL, p < 0.005) than did controls, but the concentrations of IL-8 were similar (29 11.3 vs. 34.7 10.3 pg/mL, p = ns). No statistically significant changes were seen either during recovery, in spite of intravenous corticosteroid treatment, or two months after discharge.The ELISA test used was unable to detect TNF-alpha in any of the samples obtained from either patients or controls.. The results show that 1) there is evidence of systemic inflammation during exacerbation of COPD, and 2) such systemic inflammation does not appear to be influenced significantly by intravenous corticosteroid treatment.

Topics: Adrenal Cortex Hormones; Aged; Biomarkers; C-Reactive Protein; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation; Interleukin-6; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Respiratory Insufficiency; Tumor Necrosis Factor-alpha

Topics: Asthma; Blood Proteins; Cell Separation; Cell Survival; Eosinophils; Humans; Interleukin-5; Interleukin-8; Peroxidase; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Sputum

Since asymptomatic, nonspecific airway hyperresponsiveness (BHR) may be due to an enhanced local inflammatory response, we studied molecular markers of inflammation in induced sputum from subjects with asymptomatic BHR (n = 14) compared with control subjects (n = 13) and patients with chronic obstructive pulmonary disease (COPD) (n = 10). Pulmonary lung function parameters were measured by spirometry and body plethysmography. Hyperresponsiveness was defined based on histamine challenge. Induced sputum samples were collected and the solid phase was isolated and analyzed for leukocyte numbers and differential and for cytokines (ELISA). IL-8 was 2.4-fold increased (p = 0.036) in the sputum of subjects with asymptomatic BHR (24.8 +/- 22.0 ng/mL; +/- SD) and 11.2-fold enhanced in patients with COPD (117.8 +/- 106.3 ng/mL) as compared with control subjects (10.5 +/- 7.7 ng/mL). In control subjects, no IL-5 was measured, however, sputum of those with asymptomatic BHR contained IL-5 at 0.044 +/- 0.090 ng/mL fluid and COPD patients at 1.00 +/- 2.01 ng/mL. GM-CSF could not be detected in sputum samples of any subjects investigated. Number of total leukocytes was higher in those with asymptomatic BHR and COPD (with BHR: 9.4 +/- 10.8 x 10(5); COPD: 83.5 +/- 182.5 x 10(5)) compared with persons without BHR (2.9 +/- 3.4 x 10(5)). PMN were increased in patients with asymptomatic BHR (4.1 +/- 5.3 x 10(5)) (38.8 +/- 24.7%) and COPD (32.9 +/- 71.0 x 10(5)) (75.4 +/- 18.6%) compared with controls (0.7 +/- 0.9 x 10(5)) (25.8 +/- 25.7%). In contrast to PMN counts in those with asymptomatic BHR (0.06 +/- 0.11 x 10(5)) (1.5 +/- 3.7%), eosinophil counts were only slightly increased compared with control subjects (0.01 +/- 0.02 x 10(5)) (0.6 +/- 0.9%). This study supports the hypothesis that BHR in asymptomatic people is associated with airway inflammation that may predispose to development of chronic diseases such as COPD.

Topics: Adult; Bronchial Hyperreactivity; Bronchial Provocation Tests; Enzyme-Linked Immunosorbent Assay; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Histamine; Humans; Interleukin-5; Interleukin-8; Leukocyte Count; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Mechanics; Smoking; Sputum

To investigate the activation of transcription factors and induction of cytokines from alveolar macrophages in chronic obstructive pulmonary disease (COPD).. Alveolar macrophages were collected by fibrobronchoscopy from 8 patients with chronic bronchitis, 8 patients with COPD, and 8 healthy volunteers. All patients were at stable stage. The macrophages thus collected were cultured and stimulated with lipopolysaccharide (LPS, 10 micrograms/ml). The IL-8, IL-1 beta, TNF alpha and IL-6 thus produced were measured by ELISA in the supernatant. Nuclear factor-kappa B (NF kappa B), activator protein-1 (AP-1), AP-2 and AP-3 were detected by electrophoretic mobility shift assay.. The concentration of IL-8 released from macrophages of patients with COPD at stable stage before LPS stimulation was about 3 times higher than that in the healthy control (F = 4.34, P < 0.05). The concentration of IL-8 released from macrophages in patients with COPD was increased further after LPS stimulation in comparison to that in healthy controls(F = 3.56, P < 0.05). The concentration of IL-1 beta and that of TNF alpha released from macrophages of COPD patients were further increased after LPS stimulation (P < 0.05) in the COPD patients, but there was no difference in the concentration of IL-1 beta and between the control and COPD patients before LPS stimulation. The constitutive activity of AP-1 and the activity of NF kappa B induced by LPS were higher in the patients with COPD than in the controls.. The alverlar macrophages of patients with COPD at stable stage may release higher concentration of IL-8 and IL-1 beta. LPS stimulation increases the release of IL-1 beta and TNF alpha of alveolar macrophages. Enhancement of activity of NF kappa B and AP-1 may positively regulate the production of IL-8 and IL-1 beta in the airflow obstruction.

Topics: Adult; Cytokines; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Lipopolysaccharides; Macrophages, Alveolar; Male; Middle Aged; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Transcription Factor AP-1; Transcription Factors; Tumor Necrosis Factor-alpha

A rat model with chronic bronchitis was replicated by passive inhalation of cigarette smoking fume to study its long-term effects on lung injury and nitric oxide (NO), interluekin-6 (IL-6), interleukin-8 (IL-8).. Levels of nitrogen dioxide (NO(2)) and nitrogen trioxide (NO(3)) were measured with spectrophotometry in rats indicating their level of nitric oxide (NO). Levels of IL-6 and IL-8 were determined by enzyme-linked immunosorbent assay (ELISA).. Levels of NO in serum, bronchial alveolar lavage fluid (BALF) and lung tissue in the smoking group were significantly lower than those in the normal controls (P < 0.01). But, levels of IL-6 and IL-8 were higher in the smoking group than those in the controls.. Long-term passive smoking could cause injury of lung tissue to certain extent, reduction in secretion of NO in endothelial cells and damage to pulmonary vessels.

Topics: Animals; Bronchitis, Chronic; Bronchoalveolar Lavage Fluid; Interleukin-6; Interleukin-8; Lung; Male; Nitric Oxide; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Tobacco Smoke Pollution

To study the change of cytokines and eosinophil cationic protein (ECP) level in the sputum before and after glucocorticoid (GC) inhalation treatment so as to comprehend their effect on asthmatic and chronic obstructive pulmonary diseases (COPD) patients.. A method to induce sputum with inhaled hypertonic saline was used. The level of interleukin (IL)-5, IL-8 and ECP was measured with enzyme-linked immunosorbent assay method.. The concentration of ECP decreased from (500.3 +/- 49.6) microg/L to (59.8 +/- 10.9) microg/L, the percentage of eosinophils (Eos) dropped from (11.6 +/- 1.7) x 10(-2) to (4.1 +/- 0.7) x 10(-2) and there is significant difference in the concentration of IL-5 in the group of asthmatic patients after GC treatment. However, the concentration of IL-5 in the COPD patients did not show significant change after the same therapy.. Respiratory tract inflammation in asthma is related to Eos activation and increase in ECP and IL-5 excretion, while respiratory tract inflammation in COPD is related to neutrophil increase. These changes can be considered as the indicator of airway inflammation in asthma or COPD. Through regulating the quantity and function of the inflammatory cells and inhibiting the formation of cytokines to control the asthmatic airway inflammation, GC inhalation treatment will have better effect in treating asthmatic patients than COPD patients.

Topics: Administration, Inhalation; Adolescent; Adult; Asthma; Cytokines; Eosinophil Cationic Protein; Female; Glucocorticoids; Humans; Interleukin-5; Interleukin-8; Male; Middle Aged; Neutrophil Activation; Pulmonary Disease, Chronic Obstructive; Sputum