interleukin-8 and Pneumonia

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; 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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; 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Despite improvements in the management of community-acquired pneumonia (CAP), morbidity and mortality are still high, especially in patients with more severe disease. Early and appropriate antibiotics remain the cornerstone in the treatment of CAP. However, two aspects seem to contribute to a worse outcome: an uncontrolled inflammatory reaction and an inadequate immune response. Adjuvant treatments, such as corticosteroids and intravenous immunoglobulins, have been proposed to counterbalance these effects. The use of corticosteroids in patients with severe CAP and a strong inflammatory reaction can reduce the time to clinical stability, the risk of treatment failure, and the risk of progression to acute respiratory distress syndrome. The administration of intravenous immunoglobulins seems to reinforce the immune response to the infection in particular in patients with inadequate levels of antibodies and when an enriched IgM preparation has been used; however, more studies are needed to determinate their impact on outcome and to define the population that will receive more benefit.

Topics: Adrenal Cortex Hormones; Cross Infection; Hospital Mortality; Humans; Immunity, Innate; Immunoglobulins; Interleukin-10; Interleukin-6; Interleukin-8; Pneumonia; Review Literature as Topic; Systemic Inflammatory Response Syndrome

Neutrophils may play an important role in the pathogenesis of severe asthma. Their infiltration into the airway is increased. Interleukin (IL)-8 is involved in this process, and is actually upregulated in the airways of patients. We have observed that in the absence of eosinophil chemoattractants, neutrophils stimulated by IL-8 augment eosinophil trans-basement membrane migration by releasing superoxide anion, matrix metalloproteinase, leukotriene B(4) and platelet-activating factor. These findings suggest that IL-8-stimulated neutrophils could lead eosinophils to accumulate in the airways of asthmatic patients, which might be a mechanism for corticosteroid resistance in severe asthma. However, the mechanisms of IL-8 upregulation in the airway are not completely understood. Several studies suggest that IL-17 (or T helper 17 cells; Th17) is involved in the IL-8 upregulation observed in severe asthma. We clarified that dopamine induces Th17 differentiation through dopamine D1-like receptor (D1-like-R), and that the D1-like-R antagonist attenuates Th17-mediated diseases like experimental autoimmune encephalomyelitis. Furthermore, we demonstrated that a D1-like-R antagonist significantly suppressed ovalbumin (OVA)-induced neutrophilic airway inflammation in OVA T cell receptor-transgenic DO11.10 mice through inhibiting Th17-mediated immune responses. Therefore, dopamine D1-like-R antagonists could become useful for treating Th17-mediated neutrophil-dominant severe asthma. As inhaled corticosteroids are known to be less effective for controlling neutrophilic inflammation, a more effective therapeutic strategy for neutrophil-dominant asthma should still be elucidated.

Topics: Animals; Asthma; Cell Movement; Humans; Interleukin-8; Neutrophils; Pneumonia; Receptors, Dopamine D1; Th17 Cells

Topics: Humans; Immunity, Innate; Interleukin-8; Leukotriene B4; Macrophages, Alveolar; Pneumonia; Pulmonary Fibrosis

Topics: Humans; Inflammation; Interleukin-1; Interleukin-6; Interleukin-8; Pneumonia; Pneumonia, Bacterial; Tumor Necrosis Factor-alpha

In respiratory tract infections, leukocytes are recruited to the lungs, where they help remove invading organisms through phagocytic clearance. In some instances, however, the normal inflammatory response may be as destructive as it is defensive. The neutrophils secrete a proteolytic enzyme, neutrophil elastase, which has emerged as a major culprit in the pathogenesis of inflammatory airway disease. This enzyme has been found to strip the bronchial epithelium, reduce ciliary beating, and stimulate excess mucus secretion, leading to mucus retention, bacterial proliferation, and recurrent infections. Neutrophil elastase also stimulates epithelial cell interleukin-8 secretion and produces other chemoattractant cleavage products that lead to further neutrophil recruitment. It also impairs host defenses by damaging the major opsonophagocytic receptor on the neutrophil and by weakening the efficacy of immunoglobulins. For this reason, an important goal in the treatment of respiratory tract infections should be to prevent or shorten the duration of neutrophil elastase release. A number of different approaches have been proposed or attempted in an effort to modulate the proteinase burden. These include direct inhibition of elastase and interference with the recruitment, adherence, and degranulation of neutrophils. An even more fundamental approach would start in the bone marrow, where attempts might be made to modulate or modify neutrophil precursors so as to limit the destructive potential of the mature neutrophils.

Topics: Bone Marrow Cells; Cell Adhesion; Cell Degranulation; Chemotaxis, Leukocyte; Hematopoietic Stem Cells; Humans; Immunoglobulins; Interleukin-8; Leukocyte Elastase; Neutrophil Activation; Neutrophils; Pancreatic Elastase; Phagocytosis; Pneumonia; Respiratory Tract Infections

The diagnosis of ventilator-associated pneumonia (VAP) is difficult for several reasons. Firstly, clinical markers show a large percentage of false-positive and false-negative results. Secondly, microbiological diagnosis based on quantitative cultures of protected specimen brush (PSB), bronchoalveolar lavage (BAL), and endotracheal aspirates also present false-positive and false-negative results. Furthermore, definite results are delayed for 48-72 hours. For all these reasons it would be an advantage to have a biological marker of ventilator-associated pneumonia in clinical practice. Since clinical features of pneumonia in mechanically ventilated patients are neither specific nor sensitive, rapid markers of pneumonia might be of great assistance to the clinician in deciding whether to start an empiric antibiotic regimen. A marker of ventilator-associated pneumonia could be a rapid alternative diagnostic method which permits the definite diagnosis of pneumonia. Accordingly, specific markers of VAP, namely the presence of intracellular microorganisms, the detection of elastin fibres, the antibody-coated bacteria test, the level of endotoxin in bronchoalveolar lavage fluid, the local production of interleukin-8, the levels of lactate dehydrogenase, and decreased surfactant protein A, may be important as they can provide a rapid diagnosis of VAP. Among the markers alluded to above, the search for intracellular bacteria in polymorphonuclear leukocytes or macrophages is the most widely validated technique with an excellent specificity, provided that prior antibiotics are not given. However, this technique has its own limitations; it requires a considerable time effort for the microbiologist, and also compels the performance of BAL, a technique not always harmless to the patient.

Topics: Antibody-Coated Bacteria Test, Urinary; Bacteriological Techniques; Biomarkers; Bronchoalveolar Lavage Fluid; Elastin; Endotoxins; Glycoproteins; Humans; Interleukin-8; L-Lactate Dehydrogenase; Pneumonia; Proteolipids; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants; Ventilators, Mechanical

Kalmegh (Andrographis paniculata) is commonly used for treating uncomplicated Upper Respiratory Tract Infection (URTI) in complementary and alternative system of medicine. AP-Bio®(KalmCold®) is a standardized extract derived from the leaves of A. paniculata. This study was proposed to evaluate its efficacy using validated scales and objective measures.. Participants were randomized in a ratio of 1:1:1 to receive either AP-Bio® 200 mg/day, AP-Bio® 400 mg/day or placebo for 7 days. The primary outcome measure was Wisconsin Upper Respiratory Symptom Survey (WURSS-21) score. The secondary outcome measures were nasal mucous weight, nasal muco-ciliary clearance function and Interleukin-8 in nasal wash, as well as safety and tolerability.. A total of n = 331 participants were screened and N = 300 participants were enrolled. The absolute WURSS-21 global score [mean (Standard Deviation - SD)] in the AP-Bio® 400 mg group [5.70 (5.31)] was less than the AP-Bio® 200 mg group [5.81 (4.83)] on Day-3. However, it was much higher in the placebo group [9.55 (14.27)]. AP-Bio® 400 mg group (Mean Difference - MD [Standard Error - SE] = -3.85 [1.52]; 95% CI = -6.85, - 0.85; adjusted p = 0.034) and 200 mg group (MD [SE] = -3.74 [1.51]; 95% CI = -6.73, - 0.76; adjusted p = 0.038) had significantly lower score than placebo. Similarly, on Day-3, the change in global score from baseline was significantly better in the AP-Bio® 400 mg group (MD [SE] = -3.91; [1.82] 95% CI = -7.50, - 0.32; adjusted p = 0.038) and AP-Bio® 200 mg group (MD [SE] = -3.84 [1.97]; 95% CI = -7.72, - 0.04; adjusted p = 0.044) in comparison to the placebo group. Nasal mucous weight, tissue paper counts used, and interleukin-8 showed a trend towards AP-Bio® groups having a favourable outcome when compared with placebo but did not reach statistical significance due to a small sample size. None of the study participants complained of any adverse physical symptoms. However, incident eosinophilia was noted in n = 20 participants on day 3. (n = 6 in AP-Bio® 200 mg group, n = 7 in Ap-Bio® 400 mg group and n = 13 in placebo group; p = 0.181).. Participants in both the AP-Bio® dose groups showed positive tendency towards resolution of URTI symptoms when compared with placebo on Day-3 but not on Day-5 and Day-7.

Topics: Common Cold; Double-Blind Method; Humans; Interleukin-8; Plant Extracts; Pneumonia; Respiratory System

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

Community acquired pneumonia (CAP) is a severe and often rapidly deteriorating disease. To better understand its dynamics and potential causal relationships, we analyzed time series data of cytokines, blood and clinical parameters in hospitalized CAP patients.. Time series data of 10 circulating cytokines, blood counts and clinical parameters were related to baseline characteristics of 403 CAP patients using univariate mixed models. Bivariate mixed models were applied to analyze correlations between the time series. To identify potential causal relationships, we inferred cross-lagged relationships between pairs of parameters using latent curve models with structured residuals.. IL-6 levels decreased faster over time in younger patients (P. These results suggest that IL-6 trajectories of CAP patients are associated with age and run parallel to bilirubin levels. The time series analysis also unraveled directed, potentially causal relationships between cytokines, blood parameters and clinical outcomes. This will facilitate the development of mechanistic models of CAP, and with it, improvements in treatment or surveillance strategies for this disease.. clinicaltrials.gov NCT02782013, May 25, 2016, retrospectively registered.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Community-Acquired Infections; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Middle Aged; Pneumonia; Prospective Studies; Severity of Illness Index; Vascular Cell Adhesion Molecule-1

A previous study found community-acquired pneumonia (CAP) patients with imbalance of high inflammation and discordantly low cortisol levels to benefit most from adjunctive corticosteroid treatment. Our aim was to validate this hypothesis in a preplanned secondary analysis of the randomized controlled STEP trial.. Patients included in the STEP trial receiving 50 mg prednisone or placebo for 5 days were categorized based on pro-inflammatory cytokines (Interleukin-6/8/MCP-1), CRP and cortisol levels on admission into four groups (high/low inflammation and high/low cortisol). The primary combined end-point was mortality or ICU admission within 30 days.. In total, 632 patients (315 prednisone, 317 placebo) were included in this analysis. Prednisone did not significantly reduce the risk for the primary end-point in patients with high cytokines/low cortisol and in any other subgroups. However, we noted some differences in the strength of corticosteroid effect in the different subgroups with stronger effects in patients with high cytokines [OR 0.44 (0.10,1.72)] compared to patients with low cytokines [OR 0.68 (0.30,1.5)] (P-interaction = 0.600). The effects did not differ according to cortisol levels.. The imbalance of high inflammation state and low cortisol levels did not predict treatment response to corticosteroids in patients with CAP. However, in line to previous research, inflammation as measured by cytokine levels irrespective of cortisol tended to predict treatment response to corticosteroids in CAP. Whether this concept may help to personalize corticosteroids to patients most likely benefitting from this treatment needs to be tested in future intervention trials.

Topics: Aged; Aged, 80 and over; Chemokine CCL2; Community-Acquired Infections; Double-Blind Method; Female; Glucocorticoids; Humans; Hydrocortisone; Interleukin-6; Interleukin-8; Male; Middle Aged; Pneumonia; Prednisone; Prospective Studies

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; 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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; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

The local pulmonary inflammatory response has a different temporal and qualitative profile compared with the systemic inflammatory response. Although glucocorticoids substantially downregulate the systemic release of acute-phase mediators, it is not clear whether they have comparable inhibitory effects in the human lung compartment. Therefore, we compared the anti-inflammatory effects of a pure glucocorticoid agonist, dexamethasone, on bronchoalveolar lavage and blood cytokine concentrations in response to bronchially instilled endotoxin.. In this randomized, double-blind and placebo-controlled trial, 24 volunteers received dexamethasone or placebo and had endotoxin instilled into a lung segment and saline instilled into a contralateral segment, followed by bronchoalveolar lavage.. Bronchially instilled endotoxin induced a local and systemic inflammatory response. Dexamethasone strongly blunted the systemic interleukin (IL) 6 and C-reactive protein release. In sharp contrast, dexamethasone left the local release of acute-phase mediators in the lungs virtually unchanged: bronchoalveolar lavage levels of IL-6 were only 18% lower and levels of IL-8 were even higher with dexamethasone compared with placebo, although the differences between treatments were not statistically significant (P = 0.07 and P = 0.08, respectively). However, dexamethasone had inhibitory effects on pulmonary protein extravasation and neutrophil migration.. The present study demonstrated a remarkable dissociation between the systemic anti-inflammatory effects of glucocorticoids and its protective effects on capillary leak on the one hand and surprisingly low anti-inflammatory effects in the lungs on the other.

Topics: Adult; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Dexamethasone; Double-Blind Method; Endotoxins; Female; Glucocorticoids; Healthy Volunteers; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Male; Pneumonia

Compared to conventional tidal volume ventilation, low tidal-volume ventilation reduces mortality in cased of acute respiratory distress syndrome. The aim of the present study is to determine whether low tidal-volume ventilation reduces the production of inflammatory mediators in the lungs and improves physiological status during hepatic surgery.. We randomly assigned patients undergoing hepatectomy into 2 groups: conventional tidal-volume vs. low tidal-volume (12 vs. 6 mL•kg(-1) ideal body weight) ventilation with a positive end-expiratory pressure of 3 cm H2O. Arterial blood and airway epithelial lining fluid were sampled immediately after intubation and every 3 h thereafter.. Twenty-five patients were analyzed. No significant changes were found in hemodynamics or acid-base status during the study. Interleukin-8 was significantly elevated in epithelial lining fluid from the low tidal-volume group. Oxygenation evaluated immediately after admission to the post-surgical care unit was significantly worse in the low tidal-volume group.. Low tidal-volume ventilation with low positive end-expiratory pressure may lead to pulmonary inflammation during major surgery such as hepatectomy.. The effect of ventilatory tidal volume on lung injury during hepatectomy that requires transient liver blood flow interruption. UMIN000021371 (03/07/2016); retrospectively registered.

Topics: Acid-Base Equilibrium; Adult; Aged; Aged, 80 and over; Blood Gas Analysis; Female; Hemodynamics; Humans; Interleukin-8; Liver; Male; Middle Aged; Oxygen; Pneumonia; Positive-Pressure Respiration; Postoperative Complications; Respiration, Artificial; Tidal Volume; Young Adult

Cigarette smoking, the major causative factor for the development of chronic obstructive pulmonary disease, is associated with neutrophilic airway inflammation. Cigarette smoke (CS) exposure can induce a switch from apoptotic to necrotic cell death in airway epithelium. Therefore, we hypothesized that CS promotes neutrophil necrosis with subsequent release of damage-associated molecular patterns (DAMPs), including high mobility group box 1 (HMGB1), alarming the innate immune system. We studied the effect of smoking two cigarettes on sputum neutrophils in healthy individuals and of 5-day CS or air exposure on neutrophil counts, myeloperoxidase, and HMGB1 levels in bronchoalveolar lavage fluid of BALB/c mice. In human peripheral blood neutrophils, mitochondrial membrane potential, apoptosis/necrosis markers, caspase activity, and DAMP release were studied after CS exposure. Finally, we assessed the effect of neutrophil-derived supernatants on the release of chemoattractant CXCL8 in normal human bronchial epithelial cells. Cigarette smoking caused a significant decrease in sputum neutrophil numbers after 3 hours. In mice, neutrophil counts were significantly increased 16 hours after repeated CS exposure but reduced 2 hours after an additional exposure. In vitro, CS induced necrotic neutrophil cell death, as indicated by mitochondrial dysfunction, inhibition of apoptosis, and DAMP release. Supernatants from CS-treated neutrophils significantly increased the release of CXCL8 in normal human bronchial epithelial cells. Together, these observations show, for the first time, that CS exposure induces neutrophil necrosis, leading to DAMP release, which may amplify CS-induced airway inflammation by promoting airway epithelial proinflammatory responses.

Topics: Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Cells, Cultured; Cross-Over Studies; Female; HMGB1 Protein; Humans; Immunity, Innate; Inflammation Mediators; Inhalation Exposure; Interleukin-8; Lung; Membrane Potential, Mitochondrial; Mice, Inbred C57BL; Necrosis; Neutrophils; Peroxidase; Phenotype; Pneumonia; Respiratory Mucosa; Signal Transduction; Smoke; Smoking; Sputum; Time Factors

Excessive systemic inflammatory response remains as a major problem underlying severe burns. This study aimed to assess the effect of low-dose glucocorticoid treatment in downregulating systemic inflammation in severely burned patients.. A prospective study from 2001 to 2014 at our hospital was conducted to compare the patients who received low-dose glucocorticoid during the acute phase with those who did not. Patients with burns 70% or greater of their total body surface area were included, and their plasma levels of inflammatory cytokines and clinical outcomes were compared.. A total of 69 patients were included in this study, with 31 patients receiving glucocorticoid treatment and the others not. Patient demographics including age, burn size, and incidence of inhalation injury were similar in both groups. The incidence of pulmonary infection and stress ulcer (and/or hemorrhage) was 24.2% and 3.0% in the treatment group, respectively, significantly lower than 47.8% and 19.6% of the control group (P < .05). Length of hospital stay was almost 13 days shorter in the treatment group (P < .05), whereas there was no significant difference in the overall mortality, duration of mechanical ventilation, and incidence of sepsis between the 2 groups. The enzyme-linked immunosorbent assay results confirmed that the plasma levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-8 were significantly lower in the treatment group (P < .05).. Low dose of glucocorticoid treatment during the acute phase could reduce the levels of proinflammatory cytokines in severely burned patients and subsequently decrease the incidence of pulmonary infection and stress ulcer, as well as the length of hospital stay.

Topics: Adult; Anti-Inflammatory Agents; Burns; C-Reactive Protein; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Glucocorticoids; Humans; Incidence; Inflammation; Interleukin-6; Interleukin-8; Length of Stay; Male; Middle Aged; Pneumonia; Prospective Studies; Sepsis; Stomach Ulcer; Treatment Outcome; Tumor Necrosis Factor-alpha

Inhaled lipopolysaccharide (LPS) induces a dose-dependent, acute neutrophilic response in the airways of healthy volunteers that can be quantified in induced sputum. Chemokines, such as CXCL1 and CXCL8, play an important role in neutrophilic inflammation in the lung through the activation of CXCR2 and small molecule antagonists of these receptors have now been developed. We investigated the effect of AZD8309, a CXCR2 antagonist, compared with placebo on LPS-induced inflammation measured in sputum of healthy volunteers.. Twenty healthy subjects were randomized in a double-blind placebo-controlled, cross-over study. AZD8309 (300 mg) or placebo was dosed twice daily orally for 3 days prior to challenge with inhaled LPS and induced sputum was collected 6 h later.. Treatment with AZD8309 showed a mean 77% reduction in total sputum cells (p < 0.001) and 79% reduction in sputum neutrophils (p < 0.05) compared with placebo after LPS challenge. There was also a reduction in neutrophil elastase activity (p < 0.05) and CXCL1 (p < 0.05) and trends for reductions in sputum macrophages (47%), leukotriene B4 (39%) and CXCL8 (52%).. AZD8309 inhibited LPS-induced inflammation measured in induced sputum of normal volunteers, indicating that this treatment may be useful in the treatment of neutrophilic diseases of the airways, such as COPD, severe asthma and cystic fibrosis.. NCT00860821.

Topics: Administration, Oral; Adult; Cell Count; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Interleukin-8; Leukocyte Elastase; Leukotriene B4; Lipopolysaccharides; Male; Neutrophils; Pneumonia; Pyrimidines; Receptors, Interleukin-8B; Sputum

Plasma and bronchoalveolar lavage (BAL) biomarkers related to the pathogenesis of acute lung injury (ALI) have previously been associated with poorer clinical outcomes and increased disease severity among patients with ALI. Whether these biomarkers have predictive value in a less severely ill population that excludes septic patients with high APACHE II scores is currently unknown. We tested the association of plasma and BAL biomarkers with physiological markers of ALI severity or clinically relevant outcomes in a secondary analysis of a clinical trial of activated protein C for the treatment of ALI. Plasma plasminogen activator inhibitor-1 (PAI-1) and mini-BAL protein were both significantly associated with increased oxygenation index (P = 0.02 and 0.01, respectively), whereas there was a trend toward an association between IL-6 and oxygenation index (P = 0.057). High plasma IL-6, thrombomodulin, and mini-BAL protein were all significantly associated with fewer ventilator-free days (VFDs) (P = 0.01, 0.01, and 0.05, respectively); no markers were associated with mortality, but we hypothesized that this was due to the small size of our cohort and the low death rate. To confirm these associations in a larger sample, we identified a restricted cohort of patients from the ARDS Network ALVEOLI study with similar baseline characteristics. We retested the associations of the significant biomarkers with markers of severity and clinical outcomes and studied IL-8 as an additional biomarker given its important predictive value in prior studies. In this restricted cohort, IL-6 was significantly associated with oxygenation index (P = 0.02). Both IL-6 and IL-8 were associated with decreased VFDs and increased 28-day mortality. Future studies should be focused on examining larger numbers of patients with less severe ALI to further test the relative predictive value of plasma and mini-BAL biomarkers for clinically relevant outcomes, including VFDs and mortality, and for their prospective utility in risk stratification for future clinical trials.

Topics: Acute Lung Injury; Adult; Aged; APACHE; Biomarkers; Bronchoalveolar Lavage Fluid; Cohort Studies; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Pneumonia; Predictive Value of Tests; Protein C; Pulmonary Edema; Respiratory Distress Syndrome; Respiratory Insufficiency; Risk Factors; Severity of Illness Index; Thrombomodulin

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

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

Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury.. Phase II randomized controlled trial.. Five North American medical centers.. Mechanically ventilated patients with acute lung injury ≥18 yrs of age.. Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days.. Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p < .0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups.. Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.

Topics: Acute Lung Injury; Adult; Aged; Biomarkers; Body Weight; Bronchoalveolar Lavage Fluid; Cell Count; Chemokine CCL2; Docosahexaenoic Acids; Drug Therapy, Combination; Eicosapentaenoic Acid; Enteral Nutrition; Female; Hospital Mortality; Humans; Interleukin-6; Interleukin-8; Leukotriene B4; Male; Middle Aged; Neutrophils; Pneumonia; Positive-Pressure Respiration, Intrinsic; Pulmonary Surfactant-Associated Protein D; Tidal Volume; von Willebrand Factor

Mechanical ventilation (MV) with high tidal volumes may induce or aggravate lung injury in critical ill patients. We compared the effects of a protective versus a conventional ventilatory strategy, on systemic and lung production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) in patients without lung disease.. Patients without lung disease and submitted to mechanical ventilation admitted to one trauma and one general adult intensive care unit of two different university hospitals were enrolled in a prospective randomized-control study. Patients were randomized to receive MV either with tidal volume (VT) of 10 to 12 ml/kg predicted body weight (high VT group) (n = 10) or with VT of 5 to 7 ml/kg predicted body weight (low VT group) (n = 10) with an oxygen inspiratory fraction (FIO2) enough to keep arterial oxygen saturation >90% with positive end-expiratory pressure (PEEP) of 5 cmH2O during 12 hours after admission to the study. TNF-alpha and IL-8 concentrations were measured in the serum and in the bronchoalveolar lavage fluid (BALF) at admission and after 12 hours of study observation time.. Twenty patients were enrolled and analyzed. At admission or after 12 hours there were no differences in serum TNF-alpha and IL-8 between the two groups. While initial analysis did not reveal significant differences, standardization against urea of logarithmic transformed data revealed that TNF-alpha and IL-8 levels in bronchoalveolar lavage (BAL) fluid were stable in the low VT group but increased in the high VT group (P = 0.04 and P = 0.03). After 12 hours, BALF TNF-alpha (P = 0.03) and BALF IL-8 concentrations (P = 0.03) were higher in the high VT group than in the low VT group.. The use of lower tidal volumes may limit pulmonary inflammation in mechanically ventilated patients even without lung injury.. NCT00935896.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Critical Illness; Cytokines; Female; Humans; Inflammation; Intensive Care Units; Interleukin-8; Lung Diseases; Lung Injury; Male; Middle Aged; Pneumonia; Prospective Studies; Respiration, Artificial; Tidal Volume; Tumor Necrosis Factor-alpha

The pulmonary inflammatory response and pulmonary dysfunction after cardiopulmonary bypass is a major problem in patients undergoing cardiac surgery. Propofol has anti-inflammatory and immunomodulatory properties which may attenuate this response. Thirty patients undergoing cardiopulmonary bypass were randomly assigned to receive saline (control group) or propofol (propofol group). Pulmonary thoracic compliance, respiratory index, malondialdehyde and interleukin-8 concentrations and intrapulmonary polymorphonucleocyte sequestration were measured at pre-bypass and 5, 30, 60, 90 and 120 min after unclamping the aorta. Plasma levels of interleukin-8, malondialdehyde and the respiratory index increased and reached peaks 30 min after unclamping in both groups. However, in the propofol group the increases were less than in the control group (p < 0.01). Intrapulmonary polymorphonucleocytes sequestration in the propofol group was less than in the control group 5 min after unclamping (p < 0.0001). Pulmonary thoracic compliance decreased significantly after unclamping in both groups, but the reduction was less in the propofol group (p < 0.01). These findings suggest that propofol administered during bypass could reduce the severity of pulmonary dysfunction.

Topics: Aged; Anesthetics, Intravenous; Anti-Inflammatory Agents, Non-Steroidal; Cardiopulmonary Bypass; Female; Heart Valve Prosthesis Implantation; Humans; Inflammation Mediators; Interleukin-8; Intraoperative Care; Lipid Peroxidation; Lung Compliance; Male; Malondialdehyde; Middle Aged; Neutrophils; Pneumonia; Propofol

The purpose of this study was to examine whether nitrous oxide increases the inflammatory reaction in the airway in patients undergoing minor surgery.. Twenty patients were divided into two groups at random. The patients were anesthetized by either sevoflurane with air (Group A: n=10) or sevoflurane with nitrous oxide (Group G: n=10). In addition, all patients were mechanically ventilated. Epithelial lining fluid (ELF) specimens were obtained by bronchoscopic microsampling method at both the beginning and end of surgery. The concentrations of interleukin (IL)-6 and IL-8 in the ELF were measured by enzyme immunometric assay(ELISA).. Significant differences were observed in the IL-8 concentrations in the ELF of the G group at the end of surgery in comparison with those seen at the beginning of surgery in the G group (P < 0.05), and at the end of surgery in the A group (P < 0.05). The IL-6 levels were not measured in either group.. The pulmonary immunologic function changed progressively during anesthesia, surgery and positive pressure mechanical ventilation. The data from this study suggest that the immune ability of the lung may possibly change due to the administration of nitrous oxide. As a result, our findings suggest that the postoperative inflammatory reaction in the lung may increase when sevoflurane plus nitrous oxide are used during general anesthesia.

Topics: Adult; Aged; Anesthesia, General; Biomarkers; Enzyme-Linked Immunosorbent Assay; Epithelium; Female; Humans; Inflammation Mediators; Interleukin-8; Lung; Male; Methyl Ethers; Middle Aged; Nitrous Oxide; Pneumonia; Sevoflurane

TNFalpha may contribute to the pathophysiology of airway inflammation. For example, we have recently shown that nasal administration of TNFalpha produces late phase co-appearance of granulocyte and plasma exudation markers on the mucosal surface. The objective of the present study was to examine indices of granulocyte presence and activity in response to intranasal TNFalpha challenge.. Healthy subjects and patients with allergic rhinitis (examined out of season) were subjected to nasal challenge with TNFalpha (10 microg) in a sham-controlled and crossover design. Nasal lavages were carried out prior to and 24 hours post challenge. Nasal biopsies were obtained post challenge. Nasal lavage fluid levels of myeloperoxidase (MPO) and eosinophil cationic protein (ECP) were analyzed as indices of neutrophil and eosinophil activity. Moreover, IL-8 and alpha2-macroglobulin were analyzed as markers of pro-inflammatory cytokine production and plasma exudation. Nasal biopsy numbers of neutrophils and eosinophils were monitored.. Nasal lavage fluid levels of MPO recorded 24 hours post TNFalpha challenge were increased in healthy subjects (p = 0.0081) and in patients with allergic rhinitis (p = 0.0081) (c.f. sham challenge). Similarly, alpha2-macroglobulin was increased in healthy subjects (p = 0.014) and in patients with allergic rhinitis (p = 0.0034). Lavage fluid levels of ECP and IL-8 were not affected by TNFalpha challenge. TNFalpha increased the numbers of subepithelial neutrophils (p = 0.0021), but not the numbers of eosinophils.. TNFalpha produces a nasal inflammatory response in humans that is characterised by late phase (i.e., 24 hours post challenge) neutrophil activity and plasma exudation.

Topics: Administration, Intranasal; Adult; alpha-Macroglobulins; Biopsy; Cross-Over Studies; Eosinophil Cationic Protein; Eosinophils; Female; Granulocytes; Humans; Interleukin-8; Male; Middle Aged; Nasal Lavage Fluid; Nasal Mucosa; Neutrophils; Peroxidase; Pneumonia; Rhinitis, Allergic, Seasonal; Single-Blind Method; Tumor Necrosis Factor-alpha

To examine the effect of ulinastatin (UTI) on the inflammatory responses induced by oesophagectomy.. Forty patients with esophageal cancer (without serious hypertension, heart disease, or respiratory function impairment, including 34 men and 6 women aged 46 to 70 years) scheduled for oesophagectomy via left thoracotomy were randomly divided into control group (n=20) and UTI group (n=20). Anesthesia induction and perioperative management followed the same protocols in the two groups, and in UTI group, patients received 5000 U/kg UTI while those in the control group were given the same volume of saline. Before operation (T(1)), 10 min after recovery of two-lung ventilation (T(2)), and 24 h (T(3)) and 48 h (T(4)) after operation, the venous blood sample was taken from the internal jugular vein and the plasma was separated and stored at -70 degrees C for later analysis of IL-6 and IL-8 with enzyme-linked immunosorbent assay (ELISA). The bronchoalveoar lavage fluid (BAFL) was also collected at T(1) and T(2) for IL-6 and IL-8 detection.. IL-6, IL-8 levels in the plasma and BALF collected at T(2)-T(4) increased significantly as compared with those in samples collected at T(1), and their peak concentration inplasma and BALF samples were similar. IL-6 and IL-8 levels in the UTI group were significantly lower than those in the control group during the time points of T(2)-T(4).. Inflammatory responses occur during and after oesophagectomy, which can be inhibited with UTI.

Topics: Adult; Aged; Esophageal Neoplasms; Esophagectomy; Female; Glycoproteins; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Pneumonia; Postoperative Complications; Treatment Outcome; Trypsin Inhibitors

Recombinant human deoxyribonuclease (rhDNase) has been shown to improve lung function and reduce the number of pulmonary exacerbations in patients with cystic fibrosis (CF), but its long-term effect on airway inflammation remains unknown. In this study, we used bronchoalveolar lavage (BAL) to investigate the long-term effect of rhDNase on inflammation in patients with CF having mild lung disease. A total of 105 patients with CF (> or =5 years of age) having normal lung function were randomized to receive rhDNase (2.5 mg/day) or no rhDNase. Patients with a normal percentage of neutrophils in BAL fluid at baseline were not randomized and served as the control group. The percentage of neutrophils in the pooled BAL sample was similar in both randomized groups at baseline. A significant increase in neutrophils was observed over the 3-year study period in both untreated patients and control subjects, whereas neutrophils remained unchanged in patients treated with rhDNase. Elastase activities and interleukin-8 concentrations also increased in untreated patients and remained stable in patients on rhDNase. We conclude that in patients with CF, an increase in neutrophilic airway inflammation is found that is positively influenced by rhDNase treatment.

Topics: Adolescent; Adult; Bronchoalveolar Lavage; Child; Child, Preschool; Cystic Fibrosis; Deoxyribonuclease I; Female; Follow-Up Studies; Humans; Interleukin-8; Leukocyte Count; Leukocyte Elastase; Male; Neutrophils; Peroxidase; Pneumonia; Recombinant Proteins; Time Factors

The adverse health effects of particulate matter pollution are of increasing concern. In a recent bronchoscopic study in healthy volunteers, pronounced airway inflammation was detected following exposure to diesel exhaust (DE). The present study was conducted in order to evaluate the time kinetics of the inflammatory response following exposure to DE using induced sputum from healthy volunteers. Fifteen healthy nonsmoking volunteers were exposed to DE particles with a 50% cut-off aerodynamic diameter of 10 microm 300 microg x m(-3) and air for 1 h on two separate occasions. Sputum induction with hypertonic saline was performed 6 and 24 h after each exposure. Analyses of sputum differential cell counts and soluble protein concentrations were performed. Six hours after exposure to DE, a significant increase was found in the percentage of sputum neutrophils (37.7 versus 26.2% p=0.002) together with increases in the concentrations of interleukin-6 (12.0 versus 6.3 pg x mL(-1), p=0.006) and methylhistamine (0.11 versus 0.12 microg x L(-1), p=0.024). Irrespective of exposure, a significant increase was found in the percentage of sputum neutrophils at 24 as compared to 6 h, indicating that the procedure of sputum induction itself may change the composition of sputum. This study demonstrates that exposure to diesel exhaust induces inflammatory response in healthy human airways, represented by an early increase in interleukin-6 and methylhistamine concentration and the percentage of neutrophils. Induced sputum provides a safe tool for the investigation of the inflammatory effects of diesel exhaust, but care must be taken when interpreting results from repeated sputum inductions.

Topics: Adult; Air Pollution; Chemokine CXCL1; Chemokines, CXC; Chemotactic Factors; Cross-Over Studies; Female; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-6; Interleukin-8; Kinetics; Leukocyte Count; Male; Methylhistamines; Peroxidase; Pneumonia; Single-Blind Method; Sputum; Tumor Necrosis Factor-alpha; Vehicle Emissions

Transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8), and leukotrienes are potent neutrophil chemoattractants that are released in several lung diseases. There is limited information about the release of TGF-beta in bronchoalveolar lavage fluid (BALF) of patients with pneumonia. Furthermore, it is not clear if TGF-beta is differentially expressed in different lung diseases. The aim of our study was to compare the concentrations of TGF-beta1 and TGF-beta2 in the BALF of patients with pneumonia and other lung diseases. Furthermore, correlation of the TGF-beta levels with the concentration of chemoattractant mediators as well as with indicators of macrophage and granulocyte activation should be investigated. Patients with pneumonia, interstitial lung disease (ILD), or chronic obstructive pulmonary diseases (COPD) were included. Patients with ischemic heart disease without pulmonary involvement served as controls. The concentrations of TGF-beta1 and TGF-beta2, of the chemoattractant cytokine IL-8, of leukotriene B4, and of the leukotrienes C4, D4, and E4 were measured. Neutrophil elastase and granulocyte content (PMN) were used as markers for granulocyte activation, and neopterin was used as a marker for the activation of macrophages. Significantly elevated levels of TGF-beta1 (mean = 0.216 ng/ml, p < 0.01) were found in patients with microbiologically positive pneumonia but not in patients with ILD or COPD. A significant (p < 0.001) correlation was found between the TGF-beta1 concentrations and the IL-8 levels and the percentage of granulocytes (r = 0.76, and r = 0.44, respectively). Elevated TGF-beta2 concentrations were measured in the BALF of patients with pneumonia (mean = 1.4 ng/ml, p < 0.01) and with ILD. Pneumonia was also associated with increased concentrations of leukotrienes C4, D4, and E4 (mean = 91.61 pg/ml, p < 0.05) and leukotriene B4 (mean = 203.9 pg/ml, p < 0.01), significantly elevated levels of PMN elastase (mean = 2958.26 ng/ml, p < 0.01), and neopterin (mean = 0.42 nmol/L). Our results strongly suggest that different lung diseases do differ with regard to the released cytokines. TGF-beta1 probably plays a key role in regulation of pulmonary inflammation, particularly in pneumonia.

Topics: Bronchoalveolar Lavage Fluid; Granulocytes; Humans; Interleukin-8; Leukocyte Elastase; Leukotrienes; Lung Diseases, Interstitial; Lung Diseases, Obstructive; Macrophages; Monocytes; Neopterin; Pneumonia; Transforming Growth Factor beta

To determine the effect of glucocorticoids on grain dust-induced airflow obstruction and airway inflammation.. Randomized controlled trial.. University hospital.. Health volunteers.. Two randomized, placebo-controlled trials, each studying 10 healthy volunteers who were pretreated with either triamcinolone acetonide (Azmacort) oral inhaler 4 puffs twice daily (800 microg daily) for 7 consecutive days or IV hydrocortisone (3 microg/kg/min) as a 14-h continuous infusion, then subjected to a controlled inhalation exposure to corn dust extract (CDE) (endotoxin exposure dose of 3 microg/kg). A single-blind, crossover study design was performed for each trial enrolling 10 healthy, lifetime nonsmokers, with no history of lung disease or environmental exposure to grain dust.. Following each inhalation exposure to CDE, spirometry was performed at regular intervals and BAL was performed at 4 h. Both treatment and placebo groups demonstrated significant decrements in spirometry and increments in BAL cellularity following CDE inhalation compared with placebo. Inhaled steroid treatment resulted in a significantly higher FEV1 only at the 2-h time point following CDE inhalation with no significant differences observed in the BAL total cell concentration or cellular differential compared with placebo. IV hydrocortisone treatment resulted in a significantly higher FEV1 and FVC between 2 and 4 h after CDE inhalation, as well as significant reductions in the BAL total cell, macrophage, and eosinophil concentrations. Interestingly, the concentration of tumor necrosis factor-alpha and interleukin-8 in the BAL fluid was also decreased following treatment with IV glucocorticoids.. These results demonstrate that glucocorticoids, administered IV and perhaps by inhalation, have a mildly protective effect on airflow obstruction and airway inflammation induced by inhalation of grain dust.

Topics: Administration, Inhalation; Adult; Airway Obstruction; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cell Count; Cross-Over Studies; Dust; Eosinophils; Female; Follow-Up Studies; Forced Expiratory Volume; Glucocorticoids; Humans; Hydrocortisone; Infusions, Intravenous; Interleukin-8; Leukocyte Count; Macrophages, Alveolar; Male; Placebos; Pneumonia; Premedication; Single-Blind Method; Spirometry; Triamcinolone Acetonide; Tumor Necrosis Factor-alpha; Vital Capacity; Zea mays

Pentoxifylline (PTX) has been shown to reduce sepsis-induced neutrophil sequestration in the lung and inhibit endotoxin-mediated release of tumor necrosis factor-alpha (TNF-alpha). Previously, we have shown that endotoxin appears to be the principal agent in grain dust causing airway inflammation and airflow obstruction following grain dust inhalation. To determine whether PTX affects the physiologic and inflammatory events following acute grain dust inhalation, 10 healthy, nonsmoking subjects with normal airway reactivity were treated with PTX or placebo (PL) followed by corn dust extract (CDE) inhalation (0.08 mL/kg), using a single-blinded, crossover design. Subjects received PTX (1,200 mg/d) or PL for 4 days prior to CDE inhalation and 400 mg PTX or PL on the exposure day. Both respiratory symptoms and declines in FEV1 and FVC occurred following CDE exposure in both groups, but there were no significant differences in the frequency of symptoms or percent declines from baseline in the FEV1 and FVC at any of the time points measured in the study. Elevations in peripheral blood leukocyte and neutrophil concentrations and BAL total cell, neutrophil, TNF-alpha, and interleukin-8 concentrations were measured 4 h following exposure to CDE in both the PTX- and PL-treated subjects, but no significant differences were found between treatment groups. These results suggest that pretreatment with PTX prior to inhalation of CDE, in the doses used in this study, does not alter the acute physiologic or inflammatory events following exposure to inhaled CDE.

Topics: Administration, Inhalation; Adult; Airway Obstruction; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Movement; Cross-Over Studies; Dust; Edible Grain; Endotoxins; Female; Forced Expiratory Volume; Humans; Interleukin-8; Leukocyte Count; Leukocytes; Lung; Male; Neutrophils; Pentoxifylline; Phosphodiesterase Inhibitors; Placebos; Pneumonia; Single-Blind Method; Tumor Necrosis Factor-alpha; Vital Capacity; Zea mays

The role of prematurity and pulmonary inflammation in the pathogenesis of bronchopulmonary dysplasia (BPD) is very well-defined. However, there is limited knowledge about whether the level of prematurity and surfactant therapy alter the pulmonary cytokines and endothelial growth factor (VEGF).. This study analyzed the VEGF and cytokines, including interleukin (IL)-1β, IL-6, IL-8, and IL-10, and tumor necrosis factor α (TNF-α) in the tracheal aspirate (TA) of preterm infants obtained before (within 2 h after birth) and 10-12 h after the administration of the first dose of surfactant. TA was collected from 40 infants of 35 or fewer weeks of gestation, including extremely (Group 1, n = 19), very (Group 2, n = 13), and moderate/late (Group 2, n = 8) preterm neonates. In addition to univariate analysis, controlled regression models estimated the association of perinatal factors with the tested parameters and their role in the development of BPD.. We recorded significantly lower post-partum levels of VEGF and higher IL-8, IL-1β, and TNF-α in the TA of Group 1 infants than in Group 2 and 3. Compared to the infants in Group 2 and 3, the post-surfactant increases of pulmonary VEGF, IL-8, IL-10, and TNF-α were more significant in Group 1. All tested parameters in Group 1 and 2 infants, before and after surfactant administration, were comparable. BPD was recorded in nearly 60% of the extremely preterm survivors and was significantly predicted by increased IL-8 before, and elevated TNF-α level after surfactant administration.. This study indicates the association of birth at extremely preterm gestation with reduction in pulmonary VEGF and exacerbation of pro-inflammatory cytokines followed by greater elevation post-surfactant administration levels of VEGF, IL-8, TNF-α, and IL-10 than in neonates born with gestational age of 28-35 weeks.

Topics: Bronchopulmonary Dysplasia; Cytokines; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Inflammation Mediators; Interleukin-10; Interleukin-8; Pneumonia; Pregnancy; Pulmonary Surfactants; Surface-Active Agents; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

IL-38, a recently discovered cytokine of IL-1 family, exerts immunoregulatory activities in multi-type inflammatory diseases. However, its expression level and underlying clinical importance for IL-38 in respiratory bacterial infections remain unknown.. Thirty-five patients with bacterial pneumonia and twenty age- and gender- matched healthy individuals were enrolled in the study to determine serum IL-38 concentrations by ELISA. Then, the correlation between serum IL-38 levels and clinical features were analyzed and ROC curve was used to evaluate the potential diagnostic value for bacterial infections. In vitro, LPS-stimulated human respiratory epithelial cell model was employed to explore immunomodulatory mechanism of IL-38 in pulmonary infections.. Elevated serum levels of IL-38 were determined in patients with bacterial pneumonia when compared with healthy controls. In addition, serum IL-38 levels were negatively correlated with clinical inflammation parameters, including WBC count, CRP, PCT and proinflammatory IL-6 and IL-8. In vitro, we demonstrated that recombinant IL-38 was able to remarkably inhibit expression of proinflammatory IL-6, IL-8, IL-1β and TNF-α as well as adhesion molecule ICAM-1, which were partially mediated by attenuated activation of STAT3 and NF-κB signal cascades in BEAS-2B cells. Furthermore, we identified the diagnostic efficiency of IL-38 in discriminating patients with bacterial pneumonia from healthy individuals.. Our study indicates higher serum IL-38 levels in patients with bacterial pneumonia are involved in anti-inflammatory activities in respiratory infections revealing a critical role of IL-38 in attenuating excessive pulmonary inflammation against exogenous pathogens. More importantly, IL-38 exhibited a potential novel biomarker for bacterial pneumonia. Thus, our data may provide useful insights for both clinical and basic research for bacterial pneumonia diagnosis.

Topics: Cytokines; Humans; Interleukin-6; Interleukin-8; Interleukins; Pneumonia; Pneumonia, Bacterial; Tumor Necrosis Factor-alpha

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

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

Topics: Anti-Inflammatory Agents; Bacteria; Epithelial Cells; Humans; Hydrogen Peroxide; Inflammation; Interleukin-8; Lung; Microbiota; NF-kappa B; Pneumonia

Cell and cytokine analyses from bronchoalveolar lavage (BAL) in non-critically ill patients with COVID-19 pneumonia are poorly described. This study focused on patients hospitalized in the non-intensive care unit for either suspected COVID-19 pneumonia or persistent respiratory symptoms following proven COVID-19 pneumonia. Overall, 54 patients who underwent BAL between April 2020 and February 2021 for suspected or follow-up of proven COVID-19 pneumonia were included. Based on SARS-CoV-2 polymerase chain reaction test results and clinical follow-up, three pulmonary disease groups were defined: non-COVID-19 (n = 20), acute COVID-19 (n = 13), and post-COVID-19 (n = 24) pneumonia patients. Cytological and cytokine analyses were performed on BAL fluid (IL-1β, IL-6, IL-8, IL-10, TNF-α, IFN-γ, HGF, and TGF-β), with investigators blinded to the patient groups. Lymphocytic alveolitis with plasmocytes was observed in acute COVID-19 pneumonia, returning to normal post-COVID-19. The highest cytokine levels were observed in COVID-19 patients, with significantly increased IFN-γ, IL-10, and HGF levels compared to non-COVID-19 patients, while significantly decreased IL-6, IL-8, IL-10, IFN-γ, TNF-α, and HGF levels were noted in post-COVID-19 patients. In COVID-19 patients, correlations between IL-10, TNF-α and IFN-γ concentrations were found. Lymphocytic alveolitis with plasmacytosis was found in non-critical COVID-19 pneumonia This alveolitis is associated with the presence of IL-6, IL-8, IL-10, TNF-α, IFN-γ and HGF. Alveolitis and cytokines levels decreased in post-COVID-19 pneumonia.

Topics: Bronchoalveolar Lavage; COVID-19; Cytokines; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Pneumonia; SARS-CoV-2; Tumor Necrosis Factor-alpha

Long-term mortality is increased in older patients with pneumonia. We aimed to test whether residual inflammation is predictive of one-year mortality after pneumonia.. Inflammation biomarkers (C-reactive protein [CRP], interleukin [IL]-6 and IL-8, tumor necrosis factor-α, serum amyloid A, neopterin, myeloperoxidase, anti-apolipoprotein A-1, and anti-phosphorylcholine IgM) were measured at admission and discharge in older patients hospitalized for pneumonia in a prospective study. Univariate and multivariate analyses were conducted using absolute level at discharge and relative and absolute differences between admission and discharge for all biomarkers, along with usual prognostic factors.. In the 133 included patients (median age, 83 years [interquartile range: 78-89]), one-year mortality was 26%. In univariate analysis, the relative difference of CRP levels had the highest area under the receiver operating characteristic curve (0.70; 95% confidence interval [CI] 0.60-0.80). A decrease of CRP levels of more than 67% between admission and discharge had 68% sensitivity and 68% specificity to predict survival. In multivariate analysis, lower body mass index (hazard ratio=0.87 [CI 95% 0.79-0.96], P-value=0.01), higher IL-8 (hazard ratio=1.02 [CI 95% 1.00-1.04], P-value=0.02), and higher CRP (1.01 [95% CI 1.00-1.02], P=0.01) at discharge were independently associated with mortality.. Higher IL-8 and CRP levels at discharge were independently associated with one-year mortality. The relative CRP difference during hospitalization was the best individual biomarker for predicting one-year mortality.

Topics: Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Hospitalization; Humans; Inflammation; Interleukin-6; Interleukin-8; Pneumonia; Prognosis; Prospective Studies

Exposure to high concentrations of copper is associated with pulmonary inflammation and chronic respiratory disease (CRD). Epigenetic modulation of noncoding RNAs contributes to the development of several CRDs. It is unknown whether epigenetic modulation is involved in copper mediated pulmonary inflammation and CRD. We conducted a case-control study of 101 CRD cases and 161 control subjects in Shijiazhuang, China, and evaluated circRNAs and cytokine levels (IL-6 and IL-8) by qPCR and ELISA. Urinary copper concentration was determined by inductively coupled plasma mass spectrometry. Linear mixed models and generalized linear mixed models were used to assess the associations of circRNAs with CRD, urinary copper, and cytokines. We exposed the human bronchial epithelial cell line, 16HBE, to copper and assessed the functional role of a circRNA, circ_0008882, by RNA overexpression. Cellular location of circ_0008882 was assessed by separation of nuclear and cytoplasmic RNAs. Nine circRNAs were associated with an increased risk for CRDs, while the relative expression of circ_0008882 was decreased after copper exposure in vitro and in vivo. Copper exposure stimulated 16HBE cells to release proinflammatory IL-6 and IL-8. The release of the cytokines was inhibited by overexpression of circ_0008882. These results suggest a role for circ_0008882 in the regulation of CRD associated inflammation following copper exposure.

Topics: Case-Control Studies; Chronic Disease; Copper; Cytokines; Humans; Interleukin-6; Interleukin-8; MicroRNAs; Pneumonia; Respiration Disorders; RNA; RNA, Circular

Prevalence of acute ische-mic stroke (AIS) is increased in patients with coronavirus disease 2019 (COVID-19). A proposed hypothesis is increased virus-induced propensity to hypercoagulation resulting in arterial thrombosis. Our aim was to provide evidence regarding the involvement of neutrophil extracellular trap (NET) formation (NETosis) in COVID-19 related AIS.. Twenty-six consecutively enrolled COVID-19+ pneumonia patients with AIS, 32 COVID-19+ pneumonia patients without AIS and 24 AIS patients without COVID-19 infection were included to the study. Clinical characteristics of recruited patients were collected. Serum levels of citrullinated histone H3 (H3Cit; a factor of NETosis), IL-8 and C5a (mediators associated with NETosis) were measured by ELISA (enzyme-linked immunosorbent assay).. H3Cit levels were significantly higher in COVID-19+ AIS patients, whereas all study groups showed comparable IL-8 and C5a levels. There were no significant differences among etiological subgroups of AIS patients with or without COVID-19. AIS patients with COVID-19 showed relatively increased white blood cell, lymphocyte, neutrophil, D-dimer, C-reactive protein and procalcitonin levels than control groups. H3Cit levels did not correlate with clinical/prognostic features and inflammation parameters. H3Cit and IL-8 levels were correlated in COVID-19 patients without stroke but not in COVID-19 positive or negative AIS patients.. Increased levels of inflammation parameters and H3Cit in COVID-19 related AIS suggest that NETosis may cause susceptibility to arterial thrombosis. However, H3Cit levels do not correlate with clinical severity measures and inflammation parameters diminishing the prognostic biomarker value of NETosis factors. Moreover, the link between IL-8 and NETosis appears to be abolished in AIS.. A Covid-19-betegek körében megnő az akut ischaemiás stroke (AIS) prevalenciája. Egy hipotetikus mechanizmus szerint a vírus megnöveli a hiperkoagulációs hajlamot, ami arteriális thrombosist eredményez. Vizsgálatunk célja az volt, hogy bizonyítsuk: a neutrophil extracelluláris csapdaképződés (NETosis) közreműködik a Covid-19-cel összefüggő AIS kialakulásában.. A vizsgálatba n = 26, AIS-ban szenvedő Covid-19-pneumoniás beteget, n = 32 AIS nélküli Covid-19-pneumoniás beteget és n = 24 AIS-ban igen, de Covid-19-ben nem szenvedő beteget vontunk be. Összegyűjtöttük a betegek klinikai adatait. ELISA-val mértük a citrullinált hiszton H3 (H3Cit; a NETosis egy faktora), az IL-8 és a C5a (NETosis-asszociált faktorok) szérumszintjét.. A Covid-19 + AIS betegekben szignifi­kánsan magasabb volt a H3Cit-szint, míg az IL-8- és C5a-szintek hasonlóak voltak valamennyi csoportban. A covidos és nem covidos AIS-betegek etiológiaalapú alcsoportjaiban nem találtunk szignifikáns különbségeket. A kont­rollcsoportokkal összehasonlítva, a Covid-19 + AIS betegekben megemelkedett a fehérvérsejt-, a lymphocyta-, és a neutrophilszám, továbbá megnőttek a D-dimer-, C-reaktív protein- és prokalcitoninszintek. A H3Cit-szintek nem függtek össze sem a klinikai/prognosztikus jellem­zőkkel, sem a gyulladásos paraméterekkel. A H3Cit- és az IL-8-szintek összefüggésben álltak egymással az AIS nélküli Covid-19-betegek esetében, azonban nem korreláltak a Covid-pozitív vagy -negatív AIS-betegek esetén.. A Covid-19-cel szövődött AIS esetében a gyulladásos paraméterek és a H3Cit megnövekedett szintje azt sugallja, hogy a NETosis arteriális thrombosis iránti fogékonyságot eredményezhet. Mindazonáltal az az eredmény, miszerint a H3Cit-szintek nem korrelálnak a klinikai súlyossággal és a gyulladásos paraméterekkel, lehetetlenné teszi a NETosis-faktorok prognosztikus biomarkerként való használatát. Ráadásul úgy tűnik, hogy az IL-8 és a NETosis közötti kapcsolat megszűnik AIS esetén.

Topics: COVID-19; Histones; Humans; Inflammation; Interleukin-8; Ischemic Stroke; Pneumonia; Stroke; Thrombosis

Idiopathic pulmonary fibrosis is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause. Interleukin (IL)-11 plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. In this study, we explore whether a potential antifibrotic agent fluorofenidone (FD) exerts its anti-inflammatory and antifibrotic effects through suppressing activation of the IL-11/MEK/ERK signaling pathway in vivo and in vitro. Male C57BL/6 J mice were intratracheally injected with bleomycin or saline. Fluorofenidone was administered throughout the course of the experiment. Lung tissue sections were stained with hemotoxylin and eosin, and Masson trichrome. Cytokines were measured using the enzyme-linked immunosorbent assay. The α-smooth muscle actin (α-SMA), fibronectin, and collagen I were measured using immunohistochemistry, and the phosphorylated extracellular signal-regulated kinase, phosphorylated mitogen-activated protein kinase, IL-11RA, and gp130 were measured using Western blot. The RAW264.7 cells and the normal human lung fibroblasts were treated with IL-11 and/or FD, IL-11RA-siRNA, or MEK inhibitor. The expressions of phosphorylated extracellular signal-regulated kinase, phosphorylated mitogen-activated protein kinase, IL-11RA, gp130, α-SMA, fibronectin, and collagen I were measured using Western blot and/or real-time polymerase chain reaction, and the cytokines were measured using enzyme-linked immunosorbent assay. Results showed that FD markedly reduced the expressions of IL-8, IL-18, IL-11, monocyte chemotactic protein-1, α-SMA, fibronectin, and collagen I in mice lung tissues. In addition, FD attenuated IL-11-induced expressions of α-SMA, fibronectin, and collagen I and inhibited IL-11RA, gp130, and phosphorylation of the ERK and MEK protein expression, as well as reduced the expressions of IL-8, IL-18, and monocyte chemotactic protein-1 in vitro. This study demonstrated that FD attenuated bleomycin-induced pulmonary inflammation and fibrosis in mice by inhibiting the IL-11/MEK/ERK signaling pathway.

Topics: Actins; Animals; Anti-Inflammatory Agents; Bleomycin; Chemokine CCL2; Collagen; Cytokine Receptor gp130; Eosine Yellowish-(YS); Extracellular Signal-Regulated MAP Kinases; Fibronectins; Fibrosis; Hematoxylin; Humans; Idiopathic Pulmonary Fibrosis; Interleukin-11; Interleukin-18; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Pneumonia; Pyridones; RNA, Small Interfering; Signal Transduction

To determine the association of a combined ratio change of inflammatory biomarkers at 72 h after admission on sepsis severity and prognosis from pulmonary infections.. Data on adult patients diagnosed with sepsis, or septic shock were retrospectively analyzed. Patients were divided into two groups, according to their outcome of hospitalization. Blood specimens were obtained on admission (T. Our findings suggested that a combined ratio change of inflammatory biomarkers was an effective predictor for sepsis severity and prognosis.

Topics: Adult; Biomarkers; Humans; Intensive Care Units; Interleukin-10; Interleukin-6; Interleukin-8; Pneumonia; Prognosis; Retrospective Studies; ROC Curve; Sepsis

The non-cancerous functions of Akt in the airway are understudied. In some tissues, Akt phosphorylates and activates endothelial nitric oxide synthase (eNOS) to produce nitric oxide (NO) that has anti-inflammatory effects. NO production has antibacterial and antiviral effects in the airway, and increasing NO may be a useful anti-pathogen strategy. Akt also stimulates the nuclear factor erythroid 2-related factor 2 (Nrf-2) transcription factor, which transcribes antioxidant genes. Therefore, we hypothesized that activation of the Akt/eNOS pathway, which also activates Nrf-2, may have protective effects in human airway cells against injury.. To directly test the effects of Akt signaling in the airway, we treated A549 and 16HBE cells as well as primary bronchial, nasal, and type II alveolar epithelial cells with small molecule Akt activator SC79. We examined the effects of SC79 on eNOS activation, NO production, Nrf-2 target levels, and interleukin-8 (IL-8) transcription during exposure to TNF-α or Pseudomonas flagellin (TLR5 agonist). Additionally, air-liquid interface bronchial cultures were treated with cadmium, an oxidative stressor that causes airway barrier breakdown.. SC79 induced a ~ twofold induction of p-eNOS and Nrf-2 protein levels blocked by PI3K inhibitor LY294002. Live cell imaging revealed SC79 increased acute NO production. Quantitative RT-PCR showed a ~ twofold increase in Nrf-2 target gene transcription. TNF-α or flagellin-induced IL-8 levels were also significantly reduced with SC79 treatment. Moreover, the transepithelial electrical resistance decrease observed with cadmium was ameliorated by SC79, likely by an acute increase in tight junction protein ZO-1 levels.. Together, the data presented here demonstrate SC79 activation of Akt induces potentially anti-pathogenic NO production, antioxidant gene transcription, reduces IL-8 transcription, and may protect against oxidative barrier dysfunction in a wide range of airway epithelial cells.

Topics: A549 Cells; Acetates; Anti-Inflammatory Agents; Benzopyrans; Electric Impedance; Enzyme Activation; Enzyme Activators; Epithelial Cells; Humans; Interleukin-8; Lung; NF-E2-Related Factor 2; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Pneumonia; Proto-Oncogene Proteins c-akt; Signal Transduction; Transcription, Genetic; Zonula Occludens-1 Protein

Inflammation has been believed to contribute to coronavirus disease 2019 (COVID-19). Risk factors for death of COVID-19 pneumonia have not yet been well established.In this retrospective cohort study, we included the deceased patients in COVID-19 specialized ICU with laboratory-confirmed COVID-19 from Guanggu hospital area of Tongji Hospital from February 8th to March 30th. Demographic, clinical, laboratory, and outcome data were extracted from electronic medical records using a standard data collection form. We used Spearman rank correlation and Cox regression analysis to explore the risk factors associated with in-hospital death, especially the association between inflammatory cytokines and death.A total of 205 severe/critical COVID-19 pneumonia patients were admitted in the COVID-19 specialized ICU and 75 deceased patients were included in the final analysis. The median age of the deceasing patients was 70 years (IQR 65-79). The common symptoms were fever (78.9%), cough (70.4%), and expectoration (39.4%). The BNP and CRP levels were far beyond the normal reference range. In the Spearman rank correlation analysis, IL-8 was found to be significantly associated with the time from onset to death (rs= -0.30, P = .034) and that from admission to death (rs= -0.32, P = .019). Cox regression showed after adjusting age and sex, IL-8 levels were still significantly associated with the time from onset to death (P = .003) and that from admission to death (P  = .01).IL-8 levels were associated with in-hospital death in severe/critical COVID-19 patients, which could help clinicians to identify patients with high risk of death at an early stage.

Topics: Adult; Aged; Aged, 80 and over; China; COVID-19; Critical Illness; Female; Hospital Mortality; Humans; Intensive Care Units; Interleukin-8; Male; Middle Aged; Pneumonia; Prognosis; Proportional Hazards Models; Retrospective Studies; Risk Factors; SARS-CoV-2; Severity of Illness Index

Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can be used as a prophylactic and therapeutic treatment in a murine CS-induced inflammation model. SUL-151 (4 mg/kg), budesonide (500 μg/kg), or vehicle were administered via oropharyngeal instillation in this prophylactic and therapeutic treatment setting. The number of immune cells was determined in the bronchoalveolar lavage fluid (BALF). Oxidative stress response, mitochondrial adenosine triphosphate (ATP) production, and mitophagy-related proteins were measured in lung homogenates. SUL-151 significantly decreased more than 70% and 50% of CS-induced neutrophils in BALF after prophylactic and therapeutic administration, while budesonide showed no significant reduction in neutrophils. Moreover, SUL-151 prevented the CS-induced decrease in ATP and mitochondrial mtDNA and an increase in putative protein kinase 1 expression in the lung homogenates. The concentration of SUL-151 was significantly correlated with malondialdehyde level and radical scavenging activity in the lungs. SUL-151 inhibited the increased pulmonary inflammation and mitochondrial dysfunction in this CS-induced inflammation model, which implied that SUL-151 might be a promising candidate for COPD treatment.

Topics: Animals; Bronchi; Bronchoalveolar Lavage Fluid; Cigarette Smoking; Disease Models, Animal; Epithelial Cells; Female; Humans; Interleukin-8; Lung; Mice, Inbred BALB C; Neutrophils; Oxidative Stress; Piperazines; Pneumonia; Protein Kinases

We have recently shown that a dominant-negative mutant of CXCL8, dnCXCL8, with increased glycosaminoglycan (GAG) binding affinity and inactivated GPCR signaling function is able to efficiently prevent neutrophil infiltration into murine lungs (Adage et al., 2015). Here we present evidence that chemical PEGylation of dnCXCL8 with 20 kDa and 40 kDa PEG does not significantly interfere with GAG binding affinity, nor does it influence the mutant's disabled chemotaxis function, while it strongly improved bioavailability and serum half-life of the chemokine mutant. In a murine model of lung inflammation, only the 40 kDa PEGylated dnCXCL8 showed a significant reduction of neutrophils in bronchoalveolar lavage (BAL) fluid. In combination with an almost three-fold increase (compared to non-PEGylated dnCXCL8) in plasma half-life after intravenous administration, our results prove that PEGylation of chemokine-derived biologics is an amenable way for the treatment of chronic inflammatory conditions.

Topics: Animals; Binding, Competitive; Cells, Cultured; Chemotaxis; Glycosaminoglycans; Heparitin Sulfate; Humans; Interleukin-8; Male; Mice, Inbred BALB C; Mutation; Neutrophils; Pneumonia; Polyethylene Glycols; Protein Binding

Hypersensitivity pneumonitis (HP) is an interstitial lung disease, characterized by lung inflammation (non-fibrotic HP) that may often progresses to fibrosis (Fibrotic HP). The tumor necrosis factor (TNF) and its receptors (TNFR1 and TNFR2) can be found as soluble (sol) and transmembrane (tm) forms, playing pro-inflammatory functions but also has been related to immune regulatory functions. Bronchioalveolar lavage from fibrotic and non-fibrotic HP patients was obtained, and immune cells were characterized by flow cytometry, whereas soluble proteins were analyzed by ELISA. Compare to fibrotic HP patients, HP patients with non-fibrotic disease have accumulation of pro-inflammatory CD3+ myeloid cells, cell subpopulations that have decreased tmTNFR2 expression, and low frequency of regulatory-T cells. Whereas solTNF, solTNFR2, and IL-8 are increased. These findings suggest that the TNF pathway may explain, at least partially, the differences between both HP clinical forms. The evaluation of the TNF family molecules may help to develop new therapeutic approaches.

Topics: Alveolitis, Extrinsic Allergic; Bronchoalveolar Lavage Fluid; CD3 Complex; Female; Humans; Interleukin-8; Leukocytes; Lung; Male; Membrane Proteins; Middle Aged; Myeloid Cells; Pneumonia; Pulmonary Fibrosis; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

High concentrations of particulate matter less than 2.5 μm in diameter (PM2.5) in poultry houses is an important cause of respiratory disease in animals and humans.. In this study, we focused on the synergistic induction of inflammatory injury in the respiratory system and the related molecular mechanisms induced by PM2.5 and. High-throughput 16S rDNA sequence analysis was used for characterizing the bacterial diversity and relative abundance of the PM2.5 samples, and the effects of PM2.5 and. Sequencing results indicated that the PM2.5 in poultry houses contained a high abundance of potentially pathogenic genera, such as. The results confirmed that poultry house PM2.5 in combination with

Topics: Animals; Body Weight; Interleukin-6; Interleukin-8; Mice; Mice, Inbred C57BL; NF-kappa B p50 Subunit; Particulate Matter; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Specific Pathogen-Free Organisms; Tumor Necrosis Factor-alpha

We recently demonstrated that benzo[a]pyrene (BaP), the aryl hydrocarbon receptor (AhR) ligand, directly contributes to aggravation of cutaneous allergy in a mouse model of allergic dermatitis. The present study aimed to determine whether BaP-induced AhR activation results in development of airway inflammation. Initially, the potential for a direct relationship between BaP-induced AhR activation and airway inflammation was investigated in vivo, using a mouse model of type 2 helper T cell (Th2) hapten toluene-2,4-diisocyanate (TDI)-induced airway inflammation. Mice were orally administered BaP at 48, 24, and 4 h before the final allergen challenge. Oral administration of BaP showed a significant increase in lung inflammation and eosinophil infiltration. While expression of Th2 cytokines such as interleukin 4 (IL-4) and IL-13 was not affected by exposure to BaP, AhR activation significantly increased IL-33 expression. To confirm the in vivo results, in vitro experiments were performed using the human eosinophilic leukemia cell line (EOL-1), human bronchial epithelial cell line (BEAS-2B), and human lung adenocarcinoma epithelial cell line (A549). Results indicated that pre-treatment with BaP increased expression of IL-8 in house dust mite-activated EOL-1, BEAS-2B, and A549 cells. In addition, IL-33 levels in BEAS-2B cells were significantly increased after BaP exposure. Our findings indicated that BaP-induced AhR activation is involved in the pro-inflammatory response in respiratory allergy, and that this effect may be mediated by increased IL-33 expression and eosinophil infiltration.

Topics: A549 Cells; Animals; Basic Helix-Loop-Helix Transcription Factors; Benzo(a)pyrene; Chemotaxis, Leukocyte; Disease Models, Animal; Eosinophils; Female; Humans; Interleukin-33; Interleukin-8; Lung; Mice, Inbred BALB C; Pneumonia; Receptors, Aryl Hydrocarbon; Signal Transduction; Toluene 2,4-Diisocyanate; Up-Regulation

BACKGROUND Mycoplasma pneumoniae is a major cause of community-acquired pneumonia (CAP) that is particularly prevalent in school-aged children. This study explored the potential involvement of cytokines in children with Mycoplasma pneumoniae pneumonia (MPP) infection. MATERIAL AND METHODS Children aged 3-7 years who were hospitalized due to CAP infection were enrolled and divided into 2 groups: an MPP group (n=33) and a NMPP group (n=38), along with 21 age-matched healthy controls. Clinical characteristics and laboratory data were recorded. Serum levels of IL-18, IL-33, IFN-γ, IL-5, IL-6, IL-8, and IL-13 were assessed using Luminex xMAP technology. Correlation analysis and ROC curves analysis were also performed to further explore the role of these detected cytokines in CAP. RESULTS Compared with the healthy controls, the serum expression of IL-18, IL-33, IFN-γ, IL-5, IL-6, IL-8, and IL-13 were significantly higher in the MPP and NMPP groups. Furthermore, serum IL-18 expression was found to be significantly correlated with lgE, FeNO, IL-5, IL-8, and IL-13 concentrations. Significant differences were also observed between the MPP group and NMPP group patients in levels of IL-18, IL-5, and IL-6, and further ROC analysis showed that the area under the curve (AUC) of IL-18 and IL-5 were 0.813 (95% CI: 0.710-0.917; P<0.01) and 0.844 (95% CI: 0.756-0.933; P<0.01), respectively. CONCLUSIONS IL-18, IL-33, IFN-γ, IL-5, IL-6, IL-8, and IL-13 serum levels showed significant differences in children with CAP. IL-18 and IL-5 were much higher in the MPP group compared to the NMPP group patients, whereas IL-6 levels were significantly lower in these 2 groups.

Topics: Breath Tests; Case-Control Studies; Child; Child, Preschool; Community-Acquired Infections; Cytokines; Female; Humans; Immunoglobulin E; Interferon-gamma; Interleukin-13; Interleukin-18; Interleukin-33; Interleukin-5; Interleukin-6; Interleukin-8; Male; Nitric Oxide; Pneumonia; Pneumonia, Mycoplasma

Topics: Acute-Phase Reaction; Adult; Aged; alpha 1-Antitrypsin; Betacoronavirus; Blotting, Western; Carrier Proteins; Case-Control Studies; Community-Acquired Infections; Coronavirus Infections; COVID-19; Critical Illness; Cytokines; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Female; Hospitalization; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Intensive Care Units; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Lactic Acid; Length of Stay; Male; Membrane Proteins; Middle Aged; Neutrophils; Pandemics; Phosphorylation; Pneumonia; Pneumonia, Viral; Receptors, Tumor Necrosis Factor, Type I; SARS-CoV-2; Severity of Illness Index; Thyroid Hormone-Binding Proteins; Thyroid Hormones

To investigate synergistic effect of Reduning (RDN) injection plus ribavirin against severe pneumonia induced by H1N1 influenza A virus in mice.. We established a mouse model of severe pneumonia induced by influenza A virus by infecting Balb/c mice with CA07 virus. We randomly assigned the infected mice into four groups, and treated them with normal saline (NS group), RDN (injection, 86.6 mg/kg), ribavirin (injection, 66.6 mg/kg) or double Ribavirin plus RDN group, the same dosage as used in the single treatments) for 5 d. Lung index and lung pathology were recorded or calculated in terms of the curative effective. Cytokines, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome related protein including caspase-associated recruitment domain (CARD) domain Apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC), caspase-1 and NOD-like receptor family, pyrin domain containing 3 (NLRP3), and reactive oxygen species were simultaneously investigated.. RDN plus ribavirin treatment, not RDN or ribavirin alone, provided a significant survival benefit to the influenza A virus-infected mice. The combination treatment protected the mice against severe influenza infection by attenuating the severe lung injury. The combined treatment also reduced the viral titers in mouse lungs and lung index, downregulated their immunocytokine levels, including IL-1β and IL-18, and down regulated the NLRP3, especially the transcription and translation of caspase-1. Meanwhile NS group had significantly higher reactive oxygen species (ROS) expression which could was dramatically reduced by the treatment of RDN plus ribavirin.. Our study showed that RDN combined with ribavirin could protect the mice, and reduce the lung immunopathologic damage caused by severe influenza pneumonia. The mechanism could be that it reduced ROS produce and inhibited NLRP3 inflammasome activation so that mainly lower the downstream inflammatory cytokines IL-1β and IL-18.

Topics: Animals; Drug Synergism; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Interleukin-1beta; Interleukin-8; Lung; Mice; Mice, Inbred BALB C; NLR Family, Pyrin Domain-Containing 3 Protein; Pneumonia; Ribavirin

The lung microbiome maintains the homeostasis of the immune system within the lungs. In acute respiratory distress syndrome (ARDS), the lung microbiome is enriched with gut-derived bacteria; however, the specific microbiome associated with morbidity and mortality in patients with ARDS remains unclear. This study investigated the specific patterns of the lung microbiome that are correlated with mortality in ARDS patients.. We analyzed the lung microbiome from the bronchoalveolar lavage fluid (BALF) of patients with ARDS and control subjects. We measured the copy numbers of 16S rRNA and the serum and BALF cytokines (interleukin [IL]-6, IL-8, receptor for advanced glycation end products, and angiopoietin-2).. The lung bacterial burden tended to be increased, and the alpha diversity was significantly decreased in ARDS patients. The decreased Betaproteobacteria and increased Staphylococcus, Streptococcus and Enterobacteriaceae might represent a unique microbial community structure correlated with increased serum IL-6 and hospital mortality.. The institutional review boards of Hiroshima University (Trial registration: E-447-4, registered 16 October 2019) and Kyoto Prefectural University of Medicine (Trial registration: ERB-C-973, registered 19 October 2017) approved an opt-out method of informed consent.

Topics: Aged; Aged, 80 and over; Angiopoietin-2; Bronchoalveolar Lavage Fluid; Case-Control Studies; Female; Hospital Mortality; Humans; Interleukin-6; Interleukin-8; Lung; Male; Middle Aged; Pneumonia; Prognosis; Receptor for Advanced Glycation End Products; Respiratory Distress Syndrome; Respiratory Tract Infections; Risk Assessment; Risk Factors

Cystic fibrosis (CF) results from deficient CF transmembrane conductance regulator (CFTR) protein activity leading to defective epithelial ion transport. Pulmonary degradation due to excessive inflammation is the main cause of morbidity and mortality in CF patients. By analysing miRNAs (small RNAseq) in human primary air-liquid interface cell cultures, we measured the overexpression of miR-636 in CF patients compared to non-CF controls. We validated these results in explant biopsies and determined that the mechanism underlying miR-636 overexpression is linked to inflammation. To identify specific targets, we used bioinformatics analysis to predict whether miR-636 targets the 3'-UTR mRNA regions of

Topics: Cells, Cultured; Cystic Fibrosis; Humans; I-kappa B Kinase; Interleukin-6; Interleukin-8; MicroRNAs; NF-kappa B; Pneumonia; Receptor Activator of Nuclear Factor-kappa B; Receptors, Interleukin-1 Type I; Signal Transduction

Baicalein, an isolate of secutellaria baicalensis is known for its anti-inflammatory activity. In the present study, 12-triazole derivatives of baicalein were synthesized and evaluated against RSV infected BEAS-2B cells in vitro and in mice model in vivo. The preventive effect of most active compound 5f against RSV infection was studied in detail. The compound 5f treatment increased IFN-β1 expression in BEAS-2B cells infected with RSV. In BEAS-2B cells treatment with compound 5f inhibited RSV-induced secretion of interleukin-6 and -8 cytokines. It decreased RSV-induced nitric oxide & malondialdehyde production and inhibited the RSV-mediated activation of NF-κB, COX-2, Stat3 and MAPK. The p38 phosphorylation was enhanced significantly in RSV infected cells by compound 5f pre-treatment. RT-qPCR showed that compound 5f treatment of the RSV-infected mice significantly (P < 0.05) decreased viral load through reduction in the viral replication. In the mice model of RSV-infection compound 5f treatment decreased interleukin-6, -8 and tumor necrosis factor-α expression. The level of MPO, nitric oxide and malondialdehyde was also decreased significantly by compound 5f in the RSV infected mice BALF. It also reduced the infiltration of neutrophils and lymphocytes in the BALF of RVS-infected mice. In summary, compound 5f inhibits RSV-infection and prevents pulmonary airway inflammation through the activation of IFN signalling pathway.

Topics: Animals; Cytokines; Female; Flavanones; Interferon-beta; Interleukin-6; Interleukin-8; Lymphocytes; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Pneumonia; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Respiratory Tract Infections; Ribavirin; STAT3 Transcription Factor; Triazoles; Tumor Necrosis Factor-alpha; Virus Replication

Children with CF are insulin deficient from infancy but very little is known about the impact of glucose abnormalities in early life. We aimed to identify and describe interstitial glucose levels in CF children <6 years and to evaluate the association with pulmonary infection and inflammation.. We assessed 18 children (5 females) with median age of 3.2 years (range 0·9-5.5) with Continuous Glucose Monitoring for 3 days. Bronchoalveolar lavage (BAL) fluid was cultured for known pathogenic microbial agents and assessed for total white blood cells, percentage of neutrophils and IL-8 level.. Children with CF frequently demonstrate elevated SG levels before age 6 years, which are associated with increased pulmonary inflammation and Pseudomonas aeruginosa infection. Transient SG elevations into the diabetic range (≥11.1 mmol/L) were identified in children from 1 year of age.

Topics: Australia; Blood Glucose; Bronchoalveolar Lavage Fluid; Child, Preschool; Correlation of Data; Cystic Fibrosis; Female; Humans; Hyperglycemia; Infant; Interleukin-8; Leukocyte Count; Male; Monitoring, Physiologic; Neutrophils; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections

Bronchoalveolar lavage (BAL) is a potentially useful outcome measure for clinical trials in children with CF but its use is limited by variations in approach internationally. We sought to determine if pooling adversely affected the diagnostic properties of BAL.. Children undergoing bronchoscopy for clinical reasons were included. A multi-step study protocol ensured BAL was collected and analysed both separately and as a pooled fluid.. Eighty-five children (53 CF, 32 control) were recruited. There was a high level of concordance between pooled and non-pooled samples in terms of organism identification (76%). There was good agreement (Bland Altman) between the two methods in terms of detection of inflammation independent of centre, microbiological concordance or disease status. Bi-directional variability in IL-8 levels between pooled and non-pooled samples was seen. Free neutrophil elastase (NE) was detected in 4 cases in pooled lavage when absent in non-pooled lavage. Levels of interleukin-8 (IL-8) were similar between the two groups with pooled samples showing a greater spread of values.. Pooling of BAL in children does not negatively impact on either the detection of pulmonary infection or inflammation or the observed relationship between infection and inflammation. Intra-patient variability in BAL IL-8 levels suggests regional differences in inflammation.

Topics: Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchoscopy; Child; Child, Preschool; Correlation of Data; Cystic Fibrosis; Female; Humans; Interleukin-8; Male; Pneumonia; Respiratory Tract Infections

We studied the diagnostic value of cytokines, including vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and interleukin-8 (IL-8), and the ratio of lactate dehydrogenase (LDH) to adenosine deaminase (ADA) in pleural fluid.. Prospective analysis of 44 inpatients or outpatients with pleural fluid, from December 2016 to March 2017 was conducted.. We enrolled patients with malignant pleural effusion (MPE, N = 15), empyema (N = 11), parapneumonic effusion (PPE, N = 7), chronic renal failure (CRF)/chronic heart failure (CHF) (N = 7), and tuberculous pleural effusion (TBPE, N = 4). The pleural fluid values of IL-8 and VEGF were significantly higher in empyema patients than in CRF/CHF or PPE patients. In all patients, the pleural fluid VEGF and IL-8 values were significantly positively correlated (r = 0.405, p = 0.006; r = 0.474, p = 0.047, respectively). TGF-β was elevated in patients with empyema, PPE, TBPE, and MPE. The pleural LDH-to-ADA ratio in patients with MPE or empyema/PPE was significantly higher than in patients with CRF/CHF or TBPE. LDH and ADA levels correlated significantly only in patients with MPE (r = 0.648, p = 0.009) and empyema/PPE (r = 0.978, p < 0.001).. VEGF and IL-8 production in the pleural cavity appear to accelerate the progression of PPE to empyema, by enhancing vascular permeability associated with inflammation. Sequential sampling would be needed to confirm this. The pleural LDH/ADA ratio may be a useful diagnostic tool for discriminating between various pleural effusion etiologies.

Topics: Adenosine Deaminase; Aged; Aged, 80 and over; Biomarkers; Diagnosis, Differential; Empyema, Pleural; Female; Heart Failure; Humans; Interleukin-8; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Male; Middle Aged; Pleural Effusion; Pleural Effusion, Malignant; Pneumonia; Predictive Value of Tests; Prospective Studies; Transforming Growth Factor beta; Tuberculosis; Vascular Endothelial Growth Factor A

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

Cystic fibrosis (CF) is the most common lethal genetic disease, caused by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations. CF is characterized by an ionic imbalance and thickened mucus, which impair mucociliary clearance and promote bacterial colonization and the establishment of infection/inflammation cycles. However, the origin of this inflammation remains unclear, although microRNAs (miRNAs) are suspected to be involved. MiRNAs are small non-coding RNAs that bind to the 3'-untranslated regions (UTRs) of target gene mRNA, thereby repressing their translation and/or inducing their degradation. The goal of this study was to investigate the role of microRNAs associated with pulmonary inflammation in CF patients. Through the analysis of all miRNAs (miRNome) in human primary air-liquid interface cultures, we demonstrated that miR-199a-3p is the only miRNA downregulated in CF patients compared to controls. Moreover, through RNA sequencing (transcriptome) analysis, we showed that 50% of all deregulated mRNAs are linked directly or indirectly to the NF-κB pathway. To identify a specific target, we used bioinformatics analysis to predict whether miR-199a-3p targets the 3'-UTR of IKBKB, which encodes IKKβ, a major protein in the NF-κB pathway. Subsequently, we used bronchial explants from CF patients to show that miR-199a-3p expression is downregulated compared to controls and inversely correlated with increases in expression of IKKβ and IL-8. Through functional studies, we showed that miR-199a-3p modulates the expression of IKBKB through a direct interaction at its 3'-UTR in bronchial epithelial cells from CF patients. In miR-199a-3p overexpression experiments, we demonstrated that for CF cells, miR-199a-3p reduced IKKβ protein expression, NF-κB activity, and IL-8 secretion. Taken together, our findings show that miR-199a-3p plays a negative regulatory role in the NF-κB signalling pathway and that its low expression in CF patients contributes to chronic pulmonary inflammation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Topics: 3' Untranslated Regions; Binding Sites; Case-Control Studies; Cells, Cultured; Cystic Fibrosis; Down-Regulation; Gene Expression Profiling; Humans; I-kappa B Kinase; Interleukin-8; Lung; MicroRNAs; NF-kappa B; Pneumonia; RNA, Messenger; Sequence Analysis, RNA; Signal Transduction; Tissue Culture Techniques

Particulate matter (PM) has been implicated as a risk factor for human airway disorders. However, the biological mechanisms underlying the correlation between PM exposure and adverse airway effects have not yet been fully clarified. The objective of this study was to explore the possible role of early growth response gene 1 (Egr-1) in PM-induced toxic effects in pulmonary inflammation and mucus hyperproduction in vitro and in vivo. Particulate matter exposure induced a rapid Egr-1 expression in human bronchial epithelial (HBE) cells and in mouse lungs. Genetic blockage of Egr-1 markedly reduced PM-induced inflammatory cytokines, e.g., IL6 and IL8, and MUC5AC in HBE cells, and these effects were mechanistically mediated by the nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) pathways, respectively. Egr-1-knockout mice displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Moreover, polycyclic aromatic hydrocarbons (PAHs) contained in the PM also induced Egr-1 expression, and also played a role in the inflammatory responses and mucus production. Taken together, our data reveal novel Egr-1 signaling that mediates the NF-κB and AP-1 pathways to orchestrate PM-induced pulmonary inflammation and mucus hyperproduction, suggesting that Egr-1 inhibition could be an effective therapeutic approach for airway disorders or disease exacerbations induced by airborne particulate pollution.

Topics: Air Pollution; Animals; Bronchoalveolar Lavage Fluid; Cell Line; Cells, Cultured; Early Growth Response Protein 1; Gene Expression Regulation; Humans; Interleukin-6; Interleukin-8; Mice; Mice, Knockout; Mucin 5AC; Mucus; Neutrophils; Particulate Matter; Pneumonia; Respiratory Mucosa; Specific Pathogen-Free Organisms; United States; Urban Health

IL-8-dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases, including chronic obstructive pulmonary disease, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible, pathological changes associated with elevated levels of IL-8 in the lung. To better understand the duality of IL-8-dependent host immunity to bacterial infection and lung pathology, we expressed human IL-8 transgenically in murine bronchial epithelium, and investigated the impact of overexpression on lung bacterial clearance, host immunity, and lung pathology and function. Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation and activation, and chemotaxis. There was enhanced protection against challenge with Pseudomonas aeruginosa, and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL-2, and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen OprF, indicating a regulatory T-cell phenotype. However, this enhanced bacterial immunity came at a high price of progressive lung remodeling, with increased inflammation, mucus hypersecretion, and fibrosis. There was increased expression of Ccl3 and reduced expression of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all of which resulted in impaired lung function with reduced compliance, increased resistance, and bronchial hyperreactivity as measured by whole-body plethysmography. These results show that IL-8 overexpression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodeling, and damaged tight junctions, leading to impaired lung function.

Topics: Animals; Chronic Disease; Humans; Immunity, Innate; Interleukin-8; Lung; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Pulmonary Fibrosis

To evaluate the effects of hypothermia treatment on meconium-induced inflammation.. Fifteen rats were instilled with human meconium (MEC, 1.5 mL/kg, 65 mg/mL) intratracheally and ventilated for 3 hours. Eight rats that were ventilated and not instilled with meconium served as a sham group. In MEC-hypothermia group, the body temperature was lowered to 33±0.5°C. Analysis of the blood gases, interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α in bronchoalveolar lavage (BAL) fluid samples, and histological analyses of the lungs were performed.. The BAL fluid TNF-α, IL-1β, IL-6 and IL-8 concentrations were significantly higher in the MEC-hypothermia group than in the MEC-normothermia (p < 0.001, p < 0.001, p = 0.001, p < 0.001, respectively) and sham-controlled groups (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively).. Meconium-induced inflammatory cytokine production is affected by the body temperature control.

Topics: Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Hypothermia, Induced; Interleukin-1beta; Interleukin-6; Interleukin-8; Luminescent Measurements; Lung; Male; Meconium Aspiration Syndrome; Pneumonia; Rats, Wistar; Reproducibility of Results; Treatment Outcome; Tumor Necrosis Factor-alpha

Required mechanical ventilation (MV) may contribute to bacterial dissemination in patients with Streptococcus pneumoniae pneumonia. Significant variations in plasma mitochondrial DNA (mtDNA) have been reported in sepsis according to the outcome. The impact of lung stretch during MV was addressed in a model of pneumonia. Healthy or S. pneumoniae infected rabbits were submitted to MV or kept spontaneously breathing (SB). Bacterial burden, cytokines release, mitochondrial DNA levels, integrity and transcription were assessed along with 48-hour mortality. Compared with infected SB rabbits, MV rabbits developed more severe pneumonia with greater concentrations of bacteria in the lungs, higher rates of systemic dissemination, higher levels of circulating inflammatory mediators and decreased survival. Pulmonary mtDNA levels were significantly lower in infected animals as compared to non-infected ones, whenever they were SB or MV. After a significant early drop, circulating mtDNA levels returned to baseline values in the infected SB rabbits, but remained low until death in the MV ones. Whole blood ex-vivo stimulation with Streptococcus pneumoniae resulted in a reduction of polymorphonuclear leukocytes mitochondrial density and plasma mtDNA concentrations. Thus, persistent mitochondrial depletion and dysfunction in the infected animals submitted to MV could account for their less efficient immune response against S. pneumoniae.

Topics: Adenosine Triphosphate; Animals; DNA, Mitochondrial; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-8; Lung; Male; Pneumonia; Rabbits; Respiration, Artificial; RNA, Messenger; Spleen; Streptococcus pneumoniae; Tumor Necrosis Factor-alpha

Exacerbated inflammation upon persistent barn organic dust exposure is a key contributor to the pathogenesis of lung inflammation and lung function decline. Barn dust constituents and the mechanisms contributing to the exacerbated inflammation are not clearly known. We set out to understand the inflammatory effects of Swine Barn Dust Extracts (SBDE) on human lung epithelial (BEAS2B) and macrophage (THP-1 monocyte derived) cell lines on a kinome array to determine phosphorylation events in the inflammatory signaling pathways. Upon identifying events unique to SBDE or those induced by innate immune ligands in each cell line, we validated the signaling pathway activation by transcriptional analyses of downstream inflammatory cytokines. Our findings indicate that SBDE-mediated pro-inflammatory effects are predominantly due to the induction of neutrophilic chemokine IL-8. Differentially phosphorylated peptides implicated in IL-8 induction in BEAS2B cell line include, TLR2, 4, 5, 7, 8, 9, PKC, MAP kinases (p38, JNK), inflammasomes (NLRP1, NLRP3), NF-κB and AP-1. In the THP-1 cell line, in addition to the aforementioned peptides, peptides corresponding to RIG-I-like receptors (RIG-I, MDA5) were found. This is the first report to demonstrate the application of a kinome array to delineate key inflammatory signaling pathways activated upon SBDE exposure in vitro.

Topics: Animals; Bronchi; Dust; Epithelial Cells; Humans; Immunity, Innate; Inflammasomes; Interleukin-8; Macrophages; Monocytes; NF-kappa B; Phosphorylation; Pneumonia; Protein Kinases; Signal Transduction; Swine; THP-1 Cells; Toll-Like Receptors

Acute lung injury (ALI) is characterized by alveolar epithelial damage and uncontrolled pulmonary inflammation. Mitochondrial damage-associated molecular patterns (DAMPs), including mitochondrial peptides [ N-formyl peptides (NFPs)], are released during cell injury and death and induce inflammation by unclear mechanisms. In this study, we have investigated the role of mitochondrial DAMPs (MTDs), especially NFPs, in alveolar epithelial injury and lung inflammation. In murine models of ALI, high levels of mitochondrial NADH dehydrogenase 1 in bronchoalveolar lavage fluid (BALF) were associated with lung injury scores and increased formyl peptide receptor (FPR)-1 expression in the alveolar epithelium. Cyclosporin H (CsH), a specific inhibitor of FPR1, inhibited lung inflammation in the ALI models. Both MTDs and NFPs upon intratracheal challenge caused accumulation of neutrophils into the alveolar space with elevated BALF levels of mouse chemokine KC, interleukin-1β, and nitric oxide and increased pulmonary FPR-1 levels. CsH significantly attenuated MTDs or NFP-induced inflammatory lung injury and activation of MAPK and AKT pathways. FPR1 expression was present in rat primary alveolar epithelial type II cells (AECIIs) and was increased by MTDs. CsH inhibited MTDs or NFP-induced CINC-1/IL-8 release and phosphorylation of p38, JNK, and AKT in rat AECII and human cell line A549. Inhibitors of MAPKs and AKT also suppressed MTD-induced IL-8 release and NF-κB activation. Collectively, our data indicate an important role of the alveolar epithelium in initiating immune responses to MTDs released during ALI. The potential mechanism may involve increase of IL-8 production in MTD-activated AECII through FPR-1 and its downstream MAPKs, AKT, and NF-κB pathways.

Topics: Acute Lung Injury; Alveolar Epithelial Cells; Animals; Inflammation Mediators; Interleukin-8; Male; Mice; Mice, Inbred BALB C; Mitochondria; Mitogen-Activated Protein Kinases; NF-kappa B; Peptide Fragments; Phosphorylation; Pneumonia; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Formyl Peptide; Signal Transduction

IL-36α, IL-36β and IL-36γ are cytokine members of IL-1 family. Although IL-36 expression was observed in human lung during pulmonary infections, it remains unknown whether IL-36 could act directly on lung tissue cells during pulmonary inflammatory responses. In this study, we showed that IL-36 receptor was expressed in human lung fibroblasts and bronchial epithelial cells. Correspondingly, IL-36α, IL-36β or IL-36γ up-regulated gene expression of cytokine IL-6 and chemokine CXCL8 in human lung fibroblasts and bronchial epithelial cells, and promoted IL-6 and CXCL8 release from human lung fibroblasts and bronchial epithelial cells. The production of IL-6 and CXCL8 in these lung tissues cells induced by IL-36α, IL-36β or IL-36γ was regulated by p38MAPK, ERK or Akt signaling pathways. Taken together, the above results suggest that IL-36-mediated IL-6 and CXCL8 production in human lung fibroblasts and bronchial epithelial cells may be involved in pulmonary inflammation especially caused by bacterial or viral infections.

Topics: Enzyme Activation; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Gene Expression Regulation; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Kinetics; Lung; p38 Mitogen-Activated Protein Kinases; Pneumonia; Proto-Oncogene Proteins c-akt; Receptors, Interleukin; Signal Transduction

The role of IL-17B in regulating pulmonary immunity and inflammation is unknown. In this study, we found that IL-17B concentrations were significantly elevated in adult and paediatric patients with community-acquired pneumonia relative to their corresponding healthy adult and paediatric controls. The increased concentrations of IL-17B significantly and positively correlated with chemokine IL-8 concentrations in clinical pneumonia. In vitro studies demonstrated that IL-17B could induce gene and protein expression of IL-8 in human bronchial epithelial cells, but not lung fibroblasts, which was regulated by the activation of Akt, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and nuclear factor-kappaB (NF-κB) signaling pathways. In vivo studies further showed that increased IL-17B levels significantly and positively correlated with IL-8 concentrations in experimental pneumonia. In conclusion, human pneumonia was associated with enhanced release of IL-17B, which might regulate pulmonary immunity and inflammation through the induction of IL-8 in bronchial epithelial cells.

Topics: Adult; Aged; Animals; Bronchi; Cells, Cultured; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblasts; Humans; Interleukin-17; Interleukin-8; Lung; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Middle Aged; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Pneumonia

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

Toxic effects were reported for pristine-multi-wall carbon nanotubes (p-MWCNTs) while the role of the functionalization on MWCNT-induced toxicity is not yet well defined. We evaluated on human alveolar (A549) epithelial cells and normal bronchial (BEAS-2B) cells exposed to p-MWCNTs, MWCNTs-OH and MWCNTs-COOH: uptake by TEM, cell viability by different assays, membrane damage by the LDH assay and cytokine release by ELISA. The aims of the present study were to: (i) confirm MWCNT cytotoxicity mechanisms hypothesized in our previous studies; (ii) identify the most reliable viability assay to screen MWCNT toxicity; and (iii) to test our model to clarify the role of functionalization on MWCNT-induced toxicity. In A549 cells, p-MWCNTs and MWCNTs-OH were localized free in the cytoplasm and inside vacuoles whereas MWCNTs-COOH were confined inside filled cytoplasmic vesicles. WST-1 and Trypan blue assays showed in A549 cells a similar slight viability reduction for all MWCNTs whereas in BEAS-2B cells WST1 showed a high viability reduction at the highest concentrations, particularly for MWCNTs-COOH. The MTT assay showed a false cytotoxicity as a result of MWCNTs-interference. Pristine and MWCNTs-COOH induced membrane damage, particularly in BEAS-2B cells. MWCNTs-COOH induced interleukin-6 (IL-6) and IL-8 release in A549 cells whereas p-MWCNTs induced IL-8 release in BEAS-2B cells. MWCNTs intracellular localization in A549 cells confirms the toxicity mechanisms previously hypothesized, with p-MWCNTs disrupting the membrane and vesicle-confined MWCNTs-COOH inducing inflammation. WST-1 was more reliable than MTT to test MWCNT-toxicity. BEAS-2B cells were more susceptible then A549 cells, particularly to MWCNT-COOH cytotoxicity. Our results confirm the toxicity of p-MWCNTs and demonstrate, also for the two kinds of tested functionalized MWCNTs toxic effects with a different mechanism of action.

Topics: Biological Assay; Carboxylic Acids; Cell Line, Tumor; Cell Membrane; Cell Survival; Dose-Response Relationship, Drug; Endocytosis; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Hydroxylation; Inflammation Mediators; Interleukin-6; Interleukin-8; L-Lactate Dehydrogenase; Lung; Microscopy, Electron, Transmission; Nanotubes, Carbon; Pneumonia; Reproducibility of Results; Risk Assessment; Tumor Necrosis Factor-alpha

The objective of this study was to measure plasma cytokine levels and blood neutrophil functions as well as clinical outcomes in hospitalized patients with community-acquired pneumonia (CAP) treated with or without macrolide use--a known modulator of inflammatory response.. Subjects with CAP had peripheral blood analyzed for some neutrophil functions (degranulation of secretory vesicles and specific granules, respiratory burst response and phagocytosis) and ten cytokine levels measured in serum and sputum supernatants. Neutrophil function in healthy volunteers was also measured for reference. Values were measured on the day of enrollment, days 2-4 and 5-7, depending on a patient's length of stay. Early and late clinical outcomes were also evaluated. All values were compared between those treated with or without a macrolide.. A total of 40 subjects were in this study; 14 received macrolide treatment, and 26 did not. Neutrophil function in the macrolide group was not significantly different compared to the non-macrolide group. None of the median cytokine levels or IQRs were statistically significant between the groups. However, a trend toward decreased IL-6, IL-8, and IFN-γ levels, and favorable clinical outcomes were present in the macrolide group.. This pilot study showed no statistical difference between cytokine levels or neutrophil activity for CAP patients prescribed a macrolide containing regimen. Considering the trend of lower cytokine levels in the macrolide group when comparing the 5- to 7-day time period with the non-macrolide group, a full study with an appropriate sample size may be warranted.

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Cell Degranulation; Community-Acquired Infections; Cytokines; Female; Hospital Mortality; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Length of Stay; Male; Middle Aged; Neutrophils; Phagocytosis; Pilot Projects; Pneumonia; Prospective Studies; Respiratory Burst

Inflammation is believed to play a key role in the pathophysiology of meconium aspiration syndrome (MAS).. The objective was to determine whether the recombinant human Erythropoietin (rhEPO) pretreatment could attenuate meconium-induced inflammation.. In this study, 24 ventilated adult male rats were studied to examine the effects of recombinant human EPO (rhEPO) on meconium-induced inflammation. Seventeen rats were instilled with human meconium (1.5 mL/kg, 65 mg/mL) intratracheally and ventilated for 3 hours. rhEPO (1000 U/kg) (n = 9) or saline (n = 8) was given to the animals. Seven rats that were ventilated and not instilled with meconium served as a sham-controlled group. Analysis of the blood gases, interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α in blood and bronchoalveolar lavage (BAL) fluid samples, and lung tissue myeloperoxidase levels were performed.. Intrapulmonary instillation of meconium resulted in the increase of TNF-α (p = 0.005 and p < 0.001, respectively) and IL-8 concentrations (p < 0.001 and p < 0.001, respectively) in BAL fluid in the EPO + meconium and saline + meconium groups compared with the sham-controlled group. rhEPO pretreatment prevented the increase of BAL fluid IL-1β, IL-6, and IL-8 levels (p < 0.001, p = 0.021, and p = 0.005, respectively), and serum IL-6 levels (p = 0.036).. rhEPO pretreatment is associated with improved BAL fluid and serum cytokine levels. Pretreatment with rhEPO might reduce the risk of developing of meconium-induced derangements.

Topics: Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Erythropoietin; Humans; Interleukin-6; Interleukin-8; Male; Meconium Aspiration Syndrome; Pneumonia; Premedication; Rats

Pseudomonas aeruginosa colonization, prominent inflammation with massive expression of the neutrophil chemokine IL-8, and luminal infiltrates of neutrophils are hallmarks of chronic lung disease in patients with cystic fibrosis (CF). The nociceptive transient receptor potential ankyrin (TRPA) 1 calcium channels have been recently found to be involved in nonneurogenic inflammation. Here, we investigate the role of TRPA1 in CF respiratory inflammatory models in vitro. Expression of TRPA1 was evaluated in CF lung tissue sections and cells by immunohistochemistry and immunofluorescence. Epithelial cell lines (A549, IB3-1, CuFi-1, CFBE41o

Topics: A549 Cells; Adult; Bronchi; Calcium Channels; Cystic Fibrosis; Cytokines; Epithelial Cells; Female; Gene Silencing; Humans; Interleukin-8; Lung; Male; Middle Aged; Models, Biological; Nerve Tissue Proteins; Pneumonia; Pseudomonas aeruginosa; RNA, Messenger; Tissue Donors; Transcription, Genetic; Transient Receptor Potential Channels; TRPA1 Cation Channel; Young Adult

Taraxasterol, a pentacyclic-triterpene isolated from Taraxacum officinale, has been demonstrated to have anti-inflammatory effects. However, the protective effects of taraxasterol against cigarette smoke (CS)-induced lung inflammation have not been reported. This study aimed to investigate the protective effects and mechanism of taraxasterol on CS-induced lung inflammation in mice. CS-induced mouse lung inflammation model was used to investigate the protective effects of taraxasterol in vivo. Human bronchial epithelial cells (HBECs) were used to investigate the protective mechanism of taraxasterol in vitro. The results showed that taraxasterol attenuated CS-induced lung pathological changes, inflammatory cells infiltration, inflammatory cytokines TNF-α, IL-6 and IL-1β production. Taraxasterol also up-regulated CS-induced glutathione (GSH) production. In vitro, taraxasterol was found to inhibit CS-induced reactive oxygen species production, recruitment of TLR4 into lipid rafts, NF-κB activation, and IL-8 production. Furthermore, our results showed that antioxidant N-acetyl-L-cysteine (NAC) significantly inhibited CS-induced recruitment of TLR4 into lipid rafts as well as IL-8 production. In conclusion, our results suggested that taraxasterol had protective effects of CS-induced lung inflammation.

Topics: Actins; Animals; Bronchoalveolar Lavage Fluid; Chemokines; Glutathione; Humans; Interleukin-8; Intracellular Space; Male; Membrane Microdomains; Mice; Mice, Inbred C57BL; NF-kappa B; NF-KappaB Inhibitor alpha; Pneumonia; Protein Transport; Reactive Oxygen Species; Signal Transduction; Smoke; Sterols; Tobacco Products; Toll-Like Receptor 4; Triterpenes

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

Persistant inflammatory responses to infectious agents and other components in organic dust underlie lung injury and development of respiratory diseases. Organic dust components responsible for eliciting inflammation and the mechanisms by which they cause lung inflammation are not fully understood. We studied the mechanisms by which protease activities in poultry dust extracts and intracellular oxidant stress induce inflammatory gene expression in A549 and Beas2B lung epithelial cells.. The effects of dust extracts on inflammatory gene expression were analyzed by quantitative polymerase chain reaction (qPCR), enzyme linked immunosorbent (ELISA) and western blot assays. Oxidant stress was probed by dihydroethidium (DHE) labeling, and immunostaining for 4-hydroxynonenal (4-HNE). Effects on interleukin-8 (IL-8) promoter regulation were determined by transient transfection assay.. Dust extracts contained trypsin and elastase activities, and activated protease activated receptor (PAR)-1 and -2. Serine protease inhibitors and PAR-1 or PAR-2 knockdown suppressed inflammatory gene induction. Dust extract induction of IL-8 gene expression was associated with increased DHE-fluorescence and 4-HNE staining, and antioxidants suppressed inflammatory gene induction. Protease inhibitors and antioxidants suppressed protein kinase C and NF-κB activation and induction of IL-8 promoter activity in cells exposed to dust extract.. Our studies demonstrate that proteases and intracellular oxidants control organic dust induction of inflammatory gene expression in lung epithelial cells. Targeting proteases and oxidant stress may serve as novel approaches for the treatment of organic dust induced lung diseases. This is the first report on the involvement of oxidant stress in the induction of inflammatory gene expression by organic dust.

Topics: A549 Cells; Animals; Anti-Inflammatory Agents; Antioxidants; Dust; Epithelial Cells; Gene Expression Regulation; Housing, Animal; Humans; Inflammation Mediators; Inhalation Exposure; Interleukin-8; Lung; Matrix Metalloproteinases; Organic Chemicals; Oxidative Stress; Peptide Hydrolases; Pneumonia; Poultry; Receptor, PAR-1; Receptor, PAR-2; Serine Proteinase Inhibitors; Signal Transduction; Time Factors; Transfection

Extracorporeal membrane oxygenation (ECMO) is a life-saving treatment for patients with severe refractory cardiorespiratory failure. Exposure to the ECMO circuit is thought to trigger/exacerbate inflammation. Determining whether inflammation is the result of the patients' underlying pathologies or the ECMO circuit is difficult. To discern how different insults contribute to the inflammatory response, we developed an ovine model of lung injury and ECMO to investigate the impact of smoke-induced lung injury and ECMO in isolation and cumulatively on pulmonary and circulating inflammatory cells, cytokines, and tissue remodeling. Sheep receiving either smoke-induced acute lung injury (S-ALI) or sham injury were placed on veno-venous (VV) ECMO lasting either 2 or 24 h, with controls receiving conventional ventilation only. Lung tissue, bronchoalveolar fluid, and plasma were analyzed by RT-PCR, immunohistochemical staining, and zymography to assess inflammatory cells, cytokines, and matrix metalloproteinases. Pulmonary compliance decreased in sheep with S-ALI placed on ECMO with increased numbers of infiltrating neutrophils, monocytes, and alveolar macrophages compared with controls. Infiltration of neutrophils was also observed with S-ALI alone. RT-PCR studies showed higher expression of matrix metalloproteinases 2 and 9 in S-ALI plus ECMO, whereas IL-6 was elevated at 2 h. Zymography revealed higher levels of matrix metalloproteinase 2. Circulating plasma levels of IL-6 were elevated 1-2 h after commencement of ECMO alone. These data show that the inflammatory response is enhanced when a host with preexisting pulmonary injury is placed on ECMO, with increased infiltration of neutrophils and macrophages, the release of inflammatory cytokines, and upregulation of matrix metalloproteinases.

Topics: Acute Lung Injury; Animals; Biomarkers; Bronchi; Bronchoalveolar Lavage; Compliance; Edema; Epithelial Cells; Extracorporeal Membrane Oxygenation; Immunohistochemistry; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukocyte Count; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Organ Size; Pneumonia; Pulmonary Fibrosis; Sheep; Smoking

Reversible changes in lung microstructure accompany lung inflammation, although alterations in tissue micromechanics and their impact on inflammation remain unknown. This study investigated changes in extracellular matrix (ECM) remodeling and tissue stiffness in a model of LPS-induced inflammation and examined the role of lipoxin analog 15-epi-lipoxin A4 (eLXA4) in the reduction of stiffness-dependent exacerbation of the inflammatory process. Atomic force microscopy measurements of live lung slices were used to directly measure local tissue stiffness changes induced by intratracheal injection of LPS. Effects of LPS on ECM properties and inflammatory response were evaluated in an animal model of LPS-induced lung injury, live lung tissue slices, and pulmonary endothelial cell (EC) culture. In vivo, LPS increased perivascular stiffness in lung slices monitored by atomic force microscopy and stimulated expression of ECM proteins fibronectin, collagen I, and ECM crosslinker enzyme, lysyl oxidase. Increased stiffness and ECM remodeling escalated LPS-induced VCAM1 and ICAM1 expression and IL-8 production by lung ECs. Stiffness-dependent exacerbation of inflammatory signaling was confirmed in pulmonary ECs grown on substrates with high and low stiffness. eLXA4 inhibited LPS-increased stiffness in lung cross sections, attenuated stiffness-dependent enhancement of EC inflammatory activation, and restored lung compliance in vivo. This study shows that increased local vascular stiffness exacerbates lung inflammation. Attenuation of local stiffening of lung vasculature represents a novel mechanism of lipoxin antiinflammatory action.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Humans; Interleukin-8; Lipopolysaccharides; Lipoxins; Lung Injury; Mice, Inbred C57BL; Pneumonia; Signal Transduction

Three billion people are exposed to household air pollution from biomass fuel use. Exposure is associated with higher incidence of pneumonia, and possibly tuberculosis. Understanding mechanisms underlying these defects would improve preventive strategies. We used human alveolar macrophages obtained from healthy Malawian adults exposed naturally to household air pollution and compared them with human monocyte-derived macrophages exposed in vitro to respirable-sized particulates. Cellular inflammatory response was assessed by IL-6 and IL-8 production in response to particulate challenge; phagosomal function was tested by uptake and oxidation of fluorescence-labeled beads; ingestion and killing of Streptococcus pneumoniae and Mycobacterium tuberculosis were measured by microscopy and quantitative culture. Particulate ingestion was quantified by digital image analysis. We were able to reproduce the carbon loading of naturally exposed alveolar macrophages by in vitro exposure of monocyte-derived macrophages. Fine carbon black induced IL-8 release from monocyte-derived and alveolar macrophages (P < 0.05) with similar magnitude responses (log10 increases of 0.93 [SEM = 0.2] versus 0.74 [SEM = 0.19], respectively). Phagocytosis of pneumococci and mycobacteria was impaired with higher particulate loading. High particulate loading corresponded with a lower oxidative burst capacity (P = 0.0015). There was no overall effect on killing of M. tuberculosis. Alveolar macrophage function is altered by particulate loading. Our macrophage model is comparable morphologically to the in vivo uptake of particulates. Wood smoke-exposed cells demonstrate reduced phagocytosis, but unaffected mycobacterial killing, suggesting defects related to chronic wood smoke inhalation limited to specific innate immune functions.

Topics: Adult; Aged; Air Pollutants; Air Pollution, Indoor; Cells, Cultured; Dose-Response Relationship, Drug; England; Housing; Humans; Immunity, Innate; Inflammation Mediators; Inhalation Exposure; Interleukin-6; Interleukin-8; Macrophages, Alveolar; Malawi; Middle Aged; Mycobacterium tuberculosis; Particle Size; Phagocytosis; Pneumonia; Respiratory Burst; Soot; Streptococcus pneumoniae; Wood; Young Adult

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

Inhaled cigarette smoke (CS) causes persistent lung inflammation in smokers. Interleukin 8 (IL-8) released from macrophages is a key chemokine during initiation and progression of CS-induced lung inflammation, yet its regulation is largely unknown. AMP-activated protein kinase (AMPK), a crucial energy homeostasis regulator, may modulate inflammation. Here we report that CS extract (CSE) increased the level of intracellular reactive oxygen species (ROS), activating AMPK, mitogen-activated protein kinases (MAPKs), and NF-κB, as well as inducing IL-8, in human macrophages. N-acetyl-cysteine (ROS scavenger) or hexamethonium [nicotinic acetylcholine receptor (nAChR) antagonist] attenuated the CSE-induced increase in intracellular ROS, activation of AMPK and NF-κB, as well as IL-8 induction, which suggests that nAChRs and ROS are important. Prevention of AMPK activation by compound C or AMPK siRNA reduced CSE-induced IL-8 production, confirming the role of AMPK. Compound C or AMPK siRNA also inhibited the activation of MAPKs and NF-κB by CSE, which suggests that these molecules are downstream of AMPK. Additionally, exposure of human macrophages to nicotine activated AMPK and induced IL-8 and that these effects were lessened by hexamethonium or compound C, implying that nicotine in CS may be causative. Furthermore, chronic CS exposure in mice promoted AMPK phosphorylation and expression of MIP-2 (an IL-8 homolog) in infiltrated macrophages and in lung tissues, as well as induced lung inflammation, all of which were reduced by compound C treatment. Thus, we identified a novel nAChRs-dependent, ROS-sensitive, AMPK/MAPKs/NF-κB signaling pathway, which seems to be important to CS-induced macrophage IL-8 production and possibly to lung inflammation.

Topics: AMP-Activated Protein Kinases; Animals; Blotting, Western; Cell Line; Extracellular Signal-Regulated MAP Kinases; Humans; Immunohistochemistry; Interleukin-8; Macrophages; Mice; NF-kappa B; Pneumonia; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Signal Transduction; Smoke; Tobacco Products; Transfection

It is broadly recognized that chemokine-activated neutrophils play a crucial role in the inflammation and disruption of lung tissue observed in several acute and chronic lung diseases. Since glycosaminoglycan side chains of proteoglycans act as chemokine co-receptors in inflammation, we have used a CXCL8-based dominant-negative mutant, dnCXCL8, to displace neutrophil-related chemokines in murine lungs using models of lung inflammation. Treatment with dnCXCL8 resulted in a dose-dependent reduction of neutrophil counts in bronchoalveolar lavage (BAL) of mice exposed to lipopolysaccharide after intravenous, subcutaneous and intratracheal administration. A strong and significant therapeutic effect was achieved already at a dose of 40 µg/kg of dnCXCL8. A similar dose response, but showing a broader spectrum of reduced inflammatory cells and soluble inflammatory markers, was observed in a murine model of tobacco smoke (TS)-induced lung inflammation. The broad spectrum of reduced inflammatory cells and markers can be due to the strong inhibition of neutrophil extravasation into the lung parenchyma, and/or to a relatively broad protein displacement profile of dnCXCL8 which may compete not only with wtCXCL8 for glycosaminoglycan-binding but possibly also with other related glycosaminoglycan-binding pro-inflammatory chemokines. Overall our results demonstrate that antagonizing CXCL8/glycosaminoglycan binding reduces lung inflammation as well as associated lung tissue damage due to LPS and TS and may therefore be a new therapeutic approach for lung pathologies characterized by a neutrophilic inflammatory phenotype.

Topics: Animals; Biomarkers; Endothelial Cells; Female; Gene Expression Regulation; Glycosaminoglycans; Humans; Interleukin-8; Lipopolysaccharides; Lung; Male; Mice; Microvessels; Molecular Targeted Therapy; Neutrophil Infiltration; Nicotiana; Pneumonia; Protein Engineering; Smoke; Syndecan-4

Inflammatory processes, including respiratory symptoms, can be induced among workers in composting plants exposed to bioaerosols containing microorganisms and their compounds. We evaluated inflammatory processes in the lower respiratory tract via cellular and soluble mediator profiles in induced sputum (IS). IS samples of 140 current (35% smokers) and 49 former compost workers (29% smokers) as well as 29 white-collar workers (17% smokers) were collected and analyzed for the cell count and composition, and for soluble biomarkers. Significant differences between current and former compost workers and white-collar workers were detected for total cell count (p=0.0004), neutrophils (p=0.0045), sCD14 (p=0.008), and 8-isoprostane (p<0.0001). IS of non-smoking former compost workers showed lower concentrations of IL-8, total protein, immunoreactive MMP-9 and sCD14, compared with non-smoking current compost workers. 10.1% of the study population was suffering from chronic bronchitis with significant differences (p=0.018) between former compost workers (24.5%), current workers (5%), and white-collar workers (10.3%). Significantly lower IL-8 (p=0.0002), neutrophils (p=0.001), and MMP-9 (p=0.0023) values were measured in healthy subjects compared with subjects with chronic bronchitis. In conclusion, changes in lower airways were detected by analysis of biomarkers in IS of current exposed and, to a lesser extent, in IS of former compost workers. These effects are especially pronounced in subjects with chronic bronchitis.

Topics: Adult; Air Pollutants, Occupational; Biomarkers; Blood Proteins; Bronchitis; Cell Count; Chronic Disease; Cross-Sectional Studies; Dinoprost; Female; Humans; Interleukin-8; Lipopolysaccharide Receptors; Male; Matrix Metalloproteinase 9; Middle Aged; Neutrophils; Occupational Exposure; Pneumonia; Smoking; Soil; Sputum

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

There is a strong interest in finding adequate biomarkers to aid in the diagnosis and prognosis of influenza A (H1N1)pdm09 virus infection. In this study, serum levels of inflammatory cytokines and laboratory markers were evaluated to assess their usefulness as biomarkers of influenza A (H1N1)pdm09 and their association with fatal cases. Serum samples of consecutive patients with a clinical presentation suggestive of influenza A (H1N1)pdm09 and progression to sepsis were evaluated. Serum inflammatory cytokines and routine laboratory tests were performed and correlated with positivity for influenza A (H1N1)pdm09 influenza by real time reverse transcription polymerase chain reaction and the results of three clinical severity scores (Sequential Organ Failure Assessment [SOFA], CURB-65, and Acute Physiology and Chronic Health Evaluation II [APACHE II]). High SOFA scores and some of its individual components, but not CURB-65 or APACHE II scores, correlate with fatal cases regardless of etiology. Total and unconjugated bilirubin, Ca(++), Cl(-), prothrombin times, and partial thromboplastin times discriminate influenza A (H1N1)pdm09 from other causes of community-acquired pneumonia. High levels of IL-8, IL-10, and IL-17 were increased in influenza A (H1N1)pdm09 patients when compared with controls (p<0.05). IL-6 levels were significantly elevated in influenza A (H1N1)pdm09 patients and non-(H1N1)pdm09 patients when compared with controls (p<0.05). TGF-β serum levels discern between healthy controls, influenza A (H1N1)pdm09 patients, and patients with other causes of community-acquired pneumonia. TGF-β levels were negatively correlated with SOFA on admission in influenza A (H1N1)pdm09 patients. TGF-β levels are a useful tool for differentiating influenza A (H1N1)pdm09 from other causes of pneumonia progressing to sepsis.

Topics: Adult; Bilirubin; Biomarkers; Community-Acquired Infections; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Interleukin-10; Interleukin-17; Interleukin-6; Interleukin-8; Male; Partial Thromboplastin Time; Pneumonia; Prothrombin Time; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Severity of Illness Index; Transforming Growth Factor beta

Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, which may delay appropriate cause-specific treatment.. To characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission.. The study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission.. Blood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients.. CAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).

Topics: Aged; Apoptosis Regulatory Proteins; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Community-Acquired Infections; Female; Gene Expression Profiling; Humans; Intensive Care Units; Interleukin-6; Interleukin-8; Male; Middle Aged; Pneumonia; Protein Precursors; Proteins; Tissue Array Analysis

Aspergillus fumigatus is an opportunistic fungal pathogen that typically infects the lungs of immunocompromised patients leading to a high mortality. H-Ficolin, an innate immune opsonin, is produced by type II alveolar epithelial cells and could participate in lung defences against infections. Here, we used the human type II alveolar epithelial cell line, A549, to determine the involvement of H-ficolin in fungal defence. Additionally, we investigated the presence of H-ficolin in bronchoalveolar lavage fluid from transplant patients during pneumonia. H-Ficolin exhibited demonstrable binding to A. fumigatus conidia via l-fucose, d-mannose and N-acetylglucosamine residues in a calcium- and pH-dependent manner. Moreover, recognition led to lectin complement pathway activation and enhanced fungal association with A549 cells. Following recognition, H-ficolin opsonization manifested an increase in interleukin-8 production from A549 cells, which involved activation of the intracellular signalling pathways mitogen-activated protein kinase MAPK kinase 1/2, p38 MAPK and c-Jun N-terminal kinase. Finally, H-ficolin concentrations were significantly higher in bronchoalveolar lavage fluid of patients with lung infections compared with control subjects (n = 16; P = 0·00726). Receiver operating characteristics curve analysis further highlighted the potential of H-ficolin as a diagnostic marker for lung infection (area under the curve = 0·77; P < 0·0001). Hence, H-ficolin participates in A. fumigatus defence through the activation of the lectin complement pathway, enhanced fungus-host interactions and modulated immune responses.

Topics: Alveolar Epithelial Cells; Area Under Curve; Aspergillus fumigatus; Biomarkers; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cell Line, Tumor; Complement Activation; Complement C3b; Complement Pathway, Mannose-Binding Lectin; Glycoproteins; Host-Pathogen Interactions; Humans; Immunity, Innate; Interleukin-8; Lectins; Lung; MAP Kinase Signaling System; Pneumonia; Predictive Value of Tests; Pulmonary Aspergillosis; ROC Curve; Up-Regulation

Chronic inflammation of the airways is a central component in lung diseases and is frequently associated with bacterial infections. Monitoring the pro-inflammatory capability of bacterial virulence factors in vivo is challenging and usually requires invasive methods.. Lung inflammation was induced using the culture supernatants from two Pseudomonas aeruginosa clinical strains, VR1 and VR2, isolated from patients affected by cystic fibrosis and showing different phenotypes in terms of motility, colony characteristics and biofilm production as well as pyoverdine and pyocyanine release. More interesting, the strains differ also for the presence in supernatants of metalloproteases, a family of virulence factors with known pro-inflammatory activity. We have evaluated the benefit of using a mouse model, transiently expressing the luciferase reporter gene under the control of an heterologous IL-8 bovine promoter, to detect and monitoring lung inflammation.. In vivo imaging indicated that VR1 strain, releasing in its culture supernatant metalloproteases and other virulence factors, induced lung inflammation while the VR2 strain presented with a severely reduced pro-inflammatory activity. The bioluminescence signal was detectable from 4 to 48 h after supernatant instillation. The animal model was also used to test the anti-inflammatory activity of azithromycin (AZM), an antibiotic with demonstrated inhibitory effect on the synthesis of bacterial exoproducts. The inflammation signal in mice was in fact significantly reduced when bacteria grew in the presence of a sub-lethal dose of AZM causing inhibition of the synthesis of metalloproteases and other bacterial elements. The in vivo data were further supported by quantification of immune cells and cytokine expression in mouse broncho-alveolar lavage samples.. This experimental animal model is based on the transient transduction of the bovine IL-8 promoter, a gene representing a major player during inflammation, essential for leukocytes recruitment to the inflamed tissue. It appears to be an appropriate molecular read-out for monitoring the activation of inflammatory pathways caused by bacterial virulence factors. The data presented indicate that the model is suitable to functionally monitor in real time the lung inflammatory response facilitating the identification of bacterial factors with pro-inflammatory activity and the evaluation of the anti-inflammatory activity of old and new molecules for therapeutic use.

Topics: Animals; Azithromycin; Bronchoalveolar Lavage Fluid; Cattle; Cytokines; Diagnostic Imaging; Female; Humans; Interleukin-8; Mice, Inbred BALB C; Mice, Transgenic; Peptide Hydrolases; Phenotype; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Virulence Factors

Neutrophils play a fundamental role in a number of chronic lung diseases. Among the mediators of their recruitment to the lung, CXCL8 (IL-8) is considered to be one of the major players. CXCL8 exerts its chemotactic activity by binding to its GPCR receptors (CXCR1/R2) located on neutrophils, as well as through interactions with glycosaminoglycans (GAGs) on cell surfaces including those of the microvascular endothelium. Binding to GAG co-receptors is required to generate a solid-phase haptotactic gradient and to present IL-8/CXCL8 in a proper conformation to its receptors on circulating neutrophils.. We have engineered increased GAG-binding affinity into human CXCL8, thereby obtaining a competitive inhibitor that displaces wild-type IL-8/CXCL8 from GAGs. By additionally knocking-out the GPCR binding domain of the chemokine, we generated a dominant negative protein (dnCXCL8; PA401) with potent anti-inflammatory characteristics proven in vivo in a murine model of LPS-induced lung inflammation (Adage et al., 2015). Here we have further investigated PA401 activity in this pulmonary model by evaluating plasma changes induced by LPS on white blood cells (WBC) and a broad range of inflammatory markers, especially chemokines, by addressing immediate effects of PA401 on these parameters in healthy and LPS exposed mice.. Aerosolized LPS induced a significant increase in bronchoalveolar lavage (BAL) neutrophils after 3 and 7h, as well as an increase in total WBC and changes in 21 of the 59 measured plasma markers, mostly belonging to the chemokine family. PA401 treatment in saline exposed mice didn't induce major changes in any of the measured parameters. When administered to LPS aerosolized mice, PA401 caused a significant normalization of KC/mCXCL1 and other inflammatory markers, as well as of blood WBC count. In addition, BAL neutrophils were significantly reduced, confirming the previously observed lung anti-inflammatory activity of PA401 in this experiment.. PA401 is a new promising biologic therapeutic with a novel and unique mechanism of action for interfering with neutrophilic lung inflammation, that also normalizes plasma inflammatory markers.

Topics: Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Glycosaminoglycans; Interleukin-8; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Neutrophils; Pneumonia; Recombinant Proteins

High flow nasal cannula (HFNC) has been shown to improve ventilation and oxygenation and reduce work of breathing in newborns with respiratory distress. Heliox, decreases resistance to airflow, reduces the work of breathing, facilitates the distribution of inspired gas, and has been shown to attenuate lung inflammation during the treatment of acute lung injury.. Heliox delivered by HFNC will decrease resistive load, decrease work of breathing, improve ventilation and attenuate lung inflammation during spontaneous breathing following acute lung injury in the newborn pig.. Spontaneously breathing neonatal pigs received Nitrox or Heliox by HFNC and studied over 4 hrs following oleic acid injury. Gas exchange, pulmonary mechanics and systemic inflammation were measured serially. Lung inflammation biomarkers were assessed at termination.. Heliox breathing animals demonstrated lower work of breathing reflected by lower tracheal pressure, phase angle and phase relationship. Ventilation efficiency index was greater compared to Nitrox. Heliox group showed less lung inflammation reflected by lower tissue interleukin-6 and 8.. High flow nasal Heliox decreased respiratory load, reduced resistive work of breathing indices and attenuated lung inflammatory profile while ventilation was supported at less pressure effort in the presence of acute lung injury.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Helium; Interleukin-6; Interleukin-8; Oxygen; Oxygen Inhalation Therapy; Pneumonia; Pulmonary Gas Exchange; Pulmonary Ventilation; Swine; Work of Breathing

Inhalation is an important route of aldehyde exposure, and lung is one of the main targets of aldehyde toxicity. Octanal is distributed ubiquitously in the environment and is a component of indoor air pollutants. We investigated whether octanal exposure enhances the inflammatory response in the human respiratory system by increasing the expression and release of cytokines and chemokines. The effect of octanal in transcriptomic modulation was assessed in the human alveolar epithelial cell line A549 using oligonucleotide arrays. We identified a set of genes differentially expressed upon octanal exposure that may be useful for monitoring octanal pulmonary toxicity. These genes were classified according to the Gene Ontology functional category and Kyoto Encyclopedia of Genes and Genomes analysis to explore the biological processes related to octanal-induced pulmonary toxicity. The results show that octanal affects the expression of several chemokines and inflammatory cytokines and increases the levels of interleukin 6 (IL-6) and IL-8 released. In conclusion, octanal exposure modulates the expression of cytokines and chemokines important in the development of lung injury and disease. This suggests that inflammation contributes to octanal-induced lung damage and that the inflammatory genes expressed should be studied in detail, thereby laying the groundwork for future biomonitoring studies.

Topics: Air Pollutants; Aldehydes; Cell Line, Tumor; Cell Survival; Computational Biology; Cytokines; Databases, Genetic; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Oligonucleotide Array Sequence Analysis; Pneumonia; Pulmonary Alveoli; RNA, Messenger

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

Nonmotile primary cilia are recognized as important sensory organelles during development and normal biological functioning. For example, recent work demonstrates that transcriptional regulators of the sonic hedgehog signaling pathway localize to primary cilia and participate in sensing and transducing signals regarding the cellular environment. In contrast, motile cilia are traditionally viewed as mechanical machinery, vital for the movement of solutes and clearance of bacteria and debris, but not participants in cellular sensing and signaling mechanisms. Recently, motile cilia were found to harbor receptors responsible for sensing and responding to environmental stimuli. However, no transcription factors are known to be regulated by cilia localization as a sensing mechanism in vertebrates. Using a mouse model of organic dust-induced airway inflammation, we found that the transcription factor serum response factor (SRF) localizes to motile cilia of airway epithelial cells and alters its localization in response to inflammatory stimuli. Furthermore, inhibition of SRF signaling using the small molecule CCG-1423 reduces organic dust-induced IL-8 release from bronchial epithelial cells and stimulates cilia beat frequency in ciliated mouse tracheal epithelial cells. Immunohistochemical analyses reveal that SRF localizes to the cilia of mouse brain ependymal and ovarian epithelial cells as well. These data reveal a novel mechanism by which a transcription factor localizes to motile cilia and modulates cell activities including cilia motility and inflammation response. These data challenge current dogma regarding motile cilia functioning and may lead to significant contributions in understanding motile ciliary signaling dynamics, as well as mechanisms involving SRF-mediated responses to inflammation and injury.

Topics: Adult; Aged; Anilides; Animals; Benzamides; Blotting, Western; Bronchi; Cilia; Dust; Environmental Monitoring; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Humans; Immunoenzyme Techniques; Interleukin-8; Lung Injury; Male; Mice; Mice, Inbred C57BL; Middle Aged; Pneumonia; rhoA GTP-Binding Protein; Serum Response Factor; Trachea

Acute lung injury (ALI) is accompanied by decreased lung compliance. However, a role of tissue mechanics in modulation of inflammation remains unclear. We hypothesized that bacterial lipopolysacharide (LPS) stimulates extracellular matrix (ECM) production and vascular stiffening leading to stiffness-dependent exacerbation of endothelial cell (EC) inflammatory activation and lung barrier dysfunction. Expression of GEF-H1, ICAM-1, VCAM-1, ECM proteins fibronectin and collagen, lysyl oxidase (LOX) activity, interleukin-8 and activation of Rho signaling were analyzed in lung samples and pulmonary EC grown on soft (1.5 or 2.8 kPa) and stiff (40 kPa) substrates. LPS induced EC inflammatory activation accompanied by expression of ECM proteins, increase in LOX activity, and activation of Rho signaling. These effects were augmented in EC grown on stiff substrate. Stiffness-dependent enhancement of inflammation was associated with increased expression of Rho activator, GEF-H1. Inhibition of ECM crosslinking and stiffening by LOX suppression reduced EC inflammatory activation and GEF-H1 expression in response to LPS. In vivo, LOX inhibition attenuated LPS-induced expression of GEF-H1 and lung dysfunction. These findings present a novel mechanism of stiffness-dependent exacerbation of vascular inflammation and escalation of ALI via stimulation of GEF-H1-Rho pathway. This pathway represents a fundamental mechanism of positive feedback regulation of inflammation.

Topics: Animals; Cells, Cultured; Collagen; Endothelial Cells; Extracellular Matrix; Feedback, Physiological; Fibronectins; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Lipopolysaccharides; Mice, Inbred C57BL; Pneumonia; Protein-Lysine 6-Oxidase; Rho Factor; Rho Guanine Nucleotide Exchange Factors; Signal Transduction; Vascular Cell Adhesion Molecule-1

Chronic obstructive pulmonary disease is an inflammatory lung disease mainly caused by tobacco smoke inhalation.. Fifteen healthy adult male cats were categorized into 3 groups: (1) control group, (2) exposed to cigarette smoke (CS), and (3) exposed to CS treated with tiotropium.. Increases in clinical signs and airway responsiveness in CS cats were found compared to control animals. The airway hyperresponsiveness and clinical signs were significantly attenuated by treatment with tiotropium. The CS-induced pulmonary release of interleukin-6, interleukin-8, monocyte chemotactic protein-1, and tumor necrosis factor alpha was reduced in the tiotropium group. Exposure to CS significantly increased total inflammatory cells number in bronchoalveolar lavage fluid, which was significantly attenuated by treatment with tiotropium. The number of macrophages, eosinophils and neutrophils and lymphocytes was increased after exposure to CS. Tiotropium significantly reduced the number of all these cells. Perivascular, peribronchiolar infiltration of inflammatory cells and Reid index increased in the CS group. Treatment with tiotropium significantly reduced these parameters to control level. Enhanced lipid peroxidation with concomitant reduction of antioxidants status was observed in the CS group. Tiotropium significantly reduced the serum, lung lavage, lung, and tracheal tissue lipid peroxides to near control levels. Tiotropium also decreased lung and tracheal protein leakage, and prevented the reduction of total antioxidant status in serum, lung lavage, lung and tracheal tissue of the CS group.. Cigarette smoke increases airway responsiveness and inflammation in a cat model of CS induced lung inflammation. It can effectively be reduced by treatment with tiotropium.

Topics: Animals; Antioxidants; Bronchoalveolar Lavage Fluid; Cats; Chemokine CCL2; Disease Models, Animal; Eosinophils; Interleukin-6; Interleukin-8; Lipid Peroxidation; Lipid Peroxides; Lymphocytes; Macrophages; Male; Neutrophils; Pneumonia; Scopolamine Derivatives; Smoke; Smoking; Tiotropium Bromide; Tobacco Products; Trachea; Tumor Necrosis Factor-alpha

We studied the pathogenesis and transmissibility of a novel avian-origin H7N9 influenza virus in pigs. When pigs were infected with H7N9 influenza virus, they did not show any clear clinical signs (such as sneezing, fever and loss of body weight), and they shed viruses through their noses for 2 days after infection. No transmission occurred between infected and naïve pigs. Pigs suffered from mild pneumonia, which was accompanied by the induction of inflammatory cytokines and chemokines such as IL-8 and CCL1. Taken together, our results suggest that pigs may not play an active role in transmitting H7N9 influenza virus to mammals.

Topics: Animals; Chemokine CCL1; Disease Models, Animal; Influenza A Virus, H7N9 Subtype; Interleukin-8; Lung; Orthomyxoviridae Infections; Pneumonia; RNA, Viral; Swine; Viral Load; Virus Shedding

Our previous study has demonstrated that naringin attenuates EGF-induced MUC5AC hypersecretion in A549 cells by suppressing the cooperative activities of MAPKs/AP-1 and IKKs/IκB/NF-κB signaling pathways. However, the volume of airway mucus is determined by two factors including the number of mucous cells and capacity of mucus secretion. The aim of the present study is to explore the mucoactive effects of naringin in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and beagle dogs. The results demonstrated that naringin of 12.4 mg/kg treatment significantly decreased LPS-induced enhancement of sputum volume and pulmonary inflammation, remarkably increased the subglottic sputum volume and solids content in sputum of lower trachea, while partially, but not fully, significantly increased the elasticity and viscosity of sputum in lower trachea of beagle dogs. Moreover, the MUC5AC content in BALF and goblet-cells in large airways of LPS-induced ALI mice were significantly attenuated by dexamethasone (5 mg/kg), ambroxol (25 mg/kg), and naringin (15, 60 mg/kg). However, the goblet-cells hyperplasia in small airways induced by LPS was only significantly inhibited by dexamethasone and naringin (60 mg/kg). In conclusion, naringin exhibits mucoactive effects through multiple targets which including reduction of goblet cells hyperplasia and mucus hypersecretion, as well as promotion of sputum excretion.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Dogs; Elasticity; Female; Flavanones; Goblet Cells; Hyperplasia; Interleukin-8; Leukocyte Count; Lipopolysaccharides; Male; Mice; Mucin 5AC; Mucus; Pneumonia; Sputum; Tumor Necrosis Factor-alpha; Viscosity

Thirty percent of patients with pneumonia develop pleural effusion, and of these, 20% have complicated effusion (CPPE), which may require a chest tube or surgery for resolution. The objective of the study is to compare the diagnostic yield of determining interleukin-1β and interleukin-8 in pleural fluid (PF) (PFIL-1β and PFIL-8) with respect to classic criteria (pH <7.2, lactate dehydrogenase [LD] >1,000 IU/mL, and/or glucose <60 mg/dL) in the early diagnosis of CPPE.. Of the 559 patients studied, 40 had CPPE. All underwent PF analysis: pH, glucose (PFGLUC), LD (PFLD), PFIL-1β and PFIL-8, and PF/serum ratios (PF/SIL-1β and PF/SIL-8).. The diagnostic criterion that showed the best area under the curve was the combination of PF/SIL-8 and PFIL-1β (0.906), with a statistically significant difference (P < .05) compared with the classic criterion of pH and PFGLUC or PFLD (0.826). The combination of PF/SIL-8 and PFIL-1β (cutoffs >5.73 and >9.14 pg/mL, respectively) was significantly more sensitive (72.7%) and more specific (97.9%) (P < .05) than the rest of the parameters used.. Measurement of IL-1β and IL-8 in pleural fluid may be useful in the early diagnosis of CPPE, although individually, it may not improve the results obtained with the PFLD. Further studies are needed to more firmly establish what role these new parameters can play in the diagnosis of CPPE.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Early Diagnosis; Empyema, Pleural; Glucose; Humans; Hydrogen-Ion Concentration; Interleukin-1beta; Interleukin-8; L-Lactate Dehydrogenase; Middle Aged; Pleural Effusion; Pleurisy; Pneumonia; ROC Curve; Sensitivity and Specificity; Young Adult

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

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

Klebsiella pneumoniae-associated pathology is largely mediated by neutrophilic inflammation. In this study, we administered Klebsiella pneumoniae to experimental guinea pig groups and the ELR-CXC chemokine antagonist CXCL8(3-72), ceftazidime, and dexamethasone to different groups, respectively. After 24 h, we assessed the animal's pulmonary inflammatory levels, including gross histopathology, airway neutrophilia, lung myeloperoxidase levels, expressions of CXCL8 and TNF, and airway bacterial loads. Compared with ceftazidime and dexamethasone treatments, the administration of the ELR-CXC chemokine antagonist CXCL8(3-72) alone was more effective than other methods, although it did not markedly attenuate the bacterial load. These results suggest new methods for the treatment of Klebsiella pneumoniae pathology.

Topics: Animals; Ceftazidime; Dexamethasone; Guinea Pigs; Humans; Interleukin-8; Klebsiella Infections; Klebsiella pneumoniae; Lung; Pneumonia; Receptors, Interleukin-8A; Receptors, Interleukin-8B

Plasminogen has a role in airway inflammation. Airway smooth muscle (ASM) cells cleave plasminogen into plasmin, a protease with proinflammatory activity. In this study, the effect of plasminogen on cytokine production by human ASM cells was investigated in vitro. Levels of IL-6 and IL-8 in the medium of ASM cells were increased by incubation with plasminogen (5-50 μg/ml) for 24 hours (P < 0.05; n = 6-9), corresponding to changes in the levels of cytokine mRNA at 4 hours. The effects of plasminogen were attenuated by α2-antiplasmin (1 μg/ml), a plasmin inhibitor (P < 0.05; n = 6-12). Exogenous plasmin (5-15 mU/ml) also stimulated cytokine production (P < 0.05; n = 6-8) in a manner sensitive to serine-protease inhibition by aprotinin (10 KIU/ml). Plasminogen-stimulated cytokine production was increased in cells pretreated with basic fibroblast growth factor (300 pM) in a manner associated with increases in urokinase plasminogen activator expression and plasmin formation. The knockdown of annexin A2, a component of the putative plasminogen receptor comprised of annexin A2 and S100A10, attenuated plasminogen conversion into plasmin and plasmin-stimulated cytokine production by ASM cells. Moreover, a role for annexin A2 in airway inflammation was demonstrated in annexin A2-/- mice in which antigen-induced increases in inflammatory cell number and IL-6 levels in the bronchoalveolar lavage fluid were reduced (P < 0.01; n = 10-14). In conclusion, plasminogen stimulates ASM cytokine production in a manner regulated by annexin A2. Our study shows for the first time that targeting annexin A2-mediated signaling may provide a novel therapeutic approach to the treatment of airway inflammation in diseases such as chronic asthma.

Topics: alpha-2-Antiplasmin; Animals; Annexin A2; Bronchoalveolar Lavage Fluid; Cells, Cultured; Cytokines; Disease Models, Animal; Fibrinolysin; Fibroblast Growth Factor 2; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinases; Muscle, Smooth; Myocytes, Smooth Muscle; Phosphatidylinositol 3-Kinase; Plasminogen; Pneumonia; Proto-Oncogene Proteins c-akt; Respiratory System; RNA, Messenger; Signal Transduction; Time Factors; Urokinase-Type Plasminogen Activator

Since little is known of airways inflammation in the elderly, we have carried out a study to explore the presence of some inflammatory markers in the airways of healthy subjects of different ages using a non-invasive method which is particularly suitable for aged people.. The aim of this work was to investigate whether parameters, including (1) pH, IL-8 and TNF-α in exhaled breath condensate (EBC), (2) exhaled nitric oxide levels (NO), and (3) inflammatory cell profile in induced sputum, are age-related.. Thirty healthy adults (10 subjects below the age of 30 [A], 10 subjects between 30 and 60 years [B], and 10 subjects over 60 years of age [C]), were enrolled in the study. IL-8 and TNF-α levels were measured in breath condensate. Exhaled pH was measured after deaeration/decarbonation by means of a pH-meter. A rapid-response chemiluminescence NO analyzer was used to quantify NO. Induced sputum was collected, homogenized with dithiothreitol, and cytospins for differential cell were produced.. The levels of IL-8 and TNF-α in EBC, the levels of exhaled NO, and the percentage of neutrophils in induced sputum were significantly elevated in C and B compared with A; the EBC pH level was significantly reduced in C and B compared with A. The EBC levels of IL-8, TNF-α, pH, the level of exhaled NO, and the percentage of neutrophils correlated significantly with age.. This study has shown the presence of age-related airways inflammation in healthy subjects.

Topics: Adult; Aged; Aging; Exhalation; Female; Humans; Hydrogen-Ion Concentration; Incidence; Interleukin-8; Male; Middle Aged; Neutrophils; Nitric Oxide; Pneumonia; Prospective Studies; Sputum; Tumor Necrosis Factor-alpha

ATP in airway surface liquid (ASL) controls mucociliary clearance functions via the activation of airway epithelial purinergic receptors. However, abnormally elevated ATP levels have been reported in inflamed airways, suggesting that excessive ATP in ASL contributes to airway inflammation. Despite these observations, little is known about the mechanisms of ATP accumulation in the ASL covering inflamed airways. In this study, links between cystic fibrosis (CF)-associated airway inflammation and airway epithelial ATP release were investigated. Primary human bronchial epithelial (HBE) cells isolated from CF lungs exhibited enhanced IL-8 secretion after 6 to 11 days, but not 28 to 35 days, in culture, compared with normal HBE cells. Hypotonic cell swelling-promoted ATP release was increased in 6- to 11-day-old CF HBE cells compared with non-CF HBE cells, but returned to normal values after 28 to 35 days in culture. The exposure of non-CF HBE cells to airway secretions isolated from CF lungs, namely, sterile supernatants of mucopurulent material (SMM), also caused enhanced IL-8 secretion and increased ATP release. The SMM-induced increase in ATP release was sensitive to Ca(2+) chelation and vesicle trafficking/exocytosis inhibitors, but not to pannexin inhibition. Transcript levels of the vesicular nucleotide transporter, but not pannexin 1, were up-regulated after SMM exposure. SMM-treated cultures displayed increased basal mucin secretion, but mucin secretion was not enhanced in response to hypotonic challenge after the exposure of cells to either vehicle or SMM. We propose that CF airway inflammation up-regulates the capacity of airway epithelia to release ATP via Ca(2+)-dependent vesicular mechanisms not associated with mucin granule secretion.

Topics: Adenosine Triphosphate; Calcium Signaling; Cell Size; Cells, Cultured; Chelating Agents; Connexins; Cystic Fibrosis; Epithelial Cells; Humans; Inflammation Mediators; Interleukin-8; Mucins; Mucociliary Clearance; Nerve Tissue Proteins; Nucleotide Transport Proteins; Osmotic Pressure; Pneumonia; Primary Cell Culture; Respiratory Mucosa; Secretory Vesicles; Time Factors

Capsaicin-sensitive C fibers (CapsCF) are abundantly distributed in the respiratory tract. Inflammation is one of the main contributors to lung ischemia-reperfusion (IR) injury. This study was designed to investigate the role of CapsCF in lung IR-induced inflammatory response.. Thirty-two male rabbits were randomized into four groups as follows: sham group (S), IR group (IR), large dose of capsaicin plus sham group (CS), and large dose of capsaicin plus IR group (CIR). The CS and CIR groups were pretreated with capsaicin (100 mg/kg) to induce functional ablation of CapsCF. The IR and CIR groups were subjected to 1 h lung ischemia and 3 h reperfusion. Thereafter, blood and lung tissue samples were obtained for blood gas and biochemical analyses. Levels of substance P and calcitonin gene-related peptide (CGRP), lung wet-to-dry weight ratio, and histopathologic changes as well as neutrophil counts in bronchoalveolar lavage fluids were also assessed.. Capsaicin pretreatment in the CIR group resulted in increased lung wet-to-dry ratio, neutrophil counts in bronchoalveolar lavage fluids, and lung pathologic lesions, along with higher levels of plasma tumor necrosis factor α and interleukin 8 and lower level of interleukin 10 (P < 0.05 versus IR), although capsaicin did not alter the above variables in the CS group (P > 0.05 versus S). Lung tissue CGRP was elevated more than 2-fold in the IR group (P < 0.05 versus S), but it did not significantly change in the CIR group.. Denervation of CapsCF aggravated lung IR-induced inflammation, probably by depleting the CGRP content of CapsCF. CapsCF may protect against lung IR-induced inflammation and injury.

Topics: Animals; Bronchoalveolar Lavage Fluid; Capsaicin; Cell Count; Disease Models, Animal; Dose-Response Relationship, Drug; Interleukin-8; Male; Nerve Fibers, Unmyelinated; Neutrophils; Pneumonia; Rabbits; Reperfusion Injury; Sympathectomy, Chemical; Tumor Necrosis Factor-alpha

To investigate the effect of continuous renal replacement therapy (CRRT) on the outcome of severe pneumonia in patients receiving long-term immunosuppressants.. Thirty-four patients, who had been treated with long-term immunosuppressants, were admitted for severe pneumonia. After admission, the dose of immunosuppressants including glucocorticoids was decreased, and the patients were divided into 2 groups: antibiotic treatment group (n = 16) and antibiotic + CRRT treatment group (n = 18). Before and after treatment, the changes of the patients' condition, chest CT and blood gas analysis were monitored. Biomarkers including C-reactive protein (CRP), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8(IL-8), white blood cell and neutrophil counts were determined.. After treatment, the levels of CRP[(109 ± 24) vs (40 ± 13) mg/L], IFN-γ [(151 ± 28) vs (42 ± 12) ng/L], TNF-α [(301 ± 45) vs (118 ± 28) pg/L], IL-6 [(214 ± 45) vs (76 ± 23) pg/L], IL-8[(590 ± 121) vs (159 ± 60) pg/L], white blood cell count [(14.3 ± 5.7)×10⁹/L vs (8.5 ± 2.7)×10⁹/L], and neutrophil percentage [(91.3 ± 3.1)% vs (75.3 ± 2.6)%] decreased significantly in the antibiotic + CRRT group (P < 0.05) as compared to the antibiotic treatment group. In the antibiotic + CRRT group, blood gas showed significant improvement in pH [(7.30 ± 0.12) to (7.37 ± 0.18)], SaO₂ [(80.6 ± 7.6)% to (91.9 ± 7.3)%] and PaO₂ (41 ± 6) mm Hg (1 mm Hg = 0.133 kPa) to (71 ± 9) mm Hg. The patients' condition and chest CT abnormalities also improved more rapidly in the antibiotic + CRRT group. The 6-month survival was increased by 12.9% in the antibiotic + CRRT group as compared to the antibiotic group (P < 0.05).. CRRT is effective in clearance of inflammatory mediators and may increase survival of severe pneumonia patients receiving long-term treatment of immunosuppressants.

Topics: Adult; Aged; Anti-Bacterial Agents; C-Reactive Protein; Female; Glucocorticoids; Hemofiltration; Humans; Immunosuppressive Agents; Interferon-gamma; Interleukin-6; Interleukin-8; Kidney Diseases; Lung; Male; Middle Aged; Pneumonia; Prognosis; Radiography; Renal Replacement Therapy; Retrospective Studies; Treatment Outcome; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the regulatory role of the c-JUN N-terminal kinase (JNK) pathway on interleukin (IL)-8 and tumor necrosis factor (TNF)-α expression in alveolar macrophages (AMs) of injured lung. Lung injury was induced in the New Zealand white rabbit by applying continuous mechanical ventilation with or without inhibitor of JNK (SP600125), p38 (SB203580), or ERK (PD98059). Non-ventilated rabbits (controls) were compared with the different ventilation-days groups, and untreated rabbits ventilated for 3 days (controls) were compared with the different inhibitor groups. We found that mechanical ventilation caused significant decreases in partial pressures of carbon dioxide (pCO2) and oxygen (pO2) of untreated rabbits (all times, P<0.05), but the inhibitor-treated groups showed no change in either blood-gas indicator (all times, P>0.05). Mechanical ventilation caused time-dependent increases in mRNA and protein levels of TNF-α and IL-8 in AMs and in serum of untreated rabbits, with the peak levels occurring at day 3 of ventilation. The SP600125-treated group showed significantly decreased TNF-α expression, but no significant change in IL-8 expression. Neither the SB203580- nor PD98059-treated groups showed any significant change in TNF-α or IL-8 expression. MAPKs' inhibitors could reduce mechanical ventilation-induced inflammation, and SP600125 produced the most robust decrease in inflammation. Mechanical ventilation-induced lung injury stimulates IL-8 and TNF-α expression in rabbit AMs in a time-dependent manner. The JNK pathway plays an important role in mechanical ventilation-stimulated TNF-α expression in AMs, but the injury-stimulated IL-8 expression may be regulated by other signaling pathways.

Topics: Animals; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lung; Macrophages, Alveolar; Male; Pneumonia; Rabbits; Respiration, Artificial; Tumor Necrosis Factor-alpha

This study was designed to determine the effects of peroxisome proliferator-activated receptor-gamma (PPARγ) on airway inflammatory response to cigarette smoke (CS) exposure.. For the in vivo experiments, 50 male Wistar rats were randomly assigned to one of four groups and were exposed to CS and pretreatment with a PPARγ agonist, rosiglitazone or a vehicle (saline). PPARγ antagonist bisphenol A diglycidyl ether (BADGE) or saline was administered before rosiglitazone treatment. Leukotriene B4 (LTB4) and interleukin-8 (IL-8) were measured by enzyme-linked immunosorbent assay. PPARγ and toll-like receptor 4 (TLR4) expression levels were assessed by immunohistochemistry and real-time polymerase chain reaction. For the in vitro experiments, human bronchial epithelial cells were stimulated with CS or phosphate buffer saline, pretreated with PPARγ agonist rosiglitazone or 15-deoxy-(Δ12,14)-PG J2 before CS exposure. BADGE was administered prior to the agonist treatment. PPARγ, TLR4 and inhibitor of κB (IκBα) expression levels were assessed by Western bot.. CS exposure decreased PPARγ expression, as well as increased IL-8, LTB4 and TLR4 expression levels in bronchial epithelial cells in vivo and in vitro. Moreover, PPARγ ligands counteracted CS-induced airway inflammation by reducing IL-8 and LTB4 expression levels that are associated with TLR4 and nuclear factor-kappa B (NF-κB).. CS exposure increased the pro-inflammatory activity of bronchial epithelial cells by affecting PPARγ expression. Moreover, PPARγ may play a significant role as a modulator of the TLR4-dependent inflammatory pathway through NF-κB in bronchial epithelial cells.

Topics: Animals; Benzhydryl Compounds; Bronchi; Cell Survival; Cells, Cultured; Disease Models, Animal; Down-Regulation; Epithelial Cells; Epoxy Compounds; In Vitro Techniques; Interleukin-8; Leukotriene B4; Male; NF-kappa B; Pneumonia; PPAR gamma; Rats; Rats, Wistar; Rosiglitazone; Smoking; Thiazolidinediones; Toll-Like Receptor 4; Up-Regulation

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) suppress ambient particulate matter, 10 μm (PM(10) )-induced inflammatory response in vitro. The aim of this study was to determine the effect of statins on PM(10) -induced lung inflammation in vivo.. New Zealand white rabbits were exposed to either PM(10) (1.0 mg/kg) or saline by direct intratracheal instillation three times a week for 4 weeks lovastatin 5.0 mg/kg/d. BAL fluid was assessed for cell counts and proinflammatory cytokine levels. Lung inflammation was quantified using immunohistochemical techniques and morphometric methods. Ex vivo phagocytosis assay of alveolar macrophages using PM 10 particles was performed. Distribution of PM(10) particles in lung tissues and draining lymph nodes was quantified morphometrically to evaluate the clearance of PM(10) particles.. PM(10) exposure increased the production of IL-6 and IL-8, promoted the recruitment of macrophages and polymorphonuclear leukocytes into the lung, and activated these recruited leukocytes. Lovastatin significantly suppressed all these effects. Lovastatin increased the phagocytic activity of macrophages and promoted the migration of PM 10 -laden macrophages to the regional lymph nodes.. Lovastatin attenuates the PM(10) -induced recruitment and activation of alveolar macrophages and polymorphonuclear leukocytes, reduces local proinflammatory cytokine production, and promotes the clearance of PM(10) particles from lung tissues to regional lymph nodes. These novel pleiotropic properties of statins are most likely to contribute to the downregulation of PM(10) -induced lung inflammation.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cell Movement; Disease Models, Animal; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Interleukin-6; Interleukin-8; Lovastatin; Lung; Macrophages, Alveolar; Neutrophils; Particulate Matter; Phagocytosis; Pneumonia; Rabbits

Reports on adverse health effects related to occupational exposure to toner powder are still inconclusive. Therefore, we have previously conducted an in vitro-study to characterize the genotoxic potential of three commercially available black printer toner powders in A549 lung cells. In these cell-based assays it was clearly demonstrated that the tested toner powders damage DNA and induce micronucleus (MN) formation. Here, we have studied the cytotoxic and proinflammatory potential of these three types of printer toner particles and the influence of ROS and NF-κB induction in order to unravel the underlying mechanisms. A549 cells were exposed to various concentrations of printer toner particle suspensions for 24 h. The toner particles were observed to exert significant cytotoxic effects in the WST-1 and neutral red (NR)-assays, although to a varying extent. Caspase 3/7 activity increased, while the mitochondrial membrane potential (MMP) was not affected. Particles of all three printer toner powders induced concentration-dependent formation of reactive oxygen species (ROS), as measured in the DCFH-DA assay. Furthermore, toner particle exposure enhanced interleukin-6 and interleukin-8 production, which is in agreement with activation of the transcription factor NF-κB in A549 cells shown by the electrophoretic mobility shift assay (EMSA). Therefore, it can be concluded that exposure of A549 lung cells to three selected printer toner powders caused oxidative stress through induction of ROS. Increased ROS formation may trigger genotoxic effects and activate proinflammatory pathways.

Topics: Caspases; Cell Line, Tumor; Cell Survival; Electrophoretic Mobility Shift Assay; Ferric Compounds; Humans; Interleukin-6; Interleukin-8; Lung; Membrane Potential, Mitochondrial; Neutral Red; NF-kappa B; Oxidative Stress; Particle Size; Pneumonia; Reactive Oxygen Species; Tetrazolium Salts

Local inflammatory responses in community-acquired pneumonia (CAP) remain insufficiently elucidated, especially in patients with nonsevere CAP. In this study we determined local and systemic cytokine responses in CAP patients and correlated these with disease severity and other clinical parameters. Levels of interleukin (IL)-6, IL-8, IL-10, IL-1β, tumour necrosis factor-α, interferon (IFN)-γ, IL-22, IL-17A and IL-4 were determined in bronchoalveolar lavage fluid and serum of 20 CAP patients upon admission and 10 healthy individuals. Systemic cytokine levels were also measured on days 7 and 30. In bronchoalveolar lavage fluid of CAP patients, levels of IL-6, IL-8 and IFN-γ were significantly increased compared with healthy individuals, but no correlations with disease severity were found. Systemic levels of IL-6, IL-10 and IFN-γ were significantly higher in severe CAP patients than in nonsevere CAP patients and healthy individuals. Moreover, these cytokines showed a significant correlation with the pneumonia severity index. In the total group of CAP patients, systemic IL-8 and IL-22 levels were also increased compared with healthy individuals. We therefore conclude that IL-6, IL-10 and IFN-γ are important cytokines in CAP, although differences in disease severity upon admission are only reflected by systemic levels of these cytokines.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Case-Control Studies; Community-Acquired Infections; Cytokines; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation; Interferon-gamma; Interleukin-22; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Pneumonia; Prospective Studies

Invasive fungal infections (IFIs) are a major cause of death in organ transplant patients. The murine hydrocortisone-mediated immunosuppression model of pulmonary aspergillosis is commonly used to characterise IFIs in these patients. However, this model does not take into account the effects of calcineurin inhibitors on transplant immunity to IFIs or the fungal calcineurin pathway, which is required for both virulence and antifungal drug resistance. To address these two issues, a new and clinically relevant transplant immunosuppression model of tacrolimus (FK506) and hydrocortisone-associated pulmonary aspergillosis was developed. We first characterised IFIs in 406 patients with a lung transplant. This showed that all of the patients with pulmonary aspergillosis were immunosuppressed with calcineurin inhibitors and steroids. Murine pharmacokinetic studies demonstrated that an ideal dose of 1 mg/kg/day of FK506 intraperitoneally produced blood trough levels in the human therapeutic range (5-12 ng/ml). There was increased mortality from pulmonary aspergillosis in a transplant-relevant immunosuppression model using both FK506 and hydrocortisone as compared with immunosuppression using hydrocortisone only. Lung histopathology showed neutrophil invasion and tracheobronchitis that was associated with reduced lung tumour necrosis factor-α (TNFα), JE (homologue of human MCP-1) and KC (homologue of human IL-8) at 24 hours, but increased lung TNFα, JE and KC at 48 hours when fungal burden was high. Furthermore, FK506 directly impaired fungal killing in alveolar macrophages in vitro, with FK506-mediated inhibition of the radial growth of Aspergillus fumigatus in vitro occurring at the low concentration of 5 ng/ml. Taken together, these findings show that the immunosuppressive activity of FK506 outweighs its antifungal activity in vivo. These observations demonstrate that FK506 impairs innate immune responses and leads to an incremental increase in susceptibility to IFIs when it is combined with steroids. This new and clinically relevant mouse model of invasive aspergillosis is a valuable addition to the further study of both fungal immunity and antifungal therapy in organ transplantation.

Topics: Animals; Aspergillus fumigatus; Chemokine CCL2; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Hydrocortisone; Immunosuppression Therapy; Immunosuppressive Agents; Injections, Intraperitoneal; Interleukin-8; Lung Transplantation; Male; Mice; Pneumonia; Pulmonary Aspergillosis; Risk Factors; Steroids; Survival Analysis; Tacrolimus; Tumor Necrosis Factor-alpha

To investigate the relationship among angiogenic cytokines, fibrinolytic activity and effusion size in parapneumonic effusion (PPE) and their clinical importance.. From January 2008 through December 2010, 26 uncomplicated (UPPE) and 38 complicated (CPPE) PPE were studied. Based on chest ultrasonography, there were non-loculated in 30, uni-loculated in 12, and multi-loculated effusions in 22 patients. The effusion size radiological scores, and effusion vascular endothelial growth factor (VEGF), interleukin (IL)-8, plasminogen activator inhibitor type-1 (PAI-1) and tissue type plasminogen activator (tPA) were measured on admission. Treatment outcome and pleural fibrosis, defined as radiological residual pleural thickening (RPT), were assessed at 6-month follow-up.. The effusion size and effusion VEGF, IL-8 and PAI-1/tPA ratio were significantly higher in CPPE than in UPPE, and significantly higher in multi-loculated PPE than in non-locualted and uni-loculated PPE, respectively. VEGF (cutoff value 1975 pg/ml) and IL-8 (cutoff value 1937 pg/ml) seemed best to discriminate between UPPE and CPPE. VEGF, IL-8 and effusion size correlated positively with PAI-1/tPA ratio in both UPPE and CPPE. Moreover, the level of VEGF, but not IL-8, correlated positively with effusion size in all patients (r = 0.79, p<0.001) and in UPPE (r = 0.64, p<0.001) and CPPE (r = 0.71, p<0.001) groups. The patients with higher VEGF or greater effusion were prone to have medical treatment failure (n = 10; VEGF, odds ratio 1.01, p = 0.02; effusion size, odds ratio 1.26, p = 0.01). Additionally, ten patients with RPT had larger effusion size and higher levels of VEGF and PAI-1/tPA ratio than did those without.. In PPE, VEGF and IL-8 levels are valuable to identify CPPE, and higher VEGF level or larger effusion is associated with decreased fibrinolytic activity, development of pleural loculation and fibrosis, and higher risk of medical treatment failure.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cytokines; Female; Fibrinolysis; Follow-Up Studies; Humans; Interleukin-8; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Pleura; Pleural Effusion; Pneumonia; Tissue Plasminogen Activator; Treatment Outcome; Vascular Endothelial Growth Factor A

Acute lung injury is a frequent complication after cardiopulmonary bypass (CPB). Recent studies have reported that NF-κB plays an important role in the pathogenesis of post-CPB pulmonary dysfunction. Several signaling pathways, including the TLR4 pathway, induce NF-κB leading to an inflammatory response. We designed this study to determine whether or not curcumin inhibits TLR4 and MyD88 protein levels and ameliorates lung inflammatory injury in a rat CPB model.. Sprague-Dawley rats were randomly divided into the following five groups (n = 12): sham; control (CPB); vehicle; low-dose curcumin (L-Cur); and high-dose curcumin (H-Cur). The percutaneous beating heart CPB model of rat was established. Animals were pretreated with a single intraperitoneal injection of vehicle, L-Cur (50 mg/kg), or H-Cur (200 mg/kg) 2 h prior to CPB. Blood were sampled at various time points, then lung tissues and bronchoalveolar lavage fluid were harvested 24 h after CPB.. CPB induced a marked increase in the concentrations of interleukin-8, tumor necrosis factor-α, and matrix metalloproteinase-9 in plasma, bronchoalveolar lavage fluid, and lung tissues (P < 0.05 versus sham group), whereas curcumin pretreatment reduced these inflammatory markers. Curcumin had effective inhibitory effects on the expression of TLR4, MyD88, and NF-κB in lung tissues 24 h post-CPB (P < 0.05 versus vehicle group). Administration of curcumin remarkably decreased the lung injury score (L-Cur versus vehicle group, P = 0.024; H-Cur versus vehicle group, P = 0.013).. Curcumin may be an alternative therapy for protecting CPB-induced lung injury by suppressing the expression of inflammatory cytokines. This anti-inflammatory effect of curcumin is partly related to the inhibition of TLR4, MyD88, and NF-κB.

Topics: Animals; Cardiopulmonary Bypass; Curcumin; Interleukin-8; Male; Matrix Metalloproteinase 9; Myeloid Differentiation Factor 88; NF-kappa B; Pneumonia; Rats; Rats, Sprague-Dawley; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

In addition to cigarette smoking, alcohol exposure is also associated with increased lung infections and decreased mucociliary clearance. However, little research has been conducted on the combination effects of alcohol and cigarette smoke on lungs. Previously, we have demonstrated in a mouse model that the combination of cigarette smoke and alcohol exposure results in the formation of a very stable hybrid malondialdehyde-acetaldehyde (MAA)-adducted protein in the lung. In in vitro studies, MAA-adducted protein stimulates bronchial epithelial cell interleukin-8 (IL-8) via the activation of protein kinase C epsilon (PKCɛ). We hypothesized that direct MAA-adducted protein exposure in the lungs would mimic such a combination of smoke and alcohol exposure leading to airway inflammation. To test this hypothesis, C57BL/6J female mice were intranasally instilled with either saline, 30μL of 50μg/mL bovine serum albumin (BSA)-MAA, or unadducted BSA for up to 3 weeks. Likewise, human lung surfactant proteins A and D (SPA and SPD) were purified from human pulmonary proteinosis lung lavage fluid and successfully MAA-adducted in vitro. Similar to BSA-MAA, SPD-MAA was instilled into mouse lungs. Lungs were necropsied and assayed for histopathology, PKCɛ activation, and lung lavage chemokines. In control mice instilled with saline, normal lungs had few inflammatory cells. No significant effects were observed in unadducted BSA- or SPD-instilled mice. However, when mice were instilled with BSA-MAA or SPD-MAA for 3 weeks, a significant peribronchiolar localization of inflammatory cells was observed. Both BSA-MAA and SPD-MAA stimulated increased lung lavage neutrophils and caused a significant elevation in the chemokine, keratinocyte chemokine, which is a functional homologue to human IL-8. Likewise, MAA-adducted protein stimulated the activation of airway and lung slice PKCɛ. These data support that the MAA-adducted protein induces a proinflammatory response in the lungs and that the lung surfactant protein is a biologically relevant target for malondialdehyde and acetaldehyde adduction. These data further implicate MAA-adduct formation as a potential mechanism for smoke- and alcohol-induced lung injury.

Topics: Acetaldehyde; Animals; Chemokines; Ethanol; Female; Humans; Inflammation; Inhalation Exposure; Interleukin-8; Lung Injury; Malondialdehyde; Mice; Pneumonia; Protein Kinase C; Pulmonary Surfactant-Associated Proteins; Smoke; Smoke Inhalation Injury

Airway epithelial cells in the lung are the first line of defense against pathogens and environmental pollutants. Inhalation of the environmental pollutant cadmium has been linked to the development of lung cancer and chronic obstructive pulmonary disease, which are diseases characterized by chronic inflammation. To address the role of airway epithelial cells in cadmium-induced lung inflammation, we investigated how cadmium regulates secretion of interleukin 8 (IL-8) by airway epithelial cells. We show that exposure of human airway epithelial cells to subtoxic doses of cadmium in vitro promotes a characteristic inflammatory cytokine response consisting of IL-8, but not IL-1β or tumor necrosis factor-alpha. We also found that intranasal delivery of cadmium increases lung levels of the murine IL-8 homologs macrophage inflammatory protein-2 and keracinocyte-derived chemokine and results in an influx of Gr1+ cells into the lung. We determined that inhibition of the nuclear factor-κB (NF-κB) pathway had no effect on cadmium-induced IL-8 secretion by human airway epithelial cells, suggesting that IL-8 production was mediated through an NF-κB-independent pathway. Mitogen-activated protein kinases (MAPKs) are often involved in proinflammatory signaling. Cadmium could activate the main MAPKs (i.e., p38, JNK, and Erk1/2) in human airway epithelial cells. However, only pharmacological inhibition of Erk1/2 pathway or knockdown of the expression of Erk1 and Erk2 using small interfering RNAs suppressed secretion of IL-8 induced by cadmium. Our findings identify cadmium as a potent activator of the proinflammatory cytokine IL-8 in lung epithelial cells and reveal for the first time the role of an NF-κB-independent but Erk1/2-dependent pathway in cadmium-induced lung inflammation.

Topics: Air Pollutants; Animals; Bronchi; Cadmium Compounds; Cell Line; Dose-Response Relationship, Drug; Epithelial Cells; Female; Humans; Inflammation Mediators; Inhalation Exposure; Interleukin-6; Interleukin-8; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Pneumonia; Protein Kinase Inhibitors; RNA Interference; Signal Transduction; Sulfates; Time Factors; Transfection

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

Intra-amniotic (IA) lipopolysaccharide (LPS) induces intrauterine and fetal lung inflammation and increases lung surfactant and compliance in preterm sheep; however, the mechanisms are unknown. Prostaglandins (PGs) are inflammatory mediators, and PGE(2) has established roles in fetal lung surfactant production. The aim of our first study was to determine PGE(2) concentrations in response to IA LPS and pulmonary gene expression for PG synthetic [prostaglandin H synthase-2 (PGHS-2) and PGE synthase (PGES)] and PG-metabolizing [prostaglandin dehydrogenase (PGDH)] enzymes and PGE(2) receptors. Our second study aimed to block LPS-induced increases in PGE(2) with a PGHS-2 inhibitor (nimesulide) and determine lung inflammation and surfactant protein mRNA expression. Pregnant ewes received an IA saline or LPS injection at 118 days of gestation. In study 1, fetal plasma and amniotic fluid were sampled before and at 2, 4, 6, 12, and 24 h after injection and then daily, and fetuses were delivered 2 or 7 days later. Amniotic fluid PGE(2) concentrations increased (P < 0.05) 12 h and 3-6 days after LPS. Fetal lung PGHS-2 mRNA and PGES mRNA increased 2 (P = 0.0084) and 7 (P = 0.014) days after LPS, respectively. In study 2, maternal intravenous nimesulide or vehicle infusion began immediately before LPS or saline injection and continued until delivery 2 days later. Nimesulide inhibited LPS-induced increases in PGE(2) and decreased fetal lung IL-1β and IL-8 mRNA (P ≤ 0.002) without altering lung inflammatory cell infiltration. Nimesulide decreased surfactant protein (SP)-A (P = 0.05), -B (P = 0.05), and -D (P = 0.0015) but increased SP-C mRNA (P = 0.023). Thus PGHS-2 mediates, at least in part, fetal pulmonary responses to inflammation.

Topics: Amniotic Fluid; Animals; Chorioamnionitis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Female; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Lung; Lung Compliance; Pneumonia; Pregnancy; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants; Random Allocation; RNA, Messenger; Sheep; Sulfonamides; Uterus

Exposure to diesel exhaust particles (DEP) results in lung inflammation. Regular aerobic exercise improves the inflammatory status in different pulmonary diseases. However, the effects of long-term aerobic exercise on the pulmonary response to DEP have not been investigated. The present study evaluated the effect of aerobic conditioning on the pulmonary inflammatory and oxidative responses of mice exposed to DEP.. BALB/c mice were subjected to aerobic exercise five times per week for 5 wk, concomitantly with exposure to DEP (3 mg·mL(-1); 10 μL per mouse). The levels of exhaled nitric oxide, reactive oxygen species, cellularity, interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were analyzed in bronchoalveolar lavage fluid, and the density of neutrophils and the volume proportion of collagen fibers were measured in the lung parenchyma. The cellular density of leukocytes expressing IL-1β, keratinocyte chemoattractant (KC), and TNF-α in lung parenchyma was evaluated with immunohistochemistry. The levels of IL-1β, KC, and TNF-α were also evaluated in the serum.. Aerobic exercise inhibited the DEP-induced increase in the levels of reactive oxygen species (P < 0.05); exhaled nitric oxide (P < 0.01); total (P < 0.01) and differential cells (P < 0.01); IL-6 and TNF-α levels in bronchoalveolar lavage fluid (P < 0.05); the level of neutrophils (P < 0.001); collagen density in the lung parenchyma (P < 0.05); the levels of IL-6, KC, and TNF-α in plasma (P < 0.05); and the expression of IL-1β, KC, and TNF-α by leukocytes in the lung parenchyma (P < 0.01).. We conclude that long-term aerobic exercise presents protective effects in a mouse model of DEP-induced lung inflammation. Our results indicate a need for human studies that evaluate the pulmonary responses to aerobic exercise chronically performed in polluted areas.

Topics: Air Pollutants; Animals; Bronchoalveolar Lavage Fluid; Interleukin-6; Interleukin-8; Mice; Mice, Inbred BALB C; Oxidative Stress; Physical Conditioning, Animal; Physical Exertion; Pneumonia; Reactive Oxygen Species; Tumor Necrosis Factor-alpha; Vehicle Emissions

Proteoglycans (PGs) and their associated glycosaminoglycan side chains are effectors of inflammation, but little is known about changes to the composition of PGs in response to lung infection or injury. The goals of this study were to identify changes to heparan sulfate PGs in a mouse model of gram-negative pneumonia, to identify the Toll-like receptor adaptor molecules responsible for these changes, and to determine the role of the heparan sulfate PG in the innate immune response in the lungs. We treated mice with intratracheal LPS, a component of the cell wall of gram-negative bacteria, to model gram-negative pneumonia. Mice treated with intratracheal LPS had a rapid and selective increase in syndecan-4 mRNA that was regulated through MyD88-dependent mechanisms, whereas expression of several other PGs was not affected. To determine the role of syndecan-4 in the inflammatory response, we exposed mice deficient in syndecan-4 to LPS and found a significant increase in neutrophil numbers and amounts of CXC-chemokines and total protein in bronchoalveolar lavage fluid. In studies performed in vitro, macrophages and epithelial cells treated with LPS had increased expression of syndecan-4. Studies performed using BEAS-2B cells showed that pretreatment with heparin and syndecan-4 decreased the expression of CXCL8 mRNA in response to LPS and TNF-α. These findings indicate that the early inflammatory response to LPS involves marked up-regulation of syndecan-4, which functions to limit the extent of pulmonary inflammation and lung injury.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cells, Cultured; Epithelial Cells; Heparan Sulfate Proteoglycans; Heparin, Low-Molecular-Weight; Immunity, Innate; Interleukin-8; Lipopolysaccharides; Lung; Lung Injury; Macrophages; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Neutrophils; Pneumonia; Pneumonia, Bacterial; RNA, Messenger; Syndecan-4; Tumor Necrosis Factor-alpha; Up-Regulation

Cystic fibrosis (CF) lung disease is characterized by structural changes and remodeling in airway architecture and lung parenchyma. Neutrophilic inflammation and infection lead to injury and breakdown of airway matrix constituents, including elastin. The non-invasive measurement of urinary desmosine (UDes), a breakdown product of elastin, may be reflective of ongoing lung injury and may serve as a biomarker of active short-term damage during pulmonary exacerbation. Our objectives were to measure desmosine in the urine of CF patients hospitalized for treatment of a pulmonary exacerbation and to explore the correlation between desmosine concentration and other markers of clinical improvement, including lung function and inflammatory mediators.. Urine and blood samples plus lung function measurements were collected at up to three points during hospitalization for treatment of a CF pulmonary exacerbation. We used a repeated measures model, adjusted for age and time between measurements, to compare log transformed urine desmosine concentrations across multiple time points and to correlate those concentrations with related clinical variables. Change in UDes concentration was investigated using a statistical model that incorporated normalization factors to account for variations in urinary concentration.. Desmosine was measured by radioimmunoassay (RIA) in 155 spot urine samples from 53 CF patients hospitalized for 63 pulmonary exacerbations (range of results: 0-235 pmol Des/ml). Specific gravity (SG) adjusted UDes concentration decreased significantly during admission for CF pulmonary exacerbation, P < 0.01 (average length of stay = 11 days). No correlation was observed between UDes concentration and lung function or inflammatory markers.. UDes decreased significantly following treatment for an acute pulmonary exacerbation and may be a useful biomarker of short-term injury to the CF lung. Further investigation is needed to evaluate the utility of UDes concentration in the long-term progression of CF lung disease.

Topics: Airway Remodeling; Biomarkers; C-Reactive Protein; Cohort Studies; Cystic Fibrosis; Desmosine; Disease Progression; Elastin; Female; Humans; Interleukin-8; Lung Injury; Male; Pneumonia; Prospective Studies; Respiratory Function Tests

Recently, Achromobacter xylosoxidans has been related to chronic lung diseases in patients suffering from cystic fibrosis (CF), but its involvement has not been elucidated. Some virulence properties of A. xylosoxidans isolated from Brazilian patients with CF were revealed in this work.. This study examined the production of a cytotoxic factor of A. xylosoxidans capable of stimulating the secretion of inflammatory cytokines (IL-6 and IL-8) from lung mucoepidermoid carcinoma cells (NCI-H292). The cytokines were measured using enzyme-linked immunosorbent (ELISA) assays. To investigate whether the cytotoxic factors may be endotoxins, they were treated with polymyxin B.. The culture supernatants of all A. xylosoxidans produced a heat stable, active cytotoxin in NCI-H292 cells capable of leading to intracellular vacuoles and subsequent cell contact loss, chromatin condensation, a picnotic nucleus and cell death. There was a higher concentration of proinflammatory cytokines in the NCI-H292 cells after 24 h of incubation, with the fraction greater than 50 kDa from the culture supernatant. The cytotoxin activity remained even after treatment with polymyxin B, which suggested that the release of IL-6 and IL-8 was not stimulated by lipopolysaccharide (LPS).. The cytotoxic factor produced by A. xylosoxidans may represent an important virulence factor, which when associated with CF chronic lung inflammation, may cause tissue damage and decline of lung function.

Topics: Achromobacter denitrificans; Brazil; Carcinoma, Mucoepidermoid; Cell Line, Tumor; Cell Survival; Culture Media, Conditioned; Cystic Fibrosis; Endotoxins; Gram-Negative Bacterial Infections; Humans; In Vitro Techniques; Interleukin-6; Interleukin-8; Pneumonia; Sputum; Virulence

Heaves, an obstructive neutrophilic airway inflammation of horses, is triggered by dust components such as endotoxin and has similarities to human asthma. Pulmonary intravascular macrophages (PIMs) increase horses' sensitivity to endotoxin-induced lung inflammation; however, their role in an airborne pathology remains unknown. Therefore, we investigated the role of PIMs in the development of heaves in horses. Clinical and inflammatory responses were evaluated following induction of heaves by moldy hay exposure and PIM depletion with gadolinium chloride (GC). Mares (N = 9) were exposed to four treatments: alfalfa cubes (Cb), alfalfa cubes + GC (Cb-GC), moldy hay (MH), and moldy hay + GC (MH-GC). Clinical scores and neutrophil concentrations in bronchoalveolar lavage (BAL) fluid were higher when mares received MH compared with MH-GC. BAL cells from MH-GC-treated mares had significantly lower IL-8 and TLR4 mRNA expression compared with MH-treated mares. In vitro LPS challenge significantly increased IL-8 but not TLR4 mRNA expression in BAL cells recovered from horses fed with MH, but not from the MH-GC treatment. In summary, PIM depletion attenuated clinical scores, reduced the alveolar migration of neutrophils, and decreased the expression of proinflammatory molecules in BAL cells of heaves horses, suggesting a proinflammatory role of PIMs in the development of airborne pathology.

Topics: Airway Obstruction; Animals; Asthma; Blotting, Western; Bronchoalveolar Lavage; Dust; Endotoxins; Female; Horse Diseases; Horses; Humans; Interleukin-8; Lipopolysaccharides; Macrophages, Alveolar; Neutrophils; Pneumonia; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Heavy smoking can induce airway inflammation and emphysema. Macrolides can modulate inflammation and effector T-cell response in the lungs. However, there is no information on whether erythromycin can modulate regulatory T-cell (Treg) response. This study is aimed at examining the impact of erythromycin on Treg response in the lungs in a rat model of smoking-induced emphysema. Male Wistar rats were exposed to normal air or cigarette smoking daily for 12 weeks and treated by gavage with 100 mg/kg of erythromycin or saline daily beginning at the forth week for nine weeks. The lung inflammation and the numbers of inflammatory infiltrates in bronchoalveolar lavage fluid (BALF) were characterized. The frequency, the number of Tregs, and the levels of Foxp3 expression in the lungs and IL-8, IL-35, and TNF-α in BALF were determined by flow cytometry, RT-PCR and ELISA, respectively. Treatment with erythromycin reduced smoking-induced inflammatory infiltrates, the levels of IL-8 and TNF-α in the BALF and lung damages but increased the numbers of CD4+Foxp3+ Tregs and the levels of Foxp3 transcription in the lungs, accompanied by increased levels of IL-35 in the BALF of rats. Our novel data indicated that erythromycin enhanced Treg responses, associated with the inhibition of smoking-induced inflammation in the lungs of rats.

Topics: Animals; CD4-Positive T-Lymphocytes; Enzyme-Linked Immunosorbent Assay; Erythromycin; Forkhead Transcription Factors; Interleukin-8; Pneumonia; Rats; Reverse Transcriptase Polymerase Chain Reaction; Smoking; Tumor Necrosis Factor-alpha

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

Cigarette smoke (CS), the major cause of chronic obstructive pulmonary disease, contains a variety of oxidative components that were implicated in the regulation of Src homology domain 2-containing protein tyrosine phosphatase 2 (Shp2) activity. However, the contribution of Shp2 enzyme to chronic obstructive pulmonary disease pathogenesis remains unclear. We investigated the role of Shp2 enzyme in blockading CS-induced pulmonary inflammation. Shp2 levels were assessed in vivo and in vitro. Mice (C57BL/6) or pulmonary epithelial cells (NCI-H292) were exposed to CS or cigarette smoke extract (CSE) to induce acute injury and inflammation. Lungs of smoking mice showed increased levels of Shp2, compared with those of controls. Treatment of lung epithelial cells with CSE showed elevated levels of Shp2 associated with the increased release of IL-8. Selective inhibition or knockdown of Shp2 resulted in decreased IL-8 release in response to CSE treatment in pulmonary epithelial cells. In comparison with CS-exposed wild-type mice, selective inhibition or conditional knockout of Shp2 in lung epithelia reduced IL-8 release and pulmonary inflammation in CS-exposed mice. In vitro biochemical data correlate CSE-mediated IL-8 release with Shp2-regulated epidermal growth factor receptor/Grb-2-associated binders/MAPK signaling. Our data suggest an important role for Shp2 in the pathological alteration associated with CS-mediated inflammation. Shp2 may be a potential target for therapeutic intervention for inflammation in CS-induced pulmonary diseases.

Topics: Acute Disease; Animals; Cell Line; Disease Models, Animal; Inflammation; Interleukin-8; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pneumonia; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pulmonary Alveoli; Respiratory Mucosa; Smoking; Tobacco Products

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

Severe community- and hospital-acquired pneumonia is caused by Legionella pneumophila. Lung airway and alveolar epithelial cells comprise an important sentinel system in airborne infections. Although interleukin (IL)-6 is known as a central regulator of the immune response in pneumonia, its regulation in the lung is widely unknown. Herein, we demonstrate that different L. pneumophila strains induce delayed expression of IL-6 in comparison with IL-8 by human lung epithelial cells. IL-6 expression depended, at early time points, on flagellin recognition by Toll-like receptor (TLR)5, activity of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1 and p38 mitogen-activated protein (MAP) kinase, and, at later time points, on the type-IV secretion system. In the same manner, but more rapidly, the recently described transcription factor IκBζ was induced by Legionella infection and, binding to the nuclear factor (NF)-κB subunit p50 - recruited to the il6 promoter together with CCAAT-enhancer-binding protein β and phosphorylated activator protein-1 subunit cJun. Similarly, histone modifications and NF-κB subunit p65/RelA appeared at the iκbζ and subsequently at the il6 gene promoter, thereby initiating gene expression. Gene silencing of IκBζ reduced Legionella-related IL-6 expression by 41%. Overall, these data indicate a sequence of flagellin/TLR5- and type IV-dependent IκBζ expression, recruitment of IκBζ/p50 to the il6 promoter, chromatin remodelling and subsequent IL-6 transcription in L. pneumophila-infected lung epithelial cells.

Topics: Cell Line, Tumor; Chromatin; Epithelial Cells; Flagellin; Gene Expression Regulation; Humans; I-kappa B Kinase; Interleukin-6; Interleukin-8; Legionella pneumophila; Legionellosis; Lung; NF-kappa B; Pneumonia; Promoter Regions, Genetic

Inflammation resulting from chronic bacterial infection in the lung contributes to long-term pulmonary complications in chronic pulmonary infections such as cystic fibrosis. Aerosol administration of levofloxacin as in the form of the investigational formulation MP-376 results in higher concentrations in lung tissues that are higher than those that can be attained with oral or intravenous dosing of levofloxacin. The objective of this study was to evaluate the effect of high concentrations of levofloxacin achieved with aerosol administration of MP-376 on proinflammatory cytokine secretion by immortalized human bronchial epithelia cells in vitro. Additionally, we investigated the potential mechanisms of the immunomodulatory effect of levofloxacin. In vitro studies in human lung epithelial cell lines showed that levofloxacin led to a dose-related reduction in IL-6 and IL-8 concentrations, with 300 μg mL(-1) resulting in the reduction of levels of IL-6 by fourfold and IL-8 by twofold (P<0.05); in contrast, tobramycin increased IL-6 levels by 50%, but had no effect on IL-8. Levofloxacin treatment did not affect the cytokine mRNA level and nuclear factor-κB-dependent promoter activity. These findings suggest that high concentrations of levofloxacin obtained in pulmonary tissues following the administration of aerosol MP-376 may provide additional benefits in patients with chronic pulmonary infections that are independent of its antibacterial properties.

Topics: Administration, Inhalation; Aerosols; Anti-Inflammatory Agents; Cell Line; Chronic Disease; Epithelial Cells; Gene Expression Profiling; Humans; Interleukin-6; Interleukin-8; Levofloxacin; Ofloxacin; Pneumonia; Tobramycin

Receptors for advanced glycation end-products (RAGE) are cell-surface receptors expressed by alveolar type I (ATI) epithelial cells and are implicated in mechanisms of alveolar development and sustained pulmonary inflammation.. In the present study, we tested the hypothesis that diesel particulate matter (DPM) up-regulates RAGE in rat ATI-like R3/1 cells and human primary small airway epithelial cells (SAECs), leading to an inflammatory response.. Using real-time reverse transcriptase polymerase chain reaction and immunoblotting, we found that RAGE mRNA and protein are up-regulated in cells exposed to DPM for 2 hr. Use of a luciferase reporter containing nuclear factor-κB (NF-κB) response elements revealed decreased NF-κB activation in cells transfected with small interfering RNA (siRNA) for RAGE (siRAGE) before DPM exposure compared with cells transfected with scrambled control siRNA (siControl). In addition, immunostaining revealed diminished nuclear translocation of NF-κB in DPM-exposed cells transfected with siRAGE compared with cells transfected with siControl before DPM stimulation. Enzyme-linked immunosorbent assay demonstrated that in R3/1 cells DPM induced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), two cytokines induced by NF-κB and associated with leukocyte chemotaxis during an inflammatory response. Incorporating siRAGE was sufficient to significantly decrease DPM-induced MCP-1 and IL-8 secretion compared with cells transfected with siControl.. These data offer novel insights into potential mechanisms whereby RAGE influences pulmonary inflammation exacerbated by DPM exposure. Further research may demonstrate that molecules involved in RAGE signaling are potential targets in lessening the degree of particulate matter-induced exacerbations of inflammatory lung disease.

Topics: Air Pollutants; Alveolar Epithelial Cells; Animals; Cell Line; Chemokine CCL2; Epithelial Cells; Humans; Interleukin-8; NF-kappa B; Particulate Matter; Pneumonia; Rats; Receptor for Advanced Glycation End Products; Receptors, Immunologic; RNA, Messenger; Vehicle Emissions

Microparticles (MP) are phospholipid vesicles shed by cells upon activation or apoptosis. Monocyte-derived MP upregulate the synthesis of proinflammatory mediators by lung epithelial cells; the molecular bases of such activity are unknown. Peroxisome proliferator-activated receptors (PPAR) have been demonstrated to be involved in the modulation of nuclear factor (NF)-κB transcriptional activity and inflammation. We investigated whether the upregulation of the synthesis of proinflammatory cytokines by human lung epithelial cells induced by monocyte/macrophage-derived MP involves NF-κB activation and is modulated by PPAR-γ. MP were generated by stimulation of human monocytes/macrophages with the calcium ionophore, A23187. MP were incubated with human lung epithelial cells. NF-κB translocation was assessed by electrophoretic mobility shift assay. Interleukin (IL)-8 and monocyte chemotactic protein (MCP)-1 synthesis was assessed by ELISA and RT-PCR. Stimulation of A549 alveolar cells with monocyte/macrophage-derived MP caused an increase in NF-κB activation and IL-8 and MCP-1 synthesis that was inhibited by pre-incubation with the PPAR-γ agonists, rosiglitazone and 15-deoxy-Δ12,14-prostaglandin-J2. Parallel experiments with normal human bronchial epithelial cells largely confirmed the results. The effects of PPAR-γ agonists were reversed by the specific antagonist, GW9662. Upregulation of the synthesis of proinflammatory mediators by human lung epithelial cells induced by monocyte/macrophage-derived MP is mediated by NF-κB activation through a PPAR-γ dependent pathway.

Topics: Anilides; Bronchi; Calcimycin; Cell Line; Cell-Derived Microparticles; Cells, Cultured; Chemokine CCL2; Humans; Interleukin-8; Ionophores; Monocytes; NF-kappa B; Pneumonia; PPAR gamma; Prostaglandin D2; Rosiglitazone; Thiazolidinediones; Up-Regulation

The pore-forming toxin Panton-Valentine leukocidin (PVL) is carried by community-acquired methicillin-resistant Staphylococcus aureus and associated with necrotizing pneumonia together with poor prognosis of infected patients. Although the cell-death-inducing properties of PVL have previously been examined, the pulmonary immune response to PVL is largely unknown. Using an unbiased transcriptional profiling approach, we show that PVL induces only 29 genes in mouse alveolar macrophages, which are associated with TLR signaling. Further studies indicate that PVL directly binds to TLR2 and induces immune responses via NF-κB in a TLR2, CD14, MyD88, IL-1R-associated kinase 1, and TNFR-associated factor 6-dependent manner. PVL-mediated inflammation is independent of pore formation but strongly depends on the LukS subunit and is suppressed in CD14/TLR2(-/-) cells. In vivo PVL or LukS induced a robust inflammatory response in lungs, which was diminished in CD14/TLR2(-/-) mice. These results highlight the proinflammatory properties of PVL and identify CD14/TLR2 as an essential receptor complex for PVL-induced lung inflammation.

Topics: Animals; Bacterial Toxins; Cell Line; Exotoxins; Humans; Immunity, Innate; Inflammation Mediators; Interleukin-8; Leukocidins; Lipopolysaccharide Receptors; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumonia; Signal Transduction; Staphylococcal Infections; Toll-Like Receptor 2; Up-Regulation

Cigarette smoke (CS) increases chemokine production in lung epithelial cells (LECs), but the pathways involved are not completely understood. AMP-activated protein kinase (AMPK), a crucial regulator of energy homeostasis, may modulate inflammation. Here, we show that cigarette smoke extract sequentially activated NADPH oxidase; increased intracellular reactive oxygen species (ROS) level; activated AMPK, NF-κB, and STAT3; and induced interleukin 8 (IL-8) in human LECs. Inhibition of NADPH oxidase activation by apocynin or siRNA targeting p47(phox) (a subunit of NADPH oxidase) attenuated the increased intracellular ROS level, AMPK activation, and IL-8 induction. Removal of intracellular ROS by N-acetylcysteine reduced the AMPK activation and IL-8 induction. Prevention of AMPK activation by Compound C or AMPK siRNA lessened the activation of both NF-κB and STAT3 and the induction of IL-8. Abrogation of the activation of NF-κB and STAT3 by BAY11-7085 and AG490, respectively, attenuated the IL-8 induction. We additionally show that chronic CS exposure in mice promoted AMPK phosphorylation and expression of MIP-2α (an IL-8 homolog) in LECs and lungs, as well as lung inflammation, all of which were reduced by Compound C treatment. Thus, a novel NADPH oxidase-dependent, ROS-sensitive AMPK signaling is important for CS-induced IL-8 production in LECs and possibly lung inflammation.

Topics: Acetophenones; AMP-Activated Protein Kinases; Animals; Cell Line; Humans; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Models, Animal; NADPH Oxidases; Plant Extracts; Pneumonia; Pyrazoles; Pyrimidines; Respiratory Mucosa; RNA, Small Interfering; Signal Transduction; Smoking

The chemokine receptor CCR7 regulates lymphocyte trafficking, and CCR7 deficiency induces infiltration of T and B cells adjacent to vessels in mouse lungs. Perivascular infiltration of T and B cells has also been found in human pulmonary arterial hypertension, and downregulation of the CCR7 receptor in circulating leukocytes of such patients has been observed. To investigate whether changes in the CCR7 system contribute to the pathogenesis of pulmonary hypertension, we utilized mice deficient of the CCR7 receptor. The cardiopulmonary and inflammatory responses of CCR7 depletion were evaluated in CCR7-deficient and wild-type mice. Measurements of cytokines upregulated in the animal model were also performed in patients with pulmonary hypertension and controls and in vascular smooth muscle cells. We found that mice lacking CCR7 had increased right ventricular systolic pressure, reduced pulmonary artery acceleration time, increased right ventricular/tibial length ratio, Rho kinase-mediated pulmonary vasoconstriction, and increased muscularization of distal arteries, indicating pulmonary hypertension. These mice also showed increased perivascular infiltration of leukocytes, consisting mainly of T and B cells, and increased mRNA levels of the inflammatory cytokines interleukin-12 and CX3CL1 within pulmonary tissue. Increased serum levels of interleukin-12 and CX3CL1 were also observed in patients with pulmonary hypertension, particularly in those with pulmonary hypertension associated with connective tissue disorder. In smooth muscle cells, interleukin-12 induced secretion of the angiogenic cytokine interleukin-8. We conclude that these results suggest a role for CCR7 in the development of pulmonary arterial hypertension, at least in some subgroups, possibly via pulmonary infiltration of lymphocytes and secretion of interleukin-12 and CX3CL1.

Topics: Adult; Animals; Cell Movement; Chemokine CX3CL1; Familial Primary Pulmonary Hypertension; Female; Gene Expression Regulation; Hemodynamics; Humans; Hypertension, Pulmonary; Interleukin-12; Interleukin-8; Leukocytes; Lung; Male; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Organ Size; Pneumonia; Pulmonary Artery; Receptors, CCR7; RNA, Messenger

Interleukin-4 is central to allergic pulmonary inflammatory responses, but its contribution to airway neutrophilia remains controversial. The endothelium plays a critical role in regulating leukocyte recruitment and migration during inflammation. However, its response to IL-4 is reported to either increase or decrease the production of neutrophil chemotactic factors. We hypothesized that these conflicting findings may be due to the tissue and the size of the vessels from which endothelial cells have been derived. The expression of CXCL-8 by human primary culture umbilical veins endothelial cells (HUVECs), human pulmonary artery endothelial cells (HPAECs), and human pulmonary microvascular endothelial cells (HPMECs) when stimulated with recombinant human IL-4 (rhIL-4) was studied. The chemoattractant property of the cells' supernatants for neutrophils was evaluated using Boyden chambers. The role of the nuclear factor-κB (NF-κB), and mitogen-activated protein kinases (MAPK) in IL-4-induced HPAECs was studied using Western blotting and electrophoretic mobility shift assay (EMSA). We demonstrated that IL-4 increased the mRNA expression and the protein production of CXCL-8 in HPAECs, but not in HUVECs and HPMECs. The supernatants of HAPECs stimulated by IL-4 significantly promoted neutrophils migration in a dose-dependent manner, and was significantly attenuated by an inhibitor of CXCL-8. We also found that extracellular-regulated protein kinase1/2 (ERK1/2) is activated by IL-4 in HPAECs, but not JUN-N-terminal protein kinase (JNK) or p38 MAPK pathway. Furthermore, NF-κB-DNA binding activity, phosphorylation of IκBα and p65 levels were not affected by rhIL-4 in HAPECs. These findings indicate marked functional differences in the response of micro and macro-ECs to IL-4. ERK1/2, rather than NF-κB, JNK and p38 MAPK signaling, plays a role in IL-4 induced chemokine activation. Our results suggest that inhibition of ERK1/2 may be a possible target for airway neutrophilia in allergic lung diseases.

Topics: Blotting, Western; Cells, Cultured; Chemotaxis, Leukocyte; Electrophoretic Mobility Shift Assay; Endothelial Cells; Gene Expression Regulation; Humans; Interleukin-4; Interleukin-8; Microvessels; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Pneumonia; Pulmonary Artery; Signal Transduction; Transcription, Genetic; Umbilical Veins

The investigation of novel targets for the treatment of cystic fibrosis (CF) lung inflammation is a major priority, considering that no effective therapy is available for this purpose. Consistent with the evidence that the sphingolipid (SL) ceramide regulates airway inflammation and infection in mice and patients with CF, SLs were identified as targets for treating pulmonary disorders, including CF. Because miglustat, an inhibitor of the synthesis of glycosphingolipids, reduces the Pseudomonas aeruginosa-dependent transcription of the IL-8 gene in bronchial cells, we examined the effects of miglustat and amitriptyline, another drug affecting ceramide metabolism, on the expression of 92 genes implicated in host immune defense. Infection with the P. aeruginosa strain PAO1 up-modulated the expression of 14 (27%) genes in IB3-1 cells and 15 (29%) genes in CF primary respiratory epithelia grown at an air-liquid interface, including chemokines (IL-8, growth-regulated Gro-α/β/γ proteins, and granulocyte chemotactic peptide-2 [GCP-2]), proinflammatory cytokines (IL-1α/β, IL-6, and TNF-α), and the intercellular adhesion molecule-1, nuclear factor kB1, toll like receptor 2, and human defensin B4 genes, confirming that bronchial epithelium is an important source of inflammatory mediators. Both miglustat and amitriptyline reduced the immune response, an effect that paralleled a decrease in the P. aeruginosa-induced accumulation of ceramide. Miglustat (100 mg/kg), given to C57BL/6 mice once daily for a period of 3 consecutive days before lipopolysaccharide (LPS) challenge, strongly reduced the number of neutrophils recruited in the airways and the expression of the keratinocyte-derived chemokine in lung extracts. Collectively, these results indicate that targeting the metabolism of SLs can down-modulate the recruitment of neutrophils into the lung.

Topics: 1-Deoxynojirimycin; Amitriptyline; Animals; Anti-Inflammatory Agents; Cell Line; Ceramides; Disease Models, Animal; Epithelial Cells; Gene Expression Regulation; Host-Pathogen Interactions; Humans; Immunity, Innate; Inflammation Mediators; Interleukin-8; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Pneumonia; Pseudomonas aeruginosa; Respiratory Mucosa

Interleukin (IL)-8 from pulmonary epithelial cells has been suggested to play an important role in the airway inflammation, although the mechanism remains unclear. We envisioned a possibility that pulmonary epithelial CCR3 could be involved in secretion and regulation of IL-8 and promote lipopolysaccharide (LPS)-induced lung inflammation. Human bronchial epithelial cell line NCI-H292 and alveolar type II epithelial cell line A549 were used to test role of CCR3 in production of IL-8 at cellular level. In vivo studies were performed on C57/BL6 mice instilled intratracheally with LPS in a model of acute lung injury (ALI). The activity of a CCR3-specific inhibitor (SB-328437) was measured in both in vitro and in vivo systems. We found that expression of CCR3 in NCI-H292 and A549 cells were increased by 23% and 16%, respectively, 24 h after the challenge with LPS. LPS increased the expression of CCR3 in NCI-H292 and A549 cells in a time-dependent manner, which was inhibited significantly by SB-328437. SB-328437 also diminished neutrophil recruitment in alveolar airspaces and improved LPS-induced ALI and production of IL-8 in bronchoalveolar lavage fluid. These results suggest that pulmonary epithelial CCR3 be involved in progression of LPS-induced lung inflammation by mediating release of IL-8. CCR3 in pulmonary epithelia may be an attractive target for development of therapies for ALI.

Topics: Acute Lung Injury; Animals; Cell Line; Down-Regulation; Epithelial Cells; Humans; Interleukin-8; Kinetics; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Naphthalenes; Phenylalanine; Pneumonia; Receptors, CCR3; RNA, Messenger; Time Factors; Up-Regulation

Infection by Burkholderia cenocepacia in cystic fibrosis (CF) patients is associated with poor clinical prognosis. Previously, we demonstrated that one of the highly transmissible strains, BC7, expresses cable pili and the associated 22 kDa adhesin, both of which contribute to BC7 binding to airway epithelial cells. However, the contribution of these factors to induce inflammation and bacterial persistence in vivo is not known.. Wild-type BC7 stimulated higher IL-8 responses than the BC7 cbl and BC7 adhA mutants in both CF and normal bronchial epithelial cells. To determine the role of cable pili and the associated adhesin, we characterized a mouse model of B. cenocepacia, where BC7 are suspended in Pseudomonas aeruginosa alginate. C57BL/6 mice were infected intratracheally with wild-type BC7 suspended in either alginate or PBS and were monitored for lung bacterial load and inflammation. Mice infected with BC7 suspended in PBS completely cleared the bacteria by 3 days and resolved the inflammation. In contrast, mice infected with BC7 suspended in alginate showed persistence of bacteria and moderate lung inflammation up to 5 days post-infection. Using this model, mice infected with the BC7 cbl and BC7 adhA mutants showed lower bacterial loads and mild inflammation compared to mice infected with wild-type BC7. Complementation of the BC7 cblS mutation in trans restored the capacity of this strain to persist in vivo. Immunolocalization of bacteria revealed wild-type BC7 in both airway lumen and alveoli, while the BC7 cbl and BC7 adhA mutants were found mainly in airway lumen and peribronchiolar region.. B. cenocepacia suspended in alginate can be used to determine the capacity of bacteria to persist and cause lung inflammation in normal mice. Both cable pili and adhesin contribute to BC7-stimulated IL-8 response in vitro, and BC7 persistence and resultant inflammation in vivo.

Topics: Adhesins, Bacterial; Alginates; Animals; Burkholderia cenocepacia; Burkholderia Infections; Disease Models, Animal; Epithelial Cells; Fimbriae, Bacterial; Genes, Bacterial; Glucuronic Acid; Hexuronic Acids; Humans; Interleukin-8; Lung; Mice; Mice, Inbred C57BL; Molecular Weight; Mutation; Neutrophil Infiltration; Pneumonia

The aim of this study was to investigate the value and significance of interleukin-8 in differentiation of uncomplicated parapneumonic effusion (UCPPE) from complicated parapneumonic effusion (CPPE). Using an IMMULITE 1000 Analyzer, with chemiluminescent immunometric assay, levels of interleukin-8 (IL-8) were measured in the pleural fluid of patients with UCPPE (n=30), and CPPE (n=30), and three classical parameters (pH, glucose, and LDH) in these two groups. Receiver-operating curves were to assess the sensitivity and specifity of interleukin-8 for differentiating between the two patient groups. IL-8 levels were statistically higher in the CPPE group. A positive significant correlation, was found between levels of IL-8 and and lactate dehydrogenase (LDH) (r=0.68, p<0.05). There was also a positive significant correlation between IL-8 and protein level in pleural effusion (r=0.306, r<0.01). There was a significant negative correlation between levels of IL-8 and pH (r=-0.83, p<0.05), and of IL-8 and glucose in pleural fluid (r=-0.61, p<0.05). A cut-off value of 1805.81 pg/ml, differentiated CPPE from UPPE with a sensitivity of 100% and a specifity of 98%. IL-8 may be used as an alternative marker for the complication of parapneumonic effusion.

Topics: Adult; Aged; Biomarkers; Diagnosis, Differential; Female; Glucose; Humans; Hydrogen-Ion Concentration; Interleukin-8; L-Lactate Dehydrogenase; Male; Middle Aged; Pleural Effusion; Pneumonia; Prognosis; Reproducibility of Results; Sensitivity and Specificity; Statistics as Topic

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

Natural surfactant combined with beclomethasone decreases pulmonary oxidative stress in preterm lambs with respiratory distress syndrome (RDS).. To test the hypothesis that this occurs through a decrease in pulmonary inflammation.. Preterm lambs received 200 mg/kg of natural surfactant or 200 mg/kg of natural surfactant combined with 400 or 800 μg/kg of beclomethasone. Interleukin 8 (IL-8) and macrophage migration inhibitory factor (MIF) were assayed in bronchial aspirate samples and lung mechanics were evaluated.. IL-8 increased in all the groups, but the increase was lower in the groups treated with surfactant plus 400 and 800 μg/kg of beclomethasone. MIF decreased in the surfactant group, did not vary in the surfactant plus 400 μg/kg beclomethasone group, and decreased in the surfactant plus 800 μg/kg beclomethasone group. MIF concentration was higher in the surfactant plus 800 μg/kg beclomethasone group than in the other groups.. Natural surfactant combined with beclomethasone at 800 μg/kg is effective in reducing lung inflammation in an animal model of RDS, thus explaining the associated decrease in lung oxidative stress. The increase in MIF in animals treated with surfactant plus 800 μg/kg of beclomethasone might be an important maturative and protective factor for neonatal lungs.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Beclomethasone; Disease Models, Animal; Female; Humans; Infant, Newborn; Interleukin-8; Macrophage Migration-Inhibitory Factors; Oxidative Stress; Pneumonia; Pregnancy; Pulmonary Surfactants; Respiratory Distress Syndrome, Newborn; Sheep

Combustion-derived and manufactured nanoparticles (NPs) are known to provoke oxidative stress and inflammatory responses in human lung cells; therefore, they play an important role during the development of adverse health effects. As the lungs are composed of more than 40 different cell types, it is of particular interest to perform toxicological studies with co-cultures systems, rather than with monocultures of only one cell type, to gain a better understanding of complex cellular reactions upon exposure to toxic substances. Monocultures of A549 human epithelial lung cells, human monocyte-derived macrophages and monocyte-derived dendritic cells (MDDCs) as well as triple cell co-cultures consisting of all three cell types were exposed to combustion-derived NPs (diesel exhaust particles) and to manufactured NPs (titanium dioxide and single-walled carbon nanotubes). The penetration of particles into cells was analysed by transmission electron microscopy. The amount of intracellular reactive oxygen species (ROS), the total antioxidant capacity (TAC) and the production of tumour necrosis factor (TNF)-alpha and interleukin (IL)-8 were quantified. The results of the monocultures were summed with an adjustment for the number of each single cell type in the triple cell co-culture. All three particle types were found in all cell and culture types. The production of ROS was induced by all particle types in all cell cultures except in monocultures of MDDCs. The TAC and the (pro-)inflammatory reactions were not statistically significantly increased by particle exposure in any of the cell cultures. Interestingly, in the triple cell co-cultures, the TAC and IL-8 concentrations were lower and the TNF-alpha concentrations were higher than the expected values calculated from the monocultures. The interplay of different lung cell types seems to substantially modulate the oxidative stress and the inflammatory responses after NP exposure.

Topics: Alveolar Epithelial Cells; Coculture Techniques; Dendritic Cells; Humans; Interleukin-8; Lung; Macrophages; Microscopy, Electron, Transmission; Models, Anatomic; Nanoparticles; Nanotubes, Carbon; Oxidative Stress; Pneumonia; Reactive Oxygen Species; Titanium; Tumor Necrosis Factor-alpha; Vehicle Emissions

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

Previous in vitro experiments demonstrated that acute-phase protein, alpha 1-antitrypsin (AAT), could act either as an enhancer or as a suppressor of lipopolysaccharide (LPS)-induced cell activation depending on treatment time. Here we investigate how AAT regulates inflammatory responses in the short term when administrated post LPS challenge.. Similar experimental setup was used both in vitro and in vivo: human monocytes and neutrophils were stimulated with LPS for 2 h followed by AAT for a total time of 4 h, and C57BL/6 mice were treated intranasally with LPS and 2 h later with AAT and sacrificed after 4 h. Bronchial lavage (BAL) and lung homogenates were analyzed using bio-plex cytokine assay. BAL cell counts were assessed.. Within 4 h, AAT enhanced LPS-induced tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-6, and IL-8 release from monocytes and neutrophils. Mice challenged for 4 h with LPS followed by AAT at 2 h showed no changes in BAL cell counts and higher levels of almost all measured cytokines, specifically RANTES in BAL and IL-12, IL-13, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-10 levels in lung homogenates, than in mice treated with LPS only.. Within the short term, AAT enhances the magnitude of LPS-induced specific cytokine/chemokine production, which may play an important role in amplification and resolution of acute-phase inflammatory reactions in vivo.

Topics: alpha 1-Antitrypsin; Animals; Bronchoalveolar Lavage Fluid; Cells, Cultured; Cytokines; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Monocytes; Neutrophils; Pneumonia; Tumor Necrosis Factor-alpha

Inflammation is associated with various pulmonary diseases and contributes to the pathogenesis of acute lung injury. We previously identified a proinflammatory signaling pathway triggered by G protein-coupled receptors (GPCRs) in which stimulation of G(q)-coupled GPCRs results in activation of the transcription factor NF-kappaB. Because damage to the lung causes the release of multiple mediators acting through G(q)-coupled GPCRs, this signaling pathway is likely to contribute to inflammatory processes in the injured lung. In an effort to identify novel inhibitors of lung inflammation, the National Institutes of Health Clinical Collection, a library of 446 compounds, was screened for inhibitory activity toward production of IL-8 induced by stimulation of the G(q)-coupled tachykinin 1 receptor with substance P in A549 cells. Twenty-eight compounds that significantly inhibited substance P-induced IL-8 production were identified. The most potent inhibitor was triptolide, a diterpenoid compound from Tripterygium wilfordii Hook F, a vine used in traditional Chinese medicine for the treatment of autoimmune diseases. Triptolide inhibited IL-8 production induced by substance P with an IC(50) of 2.3 x 10(-8) M and inhibited NF-kappaB activation in response to an agonist of the protease-activated receptor 2 with an IC(50) of 1.4 x 10(-8) M. Anti-inflammatory effects of triptolide were assessed in vivo using a chlorine gas lung injury model in mice. Triptolide inhibited neutrophilic inflammation and the production of KC (Cxcl1) in the lungs of chlorine-exposed mice. The results demonstrate that triptolide exhibits anti-inflammatory activity in cultured lung cells and in an in vivo model of acute lung injury.

Topics: Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Chlorine; Diterpenes; Epoxy Compounds; Humans; Interleukin-8; Lung; Mice; NF-kappa B; Phenanthrenes; Pneumonia; Substance P

Infected airway epithelial cells up-regulate the expression of chemokines, chiefly IL-8, and antimicrobial molecules including beta-defensins (BD). Acinetobacter baumannii is a cause of hospital-acquired pneumonia. We examined whether A. baumannii induced the expressions of IL-8 and BD2 by airway epithelial cells and the receptors implicated in bacterial detection. A549 and human primary airway cells released IL-8 upon infection. A. baumannii-infected cells also increased the expression of BD2 which killed A. baummannii strains. IL-8 induction was via NF-kappaB and mitogen-activated kinases p38 and p44/42-dependent pathways. A. baumannii engaged Toll-like receptor (TLR) 2 and TLR4 pathways and A549 cells could use soluble CD14 as TLRs co-receptor. A. baumannii lipopolysaccharide stimulated IL-8 release by A549 cells and sCD14 facilitated the recognition of the lipopolysaccharide. Mass spectrometry analysis revealed that A. baumannii lipid A structure matches those with endotoxic potential. These results demonstrate that airway epithelial cells produce mediators important for A. baumannii clearance.

Topics: Acinetobacter baumannii; Acinetobacter Infections; beta-Defensins; Cell Line; Epithelial Cells; Host-Pathogen Interactions; Humans; Inflammation; Inflammation Mediators; Interleukin-8; Pneumonia; Respiratory System; Signal Transduction; Up-Regulation

Acute respiratory distress syndrome (ARDS) is characterized by overwhelming lung inflammation. This study explored the inflammatory mediators in bronchoalveolar lavage fluid (BALF) for prognostic relevance in patients with infection-induced ARDS. Thirty-nine patients with infection-induced ARDS (28 pneumonia and 11 extrapulmonary sepsis) and two patients with cardiogenic lung edema as the control were included. The expression profiles of inflammatory mediators in BALF were compared between ARDS and cardiogenic lung edema. A group of inflammatory mediators that showed higher expression in ARDS was analyzed for their relationships with clinical features and outcome. We found that 17 patients who died had higher levels of interleukin (IL)-6 (P = 0.012), IL-8 (P = 0.001) and monocyte chemoattractant protein-1 (P = 0.036) in BALF compared with those who survived. Furthermore, there was an inverse relationship between the BALF levels of IL-6 (P = 0.026), IL-8 (P = 0.008) and macrophage inflammatory protein (MIP)-1 alpha (P = 0.048) and the changes of lung compliance between days 1 and 4, whereas the BALF levels of IL-8 (P = 0.033) and MIP-1 alpha (P = 0.029) were positively correlated with the changes of sequential organ failure assessment scores between days 1 and 4. In multivariate logistic regression analysis, only IL-8 (P = 0.013) and lung injury score (LIS) (P = 0.017) independently predicted the mortality, and IL-8 (P = 0.002) was most likely predictive of mortality in analysis of area under the receiver operating characteristic curve. In conclusion, we show the expression profiles of inflammatory mediators in BALF of infection-induced ARDS. Among the mediators, IL-8 is the most significant predictor for mortality, and several mediators are correlated with clinical severity. However, potential selection bias due to limited control subjects and lack of serum inflammatory mediator data suggest a necessity of further studies to confirm our findings.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Chemokine CCL3; Female; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Lung Compliance; Male; Middle Aged; Pneumonia; Prognosis; Prospective Studies; Respiratory Distress Syndrome; Sepsis; Young Adult

Cardiopulmonary bypass (CPB) stimulates systemic and pulmonary inflammation. Modified ultrafiltration (MUF) mitigates deleterious CPB effects by unclear mechanisms. We evaluated pulmonary inflammation in piglets undergoing CPB followed by MUF. Twenty-four piglets underwent 60 min of hypothermic CPB. MUF subjects (n=12) underwent hemoconcentration postCPB to the target hematocrit. Pulmonary vascular resistance (PVR), proinflammatory cytokine concentrations, and transpulmonary thromboxane gradients were determined at baseline, following CPB, and at end of the study (EOS) in MUF and control (n=12) groups. PVR significantly increased postCPB in both groups but decreased after MUF. MUF and control groups were similar in regards to systemic cytokine concentrations. Bronchoalveolar lavage concentrations of IL-6 and IL-8 significantly increased in controls throughout the study. Alveolar IL-6 and IL-8 were unchanged at EOS in MUF subjects, and IL-6 concentrations were significantly less than controls at EOS (P=0.015). Similarly, transpulmonary thromboxane gradient was significantly less at EOS in MUF subjects compared with controls (P=0.04). MUF removed circulating inflammatory mediators, lessened pulmonary hypertension, and reduced pulmonary-derived inflammatory markers, providing further evidence that MUF ameliorates pulmonary-based inflammation. These findings lend insight into mechanisms behind salutary clinical benefits of MUF after CPB.

Topics: Animals; Animals, Newborn; Blood Pressure; Bronchoalveolar Lavage Fluid; Cardiac Output; Cardiopulmonary Bypass; Down-Regulation; Hemofiltration; Inflammation Mediators; Interleukin-6; Interleukin-8; Pneumonia; Pulmonary Alveoli; Swine; Thromboxanes; Tumor Necrosis Factor-alpha; Vascular Resistance

Carbon monoxide (CO) confers anti-inflammatory protection in rodent models of lung injury when applied at low concentration. Translation of these findings to clinical therapies for pulmonary inflammation requires validation in higher mammals. We have evaluated the efficacy of inhaled CO in reducing LPS-induced lung inflammation in cynomolgus macaques. LPS inhalation resulted in profound neutrophil influx and moderate increases in airway lymphocytes, which returned to baseline levels within 2 wk following exposure. CO exposure (500 ppm, 6 h) following LPS inhalation decreased TNF-α release in bronchoalveolar lavage fluid but did not affect IL-6 or IL-8 release. Lower concentrations of CO (250 ppm, 6 h) did not reduce pulmonary neutrophilia. Pretreatment with budesonide, a currently used inhaled corticosteroid, decreased LPS-induced expression of TNF-α, IL-6, and IL-8, and reduced LPS-induced neutrophilia by ∼84%. In comparison, CO inhalation (500 ppm, for 6 h after LPS exposure) reduced neutrophilia by ∼67%. Thus, inhaled CO was nearly as efficacious as pretreatment with an inhaled corticosteroid at reducing airway neutrophil influx in cynomolgus macaques. However, the therapeutic efficacy of CO required relatively high doses (500 ppm) that resulted in high carboxyhemoglobin (COHb) levels (>30%). Lower CO concentrations (250 ppm), associated with anti-inflammatory protection in rodents, were ineffective in cynomolgus macaques and also yielded relatively high COHb levels. These studies highlight the complexity of interspecies variation of dose-response relationships of CO to COHb levels and to the anti-inflammatory functions of CO. The findings of this study warrant further investigations for assessing the therapeutic application of CO in nonhuman primate models of tissue injury and in human diseases. The study also suggests that akin to many new therapies in human diseases, the translation of CO therapy to human disease will require additional extensive and rigorous proof-of-concept studies in humans in the future.

Topics: Administration, Inhalation; Animals; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Budesonide; Carbon Monoxide; Disease Models, Animal; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Macaca fascicularis; Male; Neutrophils; Pneumonia; 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 studied the state of the thiol-disulfide system (contents of reduced and oxidized glutathione, their ratio, and concentrations of protein SH-groups and protein-bound glutathione) and functional properties of neutrophils (production of hydroxyl radicals, IL-8, and TNF-α and myeloperoxidase activity) from healthy donors under conditions of oxidative stress in vitro induced by H(2)O(2)in a final concentration of 200 μM and from patients with community-acquired pneumonia. We evaluated the role of reduced and protein-bound glutathione in the regulation of functional state of blood neutrophils from patients with community-acquired pneumonia and during oxidative stress in vitro under conditions cell incubation with N-ethylmaleimide or 1,4-dithioerythritolsulfhydryl, the blocker and protector of sulfhydryl groups, respectively.

Topics: Adult; Community-Acquired Infections; Ethylmaleimide; Female; Glutathione; Humans; Hydrogen Peroxide; Hydroxyl Radical; In Vitro Techniques; Interleukin-8; Male; Middle Aged; Neutrophils; Oxidative Stress; Peroxidase; Pneumonia; Protein Disulfide Reductase (Glutathione); Tumor Necrosis Factor-alpha

Leukotrienes (LT) and chemokines are important chemotactic compounds in regulating the recruitment and activation of immune cells during pulmonary inflammatory reactions. Results showed that LTC4 release by porcine alveolar epithelial type II cells (AEC IIs) is significantly enhanced by either LTB4 or LPS stimulation. The basal level of IL-8 gene expression in AEC IIs was only 1/3 of that observed in alveolar macrophages (AMs) while AEC IIs expressed a higher basal level of monocyte chemotactic peptide-1 (MCP-1) and also in response to LPS stimulation than do AMs. The increasing basal and LT-induced MCP-1 gene expressions after 8h of incubation were observed in AEC IIs but decreased in AMs. These findings suggest that AEC IIs play an important role in initial inflammatory reactions of the lung by releasing LTC4, and that they also modulate later inflammatory reactions, evidenced by consistent elevation of MCP-1 gene expression after and during exogenous challenge in pigs.

Topics: Animals; Cell Communication; Chemokine CCL2; Enzyme-Linked Immunosorbent Assay; Gene Expression; Interleukin-8; Leukotriene C4; Macrophages, Alveolar; Male; Pneumonia; Pulmonary Alveoli; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Swine; Swine Diseases

Previous studies in our lab have identified pre-B-cell colony enhancing factor (PBEF) as a novel biomarker in acute lung injury. This study continues to elucidate the underlying molecular mechanism of PBEF in the pathogenesis of acute lung injury in pulmonary cell culture models. Our results revealed that IL-1beta induced PBEF expression in pulmonary vascular endothelial cells at the transcriptional level and a -1535 T-variant in the human PBEF gene promoter significantly attenuated its binding to an IL-1beta-induced unknown transcription factor. This may underlie the reduced expression of PBEF and thus the lower susceptibility to acute lung injury in -1535T carriers. Furthermore, overexpression of PBEF significantly augmented IL-8 secretion and mRNA expression by more than 6-fold and 2-fold in A549 cells and HPAEC, respectively. It also significantly augmented IL-1beta-mediated cell permeability by 44% in A549 cells and 65% in endothelial cells. The knockdown of PBEF expression significantly inhibited IL-1beta-stimulated IL-8 secretion and mRNA level by 60% and 70%, respectively, and the knockdown of PBEF expression also significantly attenuated IL-1beta-induced cell permeability by 29% in epithelial cells and 24% in endothelial cells. PBEF expression also affected the expression of two other inflammatory cytokines (IL-16 and CCR3 genes). These results suggest that PBEF is critically involved in pulmonary vascular and epithelial inflammation and permeability, which are hallmark features in the pathogenesis of acute lung injury. This study lends further support to our finding that PBEF is a potential new target in acute lung injury.

Topics: Acute Lung Injury; Amino Acid Substitution; Base Sequence; Cell Line, Tumor; Cell Proliferation; Cytokines; DNA Primers; Dose-Response Relationship, Drug; Endothelial Cells; Epithelial Cells; Gene Expression; Gene Knockdown Techniques; Humans; Interleukin-16; Interleukin-1beta; Interleukin-8; Nicotinamide Phosphoribosyltransferase; Permeability; Pneumonia; Polymorphism, Single Nucleotide; Receptors, CCR3; RNA, Messenger; RNA, Small Interfering; Time Factors

The objective of the study was to observe the effects of Salvia miltiorrhiza on intercellular adhesion molecule 1 (ICAM-1) protein expression in the lungs of rats with severe acute pancreatitis (SAP) or obstructive jaundice (OJ).. A total of 288 rats were used for SAP- and OJ-associated experiments. The rats were randomly divided into sham-operated, model control, and treated group. According to the difference of time points after operation, the SAP rats of each group were subdivided into 3-, 6-, and 12-hour groups, whereas the OJ rats were divided into 7-, 14-, 21-, and 28-day groups. The contents of interleukin (IL) 6, IL-18, nitric oxide, malondialdehyde, and superoxide dismutase in serum were determined, and pathological changes and ICAM-1 protein expression in the lungs were observed.. Compared with the respective model control groups, in treated groups of SAP and OJ rats, the numbers of dead rats declined; serum superoxide dismutase content significantly increased, and serum IL-18, IL-6, and malondialdehyde contents were significantly decreased; the positive staining intensity of ICAM-1 protein in the lungs decreased significantly (P < 0.05, P < 0.01, or P < 0.001); and pathological changes in the lungs were relieved.. Salvia miltiorrhiza plays a positive role in the protection of the lungs of SAP and OJ rats.

Topics: Acute Disease; Animals; Drugs, Chinese Herbal; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Jaundice, Obstructive; Lung; Malondialdehyde; Nitric Oxide; Pancreatic Diseases; Pancreatitis; Plant Preparations; Pneumonia; Rats; Salvia miltiorrhiza; Severity of Illness Index; Superoxide Dismutase

One host susceptibility factor for ozone identified in epidemiologic studies is NAD(P)H quinone oxidoreductase 1 (NQO1). We hypothesized that after ozone exposure, NQO1 is required to increase 8-isoprostane (also known as F(2)-isoprostane) production, a recognized marker of ozone-induced oxidative stress, and to enhance airway inflammation and hyperresponsiveness. In this report, we demonstrate that in contrast to wild-type mice, NQO1-null mice are resistant to ozone and have blunted responses, including decreased production of F(2)-isoprostane and keratinocyte chemokine, decreased airway inflammation, and diminished airway hyperresponsiveness. Importantly, these results in mice correlate with in vitro findings in humans. In primary human airway epithelial cells, inhibition of NQO1 by dicumarol blocks ozone-induced F(2)-isoprostane production and IL-8 gene expression. Together, these results demonstrate that NQO1 modulates cellular redox status and influences the biologic and physiologic effects of ozone.

Topics: Animals; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cells, Cultured; Chemokines; Dicumarol; Dinoprost; Enzyme Inhibitors; Epithelial Cells; Humans; Interleukin-8; Mice; Mice, Inbred C57BL; Mice, Knockout; NAD(P)H Dehydrogenase (Quinone); NADPH Dehydrogenase; Oxidants; Oxidation-Reduction; Oxidative Stress; Ozone; Pneumonia; Time Factors

Lethal toxin (LT) is a critical virulence factor of Bacillus anthracis, the etiological agent of anthrax, whose pulmonary form is fatal in the absence of treatment. Inflammatory response is a key process of host defense against invading pathogens. We report here that intranasal instillation of a B. anthracis strain bearing inactive LT stimulates cytokine production and polymorphonuclear (PMN) neutrophils recruitment in lungs. These responses are repressed by a prior instillation of an LT preparation. In contrast, instillation of a B. anthracis strain expressing active LT represses lung inflammation. The inhibitory effects of LT on cytokine production are also observed in vitro using mouse and human pulmonary epithelial cells. These effects are associated with an alteration of ERK and p38-MAPK phosphorylation, but not JNK phosphorylation. We demonstrate that although NF-kappaB is essential for IL-8 expression, LT downregulates this expression without interfering with NF-kappaB activation in epithelial cells. Histone modifications are known to induce chromatin remodelling, thereby enhancing NF-kappaB binding on promoters of a subset of genes involved in immune response. We show that LT selectively prevents histone H3 phosphorylation at Ser 10 and recruitment of the p65 subunit of NF-kappaB at the IL-8 and KC promoters. Our results suggest that B. anthracis represses the immune response, in part by altering chromatin accessibility of IL-8 promoter to NF-kappaB in epithelial cells. This epigenetic reprogramming, in addition to previously reported effects of LT, may represent an efficient strategy used by B. anthracis for invading the host.

Topics: Animals; Antigens, Bacterial; Bacterial Toxins; Chromatin; Cytokines; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Histones; Humans; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lung; Mice; Mice, Inbred C57BL; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pneumonia; Promoter Regions, Genetic; Respiratory Mucosa

Induction of proinflammatory mediators by alveolar macrophages exposed to ambient air particulate matter has been suggested to be a key factor in the pathogenesis of inflammatory and allergic diseases in the lungs. However, receptors and mechanisms underlying these responses have not been fully elucidated. In this study, we examined whether TLR2, TLR4, and the key adaptor protein, MyD88, mediate the expression of proinflammatory cytokines and chemokines by mouse peritoneal macrophages exposed to fine and coarse PM. TLR2 deficiency blunted macrophage TNF-alpha and IL-6 expression in response to fine (PM2.5), while not affecting cytokine-inducing ability of coarse NIST Standard Reference Material (SRM 1648) particles. In contrast, TLR4(-/-) macrophages showed inhibited cytokine expression upon stimulation with NIST SRM 1648 but exhibited normal responses to PM2.5. Preincubation with polymyxin B markedly suppressed the capacity of NIST SRM 1648 to elicit TNF-alpha and IL-6, indicating endotoxin as a principal inducer of cytokine responses. Overexpression of TLR2 in TLR2/4-deficient human embryonic kidney 293 cells imparted PM2.5 sensitivity, as judged by IL-8 gene expression, whereas NIST SRM 1648, but not PM2.5 elicited IL-8 expression in 293/TLR4/MD-2 transfectants. Engagement of TLR4 by NIST SRM 1648 induced MyD88-independent expression of the chemokine RANTES, while TLR2-reactive NIST IRM PM2.5 failed to up-regulate this response. Consistent with the shared use of MyD88 by TLR2 and TLR4, cytokine responses of MyD88(-/-) macrophages to both types of air PM were significantly reduced. These data indicate differential utilization of TLR2 and TLR4 but shared use of MyD88 by fine and coarse air pollution particles.

Topics: Animals; Anti-Bacterial Agents; Cell Line; Cells, Cultured; Chemokine CCL5; Humans; Hypersensitivity; Inflammation Mediators; Interleukin-6; Interleukin-8; Macrophages; Mice; Mice, Knockout; Myeloid Differentiation Factor 88; Particulate Matter; Pneumonia; Polymyxin B; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Benzo(a)pyrene (BP) is an environmental contaminant known to favor airway inflammation likely through up-regulation of pro-inflammatory cytokines. The present study was designed to characterize its effects toward interleukin-8 (IL-8), a well-established pulmonary inflammatory cytokine. In primary human macrophages, BP was shown to induce IL-8 expression at both mRNA and secretion levels in a dose-dependent manner. Such an up-regulation was likely linked to aryl hydrocarbon receptor (AhR)-activation since BP-mediated IL-8 induction was reduced after AhR expression knock-down through RNA interference. Moreover, electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation experiments showed BP-triggered binding of AhR to a consensus xenobiotic responsive element (XRE) found in the human IL-8 promoter. Finally, BP administration to mice led to over-expression of keratinocyte chemoattractant (KC), the murine functional homologue of IL-8, in lung. It also triggered the recruitment of neutrophils in bronchoalveolar lavage (BAL) fluids, which was however fully abolished in the presence of a chemical antagonist of the KC/IL-8 receptors CXCR1/CXCR2, thus supporting the functional and crucial involvement of KC in BP-induced lung inflammation. Overall, these data highlight an AhR-dependent regulation of IL-8 in response to BP that likely contributes to the airway inflammatory effects of this environmental chemical.

Topics: Animals; Benzo(a)pyrene; Bronchoalveolar Lavage Fluid; Cell Movement; Chemotactic Factors; Chromatin Immunoprecipitation; Electrophoretic Mobility Shift Assay; Environmental Pollutants; Humans; Interleukin-8; Keratinocytes; Macrophages; Mice; Mice, Inbred C57BL; Neutrophils; Pneumonia; Receptors, Aryl Hydrocarbon; Receptors, Interleukin-8B; Response Elements; RNA Interference; Up-Regulation

Exogenous surfactant is critical in the treatment of neonates with respiratory distress syndrome. Lucinactant (Surfaxin; Discovery Laboratories, Inc.) is a surfactant replacement therapy containing sinulpeptide, which may reduce lung inflammation. This study tested whether Lucinactant reduces markers of inflammation, damage and remodeling in human airway epithelial cells exposed to hyperoxia. Calu-3 monolayers cultured at an air-liquid interface were treated apically with 140 microL of normal saline, Lucinactant or Beractant (Survanta; Abbott Laboratories, Inc.). Treated monolayers were exposed to 60% O(2)/5% CO(2) for 24 or 72 h. Transepithelial resistance (TER; p < 0.001) and cell viability (p < 0.05) were greater in both surfactant groups compared with saline; by 72 h Lucinactant cells had greater TER than Beractant (p < 0.001). Surfactant treated groups secreted less IL-8 than saline (p < 0.001), whereas Lucinactant cells secreted less IL-6 than saline and Beractant (p < 0.001). Matrix metalloproteinase 7, expressed by saline and Beractant treated cells at 24 h, was attenuated by 72 h by Beractant (p < 0.001), but was never detected in Lucinactant cells. Histology indicated less injury with Lucinactant relative to Beractant and saline. These data suggest that Lucinactant was protective compared with Beractant and control.

Topics: Anti-Inflammatory Agents; Biological Products; Cells, Cultured; Humans; Hyperoxia; Intercellular Signaling Peptides and Proteins; Interleukin-6; Interleukin-8; Matrix Metalloproteinase 2; Matrix Metalloproteinase 7; Peptides; Pneumonia; Pulmonary Alveoli; Respiratory Mucosa

Cardiopulmonary bypass (CPB) causes pulmonary inflammatory reaction. Liquid ventilation with perfluorocarbon has shown an anti-inflammatory effect on severely injured lungs. The aim of this study is to investigate the treatment effect of different ventilation modes with perfluorocarbon on pulmonary inflammatory reaction in piglets after CPB.. After receiving CPB and subsequent infusion of lipopolysaccharide (1 microg/kg), 18 piglets were randomly treated with conventional gas ventilation, total liquid ventilation (TLV), or partial liquid ventilation (PLV) for 240 min. The lung tissue and blood samples were collected at the end of observation period. The pulmonary mRNA expressions and plasmatic concentrations of interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured. Histological neutrophil count in lung parenchyma was performed.. Hemodynamics, PaCO2 and PH did not differ among groups during the observation period. Both TLV and PLV showed significantly improved oxygenation, reduced pulmonary mRNA expressions and plasmatic levels of IL-6 and IL-8, and decreased total neutrophil count in lung parenchyma when compared with conventional gas ventilation. Furthermore, TLV resulted in significantly better oxygenation, lower pulmonary mRNA expressions of IL-6 and IL-8, and less total neutrophil count when compared with PLV.. Both TLV and PLV improved oxygenation and reduced pulmonary inflammatory reaction in piglets after CPB, whereas TLV is more effective than PLV.

Topics: Animals; Animals, Newborn; Blood Gas Analysis; Cardiopulmonary Bypass; Fluorocarbons; Interleukin-6; Interleukin-8; Liquid Ventilation; Models, Animal; Neutrophils; Pneumonia; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Swine

Expression of IL-10 is decreased in lungs of preterm infants. We determined the constitutive and lipopolysaccharide (LPS)-induced IL-10 synthesis by lung inflammatory cells from preterm and term infants and examined their relationship to gestational age and/or incidence of bronchopulmonary dysplasia (BPD). A total of 37 infants; preterm neonates at gestational ages of 23-27 wk (group 1); 28-34 wk (group 2), and four full-term infants with meconium aspiration (group 3) were enrolled. One sample of lung inflammatory cells, obtained during postnatal d 1-3, and another during postnatal d 4-7 were cultured in vitro in presence or absence of 100 mug/mL of LPS. Secreted IL-10 was measured by ELISA. A positive relationship was found between gestational age and LPS-induced, but not constitutive IL-10 production within 1-3 d of life; group 1 on d 1-3 had a significant number of IL-10 nonresponders compared with group 2. All term neonates in group 3 had positive LPS-induced IL-10 response. Thus, in utero maturation of IL-10 gene expression is due to acquisition of inducibility. In contrast, constitutive IL-10 production within d 1-3 of life correlated with, and predicted the incidence of BPD in the highly vulnerable very premature infants.

Topics: Bronchopulmonary Dysplasia; Cells, Cultured; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-8; Lipopolysaccharides; Lung; Male; Pneumonia; Prospective Studies; Risk Factors

The present study investigated the effects of positive end-expiratory pressure (PEEP) on the inflammatory response in two different lung injury models: edematous lung induced by oleic acid (OA); and atelectatic lung induced by whole-lung lavage (LAV).. Japanese white rabbits (n = 28) were allocated to one of the two lung injury (OA or LAV) groups, and each group was treated with intermittent positive pressure ventilation, using zero end-expiratory pressure (ZEEP) or PEEP (1 cm H(2)O above the lower inflection point [LIP]). Thus, the animals were divided into LAV-ZEEP, LAV-PEEP, OA-ZEEP, and OA-PEEP groups. Blood and bronchoalveolar lavage fluid (BALF) were sampled 3 h after ventilatory treatment to analyze interleukin (IL)-8 levels.. Pa(O) (2) was significantly decreased after the induction of lung injury, but was significantly higher in the PEEP groups compared to the ZEEP groups for each lung injury. Serum IL-8 levels were elevated in both experimental models. Serum IL-8 levels were significantly lower in LAV-PEEP than in LAV-ZEEP, whereas no difference was noted between OA-PEEP and OA-ZEEP. BALF IL-8 levels were lower in LAV-PEEP than in LAV-ZEEP. PEEP above LIP attenuated the elevation of IL-8 in BALF and serum in atelectatic lungs, but did not attenuate these increases in the edematous lungs.. These results suggest that the protective effects of PEEP on injured lungs may depend on the underlying lung pathology.

Topics: Analysis of Variance; Animals; Blood Gas Analysis; Blood Pressure; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Interleukin-8; Oleic Acid; Pneumonia; Positive-Pressure Respiration; Proteins; Pulmonary Atelectasis; Pulmonary Edema; Rabbits; Respiration, Artificial; Respiratory Distress Syndrome; Sodium Chloride; Time Factors; Tracheostomy

Although liberalization of donor criteria may be one of the solutions to the current serious lung donor shortage, the use of non-standard donor lungs would increase the risk of post-operative complications. In the present study, we investigated the effect of sivelestat, a neutrophil elastase inhibitor, on reperfusion injury of a donor lung that was harvested from endotoxin-primed animals in a rat lung transplantation model.. Donor rats received an intraperitoneal injection of Escherichia coli endotoxin (5 mg/kg) 2 hours before lung harvesting. The donor lungs were flushed with an organ preservation solution with or without sivelestat (300 microg/ml), and the left lung was immediately transplanted to the recipient by the cuff technique.. Endotoxin priming did not cause significant lung injury before harvesting. Although these lungs looked normal macroscopically, they were found to contain numerous neutrophils in the alveolar capillaries, even after lung flushing. There was no significant difference in the neutrophil count between the lungs flushed with and without sivelestat. The endotoxin-primed donor lung without sivelestat treatment became edematous immediately after reperfusion. In addition, the recipient's native right lungs were also pathologic. Treatment with sivelestat significantly reduced injury in both the donor and the recipient's native lungs. Treatment with sivelestat also inhibited the increase in tumor necrosis factor-alpha and cytokine-induced neutrophil chemoattractant-1 levels in the recipient circulation after reperfusion.. We conclude that sivelestat could reduce lung injury after transplantation by inhibiting the deleterious burst of inflammatory reactions that are initiated by reperfusion of the lungs from endotoxin-primed rats.

Topics: Animals; Cytokines; Endotoxins; Escherichia coli; Glycine; Injections, Intraperitoneal; Interleukin-8; Leukocyte Elastase; Lung; Lung Transplantation; Male; Neutrophils; Pneumonia; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sulfonamides; Tissue and Organ Harvesting; Tumor Necrosis Factor-alpha

Lower airway tract colonization may trigger neutrophil-mediated airway inflammation. We investigated whether transient airway colonization influences airway inflammation and pulmonary function after lung transplantation (LTx). In this retrospective study, stable LTx patients with consecutive broncho-alveolar lavages (BAL), the first colonized and the second noncolonized, were included to create a Pooled group (P, n=32) and a Gram Negative (GN, n=14), Gram Positive (GP, n=9) and Fungi (F, n=9) subgroup. Similarly, LTx patients with consecutive, noncolonized BAL samples were included as Control group (C, n=19). BAL analysis (cell counts, IL6, IL8) and forced expiratory volume (FEV(1)) were compared between groups. In the P group and the GN subgroup, colonized BAL samples showed a significant increase in total cells, neutrophilia and IL8-concentration and a significant decrease in FEV(1), even when compared with the matched samples of the C group. A significant increase in neutrophilia was observed in the GP subgroup, but no other significant difference was found either in the GP and F subgroup or the C group. IL6 levels were not significantly different between groups. Transient airway colonization, especially with Pseudomonas-like GN bacteria, in stable LTx patients may be associated with IL8-dependent neutrophilic airway inflammation and a, albeit subtle, decrease in FEV(1).

Topics: Adult; Bronchoalveolar Lavage Fluid; Cell Count; Female; Forced Expiratory Volume; Humans; Interleukin-6; Interleukin-8; Lung Transplantation; Male; Middle Aged; Neutrophils; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory System; Retrospective Studies

Our previous studies demonstrated that a significant fraction of interleukin-8 (IL-8) in lung fluids from patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) is associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 immune complexes). Neutrophils have been implicated in the pathogenesis of ALI/ARDS, and moreover, it is well-established that apoptosis of neutrophils is delayed in patients with ALI/ARDS. The aim of this study was, therefore, to examine the role of anti-IL-8:IL-8 immune complexes in modulating spontaneous apoptosis of normal human neutrophils. Apoptosis was assessed by evaluating morphological changes, measuring enzymatic activity of caspase-3, and determining the extent of DNA degradation. We found that samples containing anti-IL-8:IL-8 immune complexes but not samples from which these complexes were removed inhibited neutrophil apoptosis. Furthermore, the former samples or effectively anti-IL-8:IL-8 complexes induced an increase in the level of antiapoptotic protein, Bcl-X(L). In contrast, levels of proapoptotic proteins Bax and Bak were decreased in the same conditions. Activity of both caspase-3 and caspase-9 was also suppressed by anti-IL-8:IL-8 complex-containing samples. Finally, we established that IgG receptor, FcgammaRIIa, mediates antiapoptotic activity of anti-IL-8:IL-8 complexes and that the key components of the FcgammaRIIa signaling pathway, Src, Syk, PI3 kinase, and ERK, may be involved in regulation of neutrophil apoptosis by the complexes. These studies demonstrate for the first time that anti-IL-8:IL-8 immune complexes have the ability to prolong neutrophil life.

Topics: Antibodies, Monoclonal; Antigen-Antibody Complex; Antigens, CD; Apoptosis; Autoantibodies; Caspase 3; Cells, Cultured; Down-Regulation; Humans; Interleukin-8; Neutrophils; Pneumonia; Proto-Oncogene Proteins c-bcl-2; Pulmonary Edema; Receptors, IgG; Signal Transduction

Human rhinovirus (HRV) infections are associated with exacerbations of asthma and chronic obstructive pulmonary disease that are characterized by a selective neutrophil infiltration. IL-17A, a cytokine derived primarily from activated T cells, has been linked to neutrophilic inflammation of the airways. We hypothesized that IL-17A alters the response of HRV-infected epithelial cells to modulate airway inflammatory cell populations. IL-17A synergistically enhanced HRV-16-induced epithelial production of the neutrophil chemoattractant, IL-8, as well as human beta-defensin-2 (HBD-2), a chemoattractant for immature dendritic cells and memory T cells, but suppressed viral production of the eosinophil chemoattractant, RANTES. These effects were not due to alterations of viral uptake or replication by IL-17A. The synergy between HRV-16 and IL-17A for IL-8 protein production was both dose- and time-dependent. IL-8 induction by IL-17A or HRV-16, alone and in combination, was reduced by inhibitors of the p38 and p44/42 MAPK pathways. By contrast, induction of HBD-2 depended on the activation of the p38 and JNK pathways. The ability of IL-17A to synergistically enhance HRV-induced IL-8 is mediated posttranscriptionally, since IL-8 promoter activation by the combination of the two stimuli was merely additive, whereas the combination of IL-17A and HRV-16 led to stabilization of IL-8 mRNA. Similarly, stimulation of HBD-2 promoter constructs by the combination of IL-17A and HRV-16 was no more than the sum of the individual responses. Further studies are needed to examine HBD-2 mRNA stability. Taken together, these data represent the first demonstration that IL-17A can modify epithelial responses to HRV in a manner that would be expected to favor the recruitment of neutrophils, immature dendritic cells, and memory T cells to the airways.

Topics: beta-Defensins; Blotting, Western; Bronchi; Cells, Cultured; Chemokine CCL5; Dendritic Cells; Dose-Response Relationship, Drug; Enzyme Inhibitors; Eosinophils; Epithelial Cells; Humans; Immunologic Memory; Interleukin-17; Interleukin-8; MAP Kinase Signaling System; Neutrophils; Picornaviridae Infections; Pneumonia; Promoter Regions, Genetic; Respiratory Mucosa; Rhinovirus; RNA Stability; Signal Transduction; Virus Replication

In vitro studies with the organic extracts of diesel particles have suggested that hydrocarbons such as PAH may play a role in an inflammatory response, but these have been limited by the possible artifacts introduced in the particle collection and processing. In this study, we avoid these artifacts and use an activated carbon denuder to remove hydrocarbons from the exhaust stream to investigate their role in the inflammatory response. Human bronchial epithelial cells (16HBE14o) were exposed at the air-cell interface to diluted and aged exhaust from a diesel generator operated at partial and no load conditions. When particles were removed with a filter before cell exposure, exhaust gases accounted for almost half of the response compared to the whole exhaust. Removal of gas phase and a portion of the particle phase hydrocarbons with the denuder decreased the interleukin-8 (IL-8) secretion to unexposed levels.

Topics: Adsorption; Atmosphere Exposure Chambers; Cell Line; Filtration; Humans; Hydrocarbons; Interleukin-8; Lung; Particle Size; Pneumonia; Vehicle Emissions

The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1beta recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1beta production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Bone Marrow Transplantation; Chronic Disease; Disease Models, Animal; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Interleukin-8; Lymphokines; Mice; Mice, Knockout; Myeloid Differentiation Factor 88; Pneumonia; Pulmonary Fibrosis; Receptors, Interleukin-1 Type I; Recombinant Proteins; Respiratory Distress Syndrome; Sialoglycoproteins; Signal Transduction; Transplantation Chimera

To determine if tracheal lavage concentrations of the transcription factor NF-kappaB, which is activated by risk factors associated with bronchopulmonary dysplasia (BPD) and induces expression of cytokines associated with BPD, is related to BPD in premature infants.. Serial tracheal lavage samples from intubated premature infants were analysed for cell count and concentrations of interleukin (IL)8 and NF-kappaB, corrected for dilution by secretory component concentrations.. Level III university hospital neonatal intensive care unit.. Thirty three intubated infants (mean (SD) birth weight 903 (258) g, median gestation 27 weeks (range 24-31)) in the first 14 days of life.. Tracheal effluent NF-kappaB, IL8, and cell counts, corrected for dilution by secretory component measurement.. Square root transformed NF-kappaB concentrations were significantly related to signs of inflammation (cell count, p = 0.002; IL8, p = 0.019) and to simultaneous fraction of inspired oxygen in samples from the first 3 days of life (r = 0.512, p<0.003). Of the 32 subjects with samples in the first 3 days of life, the half who either died or had BPD had higher NF-kappaB concentrations than those without BPD (square root concentration 0.097 (0.043) v 0.062 (0.036) microg/microg protein/microg secretory component, p = 0.018).. Tracheobronchial lavage NF-kappaB concentrations are related to lung inflammation, oxygen exposure, and pulmonary outcome in intubated preterm infants. NF-kappaB activation may be an early critical step leading to BPD.

Topics: Biomarkers; Birth Weight; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Interleukin-8; Intubation, Intratracheal; Leukocyte Count; NF-kappa B; Oxygen Inhalation Therapy; Pneumonia; Prognosis; Trachea

To improve monitoring of lung diseases, we analyzed cytokines in exhaled breath condensate (EBC). The main challenge in measurement of cytokines in EBC is the low protein content, which requires concentration steps that conflict with the need for excessive fluid required by most commonly used kits.. Here, a multiplex bead array for the detection of interleukins (IL) -1beta, -6, -8, -10, TNF-alpha, and IL-12p70 was modified and validated for analysis in EBC samples. Furthermore, 33 healthy volunteers and 11 patients with acute lung injury were investigated.. In patients with inflammatory lung diseases, cytokine levels for all investigated cytokines were higher in comparison to healthy smokers or healthy volunteers.. Multiplexed immunoassays in highly sensitive approaches allow for cytokine detection in EBC. We found significant differences between patients and controls for all investigated cytokines.

Topics: Adult; Aged; Breath Tests; Cytokines; Female; Flow Cytometry; Humans; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-6; Interleukin-8; Male; Middle Aged; Pneumonia; Reproducibility of Results; Respiration, Artificial; Respiratory Distress Syndrome; Smoking; Tumor Necrosis Factor-alpha

Chronic Pseudomonas aeruginosa lung infection is the major reason for premature death in patients with cystic fibrosis (CF). Infected patients experience a progressive deterioration of the lung tissue caused by a persistent accumulation of PMNs. We investigated if the pulmonary accumulation of PMNs is reflected as a migration of PMNs through the blood in chronically infected CF patients.. Blood and sputum samples from 37 stable, chronically (CF+P) and 6 non-infected (CF-P) CF patients without exacerbations were compared using FACS, leukocyte counting, and ELISA. Within the CF+P patients, the blood parameters were compared to the lung function (FEV1 and FVC) and to the sputum. Similar measurements were performed on 15 chronically infected CF patients before and after elective antibiotic treatment.. In the CF+P patients the concentration of G-CSF in the sera and PMNs in the blood was increased and correlated to poor lung function. However, only the concentration of G-CSF in the sera was correlated to the concentration of TNF-alpha in the sputum. After the antibiotic treatment, the lung function was improved and the concentration of PMNs in the blood and G-CSF in the sera was reduced.. G-CSF in the sera may contribute to the pulmonary inflammation in CF patients with chronic P. aeruginosa lung infection by regulating the number of PMNs available for migration and may be considered as an indicator of clinical status.

Topics: Adolescent; Adult; Blood Cell Count; Cell Movement; Cystic Fibrosis; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Neutrophils; Pneumonia; Pseudomonas Infections; Tumor Necrosis Factor-alpha

The susceptibility of neonates to pulmonary and systemic infection has been associated with the immaturity of both lung structure and the immune system. Surfactant protein (SP) D is a member of the collectin family of innate immune molecules that plays an important role in innate host defense of the lung.. We tested whether treatment with recombinant human SP-D influenced the response of the lung and systemic circulation to intratracheally administered Escherichia coli lipopolysaccharides.. After intratracheal lipopolysaccharide instillation, preterm newborn lambs were treated with surfactant and ventilated for 5 h.. Survival rate, physiologic lung function, lung and systemic inflammation, and endotoxin level in plasma were evaluated.. In control lambs, intratracheal lipopolysaccharides caused septic shock and death associated with increased endotoxin in plasma. In contrast, all lambs treated with recombinant human SP-D were physiologically stable and survived. Leakage of lipopolysaccharides from the lungs to the systemic circulation was prevented by intratracheal recombinant human SP-D. Recombinant human SP-D prevented systemic inflammation and decreased the expression of IL-1beta, IL-8, and IL-6 in the spleen and liver. Likewise, recombinant human SP-D decreased IL-1beta and IL-6 in the lung and IL-8 in the plasma. Recombinant human SP-D did not alter pulmonary mechanics following endotoxin exposure. Recombinant human SP-D was readily detected in the lung 5 h after intratracheal instillation.. Intratracheal recombinant human SP-D prevented shock caused by endotoxin released from the lung during ventilation in the premature newborn.

Topics: Animals; Animals, Newborn; Cause of Death; Disease Models, Animal; Endotoxins; Escherichia coli; Female; Gestational Age; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Intubation, Intratracheal; Lipopolysaccharides; Lung; Male; Pneumonia; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactants; Respiration, Artificial; Respiratory Mechanics; Sheep; Shock, Septic; Survival Rate

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

Macrophages release cytokines that may contribute to pulmonary inflammation in conditions such as chronic obstructive pulmonary disease. Thus, inhibition of macrophage cytokine production may have therapeutic benefit. p38 MAPK may regulate cytokine production, therefore, the effect of two p38 MAPK inhibitors, SB239063 and SD-282, on the release of TNF-alpha, GM-CSF and IL-8 from human macrophages was investigated.. Cytokine release was measured by ELISA. Immunoblots and mRNA expression studies were performed to confirm p38 MAPK isoform expression and activity. Macrophages were isolated from lung tissue of current smokers, ex-smokers and emphysema patients and exposed to lipopolysaccharide. These cells then released cytokines in a concentration-dependent manner.. SB239063 only inhibited TNF-alpha release (EC50 0.3 +/- 0.1 microM). Disease status had no effect on the efficacy of SB239063. SD-282 inhibited both TNF-alpha and GM-CSF release from macrophages (EC50 6.1 +/- 1.4 nM and 1.8 +/- 0.6 microM respectively) but had no effect on IL-8 release. In contrast, both inhibitors suppressed cytokine production in monocytes.. The differential effects of p38 MAPK inhibitors between macrophages and monocytes could not be explained by differences in p38 MAPK isoform expression or activity. However, the stability of TNF-alpha mRNA was significantly increased in macrophages compared to monocytes. These data suggest a differential involvement for p38 MAPK in macrophage cytokine production compared with monocytes. These effects are not due to lack of p38 activation or p38alpha expression in macrophages but may reflect differential effects on the stability of cytokine mRNA.

Topics: Blotting, Western; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Imidazoles; Indoles; Interleukin-8; Lipopolysaccharides; Macrophages, Alveolar; Male; Middle Aged; Mitogen-Activated Protein Kinase 12; Mitogen-Activated Protein Kinase 14; Monocytes; Pneumonia; Protein Kinase Inhibitors; Pyrimidines; RNA Stability; Tumor Necrosis Factor-alpha

To investigate whether FK506 (tacrolimus) can inhibit Fas- or A23187-induced interleukin (IL)-8 expression and cell death in A549 human alveolar epithelial cells, plus Fas-mediated acute lung injury in vivo.. Assays for IL-8, cell death, and caspase-3 activity were performed. A549 cells were treated with 25 micromol A23187 or 0.2 microg/ml agonistic anti-Fas antibody plus 5 ng/ml interferon-gamma (IFN-gamma). Tacrolimus was treated at 0.1-10 ng/ml. For in vivo experiment, agonistic anti-Fas antibody (Jo2) at 2.5 microg/g was intratracheally instilled into C57BL/6 mice. Neutrophils and protein contents in bronchoalveolar lavage (BAL) fluid were measured within 24 h of instillation. Mice were orally treated with 32 mg/kg of tacrolimus 24 h and 1 h prior to instillation.. Both Fas and A23187 caused significant IL-8 expression and cell death in A549 cells. Tacrolimus inhibited A23187-induced IL-8 expression alone while it protected all Fas-mediated responses. Mice instilled intratracheally with Jo2 at 2.5 microg/g had significant increases in neutrophils, protein contents in BAL fluid and in expression of chemoattractants for neutrophils. These increases were reversed by tacrolimus.. Tacrolimus serves as a therapeutic option for improving lung injury through inhibition of Fas-mediated inflammation.

Topics: Animals; Antibodies, Monoclonal; Calcimycin; Caspase 3; Cell Death; Cell Line; Dose-Response Relationship, Drug; fas Receptor; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Humans; Immunosuppressive Agents; Inflammation; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Pneumonia; Pulmonary Alveoli; Respiratory Mucosa; RNA, Messenger; Tacrolimus

In this study, we sought the possibility of a new therapeutic strategy for dampening endotoxin-induced inflammation using soluble form of extracellular rTLR4 domain (sTLR4) and soluble form of rMD-2 (sMD-2). Addition of sTLR4 plus sMD-2 was significantly effective in inhibiting LPS-elicited IL-8 release from U937 cells and NF-kappaB activation in the cells transfected with TLR4 and MD-2 when compared with a single treatment with sTLR4 or sMD-2. Thus, we investigated the role of the extracellular TLR4 domain in interaction of lipid A with MD-2. Biotinylated sTLR4 failed to coprecipitate [(3)H]lipid A when it was sedimented with streptavidin-agarose, demonstrating that the extracellular TLR4 domain does not directly bind lipid A by itself. The amounts of lipid A coprecipitated with sMD-2 significantly increased when coincubated with sTLR4, and sTLR4 increased the affinity of lipid A for the binding to sMD-2. Soluble CD14 is required for the sTLR4-stimulated increase of lipid A binding to sMD-2. We also found that addition of sTLR4 plus sMD-2 inhibited the binding of Alexa-conjugated LPS to the cells expressing TLR4 and MD-2. Murine lungs that had received sTLR4 plus sMD-2 with LPS did not show any findings indicative of interstitial edema, neutrophil flux, and hemorrhage. Co-instillation of sTLR4 plus sMD-2, but not sTLR4 or sMD-2 alone, significantly decreased neutrophil infiltration and TNF-alpha levels in bronchoalveolar lavage fluids from LPS-treated mice. This study provides novel usage of sTLR4 and sMD-2 as an antagonist against endotoxin-induced pulmonary inflammation.

Topics: Animals; Cell Line; Cell Membrane; Extracellular Fluid; Female; Interleukin-8; Lipid A; Lipopolysaccharide Receptors; Lipopolysaccharides; Lymphocyte Antigen 96; Mice; Mice, Inbred BALB C; NF-kappa B; Pneumonia; Protein Binding; Recombinant Proteins; Toll-Like Receptor 4

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

Lung disease in cystic fibrosis (CF) is established in early childhood with recurrent bacterial infections and inflammation. Using spirometry, the effect of this early lung damage cannot be measured until a child is 6 years of age when some irreversible lung damage may already have occurred. Techniques for measurement of lung function in infants and young children include raised volume rapid thoracic compression (RVRTC) and low frequency forced oscillation (LFFOT). The aim of this study was to investigate the role of inflammation and infection on a population of infants and young children with CF and to determine whether lung function in this population (measured by LFFOT) is affected by early lung disease.. Lung function was measured by LFFOT in 24 children undergoing bronchoalveolar lavage (BAL) on 27 occasions as part of an annual programme while still under general anaesthesia. Following lung function testing, three aliquots of saline were instilled into the right middle or lower lobe. The first aliquot retrieved was processed for the detection of microbes, and the remaining aliquots were pooled to assess inflammatory markers (cytology, IL-8, NE, LTB(4)).. Inflammation (percentage and number of neutrophils) was significantly higher in children with infections (p<0.001, p = 0.04, respectively), but not in those with symptoms. Several markers of inflammation significantly correlated with LFFOT parameters (R, G, and eta).. Infections and inflammation are established before symptoms are apparent. Inflammation is correlated with measures of parenchymal changes in lung function measured by LFFOT.

Topics: Airway Resistance; Bronchoalveolar Lavage Fluid; Child, Preschool; Cystic Fibrosis; Female; Humans; Infant; Interleukin-8; Male; Oscillometry; Pneumonia; Respiratory Function Tests; Respiratory Tract Infections

We had previously demonstrated that lung cancer cells, upon contact with macrophages, could be induced to secrete angiogenic factors to promote tumor angiogenesis. In this study, we focused on the paracrine and autocrine regulation of interleukin (IL)-8 expression in sensitized lung cancer cells after interacting with macrophages. We found that the IL-8 mRNA expression in lung cancer cells significantly increased after coculture with phorbol myristate acetate-treated THP-1 cells and human primary lung macrophages. Fresh lung cancer CL1-5 cells cocultured with macrophage-sensitized lung cancer cells still had a 35% of increase in IL-8 mRNA expression. The addition of anti-inflammatory agents pyrrolidine dithiocarbamate, pentoxifylline, aspirin, and dexamethasone could completely suppress the expression of IL-8 mRNA in fresh/sensitized lung cancer cell cocultures. Human recombinant tumor necrosis factor (TNF)-alpha and IL-1alpha could induce IL-8 expression in lung cancer cells in a dose-dependent manner. Neutralization with TNF-alpha and IL-1alpha antibodies in cocultures decreased the levels of IL-8 expression in sensitized lung cancer cells. Nuclear factor-kappaB transcriptional activity was also suppressed by the same antibodies, as confirmed by a reporter gene assay and the electrophoretic mobility shift assay. Our results highly suggest that both autocrine and paracrine regulation are involved in IL-8 expression of lung cancer cells cocultured with macrophage. Also, the regulations of IL-8 expression in lung cancer cells were through the nuclear factor-kappaB pathway and modulated by TNF-alpha and IL-1alpha.

Topics: Antibodies; Autocrine Communication; Carcinogens; Coculture Techniques; Dose-Response Relationship, Drug; Fibroblasts; Gene Expression; Humans; Interleukin-1; Interleukin-8; Lung Neoplasms; Macrophages, Alveolar; Monocytes; NF-kappa B; Paracrine Communication; Pneumonia; Respiratory Mucosa; RNA, Messenger; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Septic acute lung injury (ALI) causes high morbidity and mortality in intensive care service as a result of biotrauma and dysfunction in the lungs and other organ systems. We hypothesized that surfactant and/or inhaled nitric oxide (iNO) may have different effects in modulation of inflammatory injury in septic ALI. Twenty-four healthy, 6-9 kg piglets were anesthetized, and intraperitoneally injected with Escherichia coli, followed by a low tidal volume ventilation until sepsis and ALI developed within 4-6 h. They were then randomly treated in groups (n=6 each) as: control (C), inhaled NO at 10 ppm (NO), surfactant at 100mg/kg (Surf), or both surfactant and iNO (SNO). A normal control group (N) was sham-injected and similarly ventilated. Over the 24 h of treatment period, both Surf, and SNO groups had significantly improved PaO2/FiO2, dynamic compliance and resistance of respiratory system. At 24h, the best alveolar aeration and least protein leakage, the lowest wet-to-dry lung weight ratio and lung injury score were found in SNO. Activity of nuclear factor kappa B (NF-kappaB) and myeloperoxidase, interleukin 8 mRNA expression and melondialdehyde were significantly increased, and IL-10 mRNA decreased, in lung tissue of the C group, but were significantly altered in the SNO group, and moderately altered in either NO or Surf group. We conclude that the effects of lung protection by surfactant and/or iNO in this model may be different in modulation of inflammatory cytokine mRNA expression and activity of NF-kappaB, and iNO did not have adverse effects.

Topics: Acute Disease; Administration, Inhalation; Analysis of Variance; Animals; Bronchoalveolar Lavage Fluid; Electrophoretic Mobility Shift Assay; Escherichia coli Infections; Fibroblast Growth Factor 7; Interleukin-10; Interleukin-8; Lung; Male; Malondialdehyde; Methemoglobin; NF-kappa B; Nitrates; Nitric Oxide; Nitrites; Oligonucleotide Probes; Peroxidase; Pneumonia; Protein Binding; Pulmonary Surfactants; Pulmonary Ventilation; Respiratory Insufficiency; RNA, Messenger; Swine

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 aim of this study was to determine whether nasal inflammation reflects pulmonary inflammation in young children with cystic fibrosis (CF), as assessed by inflammatory markers in nasal wash (NW) and bronchoalveolar lavage (BAL), respectively.. CF patients younger than 6 years of age who were to undergo bronchoscopy for routine BAL from May 2000 to October 2001 were recruited for this study. NW was collected immediately after the patient was sedated for bronchoscopy. Total cell counts (TCC), differential cell counts and interleukin (IL)-8 levels (enzyme-linked immunosorbent assay) were assessed in NW and BAL.. In total, 19 children with CF (mean age, 1.9 years; SD, 1.7 years) were included in the study. There was a significant relationship between IL-8 and the percentages of neutrophils in NW (r (2) = 0.76; P < 0.001) and in BAL fluid (r 2 = 0.62; P = 0.006). Similarly, IL-8 concentrations in the NW correlated with those in the BAL (r 2 = 0.48; P = 0.036) and neutrophil percentages in NW correlated significantly with those in BAL (r 2 = 0.7; P = 0.004).. When measured under 'ideal' conditions, nasal IL-8 reflects lower airway levels and may reflect the inflammatory stimulus that results in neutrophilic inflammation. These data encourage further assessment of nasal wash under clinically appropriate conditions to determine its utility for assessing inflammation in young children with CF.

Topics: Biomarkers; Bronchoalveolar Lavage Fluid; Cell Count; Chemokines, CXC; Child, Preschool; Cystic Fibrosis; Early Diagnosis; Female; Humans; Infant; Interleukin-8; Male; Nasal Lavage Fluid; Nasal Provocation Tests; Neutrophils; Pneumonia

Oxidative stress seems to contribute to cardiopulmonary bypass (CPB)-related postoperative complications. Pediatric patients are particularly prone to these complications. With this in mind, we measured oxidative stress markers in blood plasma of 20 children undergoing elective heart surgery before, during, and up to 48 h after cessation of CPB, along with inflammatory parameters and full analysis of iron status. Ascorbate levels were decreased by approximately 50% (P < 0.001) at the time of aorta cross-clamp removal (or pump switch-off in 4 patients with partial CPB), and associated with corresponding increases in dehydroascorbate (P < 0.001, r = -0.80) and malondialdehyde (P < 0.01, r = -0.59). In contrast to the immediate oxidative response, peak levels of IL-6 and IL-8 were not observed until 3-12 h after CPB cessation. The early loss of ascorbate correlated with duration of CPB (P < 0.002, r = 0.72), plasma hemoglobin after cross-clamp removal (P < 0.001, r = 0.70), and IL-6 and IL-8 levels at 24 and 48 h after CPB (P < 0.01), but not with postoperative lactate levels, strongly suggesting that hemolysis, and not inflammation or ischemia, was the main cause of early oxidative stress. The correlation of ventilation time with early changes in ascorbate (P < 0.02, r = 0.55), plasma hemoglobin (P < 0.01, r = 0.60), and malondialdehyde (P < 0.02, r = 0.54) suggests that hemolysis-induced oxidative stress may be an underlying cause of CPB-associated pulmonary dysfunction. Optimization of surgical procedures or therapeutic intervention that minimize hemolysis (e.g., off-pump surgery) or the resultant oxidative stress (e.g., antioxidant treatment) should be considered as possible strategies to lower the rate of postoperative complications in pediatric CPB.

Topics: Ascorbic Acid; C-Reactive Protein; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Child; Child, Preschool; Dehydroascorbic Acid; Heart Defects, Congenital; Hemolysis; Humans; Infant; Interleukin-6; Interleukin-8; Iron; Ischemia; Malondialdehyde; Neutrophils; Oxidative Stress; Pneumonia; Postoperative Complications; Prospective Studies

Respiratory syncytial virus (RSV) is an important cause of upper respiratory infections and is known to play a causal role in the pathogenesis of rhinitis, sinusitis, acute otitis media, and pneumonia. RSV appears to prime the respiratory tract to secondary inciting events, such as bacterial or antigen challenges. To study the proinflammatory priming effects of RSV infection, cytokine expression was measured in well-differentiated human nasal epithelial cells (WD-NE) after RSV infection alone or after subsequent tumor necrosis factor (TNF)-alpha stimulation.. In vitro investigation.. Human nasal epithelial cells were obtained from surgical specimens and allowed to differentiate in air-liquid interface cultures until ciliation and mucus production were evident. Two experimental paradigms were used. First, accumulation of cytokines in the media was measured by real-time, quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay after RSV infection alone. In the second set of experiments, cytokines were also measured after TNF-alpha stimulation in both RSV-infected and uninfected cultures.. RSV infection of WD-NE resulted in significant accumulations of interleukin (IL)-6, IL-8, and RANTES when compared with findings in control samples. Real-time, quantitative RT-PCR demonstrated significant increases in IL-8 gene expression following RSV infection when compared to controls. Secondary TNF-alpha stimulation following well-established (i.e., 72 h) RSV infection induced marked increases in IL-6, IL-8, and RANTES when compared with both RSV infection alone and TNF-alpha stimulation alone.. These findings suggest that RSV infection primes nasal epithelial cells to secondary proinflammatory challenge, resulting in a hyperimmune response. RSV-induced priming of a hyperimmune response may be important in the pathogenesis of sinusitis, acute otitis media, and pneumonia.

Topics: Chemokine CCL5; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Interleukin-6; Interleukin-8; Nasal Mucosa; Otitis Media; Pneumonia; Respiratory Syncytial Virus Infections; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha

Cardiopulmonary bypass (CPB) is associated with an inflammatory process that leads to lung injury. In this study, we hypothesized that inhaled nitric oxide (INO) possesses the ability to modulate CPB-induced inflammation. Fifteen male pigs were randomly divided into 3 groups: Sham, CPB+LPS (CPB and lipopolysaccharide), and CPB+LPS+INO. INO (20 parts per million) was administered for 24 h after anesthesia. CPB was performed for 90 min, and LPS was infused (1 microg/kg) after CPB. Bronchoalveolar lavage (BAL) fluid and blood were collected at T0 (before CPB), at 4 h, and at 24 h. At 24 h, BAL interleukin-8 (IL-8) levels were not increased as expected in the CPB+LPS group compared with the Sham group, but they were reduced significantly in the CPB+LPS+INO group. Cell hypo reactivity observed in the groups receiving LPS also seemed to downregulate endothelial nitric oxide synthase NOS protein expression relative to the Sham group. Nitrite and nitrate (NOx) concentrations were decreased significantly in the groups without INO. Moreover, animals treated with INO showed higher rates of pulmonary apoptosis compared with their respective controls. These results demonstrate that NOx production is reduced after CPB and that INO acts on the inflammatory process by diminishing neutrophils and their major chemoattractant, IL-8. INO also increases cell apoptosis in the lungs under inflammatory conditions, which may explain, in part, how it resolves pulmonary inflammation.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Apoptosis; Bronchoalveolar Lavage Fluid; Cardiopulmonary Bypass; Disease Models, Animal; Interleukin-8; Lipopolysaccharides; Lung; Male; Neutrophils; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Pneumonia; Swine

In an ovalbumin (OVA)-driven murine model of allergic pulmonary inflammation, we have shown previously that moderate-intensity aerobic exercise training attenuates inflammatory responses, disease progression, and NF-kappaB activation within the sensitized lung. Glucocorticoids (GCs), potent anti-inflammatory agents, have been shown to alter transcriptional events that are important in asthmatic pathogenesis, such as NF-kappaB activation. Notably, exercise training can alter the production and signaling capacity of endogenous GCs. Because GCs exert their anti-inflammatory effects through binding to intracellular glucocorticoid receptors (GRs), we examined the role of the GR in facilitating the anti-inflammatory effects of exercise. Results show that, in exercised OVA-sensitized mice, treatment with the GR antagonist RU486 blocked the exercise-induced reductions in cellular infiltration of the airways (p < .05), KC and soluble VCAM-1 protein levels in the bronchoalveloar lavage fluid (p < .05), and NF-kappaB translocation and DNA binding within the lung to levels similar to those observed in sedentary OVA-sensitized mice. Importantly, RU486 treatment also blocked exercise-induced increases in GR nuclear translocation to the levels seen in sensitized control mice. Together, these results suggest that GR nuclear translocation and NF-kappaB activation play roles in mediating the anti-inflammatory effects of exercise in allergen-mediated lung pathology.

Topics: Aerobiosis; Allergens; Animals; Bronchoalveolar Lavage Fluid; DNA; Electrophoretic Mobility Shift Assay; Female; Hormone Antagonists; Inflammation; Interleukin-8; Mice; Mice, Inbred BALB C; Mifepristone; NF-kappa B; Ovalbumin; Physical Conditioning, Animal; Physical Exertion; Pneumonia; Receptors, Glucocorticoid; Sample Size; Vascular Cell Adhesion Molecule-1

Mycoplasma pneumoniae is a common cause of lower respiratory disease. Several studies have suggested that respiratory infection by M pneumoniae is associated with reactive airway disease and asthma. Interleukin (IL)-8 has been suggested to have a role in the pathogenesis of the allergic inflammation of bronchial asthma, and is well known to be expressed in bronchial epithelial cells.. An examination was carried out into the effect of M pneumoniae lysate (MPL) and the role of mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinase (ERK) on IL-8 expression in human lung epithelial cells. A549 cells were seeded at a density of 5 x 10(4) cells per well and incubated in basal medium for a further 24 h. IL-8 levels were determined by an enzyme-linked immunosorbent assay. MAPK phosphorylation was assessed by Western blotting.. In A549 cells, MPL induced IL-8 release in a time- and dose-dependent manner. Pretreatment with PD 98059, which blocks the activation of MAPK/ERK kinase 1, inhibited MPL-induced IL-8 production by 64.4% at 25 micromol/L. Stimulation of A549 cells by MPL also caused an increase in the activity of ERK, compared with the nonstimulated cells. The MPL stimulation had no effect on the activities of p38.. These observations suggest that activation of ERK by MPL may be one of the mechanisms that result in an increase of the production of IL-8.

Topics: Blotting, Western; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Gene Expression Regulation, Enzymologic; Humans; Interleukin-8; Lung; MAP Kinase Kinase Kinase 3; Mitogen-Activated Protein Kinases; Mycoplasma pneumoniae; Phosphorylation; Pneumonia; Reverse Transcriptase Polymerase Chain Reaction

Biochemical and inflammatory markers in pleural inflammation were evaluated in pediatric cases of parapneumonic effusions, and interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha concentrations were tested for possible differentiation of the complicated nature of effusions.. Twenty-eight patients (12 female) who were admitted to Hacettepe University Childrens' Hospital over a 2-year period were included in the study.. Patients were grouped according to the stage of effusion. Pleural fluid leukocyte count, neutrophil ratio, pH, protein, glucose levels, lactate dehydrogenase (LDH) levels, TNF-alpha levels, IL-8 levels, and nitrite levels were obtained.. Of these patients, 13 had empyema, 10 had complicated parapneumonic effusions (CPEs), and 5 had uncomplicated parapneumonic effusions (UPEs). Protein and glucose levels decreased, leukocyte count, neutrophil ratio, TNF-alpha levels, nitrite levels, and IL-8 levels increased progressively as the stage of the disease progressed. IL-8 levels, but not TNF-alpha and nitrite levels, were statistically different among the groups. IL-8, TNF-alpha, and nitrite levels all correlated positively with each other (all p < or = 0.001), and pH correlated negatively with these markers (all p < or = 0.001). At a cutoff value of 76.6 pg/mL, TNF-alpha discriminated between CPEs and UPEs with a sensitivity of 50%, a specificity of 100%, and an accuracy of 78%. At a cutoff value of 701.6 pg/mL, IL-8 differentiated CPE and UPE with a sensitivity of 80%, a specificity of 80%, and an accuracy of 86%.. Progressive changes in common biochemical markers (ie, pH, and protein, glucose, and LDH levels) are interrelated during stages of pleural inflammation. IL-8 may be used as an alternative marker for discriminating between CPEs and UPEs in pediatric parapneumonic effusions.

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Female; Humans; Infant; Interleukin-8; L-Lactate Dehydrogenase; Male; Nitric Oxide; Pleural Effusion; Pneumonia; Proteins; Tumor Necrosis Factor-alpha

In order to define the significance of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) upon progression from sepsis or severe sepsis to septic shock a prospective study was designed with 90 enrolled patients with septic syndrome due to ventilator-associated pneumonia. Blood was sampled on seven consecutive days upon initiation of symptoms and concentrations of tumour necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), IL-8 and sTREM-1 were estimated in serum by an enzymeimmunoassay. No differences in concentrations of TNFalpha, IL-6 and IL-8 were found between patients with sepsis, severe sepsis and septic shock on the first day of presentation of symptoms. Patients presenting with septic shock had concentrations of sTREM-1 significantly higher than both patients with sepsis and severe sepsis on the first day; no difference was found between patients with sepsis and severe sepsis. A positive correlation was detected between sTREM-1 and the white blood cell count. Serum levels of sTREM-1 were significantly lower in patients where VAP resolved compared to those where VAP did not resolve; similar findings were noted between patients who eventually survived and those who died. IL-6 followed the kinetics of sTREM-1 in correlation to patients's prognosis; levels of TNFalpha and IL-8 were unrelated to prognosis. It is concluded that sTREM-1 is particularly increased upon evolution from sepsis or severe sepsis to septic shock. Its sustained increase is an indication of poor outcome. The underlined pathophysiological role of sTREM-1 for the transition from sepsis or severe sepsis to septic shock might constitute a novel target for immunomodulatory therapy.

Topics: Aged; Disease Progression; Female; Humans; Interleukin-6; Interleukin-8; Male; Membrane Glycoproteins; Middle Aged; Pneumonia; Prospective Studies; Receptors, Immunologic; Sepsis; Shock, Septic; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

Low-density gas mixtures, such as heliox, were shown to reduce the work of breathing and facilitate the distribution of inspired gas. Since supplemental ventilatory and oxygen requirements may lead to pulmonary inflammation and structural alterations, we hypothesized that by reducing these requirements, heliox breathing may attenuate the acute inflammatory and structural changes associated with acute lung injury. Spontaneously breathing neonatal pigs were anesthetized, instrumented, supported with continuous positive airway pressure (CPAP), injured with oleic acid, and randomized to nitrox (n = 6) or heliox (n = 5).F(I)O(2) was titrated for pulse oximetry (SpO(2)) 95 +/- 2% for 4 hr. Gas exchange and pulmonary mechanics were measured. Lungs were analyzed for myeloperoxidase (MPO), interleukin-8 (IL-8), and histomorphometery. Relationships between physiologic indices and cumulative lung structure and inflammatory indices were evaluated. With heliox, compliance was significantly greater, while tidal volume, frequency, minute ventilation, F(I)O(2), arterial carbon dioxide tension (PaCO(2)), MPO, and IL-8 were significantly lower compared to nitrox. The expansion index and number of exchange units were significantly greater with heliox, while the exchange unit area (EUA) was smaller. MPO was significantly and positively correlated with F(I)O(2) (r = 0.76) and EUA (r = 0.63), and negatively correlated with number of open exchange units/field (r = -0.73). Compared to breathing nitrox, these data indicate that heliox improved the distribution of inspired gas, thereby recruiting more gas exchange units, improving gas exchange efficiency, reducing ventilatory and oxygen requirements, and attenuating lung inflammation. These data suggest that heliox breathing may have the combined therapeutic benefits of attenuating lung inflammation by reducing mechanical and oxidative stress in the clinical management of acute lung injury.

Topics: Animals; Animals, Newborn; Continuous Positive Airway Pressure; Disease Models, Animal; Helium; Interleukin-8; Lung; Nitrogen; Oximetry; Oxygen; Peroxidase; Pneumonia; Respiratory Function Tests; Respiratory Mechanics; Swine

CXC chemokine receptor 2 (CXCR2) antagonism alone can reduce neutrophil infiltration of some inflammatory sites, but the CXCR1 and CXCR2 critically regulate neutrophil responses to Glu-Leu-Arg-CXC chemokines. Herein, we assessed a combined CXCR1/CXCR2 antagonist, CXC chemokine ligand 8(3-74) [CXCL8(3-74)]K11R/G31P, for its ability to blunt neutrophil-influx and ancillary pathology in severe endotoxemia. Guinea pigs challenged via the airways with Escherichia coli lipopolysaccharide (LPS; 5 microg/kg) were given CXCL8(3-74)K11R/G31P (subcutaneously) before or after the onset of symptoms. The airways of the LPS-challenged animals contained high levels of endogenous pyrogens interleukin (IL)-1 and tumor necrosis factor (TNF) at 2-4 h, and the animals developed pyrexia, which peaked at approximately 6 h; strong pulmonary, neutrophilic inflammation; and marked pleural hemorrhagic consolidation, as assessed at approximately 15 h. CXCL8(3-74)K11R/G31P treatment before LPS challenge reduced lung pleural hemorrhagic consolidation and airway neutrophilia by >90% and essentially abrogated the IL-1, TNF, and fever responses. When given 3 or 6 h after LPS, CXCL8(3-74)K11R/G31P reduced pulmonary neutrophilia by up to 85% and pleural hemorrhagic consolidation by 50-85%. The 3-h treatment reduced the 6- to 24-h fever response to background. Delays of 6 or 9 h in beginning treatment had significant effects on the fever decay curve, but only the 6-h treatment had a significant effect on the 24-h fever. These results indicate that combined CXCR1/CXCR2 antagonism can have significant therapeutic effects on pulmonary inflammation and hemorrhage, as well as pyrexia in endotoxemic animals.

Topics: Animals; Chemokines, CXC; Chemotaxis, Leukocyte; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxemia; Female; Fever; Guinea Pigs; Hemorrhage; Interleukin-8; Lipopolysaccharides; Lung; Neutrophil Infiltration; Neutrophils; Peptide Fragments; Pneumonia; Pulmonary Artery; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Time Factors; Treatment Outcome

Pulmonary intravascular macrophages (PIMs) are present in ruminants and horses. These species are highly sensitive to acute lung inflammation compared with non-PIM-containing species such as rats and humans. There is evidence that rats and humans may also recruit PIMs under certain conditions. We investigated precise contributions of PIMs to acute lung inflammation in a calf model. First, PIMs were recognized with a combination of in vivo phagocytic tracer Monastral blue and postembedding immunohistology with anti-CD68 monoclonal antibody. Second, gadolinium chloride depleted PIMs within 48 h of treatment (P < 0.05). Finally, PIMs contain TNF-alpha, and their depletion reduces cells positive for IL-8 (P < 0.05) and TNF-alpha (P < 0.05) and histopathological signs of acute lung inflammation in calves infected with Mannheimia hemolytica. The majority of IL-8-positive inflammatory cells in lung septa of infected calves were platelets. Platelets from normal cattle contained preformed IL-8 that was released upon in vitro exposure to thrombin (P < 0.05). These novel data show that PIMs, as the source of TNF-alpha, promote recruitment of inflammatory cells including IL-8-containing platelets to stimulate acute inflammation and pathology in lungs. These data may also be relevant to humans due to our ability to recruit PIMs.

Topics: Acute Disease; Animals; Blood Platelets; Cattle; Interleukin-8; Leukocyte Count; Macrophages, Alveolar; Male; Mannheimia haemolytica; Pasteurellaceae Infections; Pneumonia; Tumor Necrosis Factor-alpha

Individuals with alpha(1)-antitrypsin (alpha(1)-AT) deficiency are at risk for early-onset destructive lung disease as a result of insufficient lower respiratory tract alpha(1)-AT and an increased burden of neutrophil products such as elastase. Human neutrophil peptides (HNP), the most abundant protein component of neutrophil azurophilic granules, represent another potential inflammatory component in lung disease characterized by increased numbers of activated or deteriorating neutrophils. The purpose of this study was to determine the role of HNP in lower respiratory tract inflammation and destruction occuring in alpha(1)-AT deficiency. alpha(1)-AT-deficient individuals (n = 33) and healthy control subjects (n = 21) were evaluated by bronchoalveolar lavage. HNP concentrations were significantly higher in alpha(1)-AT-deficient individuals (1,976 +/- 692 vs. 29 +/- 12 nM, P < 0.0001), and levels correlated with markers of neutrophil-mediated lung inflammation. In vitro, HNP produced a dose-dependent cytotoxic effect on alveolar macrophages and stimulated production of the potent neutrophil chemoattractants leukotriene B(4) and interleukin-8 by alveolar macrophages, with a 6- to 10-fold increase in chemoattractant production over negative control cultures (P < 0.05). A synergistic effect was noted between HNP and neutrophil elastase with regard to leukotriene B(4) production. Importantly, the proinflammatory effects of HNP were blocked by alpha(1)-AT. HNP likely play an important role in amplifying and maintaining neutrophil-mediated inflammation in the lungs.

Topics: Adult; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; alpha-Defensins; Bronchoalveolar Lavage Fluid; Cells, Cultured; Cytotoxicity Tests, Immunologic; Dose-Response Relationship, Immunologic; Female; Humans; Interleukin-8; Leukocyte Elastase; Leukotriene B4; Macrophages, Alveolar; Male; Middle Aged; Neutrophils; Pneumonia

Previously, we have reported marked pulmonary inflammation in infants who develop chronic lung disease of prematurity. We revisited these infants who did not have clinical or laboratory evidence of infection and searched for Ureaplasma urealyticum, group B streptococci, and other microbes by reverse transcription-PCR performed on RNA extracted from 93 bronchoalveolar lavage samples. From infants ventilated for respiratory distress syndrome, 6 (gestation, 28 wk; birthweight, 880 g) were positive for U. urealyticum and 11 (25 wk, 800 g) were negative. Five (83%) positive and four (36%) negative infants developed chronic lung disease. Each infant was colonized with either biovar 1 or biovar 2 but not both. U. urealyticum was very weakly detectable in two infants on d 1 but was detected in five of six infants at d 10. Furthermore, pulmonary neutrophils, alveolar macrophages, soluble intercellular adhesion molecule-1, and IL-1beta on d 10 and IL-6 and IL-8 at d 1 were significantly increased in the positive group. A variety of organisms were identified in six samples between 14 and 21 d of age, but all samples were negative for group B streptococci. Our data suggest that U. urealyticum colonization is associated with the development of pulmonary inflammation in infants who subsequently develop chronic lung disease.

Topics: Acute Disease; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Chronic Disease; Humans; Infant, Newborn; Infant, Premature; Interleukin-1; Interleukin-6; Interleukin-8; Pneumonia; Risk Factors; RNA, Bacterial; RNA, Ribosomal; Ureaplasma Infections; Ureaplasma urealyticum

We have been interested in elucidating how simultaneous stimuli modulate inflammation-related signal transduction pathways in lung parenchymal cells. We previously demonstrated that exposing respiratory epithelial cells to 95% oxygen (hyperoxia) synergistically increased tumor necrosis factor-alpha (TNF-alpha)-mediated activation of NF-kappaB and NF-kappaB-dependent gene expression by a mechanism involving increased activation of IkappaB kinase (IKK). Because the signal transduction mechanisms induced by IL-1beta are distinct to that of TNF-alpha, herein we sought to determine whether hyperoxia modulates IL-1beta-dependent signal transduction. In A549 cells, simultaneous treatment with hyperoxia and IL-1beta caused increased activation of IKK, prolonged the degradation of IkappaBalpha, and prolonged the nuclear translocation and DNA binding of NF-kappaB compared with cells treated with IL-1beta alone in room air. Hyperoxia did not affect IL-1beta-dependent degradation of the interleukin receptor-associated kinase differently from treatment with IL-beta alone. In contrast to the effects on the IKK/IkappaBalpha/NF-kappaB pathway, simultaneous treatment with hyperoxia and IL-1beta did not augment NF-kappaB-dependent gene expression compared with treatment with IL-1beta alone. Similar observations were made in a different human respiratory epithelial cell line, BEAS-2B cells. In addition, simultaneous treatment with hyperoxia and IL-1beta caused hyperphosphorlyation of the NF-kappaB p65 subunit compared with treatment with IL-1beta alone. In summary, concomitant treatment of A549 cells with hyperoxia and IL-1beta augments activation of IKK, prolongs degradation of IkappaBalpha, and prolongs nuclear translocation and DNA binding of NF-kappaB. This activation, however, is not coupled to increased expression of NF-kappaB-dependent genes, and the mechanism of this decoupling is not related to decreased phosphorylation of p65.

Topics: Cell Line; Epithelial Cells; Gene Expression; Humans; Hyperoxia; I-kappa B Kinase; I-kappa B Proteins; Interleukin-1; Interleukin-1 Receptor-Associated Kinases; Interleukin-8; NF-kappa B; NF-KappaB Inhibitor alpha; Oxidative Stress; Phosphorylation; Pneumonia; Promoter Regions, Genetic; Protein Kinases; Protein Serine-Threonine Kinases; Respiratory Mucosa; Signal Transduction; Transcription Factor RelA

Preterm delivery is frequently preceded by chorioamnionitis, resulting in exposure of the fetal lung to inflammation. We hypothesized that ventilation of the antenatally inflamed lung would result in amplification of the lung injury. Therefore, we induced fetal lung inflammation with intra-amniotic endotoxin (10 mg of Escherichia coli 055:B5) 4 days before premature delivery at 130 days of gestation. Lung function and lung inflammation after surfactant treatment and 4 h of mechanical ventilation were evaluated. Inflammatory cell numbers in amniotic fluid were increased >10-fold by antenatal endotoxin exposure. Antenatal endotoxin exposure had minimal effects on blood pressure, heart rate, lung compliance, and blood gas values. The endotoxin-exposed lungs required higher ventilation pressures. Ventilation did not increase the number of inflammatory cells or the protein in bronchoalveolar lavage fluid of the endotoxin-exposed animals above that measured in endotoxin-exposed fetuses that were not ventilated. IL-1beta, IL-6, and IL-8 mRNA in cells from bronchoalveolar lavage fluid were increased by antenatal endotoxin exposure but not changed by ventilation. IL-1beta and IL-8 protein was increased in lung tissue by 4 h of ventilation. Very little inflammation was induced by ventilation in this premature lamb model of surfactant treatment and gentle ventilation. After lung inflammation was induced by intra-amniotic endotoxin injection, ventilation did not increase lung injury.

Topics: Animals; Biomarkers; Birth Weight; Bronchopulmonary Dysplasia; Chorioamnionitis; Endotoxins; Female; Humans; Infant, Newborn; Interleukin-1; Interleukin-6; Interleukin-8; Obstetric Labor, Premature; Pneumonia; Pregnancy; Respiration, Artificial; RNA, Messenger; Sheep

The impact of high frequency oscillatory ventilation (HFOV) compared with intermittent mandatory ventilation (IMV) on oxygenation and pulmonary inflammatory response was studied in a surfactant depleted piglet model. After establishment of lung injury by bronchoalveolar lavage, piglets either received HFOV (n =5) or IMV (control; n = 5) for eight hours. PaO(2) was higher and mean pulmonary arterial pressure (MPAP) was lower with HFOV (HFOV versus control, mean +/- SEM; endpoint PaO(2): 252 +/- 73 versus 68 +/- 8.4 mm Hg; p < 0.001; MPAP: 22 +/- 2.3 versus 34 +/- 2.5 mm Hg; p < 0.01). mRNA expression of interleukin (IL)-1 beta, IL-6, IL-8, IL-10, TGF-beta 1, Endothelin-1, and adhesion molecules (E-selectin, P-selectin, ICAM-1) in lung tissue was quantified by real time PCR normalized to beta-actin and hypoxanthine-guanine-phosphoribosyl-transferase (HPRT). mRNA expression of all cytokines and adhesion molecules/HPRT was higher in controls (e.g.: HFOV versus control, mean +/- SEM; IL-1 beta/HPRT: 1.6 +/- 0.3 versus 23.1 +/- 8.6 relative units (RU), p < 0.001; IL-8/HPRT: 8.5 +/- 2.0 versus 63.5 +/- 15.2 RU, p < 0.001). IL-8/HPRT gene expression was quantified in microdissected single cells. With HFOV, IL-8 gene expression was highly reduced in alveolar macrophages: 10 +/- 3.4 copies IL-8 mRNA/copy HPRT mRNA versus 356 +/- 142; p < 0.05 (bronchiolar epithelial cells: 33 +/- 16 versus 208 +/- 108; alveolar septum: 2.1 +/- 1.3 versus 26 +/- 11; bronchiolar smooth muscle cells: 1.3 +/- 0.3 versus 2.8 +/- 1.0; vascular smooth muscle cells: 0.7 +/- 0.3 versus 1.1 +/- 0.4). In conclusion, HFOV improved oxygenation, reduced pulmonary arterial pressure and attenuated pulmonary inflammatory response.

Topics: Animals; Gene Expression; High-Frequency Ventilation; Hydrogen-Ion Concentration; Hypoxanthine Phosphoribosyltransferase; Interleukin-1; Interleukin-10; Interleukin-8; Lung; Macrophages, Alveolar; Muscle, Smooth, Vascular; Pneumonia; Pulmonary Circulation; Pulmonary Gas Exchange; Pulmonary Surfactants; RNA, Messenger; Swine

There is conflicting evidence in the literature as to the predominant mechanism and also the compositional element(s) that drives the pulmonary inflammatory response of ambient particulate matter (PM). We have investigated the inflammogenic potential of coarse (2.5-10 microm) and fine (<2.5 microm) PM from both a rural and an industrial location in Germany, using bronchoalveolar lavage (BAL) of rat lungs 18 h post intratracheal instillation with PM. Irrespective of the sampling location, the coarse fraction of PM(10) but not its fine counterpart caused neutrophilic inflammation in rat lungs, in the absence of any severe pulmonary toxicity as indicated by the lack of an increase in lavage protein and lactate dehydrogenase levels. The rural sample of coarse PM also caused a significant increase in the tumor necrosis factor alpha (TNFalpha) content as well as glutathione depletion in the BAL fluid. The contrasting inflammatory responses of the different samples could not be explained by differences in the concentrations of soluble Fe, Cu, V, Ni, Cr, or Al or by the.OH generating capacities of the PM suspensions. However, the effects of the different PM samples were clearly associated with their endotoxin content, as well as their ability to induce interleukin (IL)-8 and TNFalpha from whole blood in vitro. In conclusion, on an equal mass basis, coarse but not fine PM samples from our sampling campaign induced an inflammatory reaction in the lung in the absence of gross cellular lung damage, following intratracheal instillation. Our data also indicate, in accordance with previous independent in vitro observations, that endotoxin or related contaminants may play a role in these in vivo effects.

Topics: Air Pollutants; Animals; Bronchoalveolar Lavage Fluid; Endotoxins; Female; Germany; Glutathione; Hydroxyl Radical; Instillation, Drug; Interleukin-8; L-Lactate Dehydrogenase; Leukocyte Count; Lung; Metals, Heavy; Neutrophils; Particle Size; Pneumonia; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

To determine the role of respiratory epithelial cells in the inflammatory response to inhaled endotoxin, we selectively inhibited NF-kappa B activation in the respiratory epithelium using a mutant I kappa B-alpha construct that functioned as a dominant negative inhibitor of NF-kappa B translocation (dnI kappa B-alpha). We developed two lines of transgenic mice in which expression of dnI kappa B-alpha was targeted to the distal airway epithelium using the human surfactant apoprotein C promoter. Transgene expression was localized to the epithelium of the terminal bronchioles and alveoli. After inhalation of LPS, nuclear translocation of NF-kappa B was evident in bronchiolar epithelium of nontransgenic but not of transgenic mice. This defect was associated with impaired neutrophilic lung inflammation 4 h after LPS challenge and diminished levels of TNF-alpha, IL-1 beta, macrophage inflammatory protein-2, and KC in lung homogenates. Expression of TNF-alpha within bronchiolar epithelial cells and of VCAM-1 within peribronchiolar endothelial cells was reduced in transgenic animals. Thus targeted inhibition of NF-kappa B activation in distal airway epithelial cells impaired the inflammatory response to inhaled LPS. These data provide causal evidence that distal airway epithelial cells and the signals they transduce play a physiological role in lung inflammation in vivo.

Topics: Administration, Inhalation; Animals; Bronchi; Bronchitis; Cell Line; Cytokines; Genes, Dominant; Humans; I-kappa B Proteins; Interleukin-8; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; NF-kappa B; NF-KappaB Inhibitor alpha; Peroxidase; Pneumonia; Promoter Regions, Genetic; Pulmonary Alveoli; Pulmonary Surfactant-Associated Protein C; Respiratory Mucosa

Increased levels of proinflammatory cytokines are present in bronchoalveolar lavage fluid in various lung diseases. Redox-sensitive transcription factors such as NF-kappaB regulate gene transcription for these cytokines. We therefore studied the effect of a new thiol antioxidant compound, Nacystelyn (NAL), on IL-8 regulation in a human macrophage-derived cell line (THP-1). LPS (10 microg/ml) increased IL-8 release compared with control levels. This LPS activation was inhibited by coincubation with NAL (1 and 5 mM). Pretreatment with cycloheximide or okadaic acid, protein synthesis, and serine/threonine phosphatase inhibitors, respectively, did not modify inhibition of IL-8 release caused by NAL. NF-kappaB and C/EBP DNA binding were increased after LPS treatment compared with control, an effect inhibited by cotreatment with NAL. Activator protein (AP)-1 DNA binding was unaffected. The enhanced neutrophil chemotaxis produced by conditioned media from LPS-treated cells was inhibited when cells were cotreated with NAL. The selectivity of NAL inhibition upon IL-8 expression was studied. LPS-treated THP-1 cells also had higher levels of TNF-alpha, transforming growth factor (TGF)-beta1 and -3, MIP-1alpha and -beta, and RANTES gene expression. However, only LPS-induced IL-8 and TGF-beta1 expressions were inhibited by NAL. An anti-inflammatory effect of NAL was confirmed in vivo as shown by a reduction in LPS-induced neutrophil recruitment to the lungs following instillation of NAL into the lungs. Our studies demonstrate that NAL has anti-inflammatory properties in vitro and in vivo, may therefore have a therapeutic role in lung inflammation, and has the advantage over other antioxidant agents in that it may be administrated by inhalation.

Topics: Acetylcysteine; Animals; Antioxidants; Cells, Cultured; Chemotaxis; Cycloheximide; Enzyme Inhibitors; Gene Expression; Humans; In Vitro Techniques; Interleukin-8; Lipopolysaccharides; Lysine; Male; Monocytes; Neutrophils; Okadaic Acid; Pneumonia; Protein Synthesis Inhibitors; Rats; Rats, Wistar; RNA, Messenger; Transcription Factors

Previous animal studies have identified a role for activation of innate immunity in the pathogenesis of ventilator-associated lung injury. These studies have used large tidal volume ventilation to study the effect of alveolar overdistension on induction of inflammatory pathways. We hypothesized an alternative mechanism for the pathogenesis of lung injury in which moderate tidal volume ventilation does not independently cause clinical inflammation but rather interacts with innate immune activation by bacterial products, resulting in an enhanced inflammatory response. We measured cytokine expression and lung injury in normal and lipopolysaccharide (LPS)-treated anesthetized rabbits randomized to either spontaneous respiration or mechanical ventilation. Outcome parameters were analyzed by two-way factorial analysis of variance to identify synergism between ventilation and systemic LPS. Mechanical ventilation alone resulted in minimal cytokine expression in the lung but did enhance LPS-induced expression of tumor necrosis factor-alpha, the CXC chemokines interleukin-8 and growth-related protein-alpha, and the CC chemokine monocyte chemoattractant protein-1. Increased mRNA expression and activation of the transcription factors nuclear factor-kappaB and activator protein-1 accompanied the cytokine responses. We conclude that moderate volume ventilation strategies augment the innate immune response to bacterial products in the lung and may play a role in the development of acute lung injury in patients with sepsis.

Topics: Albumins; Animals; Blood Pressure; Chemokine CCL2; Chemokines, CXC; Cytokines; Interleukin-8; Lipopolysaccharides; Pneumonia; Pulmonary Alveoli; Rabbits; Respiration, Artificial; Specific Pathogen-Free Organisms; Tidal Volume; Tumor Necrosis Factor-alpha

Because we already showed (Brégeon, F., Roch, A., Delpierre, S., Ghigo, E., Autillo-Touati, A., Kajikawa, O., Martin, T., Pugin, J., Portugal, H., Auffray, J., Jammes, Y., 2002. Conventional mechanical ventilation of healthy lungs induced pro-inflammatory cytokine gene transcription, Respir. Physiol. Neurobiol. 132, 191-203) that non-injurious mechanical ventilation (MV) elicited inflammatory signal in paralyzed rabbits having normal lungs, we examined the role of neuromuscular blockade in the pulmonary inflammatory response. In the bronchoalveolar lavage fluid (BALF), leukocyte count, MCP-1 and IL-8 cytokine concentrations (ELISA) and mRNAs (reverse transcription polymerase chain reaction, RT-PCR) were measured in paralyzed (P) or non-paralyzed (NP) rabbits ventilated for a 6-h period. Compared to the P group and despite the tidal volume was the same, we measured in the NP one a lower compliance of the respiratory system (Crs,stat), a longer inspiratory time (Ti), a negative inspiratory tracheal pressure (Ptr) wave preceding the pump-induced positive pressure wave, and a higher peak tracheal pressure. Moreover, in NP animals, gross autopsy showed negligible lung abnormalities, and marked reduction of leukocyte count and lung cytokines (P < 0.05). Thus, the absence of neuromuscular blockade decreased the pulmonary chemotactic response to MV suggesting that the total suppression of negative pressure waves elicited by the diaphragmatic (di) contractions could be involved in this lung response to positive pressure MV.

Topics: Air Pressure; Animals; Bronchoalveolar Lavage Fluid; Cell Count; Chemokine CCL2; Diaphragm; Enzyme-Linked Immunosorbent Assay; Interleukin-8; Leukocytes; Male; Muscle Contraction; Paralysis; Pneumonia; Positive-Pressure Respiration; Pulmonary Gas Exchange; Rabbits; Respiration, Artificial; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tidal Volume; Time Factors

Chronic alcoholic patients have a threefold to fourfold increased risk for developing a severe infection or septic shock after surgery, which might be due to altered immune response. The aim of this outcome matched study was to investigate proinflammatory and anti-inflammatory immune parameters during the course of infection and subsequent septic shock in chronic alcoholic patients, and to compare these parameters with those in nonalcoholic patients.. Twenty-eight patients from a cohort of fifty-six with either pneumonia or peritonitis and subsequent septic shock were selected. Fourteen patients were chronic alcoholics whereas fourteen were nonalcoholic patients. Chronic alcoholic patients met criteria (Diagnostic and Statistical Manual of Mental Disorders IV, of the American Psychiatric Association) for alcohol abuse or dependence. Measurements were performed during the onset of infection (within 24 hours after the onset of infection), in early septic shock (within 12 hours after onset of septic shock) and in late septic shock (72 hours after the onset). Blood measurements included proinflammatory and anti-inflammatory cytokines.. Chronic alcoholic patients exhibited significantly lower plasma levels of IL-8 (P < 0.010) during the onset of infection than did matched nonalcoholic patients. In early septic shock, chronic alcoholic patients had significantly decreased levels of IL-1beta (P < 0.015), IL-6 (P < 0.016) and IL-8 (P < 0.010). The anti-inflammatory parameters IL-10 and tumour necrosis factor receptors I and II did not differ between alcoholic and nonalcoholic patients.. At the onset of infection and during early septic shock, chronic alcoholic patients had lower levels of proinflammatory immune parameters than did nonalcoholic patients. Therefore, immunomodulatory therapy administered early may be considered in chronic alcoholic patients at the onset of an infection because of their altered proinflammatory immune response.

Topics: Adult; Aged; Alcoholism; Case-Control Studies; Chronic Disease; Humans; Interleukin-1; Interleukin-10; Interleukin-8; Middle Aged; Peritonitis; Pneumonia; Predictive Value of Tests; Receptors, Tumor Necrosis Factor; Risk Factors; Shock, Septic; Tumor Necrosis Factor-alpha

Streptococcus pneumoniae is the major cause of community-acquired pneumonia and one of the most common causes of death by infectious disease in industrialized countries. Little is known concerning the mechanisms of target cell activation in this disease. The present study shows that NF-kappaB and p38 MAPK signaling pathways contribute to chemokine synthesis by lung epithelial cells in response to pneumococci. In infected lungs of mice pneumococci stimulate expression of the interleukin (IL)-8 homolog keratinocyte-derived chemokine and granulocyte-macrophage colony-stimulating factor, as well as activate p38 MAPK. Human bronchial epithelium was chosen as a cellular model, because it establishes the first barrier against pathogens, and little is known about its function in innate immunity. Pneumococci infection induces expression of IL-8 and granulocyte-macrophage colony-stimulating factor as well as activation of p38 MAPK in human bronchial epithelial cells (BEAS-2B). Inhibition of p38 MAPK activity by SB202190 and SB203580 blocks pneumococci-induced cytokine release. In mouse lungs in vivo as well as in cultured cells, pneumococci activate NF-kappaBinanIkappaB kinase-dependent manner. Inhibition of p38 MAPK by chemical inhibitors or by RNA interference targeting p38alpha reduces pneumococci-induced NF-kappaB-dependent gene transcription. Blockade of p38 activity did not affect inducible nuclear translocation and recruitment of NF-kappaB/RelA to the IL-8 promotor but did reduce the level of phosphorylated RelA (serine 536) at IL-8 promotor and inhibited pneumococci-mediated recruitment of RNA polymerase II to IL-8 promotor. Thus, p38 MAPK contributes to pneumococci-induced chemokine transcription by modulating p65 NF-kappaB-mediated transactivation.

Topics: Animals; Blotting, Western; Bronchi; Cell Nucleus; Cells, Cultured; Chemokines; Chromatin Immunoprecipitation; Cytokines; Dimerization; Dose-Response Relationship, Drug; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Gene Expression Regulation, Enzymologic; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Imidazoles; Inflammation; Interleukin-8; Lung; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pneumonia; Promoter Regions, Genetic; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA Polymerase II; RNA, Complementary; Serine; Signal Transduction; Streptococcus pneumoniae; Time Factors; Transcription, Genetic; Transfection

Chronic bronchitis is a frequent underlying disease in community-acquired pneumonia (CAP). It is unclear to what extent an impaired or exaggerated innate immune response contributes to disease manifestations and severity. To assess the role of neutrophil activation and recruitment during acute pneumonic episodes, peripheral polymorphonulcear neutrophil (PMN) activation, chemotactic activity, interleukin-8 (CXCL-8) and CXCL-8 receptor (CXCR) expression and apoptosis rate were evaluated in CAP patients with and without chronic bronchitis. In addition, the expression of CXCRs and CXCL-8 was assessed on pulmonary neutrophils in chronic bronchitis patients to compare the activation of the chemokine system in different compartments. CAP severity was assessed by the simplified acute physiology score II and the prognosis of disease was assessed by the pneumonia severity index (PSI). An increased chemotactic activity of PMN from chronic bronchitis patients with CAP was found, which was not related to the expression of CXCRs. In addition, a decreased apoptosis rate of PMN was observed. Chemotactic activity was related to the PSI. Comparison of peripheral and pulmonary PMN revealed enhanced CXCL-8 levels and a decreased CXCR expression in the lung. In conclusion, neutrophil function in patients with chronic bronchitis and community-acquired pneumonia is characterised by an increased chemotactic activity combined with a decreased apoptosis rate. The downregulation of interleukin-8 receptors in the pulmonary compartment deserves further investigation.

Topics: Aged; Apoptosis; Bronchitis; Chemotaxis, Leukocyte; Chronic Disease; Community-Acquired Infections; Female; Humans; Interleukin-8; Male; Neutrophils; Pneumonia; Receptors, Interleukin-8B

Antenatal betamethasone (Beta) is widely used in women with asymptomatic chorioamnionitis at risk for preterm delivery, but its effects on fetal inflammation are unstudied. Groups of ewes at 109 +/- 1 days of gestation received the following treatments: intra-amniotic (IA) saline (control), 0.5 mg/kg intramuscular Beta, 10 mg IA endotoxin (Endo), and Beta + 2 h later Endo (Beta + Endo). Beta suppressed Endo-induced lung inflammation at 1 day. However, compared with Endo 5 days after treatment, Beta + Endo lambs had increased alveolar neutrophils, proinflammatory cytokine mRNA expression, and serum amyloid A3 (SAA3) mRNA expression. IL-1beta mRNA expression was localized to the inflammatory cells, whereas SAA3 mRNA expression was induced in the bronchial epithelium and the inflammatory cells. Compared with Endo, Beta + Endo lambs had increased lung inflammation but equivalent lung volumes 15 days after treatment. The late increase in inflammation in the Beta + Endo animals suggests that glucocorticoids impair the ability of the preterm lung to downregulate Endo-induced inflammation after fetal clearance of the glucocorticoids. These results have implications for lung inflammation and bronchopulmonary dysplasia in preterm infants exposed to chorioamnionitis and maternal glucocorticoids.

Topics: Acute-Phase Reaction; Animals; Betamethasone; Bronchoalveolar Lavage Fluid; Chorioamnionitis; Drug Synergism; Endotoxins; Female; Gene Expression; Glucocorticoids; Hydrocortisone; Interleukin-1; Interleukin-6; Interleukin-8; Lung; Lymphocyte Count; Lymphocytes; Monocytes; Neutrophils; Pneumonia; Pregnancy; Serum Amyloid A Protein; Sheep; Tumor Necrosis Factor-alpha

Inflammation plays a critical role in lung disease progression in cystic fibrosis (CF). This inflammatory process is dominated by a neutrophil influx in the airways. To determine whether the accumulation of neutrophils in the airways of CF patients is associated with an altered function, we analyzed the capacity of neutrophils isolated from the lung compartment and the blood to release the major neutrophil pro- and anti-inflammatory cytokines IL-8 and IL-1-receptor antagonist (ra) spontaneously and in the presence of LPS. Comparison of cytokine production by blood neutrophils from CF patients and from control subjects showed significantly increased IL-8 and decreased IL-1ra release by CF neutrophils. Comparison of cytokine production by airway and blood neutrophils from CF patients also documented distinct profiles: the spontaneous release of IL-8 and IL-1ra by airway neutrophils was significantly higher than that from blood neutrophils. Culture in the presence of LPS failed to further enhance cytokine production. Analysis of the effect of dexamethasone confirmed the difference in the responsiveness of lung and blood neutrophils in CF. Used at a concentration effective in reducing IL-8 production by blood neutrophils, dexamethasone (10(-6) M) was unable to repress secretion of IL-8 by airway neutrophils. In addition, comparison of cytokine production by airway neutrophils from children with CF and children with dyskinetic cilia syndrome also documented distinct profiles of secretion. These results are consistent with a dysregulated cytokine production by lung and blood neutrophils in CF. They provide support to the hypothesis that not only the CF genotype but also the local environment may modify the functional properties of the neutrophils.

Topics: Adolescent; Cells, Cultured; Child; Cystic Fibrosis; Dexamethasone; Female; Glucocorticoids; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-8; Lung; Male; Neutrophils; Pneumonia; Sialoglycoproteins

The aim of this study was to identify cell types involved in the anti-inflammatory effect of ventilation with perfluorocarbon in vivo. Fifteen anesthetized, surfactant-depleted piglets received either aerosolized perfluorocarbon (Aerosol-PFC), partial liquid ventilation (rLV) at functional residual capacity (FRC) volume (FRC-PLV), or intermittent mandatory ventilation (control). After laser-assisted microdissection of different lung cell types, mRNA expression of IL-8 and ICAM-1 was determined using TaqMan real-time PCR normalized to hypoxanthine phosphoribosyltransferase (HPRT). IL-8 mRNA expression (means +/- SE; control vs. Aerosol-PFC) was 356 +/- 142 copies IL-8 mRNA/copy HPRT mRNA vs. 3.5 +/- 1.8 in alveolar macrophages (P <0.01); 208 +/- 108 vs. 2.7 +/- 0.8 in bronchiolar epithelial cells (P <0.05); 26 +/- 11 vs. 0.7 +/- 0.2 in alveolar septum cells (P <0.01); 2.8 +/- 1.0 vs. 0.8 +/- 0.4 in bronchiolar smooth muscle cells (P <0.05); and 1.1 +/- 0.4 vs. 0.2 +/- 0.05 in vascular smooth muscle cells (P <0.05). With FRC-PLV, IL-8/HPRT mRNA expression was significantly lower in macrophages, bronchiolar epithelial, and vascular smooth muscle cells. ICAM-1 mRNA expression in vascular endothelial cells remained unchanged. Predominantly, alveolar macrophages and bronchiolar epithelial cells were involved in the inflammatory pulmonary process. The anti-inflammatory effect of Aerosol-PFC was most pronounced.

Topics: Animals; Dissection; Fluorocarbons; Hypoxanthine Phosphoribosyltransferase; Immunohistochemistry; Intercellular Adhesion Molecule-1; Interleukin-8; Lasers; Macrophages, Alveolar; Miniaturization; Muscle, Smooth, Vascular; Oxygen; Pneumonia; Polymerase Chain Reaction; Pulmonary Alveoli; Pulmonary Surfactants; Respiratory Mucosa; RNA, Messenger; Swine

TNF-alpha has been associated with chorioamnionitis and the subsequent development of bronchopulmonary dysplasia in preterm infants. We asked whether bioactive recombinant ovine TNF-alpha could induce chorioamnionitis, lung inflammation, lung maturation, and systemic effects in fetal sheep. We compared the responses to IL-1alpha, a cytokine known to induce these responses in preterm sheep. Intra-amniotic TNF-alpha caused no chorioamnionitis, no lung maturation, and a very small increase in inflammatory cells in the fetal lung after 5 h, 2 days (d), and 7 d. In contrast, IL-1alpha induced inflammation and lung maturation. TNF-alpha given into the airways at birth increased granulocytes in the bronchoalveolar lavage fluid of ventilated preterm lungs and decreased the mRNA for surfactant protein C but did not adversely effect postnatal lung function. An intravascular injection of IL-1alpha caused a systemic inflammatory response in fetal sheep, whereas there was no fetal response to intravascular TNF-alpha. Fetal and newborn preterm sheep are minimally responsive to TNF-alpha. Therefore, the presence of a mediator such as TNF-alpha in a developing animal does not necessarily mean that it is causing the responses anticipated from previous results in adult animals.

Topics: Amniotic Fluid; Animals; Animals, Newborn; Antineoplastic Agents; Chorioamnionitis; Female; Gene Expression; Gestational Age; Injections, Spinal; Interleukin-1; Interleukin-6; Interleukin-8; Lung; Pneumonia; Pregnancy; Recombinant Proteins; Respiration, Artificial; Sheep; Tumor Necrosis Factor-alpha

It has been shown that application of the open-lung concept (OLC) during high-frequency oscillatory ventilation (HFOV) attenuates pulmonary inflammation. We hypothesized that this attenuation could also be achieved by applying the OLC during positive-pressure ventilation (PPV). After repeated whole-lung lavage, newborn piglets were assigned to one of three ventilation groups: (1) PPV(OLC); (2) HFOV(OLC), or (3) conventional PPV (PPV(CON)). After a ventilation period of 5 h, analysis of bronchoalveolar lavage fluid showed a reduced influx of polymorphonuclear neutrophils, interleukin 8, and thrombin activity in both OLC groups as compared with the PPV(CON) group. There were no differences in tumor necrosis factor alpha levels. We conclude that application of the OLC during PPV reduces pulmonary inflammation as compared with conventional PPV and that the magnitude of this reduction is comparable to that of HFOV.

Topics: Animals; Animals, Newborn; Bronchoalveolar Lavage Fluid; Interleukin-8; Leukocyte Count; Neutrophils; Pneumonia; Positive-Pressure Respiration; Swine; Thrombin; Tumor Necrosis Factor-alpha

Excessive neutrophil recruitment is implicated in the pathogenesis of chronic lung diseases by causing collateral tissue damage. The cells move from the circulation in response to chemokines, such as interleukin (IL)-8, that are secreted by several lung cell types including epithelial cells. This study has investigated factors present in bronchial secretions that are responsible for IL-8 expression and secretion by epithelial cells and hence initiate or perpetuate the recruitment of neutrophils. A549 epithelial cells were stimulated with proinflammatory molecules likely to be of relevance in the lung. Tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide stimulated IL-8 production from epithelial cells in a dose- and time-dependent manner, and these effects were abrogated by specific antibodies or inhibitors. Bronchial secretions also stimulated IL-8 production, and lipopolysaccharide accounted for approximately 33% of this activity. An abundant 32-kD protein capable of stimulating IL-8 production was isolated from the secretion and identified as neutrophil cytoplasmic protein myeloid-related protein (MRP)-14, which is the heavy polypeptide chain in the MRP-8/14 heterodimer. Abrogation of MRP-14 activity with a specific antibody also reduced the IL-8-stimulating potential of bronchial secretions, suggesting it was a significant stimulus to IL-8 production in the lung and may amplify the neutrophilic inflammation seen in bronchial disease.

Topics: Antibodies; Bronchi; Calgranulin A; Calgranulin B; Cells, Cultured; Humans; Interleukin-1; Interleukin-8; Lipopolysaccharides; Lung Diseases; Neutrophil Activation; Pancreatic Elastase; Pneumonia; Respiratory Mucosa; Tumor Necrosis Factor-alpha

Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-alpha were frequently measured during the first 30 days after allogeneic bone marrow transplantation (BMT) in 84 consecutive adult patients. Major transplant-related complications (MTCs) occurred in 33% of cases and included veno-occlusive liver disease, idiopathic pneumonia syndrome, severe endothelial leakage syndrome and >grade II acute graft-versus-host disease. Compared with patients having minor complications, those with MTCs developed higher levels at times of maximal clinical signs (all cytokines, P<0.001), between days 0-5 post-BMT (IL-6 and IL-8, P<0.05) and days 6-10 (L-6, P<0.001; IL-8 and TNF, P<0.01) post-BMT. We could not discriminate patterns of cytokine release that were specific for any subtype of MTC. Higher levels of IL-8 during days 0-5 were associated (P=0.044) with early (<40 days) death. Multivariate analysis including patient and transplant characteristics as well as post-BMT levels of C-reactive protein showed that high average levels of one or more of the cytokines within the first 10 days post-BMT were independently associated with MTC (Odd's ratio: 2.3 [1.2-4.5], P=0.011). This study shows that systemic release of proinflammatory cytokines contributes to the development of MTC and provides a rationale for pre-emptive anti-inflammatory treatment in selected patients.

Topics: Adult; Bacteremia; Bone Marrow Transplantation; C-Reactive Protein; Capillary Leak Syndrome; Female; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Interleukin-6; Interleukin-8; Leukemia; Male; Neural Tube Defects; Pneumonia; Risk Factors; Transplantation Conditioning; Transplantation, Homologous; Tumor Necrosis Factor-alpha

Lung inflammation plays an important role in the pathogenesis of chronic lung disease in preterm infants. To test the hypothesis that prolonged mechanical ventilation induces pulmonary inflammation, we analyzed pro- and anti-inflammatory mediators in bronchoalveolar lavage fluid obtained from ventilated preterm infants having respiratory distress syndrome. Our results show a strong correlation between the duration of mechanical ventilation and the amount of proinflammatory mediators. However, the anti-inflammatory cytokine interleukin 10 remained stable during the whole period of mechanical ventilation. These data support the hypothesis that prolonged mechanical ventilation contributes to the development of chronic lung disease by the induction of lung inflammation without adequate stimulation of the counterregulatory cytokine interleukin 10 in preterm infants with respiratory distress syndrome.

Topics: Bronchoalveolar Lavage Fluid; Chemokine CXCL5; Chemokines, CXC; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-8; Lung Diseases; Pancreatic Elastase; Pneumonia; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Time Factors

To test whether the inflammatory potential of dust samples might be used to differentiate schools with high and low prevalence of building related symptoms (BRS) among the occupants.. Ten schools with high prevalence of BRS and 10 schools with low prevalence were selected. Dust collected from floors, horizontal surfaces, and exhaust outlets was tested at five concentrations on the lung epithelial cell line A549. The potency of the dust (PF) to stimulate IL-8 secretion was calculated from the initial linear part of the dose-response curves. The organic fraction of the dust samples was determined by incineration.. The schools with low prevalence of symptoms had a BRS% of 4.4-11.0 and the schools with high prevalence a BRS% of 19.6-31.9. The PF of floor dust and surface dust correlated, and the PF was associated with the organic content of the dust. The schools with low prevalence of symptoms had a significantly lower PF than the schools with high prevalence. Using the cut point value of 4.5 ng IL-8/mg floor dust, significantly more high prevalence schools were found above the cut point than below.. The PF of the floor dust samples correlated significantly with the prevalence of symptoms in the schools. The content of endotoxin and microorganisms did not seem to explain the inflammatory potential of the dust or BRS, and the substances in the dust causing the inflammatory potential are presently unknown.

Topics: Adolescent; Air Pollution, Indoor; Allergens; Cell Line; Cross-Sectional Studies; Denmark; Dust; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Humans; Interleukin-8; Male; Pneumonia; Prevalence; Respiratory Mucosa; Schools; Sick Building Syndrome

Chorioamnionitis is frequent in preterm labor and increases the risk of bronchopulmonary dysplasia. We hypothesized that intra-amniotic endotoxin injures the lung in utero, causing a sequence of inflammation and tissue injury similar to that which occurs in the injured adult lung. Preterm lamb lungs at 125 days gestational age were evaluated for indicators of inflammation, injury, and repair 5 h, 24 h, 72 h, and 7 days after 4 mg of intra-amniotic endotoxin injection. At 5 h, the epithelial cells in large airways expressed heat shock protein 70, and alveolar interleukin-8 was increased. Surfactant protein B (SP-B) decreased in alveolar type II cells at 5 h, and SP-B in lung tissue and alveolar lavage fluid increased by 72 h. By 24 h, neutrophils were recruited into the large airways, and cell death was the highest. Alveolar type II cells decreased by 25% at 24 h, and proliferation was highest at 72 h, consistent with tissue remodeling. Intra-amniotic endotoxin caused surfactant secretion, inflammation, cell death, and remodeling as indications of lung injury. The recovery phase was accompanied by maturational changes in the fetal lung.

Topics: Amniotic Fluid; Animals; Apoptosis; Cell Division; Embryo, Mammalian; Endotoxins; Female; HSP70 Heat-Shock Proteins; Interleukin-8; Lung; Pneumonia; Proteolipids; Pulmonary Alveoli; Pulmonary Surfactants; Sheep; Wound Healing

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

Staphylococcus aureus alpha-toxin is a pore-forming bacterial exotoxin that has been implicated as a significant virulence factor in human staphylococcal diseases. In primary cultures of rat pneumocyte type II cells and the human A549 alveolar epithelial cell line, purified alpha-toxin provoked rapid-onset phosphatidylinositol (PtdIns) hydrolysis as well as liberation of nitric oxide and the prostanoids PGE(2), PGI(2), and thromboxane A(2). In addition, sustained upregulation of proinflammatory interleukin (IL)-8 mRNA expression and protein secretion occurred. "Priming" with low-dose IL-1beta markedly enhanced the IL-8 response to alpha-toxin, which was then accompanied by IL-6 appearance. The cytokine response was blocked by the intracellular Ca(2+)-chelating reagent 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, the protein kinase C inhibitor bis-indolyl maleimide I, as well as two independent inhibitors of nuclear factor-kappaB activation, pyrrolidine dithiocarbamate and caffeic acid phenethyl ester. We conclude that alveolar epithelial cells are highly reactive target cells of staphylococcal alpha-toxin. alpha-Toxin pore-associated transmembrane Ca(2+) flux and PtdIns hydrolysis-related signaling with downstream activation of protein kinase C and nuclear translocation of nuclear factor-kappaB are suggested to represent important underlying mechanisms. Such reactivity of the alveolar epithelial cells may be relevant for pathogenic sequelae in staphylococcal lung disease.

Topics: Animals; Bacterial Toxins; Cell Line; Epithelial Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Hemolysin Proteins; Inflammation Mediators; Inositol Phosphates; Interleukin-6; Interleukin-8; Male; Pneumonia; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sepsis; Signal Transduction; Staphylococcus aureus

The effect of inhaled nitric oxide (NO) on inflammatory process in acute lung injury (ALI) is unclear. The aims of this study were to 1) examine whether inhaled NO affects the biochemical lung injury parameters and cellular inflammatory responses and 2) determine the effect of inhaled NO on the activation of nuclear factor-kappa B (NF-kappa B) in lipopolysaccharide (LPS)-induced ALI. Compared with saline controls, rabbits treated intravenously with LPS showed increases in total protein and lactate dehydrogenase in the bronchoalveolar lavage (BAL) fluid, indicating ALI. LPS-treated animals with NO inhalation (LPS-NO) showed significant decreases in these parameters. Neutrophil numbers in the BAL fluid, the activity of reactive oxygen species in BAL cells, and the levels of interleukin (IL)-1 beta and IL-8 in alveolar macrophages were increased in LPS-treated animals. In contrast, neutrophil numbers and these cellular activities were substantially decreased in LPS-NO animals, compared with LPS-treated animals. NF-kappa B activation in alveolar macrophages from LPS-treated animals was also markedly increased, whereas this activity was effectively blocked in LPS-NO animals. These results suggest that inhaled NO attenuates LPS-induced ALI and pulmonary inflammation. This attenuation may be associated with the inhibition of NF-kappa B activation.

Topics: Acute Disease; Administration, Inhalation; Animals; Bronchoalveolar Lavage Fluid; Cell Movement; Interleukin-1; Interleukin-8; L-Lactate Dehydrogenase; Lipopolysaccharides; Macrophages, Alveolar; Neutrophils; NF-kappa B; Nitric Oxide; Pneumonia; Proteins; Rabbits; Reactive Oxygen Species

The effect of new ventilation strategies on initial pulmonary inflammatory reaction was studied in a surfactant-depleted piglet model. Sixty minutes after induction of lung injury by bronchoalveolar lavage, piglets received either aerosolized FC77 (aerosol-PFC, 10 mL/kg/h, n = 5) or partial liquid ventilation (PLV) with FC77 at functional residual capacity volume (FRC-PLV, 30 mL/kg, n = 5), or at low volume (LV-PLV, 10 mL/kg per hour, n = 5), or intermittent mandatory ventilation (control, n = 5). After 2 h, perfluorocarbon application was stopped and intermittent mandatory ventilation continued for 6 h. After a total experimental period of 8 h, animals were killed and lung tissue obtained. mRNA expression of IL-1beta, IL-6, IL-8, and TGF-beta in porcine lung tissue was quantified using TaqMan real-time PCR and normalized to beta-actin (A) and hypoxanthine-guanine-phosphoribosyl-transferase (H). In the aerosol-PFC group, IL-1beta, IL-6, IL-8, and transforming growth factor (TGF)-beta mRNA expression in lung tissue was significantly lower than in the control group. Reduction was 95% for IL-1beta/H (p < 0.001), 73% for IL-6/H (p < 0.05), 87% for IL-8/H (p < 0.001), and 38% for TGF-beta/H (p < 0.01). A lower mRNA gene expression was also determined for IL-1beta and IL-8 when the aerosol-PFC group was compared with the LV-PLV group [91% for IL-1beta/H (p < 0.001), 75% for IL-8/H (p < 0.001)]. In the FRC-PLV group, mRNA expression of IL-1beta was significantly lower than in the control (p < 0.05) and LV-PLV (p < 0.01) group. In a surfactant-depleted piglet model, aerosol therapy with perfluorocarbon but not LV-PLV reduces the initial pulmonary inflammatory reaction at least as potently as PLV at FRC volume.

Topics: Aerosols; Animals; Bronchopulmonary Dysplasia; Disease Models, Animal; Fluorocarbons; Humans; Infant, Newborn; Interleukin-1; Interleukin-6; Interleukin-8; Lung; Pneumonia; Pulmonary Surfactants; RNA, Messenger; Swine; Transforming Growth Factor beta; Ventilation

The lung of the preterm infant is easily injured and an initial indication of the injury is an inflammatory response. Surfactant treatment and gentle ventilation will minimize the initiation and progression of injury. We asked if the initial lung injury response differed when preterm ventilated lambs were treated with complete natural sheep surfactant, a lipid extract of sheep surfactant, a surfactant used to treat RDS (Survanta), or a synthetic surfactant containing recombinant SP-C (Venticute). We used a gentle style of ventilation and a positive end expiratory pressure of 4 cmH(2)0 to minimize injury. The surfactants were not distinguishable based on gas exchange, compliance or lung gas volumes over the 6h ventilation period. When compared with unventilated controls the ventilated lambs had increased protein and inflammatory cells in alveolar lavages. The cells from the alveolar lavages produced more H(2)0(2), expressed more surface adhesion antigens and CD-14 receptors, and expressed more mRNA for the pro-inflammatory cytokines IL-1 beta and IL-8 than did cells from unventilated lungs. Lung tissue expressed primarily increased IL-6 mRNA relative to unventilated controls. However, there were no consistent differences in any of the inflammatory indicators between the different surfactant treated groups. Because endotoxin free natural surfactant containing SP-A was not superior to three other surfactants containing differing amounts of the surfactant proteins, additions of these proteins to clinical surfactants may not decrease the indicators of lung inflammation that accompany the initiation of ventilation of the preterm lung.

Topics: Animals; Bronchoalveolar Lavage Fluid; Female; Flow Cytometry; Gene Expression; Gestational Age; Interleukin-6; Interleukin-8; Lung; Lung Injury; Pneumonia; Pregnancy; Proteolipids; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants; Respiration, Artificial; RNA, Messenger; Sheep; Tumor Necrosis Factor-alpha

The anti-inflammatory effect of acetylsalicylic acid (ASA) has been thought to be secondary to the inhibition of prostaglandin synthesis. Because doses of ASA necessary to treat chronic inflammatory diseases are much higher than those needed to inhibit prostaglandin synthesis, a prostaglandin-independent pathway has been emerging as the new anti-inflammatory mechanism of ASA. Here, we examined the effect of ASA on the interleukin (IL)-1 beta- and tumor necrosis factor (TNF)-alpha-induced proinflammatory cytokine expression and evaluated whether this effect is closely linked to the nuclear factor (NF)-kappa B/I kappa B-alpha pathway. A high dose of ASA blocked IL-1 beta- and TNF-alpha-induced TNF-alpha and IL-8 expression, respectively. ASA inhibited TNF-alpha-induced activation of NF-kappa B by preventing phosphorylation and subsequent degradation of I kappa B-alpha in a prostanoid-independent manner. TNF-alpha-induced activation of I kappa B kinase was also suppressed by ASA pretreatment. These observations suggest that the anti-inflammatory effect of ASA in lung epithelial cells may be due to suppression of I kappa B kinase activity, which thereby inhibits subsequent phosphorylation and degradation of I kappa B-alpha, activation of NF-kappa B, and proinflammatory cytokine expression in lung epithelial cells.

Topics: Aspirin; Bronchi; Cells, Cultured; Cyclooxygenase Inhibitors; DNA-Binding Proteins; Humans; I-kappa B Kinase; I-kappa B Proteins; Interleukin-1; Interleukin-8; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Pneumonia; Prostaglandins; Protein Serine-Threonine Kinases; Respiratory Mucosa; Tumor Necrosis Factor-alpha

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been linked to several physiologic pathways including those related to the regulation of intestinal inflammation. We sought to determine whether PPAR gamma could function as an endogenous anti-inflammatory pathway in a murine model of intestinal ischemia-reperfusion (I/R) injury.. PPAR gamma-deficient and wild-type mice were examined for their response to I/R procedure. Treatment with a PPAR gamma-specific ligand was also performed.. In a murine model of intestinal I/R injury, we observed more severe injury in PPAR gamma-deficient mice and protection against local and remote tissue injury in mice treated with a PPAR gamma-activating ligand, BRL-49653. Activation of PPAR gamma resulted in down-regulation of intercellular adhesion molecule 1 expression by intestinal endothelium and tissue tumor necrosis factor alpha messenger RNA levels most likely by inhibition of the NF-kappa B pathway.. These data strongly suggest that an endogenous PPAR gamma pathway exists in tissues that may be amenable to therapeutic manipulation in I/R-related injuries.

Topics: Animals; Cells, Cultured; Colitis; Epithelial Cells; Gastric Mucosa; Gene Expression; Hypoglycemic Agents; In Vitro Techniques; Intercellular Adhesion Molecule-1; Interleukin-8; Intestinal Mucosa; L-Lactate Dehydrogenase; Liver; Mice; Mice, Inbred BALB C; Mice, Knockout; NF-kappa B; Peroxidase; Pneumonia; Receptors, Cytoplasmic and Nuclear; Reperfusion Injury; RNA, Messenger; Rosiglitazone; Stomach; Thiazoles; Thiazolidinediones; Transcription Factors; Tumor Necrosis Factor-alpha

In the host defence of the lung neutrophils (PMN) play a central role. Apart from antimicrobial properties, recent data indicate that PMN also exert anti-inflammatory effects by stimulation and release of cytokine antagonists such as interleukin-1 receptor antagonist (IL-1ra).. Cytokine release from lipopolysaccharide stimulated whole blood was studied in 18 patients with community acquired pneumonia (CAP) and severe co-morbidities at admission and after 24 hours. Release of IL-1ra, interleukin-1beta (IL-1beta), tumour necrosis factor alpha (TNFalpha), soluble TNF receptor type I (sTNF-RI), and IL-8 was determined by ELISA.. The mean (SD) leucocyte level at admission was 12.5 (4.1)/nl. There was a significant correlation between the release of anti-inflammatory cytokines such as IL-1ra and sTNF-RI and the leucocyte count at admission and after 24 hours. Additional in vitro experiments showed that co-incubation of peripheral blood mononuclear cells with autologous PMN led to a marked dose dependent increase in IL-1ra and sTNF-RI release.. These results indicate that PMN may be responsible for the increase in anti-inflammatory cytokines in CAP. Strategies to increase neutrophil counts may exert beneficial effects, not only by augmenting the antimicrobial activity but also by modulating the inflammatory cytokine response.

Topics: Adult; Aged; Aged, 80 and over; Cells, Cultured; Community-Acquired Infections; Cytokines; Enzyme-Linked Immunosorbent Assay; Etanercept; Female; Humans; Immunoglobulin G; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-8; Leukocyte Count; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Middle Aged; Neutrophils; Pneumonia; Receptors, Tumor Necrosis Factor; Sialoglycoproteins; Tumor Necrosis Factor-alpha

Chronic lung disease (CLD) of the newborn is associated with pulmonary inflammation. However, the origin of this inflammation is not known. We evaluated the impact of airway infection on bronchoalveolar inflammation in mechanically ventilated preterm infant at risk for CLD (n = 68). Mean and maximum concentrations of the inflammatory mediators (IM) interleukin-1 and interleukin-8 were assayed in the tracheobronchial aspirate fluid (TAF) of neonates with perinatal airway infection (Ureaplasma urealyticum, or bacteria), postnatal nosocomial airway infection, or respiratory disease without airway infection from days 1-10 of postnatal age. Patients with CLD (n = 23;) exhibited increased levels of IM in TAF compared to neonates without CLD. Within the three subgroups, concentrations of IM were increased in CLD patients with perinatal infection and in CLD patients with respiratory disease without airway infection, but not in CLD patients with nosocomial airway infection. Although airway colonization with Gram-negative bacteria was more frequently found in CLD patients within the first month of life, there were no differences between levels of IM in patients colonized with Gram-negative bacteria or coagulase-negative staphyloccoci. We conclude that perinatal infections with Ureaplasma urealyticum or bacteria and respiratory disease without infection, but not nosocomial airway infection, contribute to the bronchopulmonary inflammatory response in neonates with CLD.

Topics: Cross Infection; Female; Humans; Immunoglobulin A, Secretory; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Inflammation Mediators; Interleukin-1; Interleukin-8; Lung Diseases; Male; Perinatal Care; Pneumonia; Prospective Studies; Respiration, Artificial; Respiratory Tract Infections; Trachea; Ureaplasma Infections

Studies into the effects of ultrafine particles in the lung have shown adverse effects considered to be due in part to the particle size. Air pollution particles (PM(10)) are associated with exacerbations of respiratory disease and deaths from cardiovascular causes in epidemiological studies and the ultrafine fraction of PM(10) has been hypothesized to play an important role. The aim of the present study was to investigate proinflammatory responses to various sizes of polystyrene particles as a simple model of particles of varying size including ultrafine. In the animal model, we demonstrated that there was a significantly greater neutrophil influx into the rat lung after instillation of 64-nm polystyrene particles compared with 202- and 535-nm particles and this was mirrored in other parameters of lung inflammation, such as increased protein and lactate dehydrogenase in bronchoalveolar lavage. When surface area instilled was plotted against inflammation, these two variables were directly proportional and the line passed through zero. This suggests that surface area drives inflammation in the short term and that ultrafine particles cause a greater inflammatory response because of the greater surface area they possess. In vitro, we measured the changes in intracellular calcium concentration in mono mac 6 cells in view of the potential role of calcium as a signaling molecule. Calcium changes after particle exposure may be important in leading to proinflammatory gene expression such as chemokines. We demonstrated that only ultrafine polystyrene particles induced a significant increase in cytosolic calcium ion concentration. Experiments using dichlorofluorescin diacetate demonstrated greater oxidant activity of the ultrafine particles, which may explain their activity in these assays. There were significant increases in IL-8 gene expression in A549 epithelial cells after treatment with the ultrafine particles but not particles of other sizes. These findings suggest that ultrafine particles composed of low-toxicity material such as polystyrene have proinflammatory activity as a consequence of their large surface area. This supports a role for such particles in the adverse health effects of PM(10).

Topics: Animals; Bronchoalveolar Lavage Fluid; Calcium; Epithelial Cells; Female; Humans; Interleukin-8; Intubation, Intratracheal; L-Lactate Dehydrogenase; Lung; Microspheres; Monocytes; Neutrophil Activation; Neutrophils; Oxidative Stress; Particle Size; Pneumonia; Polystyrenes; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Surface Properties; Tumor Cells, Cultured

Activation of alveolar macrophages is characterised by specific alterations to the expression pattern of surface markers under certain pathological conditions. MRP8/MRP14 and CD11b are involved in the regulation of macrophage migration and adhesion. HLA-DR regulates the antigen presentation by alveolar macrophages. The aim of this study was to investigate the phenotype of alveolar macrophages in pneumonia particularly in relationship to the changes in concentrations of TGF-beta1 and IL-8. Using cytofluorimetry, we analysed the surface expression of MRP8/MRP14, CD11b, and HLA-DR on alveolar macrophages of 42 pneumonia (PN) patients, 14 patients with interstitial lung diseases (ILD), five patients with chronic obstructive lung disease (COPD), and 58 patients without lung disease. Phenotypic characteristics were correlated to the concentration of TGF-beta1 and IL-8 in the bronchoalveolar lavage fluid (BALF) of the same patients. The direct influence of TGF-beta1 and IL-8 on expression of MRP8/MRP14, CD11b and HLA-DR of cultured monocytes and MonoMac cells was analysed. Significantly more MRP8/MRP14 and CD11b positive macrophages and less HLA-DR-positive macrophages were found in PN but not in ILD or COPD. The percentage of CD11b-positive macrophages correlated with the TGF-beta1 as well as the IL-8 concentrations. The amount of HLA-DR-positive macrophages correlated negatively to the concentration of TGF-beta1 and IL-8. These findings document a significant activation of alveolar macrophages during pneumonia. TGF-beta1 led to a modulation of HLA-DR and MRP8/MRP14-antigen expression in vitro. In conclusion, it was shown that in pneumonia but not in ILD or COPD alveolar macrophages were characterised by an increased MRP8/MRP14 and CD11b expression and a diminished HLA-DR expression. The characterisation of subpopulations within the alveolar macrophages may be a useful tool for the monitoring of disease progression.

Topics: Antigens, Differentiation; Calcium-Binding Proteins; Calgranulin A; Calgranulin B; Cells, Cultured; HLA-DR Antigens; Humans; Interleukin-8; Macrophage-1 Antigen; Macrophages, Alveolar; Pneumonia; S100 Proteins; Transforming Growth Factor beta

To study the inflammatory responses of small-airway epithelium in smokers, we harvested enough living epithelial cells (1.97 x 10(6) +/- 0.74 x 10(6)) with a new ultrathin fiberscope from the very peripheral airways of 22 current smokers and 17 subjects who never smoked after informed consent was obtained. The cells were keratin positive and composed mainly of nonciliated cells. The expression levels of inflammatory markers [interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1] were evaluated with RT-PCR. The magnitude of the mRNA levels corrected by beta-actin transcripts of IL-8 and ICAM-1 was significantly higher in the smokers than in the nonsmokers (P < 0.001). Furthermore, among current smokers, IL-8 mRNA levels correlated positively with the extent of smoking history [in pack. years (packs/day x no. of years of smoking); r = 0.754, P < 0.001]. Spontaneously released IL-8 and soluble ICAM-1 levels (n = 12) from cultured epithelial cells were elevated in subjects with a smoking history than in those without it (IL-8, 1,580 +/- 29.6 vs. 354 +/- 39.4 pg. 10(6) cells(-1). 24 h(-1); P < 0.001; soluble ICAM-1, 356.0 +/- 45.9 vs. 112.9 +/- 12.9 pg. 10(6) cells(-1). 24 h(-1); P < 0.01 by Student's t-test ). In contrast, the epithelial cells from the main bronchi did not show such differences between smokers and nonsmokers. Our study highlighted a close link between smoking and the expression of inflammatory mediators such as IL-8 and ICAM-1 in small airways. Our results also suggested that this new ultrathin bronchofiberscope promised a good approach for the evaluation of cellular changes in the small airways.

Topics: Biopsy; Bronchi; Bronchoscopy; Cell Count; Cell Survival; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Gene Expression; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Middle Aged; Pneumonia; Respiratory Function Tests; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Smoking

Interleukin (IL)-8 is a C-X-C chemokine that plays an important role in acute inflammation through its G protein-coupled receptors CXCR1 and CXCR2. In this study, we investigated the role of IL-8 as an autocrine regulator of IL-8 production and the signaling mechanisms involved in human peripheral blood mononuclear cells (MNCs). Sepharose-immobilized IL-8 stimulated a sevenfold increase in IL-8 production within 2 h. IL-8 induced the expression of its own message, and IL-8 biosynthesis was inhibited by cycloheximide and actinomycin D, indicating de novo RNA and protein synthesis. In contrast to MNCs, polymorphonuclear neutrophils did not respond to the immobilized IL-8 with IL-8 production despite cell surface expression of CXCR1 and CXCR2. Melanoma growth-stimulatory activity/growth-related protein-alpha (MGSA/GROalpha), which binds CXCR2 but not CXCR1, was unable to either stimulate IL-8 secretion in MNCs or desensitize these cells to respond to immobilized IL-8. The involvement of mitogen-activated protein kinase (MAPK) in IL-8-induced IL-8 biosynthesis was suggested by the ability of PD-98059, an inhibitor of MAPK kinase, to block this function. Furthermore, IL-8 induced a significant increase in extracellular signal-regulated kinase 2 phosphorylation, whereas MGSA/GROalpha was much less effective. These findings support the role of IL-8 as an autocrine regulator of IL-8 production and suggest that this function is mediated by CXCR1 through activation of MAPK.

Topics: Antibodies, Monoclonal; Autocrine Communication; Chemokine CXCL1; Chemokines, CXC; Chemotactic Factors; Cycloheximide; Dactinomycin; Enzyme Inhibitors; Flavonoids; Flow Cytometry; Growth Inhibitors; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Monocytes; Pneumonia; Protein Biosynthesis; Protein Synthesis Inhibitors; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Transcription, Genetic

Neutrophil cytotoxity and activated macrophages have been implicated in the pathogenesis of alcohol-induced liver disease. The aim of this study was to relate plasma levels of neopterin, a marker of activation of the cellular immune system, and IL-8, a neutrophil chemotactic factor, with severity of liver disease and prognosis in patients with alcohol-induced cirrhosis.. Plasma concentrations of neopterin and IL-8 were assessed in 81 patients with alcohol-induced cirrhosis admitted to the Department of Medicine B, Bispebjerg Hospital, Copenhagen, Denmark, and in 16 healthy controls. After a median follow-up period of 5 years, mortality and death causes were registered. The patients were divided into groups according to the major contributing cause of death: infection, upper gastrointestinal bleeding or hepatic coma.. Neopterin and IL-8 levels were increased in the cirrhosis patients, but not significantly related to Child-Pugh classification. Five-year mortality was 67%. High neopterin levels (>upper quartile) were an independent predictor of death (p=0.01, Log rank and p<0.02, Cox). High IL-8 levels (>upper quartile) were of no significant prognostic value for overall mortality. Causes of death related mortality were as follows (Log rank): Neopterin; p=0.009, p=0.84 and p=0.94, and IL-8; p=0.36, p=0.002 and p=0.27, respectively, according to infection, bleeding and coma as causes of death.. Neopterin and IL-8 plasma levels are raised in patients with alcohol-induced cirrhosis, and are predictive of mortality associated with infections and upper gastrointestinal bleeding, respectively.

Topics: Cause of Death; Follow-Up Studies; Gastrointestinal Hemorrhage; Hepatic Encephalopathy; Humans; Interleukin-8; Liver Cirrhosis, Alcoholic; Neopterin; Pneumonia; Prognosis; Prospective Studies; Survival Analysis; Survival Rate

Tumor infiltrate, predominantly constituted by lymphocytes, may represent an important prognostic factor in bronchioloalveolar carcinoma (BAC), in addition to tumor extension and histological type. In the present study, we determined the presence, the origin, and the prognostic importance of neutrophils that also participate in leukocyte infiltrates of BAC. Neutrophil alveolitis was determined immunohistochemically in both lung biopsies and bronchoalveolar lavage (BAL) fluid samples from 29 patients with histologically proved BAC. The local expression of interleukin (IL)-8 was determined by immunohistochemical and immunoenzymatic techniques. Neutrophil counts were analyzed in relation to the clinical outcome of patients by the Kaplan-Meier method and Cox's univariate and stepwise multivariate models. Lymphocytes and neutrophils dominated the inflammatory cell population in the lower respiratory tract of patients with BAC. Neutrophils were located mainly in the alveolar lumen and seldom in alveolar wall whereas lymphocytes were exclusively present in alveolar wall. A relationship was observed between the number of neutrophils and the level of IL-8 in BAL fluid suggesting the involvement of that chemokine in neutrophil recruitment. The tumor cells were the predominant cells that appeared to express IL-8 by immunolocalization. The presence of increased numbers of neutrophils was significantly associated with a poorer outcome in patients with BAC (P = 0.02). In a multivariate analysis, the neutrophil percentage in BAL fluid was an independent predictor of clinical outcome. The risk of death was increased substantially (rate ratio, 5.2; 95% confidence interval, 1.1 to 24.7) among patients with BAL neutrophil percentage of > or = 39% (median of the distribution) as compared with the others. In BAC, neutrophils accumulate in the alveolar lumen. Elaboration of IL-8 by tumor cells may be responsible for this event, which is associated with a significantly higher risk of death.

Topics: Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Aged, 80 and over; Bronchoalveolar Lavage Fluid; Female; Humans; Interleukin-8; Lung Neoplasms; Male; Middle Aged; Neutrophils; Pneumonia; Prognosis; Pulmonary Alveoli

Defensins, also known as human neutrophil peptides, are antimicrobial peptides present in the azurophil granules of neutrophils. We measured their level in pleural effusion in various pulmonary diseases to investigate whether they could be used as a diagnostic marker in the differential diagnosis of specific pleural diseases.. We analyzed pleural effusion samples collected from 61 patients, including 50 exudates (11 with empyema, 3 parapneumonic, 15 tuberculous, 18 neoplastic, 3 miscellaneous) and 11 transudates as controls.. Defensins were measured by radioimmunoassay and also analyzed by reverse-phase high-performance liquid chromatography. The concentrations of interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF) in pleural effusion fluid were measured by enzyme-linked immunosorbent assay to examine the correlation between these cytokines and defensins.. The concentration of defensins in all samples of empyema was >5,100 ng/mL and the mean concentration (13,265.8+/-1,895.2 ng/mL) in these samples was the highest among other groups. The concentration in the other 50 pleural effusion samples tested was <2,800 ng/mL. Defensins were mostly of the mature type in empyema. Pleural effusion levels of IL-8 and G-CSF in patients with empyema were also significantly higher than those in other samples. There was a significant correlation between defensins and IL-8 or G-CSF in pleural effusion fluid (r=0.762, and 0.827, respectively).. Our results suggest that the high effusion concentrations of defensins in pleural effusion may constitute an important component of the host defense system or may have a cytotoxic role in empyema. Our results also indicate that the high levels of IL-8 and G-CSF in empyema may indirectly explain the elevated levels of defensins by increasing the number of neutrophils in the pleural space.

Topics: Biomarkers; Blood Proteins; Chromatography, High Pressure Liquid; Defensins; Diagnosis, Differential; Empyema, Pleural; Empyema, Tuberculous; Enzyme-Linked Immunosorbent Assay; Female; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Pleural Effusion; Pleural Effusion, Malignant; Pneumonia; Radioimmunoassay

Interleukin (IL)-8 is a potentially important cytokine in allergic respiratory responses since it is released by many resident lung cells, and it is a potent granulocyte chemoattractant. Therefore, we induced an immunoglobulin (Ig)E-mediated response in human lung samples and studied whether IL-8 was produced in sufficient quantities to promote human neutrophil and eosinophil migration across naked filters and endothelial and pulmonary epithelial monolayers cultured on these filters. Fresh human lung fragments from 16 thoracotomy specimens were treated with either a 1:100 dilution of anti-IgE or buffer (control) for 30 min. All anti-IgE treated lung samples had significant release of histamine and neutrophil and eosinophil chemotactic activity. Fourteen of the 16 lung samples had a significant increase in IL-8 subsequent to anti-IgE treatment (p<0.01). Anti-IL-8 antibody (4 microg x mL[-1]) inhibited 42% and 53% of neutrophil and eosinophil chemotactic activity respectively, contained in supernatants from anti-IgE-treated lung samples. Finally, we found that IL-8 at a concentration near that measured after anti-IgE treatment of lung samples (2,000 pg x mL[-1]) induced neutrophil and eosinophil migration through naked filters and endothelial and pulmonary epithelial cell monolayers. Thus, human lung IgE-mediated responses in vitro results in the rapid release of interleukin-8 in amounts sufficient to affect a biological response, granulocyte transcellular migration, indicating that interleukin-8 may play a significant role in allergic respiratory diseases.

Topics: Antibodies; Cell Line; Cell Movement; Histamine; Humans; Immunoglobulin E; Interleukin-8; Lung; Pneumonia

Epidemiologic data show that air pollution particulates cause adverse pulmonary health effects, especially in individuals with preexisting lung disease. We sought to model in vitro preexisting lung inflammation in order to investigate the hypothesis that "primed" lung epithelial cells will exhibit enhanced phlogistic responses [e.g., interleukin-8 (IL-8) production] to particulate air pollution. Exposure of tumor necrosis factor alpha (TNF-alpha) primed or control A549 cells to the air pollution particulates, residual oil fly ash (ROFA), and the known pathogenic dust alpha-quartz, but not inert TiO2, caused increased IL-8 production in primed cells compared to normal cells in a concentration-dependent manner (particle concentration range 0-200 microg/ml). We hypothesized that oxidant mechanisms may be involved in the cellular response to particulates. Addition of the antioxidant N-acetylcysteine (NAC, 1.0 mM) decreased ROFA and alpha-quartz-mediated IL-8 production by approximately 50% in normal and TNF-alpha-primed A549 cells. In addition, exposure of A549 cells to ROFA caused a substantial (and NAC inhibitable) increase in oxidant levels as measured by fluorometry (DCFH oxidation). These data suggest that (1) lung epithelial cells primed by inflammatory mediators can show enhanced cytokine production after exposure to air pollution particulates, and (2) oxidant stress is a key mechanism for this response.

Topics: Acetylcysteine; Adenocarcinoma, Bronchiolo-Alveolar; Air Pollution; Antioxidants; Carbon; Chromans; Coal Ash; Dose-Response Relationship, Drug; Epithelial Cells; Flow Cytometry; Fluoresceins; Free Radical Scavengers; Humans; Industrial Waste; Interleukin-8; Lung; Lung Neoplasms; Oxidative Stress; Particle Size; Particulate Matter; Petroleum; Piperazines; Pneumonia; Quartz; Titanium; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Recently, some investigators have observed elevated concentrations of chloride in the airway surface fluid (ASF) overlying respiratory epithelia from cystic fibrosis (CF) patients compared with ASF overlying non-CF epithelia. Others have shown that this elevated ASF salt concentration can inactivate human beta-defensin-1, an antimicrobial peptide secreted by respiratory epithelia. This could impair the primary epithelial defense against bacteria in the CF airway, thereby forcing a greater reliance on polymorphonuclear leukocyte (PMN)-mediated defenses. Pseudomonas aeruginosa (Psa) flourishes in the CF airway despite the presence of abundant PMN. We therefore investigated whether elevated ASF chloride concentration in CF might also compromise PMN function. We employed a cell-culture model in which halide concentrations and osmolarity were varied independently. We examined the effects of chloride concentration on three aspects of PMN function: recruitment of PMN to the airway (production of interleukin-8 [IL-8]), PMN antimicrobial activity (killing of Psa), and PMN clearance from the airways (apoptosis and lysis). We found that exposure to elevated chloride concentration increased PMN synthesis of IL-8, decreased PMN killing of Psa, and accelerated PMN apoptosis and lysis. In CF airways, elevated chloride therefore could contribute to the increased number of PMN recruited into the airways, the increased survival of Psa, and the increased quantity of toxic mediators released by PMN into the airways. These effects of elevated chloride on PMN function may provide another causal link between loss of cystic fibrosis transmembrane conductance regulator function and CF lung disease.

Topics: Adult; Apoptosis; Cells, Cultured; Chlorides; Cystic Fibrosis; Dose-Response Relationship, Drug; Humans; Interleukin-8; Lung; Neutrophil Activation; Neutrophils; Phagocytosis; Pneumonia; Pseudomonas aeruginosa

Lung function deteriorates with age and is associated with elastin loss, loss of elastic recoil and decline in diffusing capacity for carbon monoxide. To determine whether increased numbers of neutrophils can be found in the lower respiratory tract in healthy, clinically normal individuals who are more advanced in age, we performed bronchoalveolar lavage (BAL) on individuals in three discontinuous age groups (Group I, 19-36 years; Group II, 45-55 years; Group III, 64 83 years). We found that neutrophils were increased in many individuals in Group III compared to Group I. The neutrophil cell differential count was 1.44+/-0.18% (mean+/-S.E.M.) for Group I versus 3.88+/-0.81% for Group III (P < 0.01) and neutrophils x 10(3)/ml BAL fluid was 1.7+/-0.2 versus 7.2+/-1.7 for Group I versus Group III, respectively (P < 0.01). Similarly, interleukin-8 (IL-8) (8.5+/-1.7 vs 36.8+/-9.4 pg/ml, P < 0.01) and neutrophil elastase (NE) complexed to alpha1-antiprotease (1.2+/-0.1 vs 16.6+/-7.1 ng/ml, P < 0.02) were significantly elevated in the oldest versus youngest age group, although alpha1-antiprotease (582+/-86 vs 1178+/-148 ng/ml, P < 0.01) and elastase inhibitory capacity (EIC) (8.1+/-1.3 vs 17.7+/-1.9 micromol/ml, P < 0.01) were also significantly increased in the oldest age group. This cross-sectional investigation suggests that low-grade inflammation exists in the air spaces of many clinically normal, older individuals.

Topics: Adult; Aged; Aged, 80 and over; Bronchoalveolar Lavage Fluid; Cross-Sectional Studies; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Leukocyte Count; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Pneumonia; Reference Values

Our study investigated the presence of IL-8 in pleural exudates from tuberculosis patients (TBP) (n = 13), and evaluated whether it was related with the profile of major immunocompetent cells present in their pleural and peripheral compartments. To allow comparisons, an additional group of patients with parapneumonic pleural effusions (PNE) (n = 7) was included. Blood peripheral immunophenotypic studies were also carried out in 12 age-matched healthy controls (Co), and 39 tuberculosis patients classified, according to the extent of pulmonary involvement, into mild (n = 9), and advanced (n = 30) cases. Patients were recruited before starting therapy, had HIV negative serology, and showed no age differences among groups (mean +/- SD., 40.7 +/- 14.7 years). IL-8 concentrations were measured by an ELISA method while immunophenotypic analysis was performed by using FITC-conjugated monoclonal antibodies reacting against the following cell surface molecules: CD3, CD4, CD8, CD25 (IL-2R+ cells), CD19, and CD68. IL-8 was detected in all pleural exudates though levels in the TB patients, 384 +/- 110 pg/ml, appeared significantly higher than the PNE group, 185 +/- 110 pg/mg, (P < 0.015, mean +/- S.D.). In turn, the former group presented values of pleural CD3+, CD4+, and CD25, which were found increased in comparison with PNE patients (P < 0.01). Unlike the pleural compartment, patients with TBP showed a marked and significant decrease in their circulating levels of cells bearing the CD3, CD4, CD19, CD25, and CD68 phenotypes not only when comparing with Co but also with PNE and mild patients. Differences between the levels of pleural and peripheral T-cells from TBP patients may be the reflection of an important influx of T-lymphocytes from the circulatory system to the pleural cavity, probably linked to the presence of chemotactic factors within the pleural fluid like IL-8.

Topics: Adolescent; Adult; Aged; Chemotaxis, Leukocyte; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunocompetence; Immunophenotyping; Interleukin-8; Lymphocyte Count; Lymphocyte Subsets; Male; Middle Aged; Pleural Effusion; Pneumonia; Tuberculosis, Pleural; Tuberculosis, Pulmonary

Systemic inflammatory response syndrome (SIRS) and infections are frequently associated with the development and progression of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS). We investigated, at onset and during the progression of ARDS, the relationships among (1) clinical variables and biological markers of SIRS, (2) infections defined by strict criteria, and (3) patient outcome. Biological markers of SIRS included serial measurements of inflammatory cytokines (IC)-tumor necrosis factor-alpha (TNF-alpha) and interleukins (IL) 1 beta, 2, 4, 6, and 8-in plasma and BAL fluid.. We prospectively studied two groups of ARDS patients: 34 patients treated conventionally (group 1) and nine patients who received glucocorticoid rescue treatment for unresolving ARDS (group 2). Individual SIRS criteria and SIRS composite score were recorded daily for all patients. Plasma IC levels were measured by enzyme-linked immunosorbent assay on days 1, 2, 3, 5, 7, 10, and 12 of ARDS and every third day thereafter while patients received mechanical ventilation. Unless contraindicated, bilateral BAL was performed on day 1, weekly, and when ventilator-associated pneumonia was suspected. Patients were closely monitored for the development of nosocomial infections (NIs).. ICU mortality was similar among patients with and without sepsis on admission (54% vs 40%; p < 0.45). Among patients with sepsis-induced ARDS, mortality was higher in those who subsequently developed NIs (71% vs 18%; p < 0.05). At the onset of ARDS, plasma TNF-alpha, IL-1 beta, IL-6, and IL-8 levels were significantly higher (p < 0.0001) in nonsurvivors (NS) and in those with sepsis (p < 0.0001). The NS group, contrary to survivors (S), had persistently elevated plasma IC levels over time. In 17 patients, 36 definitive NIs (17 in group 1 and 19 in group 2) were diagnosed by strict criteria. No definitive or presumed NIs caused an increase in plasma IC levels above patients' preinfection baseline. Daily SIRS components and SIRS composite scores were similar among S and NS and among patients with and without sepsis-induced ARDS, were unaffected by the development of NI, and did not correlate with plasma IC levels.. Sepsis as a precipitating cause of ARDS was associated with higher plasma IC levels. However, NIs were not associated with an increase in SIRS composite scores, individual SIRS criteria, or plasma IC levels above patients' preinfection baseline. SIRS composite scores over time were similar in S and NS. SIRS criteria, including fever, were found to be nonspecific for NI. Irrespective of etiology of ARDS, plasma IC levels, but not clinical criteria, correlated with patient outcome. These findings suggest that final outcome in patients with ARDS is related to the magnitude and duration of the host inflammatory response and is independent of the precipitating cause of ARDS or the development of intercurrent NIs.

Topics: Adult; Bacterial Infections; Biomarkers; Bronchoalveolar Lavage Fluid; Cause of Death; Critical Care; Cross Infection; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Glucocorticoids; Humans; Interleukin-1; Interleukin-2; Interleukin-4; Interleukin-6; Interleukin-8; Male; Multiple Organ Failure; Outcome Assessment, Health Care; Pneumonia; Prospective Studies; Respiration, Artificial; Respiratory Distress Syndrome; Survival Rate; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

The acute phase protein, C-reactive protein (CRP), can increase more than a thousandfold during acute inflammatory states, and it is known to modulate neutrophil-mediated inflammatory responses. We have previously shown that CRP inhibits chemotaxis of C5a-stimulated neutrophils in vitro and that rabbits with elevated CRP blood levels exhibit diminished pulmonary vascular permeability and neutrophil infiltration in a model of alveolitis. To study the effect of CRP on alveolitis induced by different chemoattractants, transgenic mice capable of expressing rabbit CRP in a dietary-inducible fashion were treated with inflammatory doses of the chemoattractants. Intratracheal installation of FMLP (8 x 10(-10) mol), LTB4 (2 x 10(-11) mol), or IL-8 (5 x 10(-12) mol) in normal CF1 mice resulted in significant (p<0.05) influx of neutrophils and protein into the alveolar space. Transgenic mice with elevated plasma levels of CRP showed significantly (p<0.05) diminished infiltration of neutrophils into bronchoalveolar lavage fluid (BALF) and significant reduction in BALF protein compared with that in normal mice. Rabbit CRP (10 to 500 micrograms/ml) inhibited in vitro neutrophil chemotaxis in a concentration-dependent fashion when stimulated by the various chemoattractants examined. These data show that rabbit CRP can modify both in vivo and in vitro neutrophil responses to several classes of chemoattractants and that CRP has a significant protective effect in alveolitis by reducing neutrophil influx and protein leakage into the lung.

Topics: Animals; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Capillary Permeability; Cell Movement; Chemotactic Factors; Chemotaxis, Leukocyte; Complement C5a; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Interleukin-8; Leukotriene B4; Lung; Mice; Mice, Inbred Strains; Mice, Transgenic; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pneumonia; Proteins; Pulmonary Alveoli; Rabbits

Excessive release of proinflammatory cytokines has been involved in pathogenesis of acute respiratory distress syndrome.. Since injured patients with chest trauma reveal a high risk for posttraumatic acute respiratory distress syndrome, local and systemic release of proinflammatory cytokines and their naturally occurring inhibitors were determined in the early posttraumatic period.. Proinflammatory and anti-inflammatory mediators were measured in plasma and bronchoalveolar lavage fluid (BALF) from 16 patients with multiple injuries including severe chest injury (Injury Severity Score of 34.4 +/- 2.3 points) and compared with healthy volunteers (n = 17).. Tumor necrosis factor-alpha was detectable neither in plasma nor in BALF. Interleukin-1beta and interleukin-8 were significantly increased in BALF from injured patients, while plasma levels were similar in both groups. Soluble tumor necrosis factor receptors p55 and p75 and interleukin-1ra were markedly elevated in plasma (p < or = 0.01) and BALF (p < or = 0.001) from injured patients compared with controls.. Highly increased concentrations of proinflammatory cytokines in BALF, but not in circulation, indicate a strong local inflammatory response early after multiple injuries combined with chest injury rather than severe systemic inflammation. In contrast, anti-inflammatory mechanisms seem to be activated locally and systemically.

Topics: Adult; Bronchoalveolar Lavage Fluid; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Injury Severity Score; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-8; Male; Middle Aged; Multiple Trauma; Pneumonia; Sialoglycoproteins; Thoracic Injuries; Tumor Necrosis Factor-alpha

Pulmonary neutrophil entrapment and resultant oxidative injury is thought to be the primary mechanism of cardiopulmonary bypass (CPB) induced lung injury. Interleukin-8 (IL-8), a potent neutrophil chemoattractant induced by cytokines, including tumor necrosis factor-alpha (TNF), is found in increased concentrations in bronchial alveolar lavage fluid (BALF) in lung inflammation. Since aprotinin reduces TNF release during CPB, the effects of aprotinin on BALF IL-8 concentrations and neutrophil levels were determined after CPB in adult humans. Study patients were equally divided into a control group (n = 8, Group 1) and an aprotin-intreated group (n = 8, Group 2). In vitro neutrophil chemotaxis was done with volunteer neutrophils using three different chemoattractants: 1) N-formyl-1-methionyl-1-leucyl-1-phenylalanine (FMLP); 2) the supernatant of a human bronchial epithelial cell culture line, A549, after 24 h of TNF stimulation with or without aprotinin or N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK) (a potent protease inhibitor), and 3) BALF. Aprotinin treatment significantly (P < 0.05) reduced post-CPB BALF IL-8 concentrations and percentage of neutrophils. In vitro, BALF from Group 1 had significantly greater chemotactic ability when compared with Group 2. The TNF stimulated A549 cell culture supernatant had significantly (P < 0.05) greater chemotactic ability than control supernatant, while aprotinin and TLCK significantly (P < 0.05) reduced this chemotactic ability. These results demonstrate that aprotinin blunts IL-8 production and reduces neutrophil lung accumulation post-CPB.

Topics: Adult; Aged; Aprotinin; Bronchi; Bronchoalveolar Lavage Fluid; Cardiopulmonary Bypass; Cell Culture Techniques; Chemotactic Factors; Chemotaxis, Leukocyte; Culture Media, Conditioned; Hemostatics; Humans; Interleukin-8; Leukocyte Count; Lung; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophil Activation; Neutrophils; Pneumonia; Protein Synthesis Inhibitors; Tosyllysine Chloromethyl Ketone; Tumor Necrosis Factor-alpha

The aim of this study was to investigate whether bronchoalveolar lavage (BAL) and serum levels of proinflammatory cytokines discriminate between different entities of patients with acute respiratory failure. BAL and circulating concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) were measured in 74 mechanically-ventilated patients and 17 healthy controls. Patients were classified as cardiogenic pulmonary oedema (CPO), acute respiratory distress syndrome (ARDS), primary severe pneumonia (PN) and a combined group (PN+ARDS). In all patients with ARDS and/or PN, markedly elevated BAL levels of IL-6 and IL-8 were detected, which were significantly greater than levels in CPO and healthy controls. Absolute quantities and time-course of these cytokines did not differentiate between the absence and presence of lung infection, or different categories of PN. Similarly, circulating IL-6 levels were comparably elevated in patients with ARDS and/or PN, whereas circulating IL-8 concentrations were inconsistently increased. TNF-alpha was rarely detected in BAL samples, but increased serum concentrations were measured in ARDS and/or PN patients. Bronchoalveolar lavage levels of interleukin-6 and interleukin-8, but not tumour necrosis factor-alpha, and serum concentrations of interleukin-6 are consistently elevated in acute respiratory distress syndrome and/or severe pneumonia, discriminating these entities from cardiogenic pulmonary oedema. Alveolar and systemic cytokine profiles do not differentiate between acute respiratory distress syndrome in the absence of lung infection and states of severe primary or secondary pneumonia, which evidently present with comparable local and systemic inflammatory sequelae.

Topics: Acute Disease; Bacterial Infections; Bronchoalveolar Lavage Fluid; Cardiac Output, Low; Cytokines; Discriminant Analysis; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Pneumonia; Pneumonia, Bacterial; Positive-Pressure Respiration; Pulmonary Edema; Pulmonary Heart Disease; Respiratory Distress Syndrome; Respiratory Insufficiency; Survival Rate; Tumor Necrosis Factor-alpha

A novel bovine neutrophil-activating peptide, bovine ENA (boENA), was identified in the conditioned media of endotoxin-stimulated bovine monocytes and alveolar macrophages. The chemotactic peptide was purified to homogeneity from conditioned media by cation-exchange chromatography and several steps of reversed-phase high-performance liquid chromatography. The partial amino acid sequence of boENA was: VVRELRCVCLTTTPGIHPKTVSDLQVIAAGPVCSKVEVIATLKNGXXV. Its cysteine molecules are positioned identically to those of the C-X-C family of human proinflammatory peptides. BoENA shows structural (73% identity in amino acid sequence) and functional homology to human ENA-78, a product of the human type II epithelial cell line A549, as demonstrated in assays for chemotaxis, aggregation, shape change, and a rise in intracellular free calcium. The immunohistochemical identification of boENA in the hyperplastic type II alveolar epithelial cells and in pulmonary alveolar leukocytes of pneumonic bovine lungs strongly supports a role for ENA-78 in the genesis of pulmonary inflammation.

Topics: Acute Disease; Amino Acid Sequence; Animals; Cattle; Cytokines; Female; Immunohistochemistry; Interleukin-8; Macrophages; Molecular Sequence Data; Monocytes; Pneumonia; Structure-Activity Relationship

Cryptogenic organizing pneumonia (COP) is a fibrotic process that primarily involves the alveolar spaces, alveolar ducts, and small conducting airways. The pathogenesis is not understood. Recent histopathologic studies have shown that during the cellular phase of COP, fibronectin deposits are present in the lung. Moreover, a neutrophil alveolitis is frequently seen in COP. Little is known about the involvement of alveolar macrophages in the pathogenesis of COP. However, alveolar macrophages are the principal resident cells in the airways, and they are thought to play a central role in the fibrotic process by virtue of their ability to express and release cytokines such as interleukin-8 (IL-8; a neutrophil chemotactic factor) and fibronectin (FN; a fibrogenic matrix-associated protein). We have quantified the spontaneous gene expression of IL-8 and FN by alveolar macrophages from five nonsmoking individuals with COP and compared them with 10 normal, healthy volunteers (five smokers, five nonsmokers). Expression of IL-8 and FN was measured by a quantitative assay employing reverse transcription of mRNA and the polymerase chain reaction. beta-actin mRNA expression was quantified as an internal standard, and the expression of FN and IL-8 transcripts was calculated as a ratio with beta-actin. The mean +/- SEM of the IL-8/beta-actin ratio in alveolar macrophages from patients with COP was 0.45 +/- 0.07, which was significantly higher than the level from either normal smokers (0.19 +/- 0.02, P = 0.008) or normal nonsmokers (0.16 +/- 0.01, P = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Base Sequence; Bronchiolitis Obliterans; Female; Fibronectins; Gene Expression Regulation; Humans; Interleukin-8; Kinetics; Macrophages, Alveolar; Male; Middle Aged; Molecular Sequence Data; Pneumonia; Polymerase Chain Reaction; RNA, Messenger; Transcription, Genetic

Topics: AIDS-Related Opportunistic Infections; Bacterial Infections; Biomarkers; Bronchoalveolar Lavage Fluid; Enzyme-Linked Immunosorbent Assay; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-8; Pneumonia; Pneumonia, Pneumocystis; Tuberculosis

Concurrent pulmonary inflammation and neutrophil infiltration are characteristic of children with cystic fibrosis (CF). The production of the major neutrophil chemotactic cytokine IL-8 by alveolar macrophages or other cells could be of great importance in the pathology of acute lung disease, but its role in the persistent lung inflammation characteristic of CF has not been evaluated. In this study, we have measured, by ELISA, the concentration of IL-8 in sputum, bronchoalveolar lavage, and sera specimens obtained from children with CF. For comparison, IL-8 in bronchoalveolar lavage obtained from asthmatic patients and from non-CF children with or without lung infection and in sera from age-matched controls was measured. High levels of IL-8 were measured in sputum (mean = 2952 pM) and in bronchoalveolar lavage (mean = 6624 pM) from CF patients. In both cases, there was a significant correlation between clinical status (Schwachman score) and IL-8 levels. This was not true for IL-8 levels measured in sera, which nevertheless were significantly higher in CF patients (p = 0.0001) than in normal controls in the over-10-y age group.

Topics: Adolescent; Biomarkers; Bronchoalveolar Lavage Fluid; Child; Child, Preschool; Cystic Fibrosis; Humans; Inflammation; Interleukin-8; Pneumonia; Sputum

Pleural effusions secondary to various diseases are associated with the presence of different inflammatory cells. The role of selective chemotactic cytokines in the recruitment of phagocytes to the pleural space is unclear. IL-8 and monocyte chemotactic peptide-1 (MCP-1) are recently described cytokines that are chemotactic for neutrophils and monocytes, respectively. We prospectively studied 63 patients, using strictly defined criteria for their selection. IL-8 concentrations were elevated in both empyema fluid (9.15 +/- 0.89 ng/ml) and parapneumonic effusions (4.7 +/- 0.697 ng/ml) when compared with pleural effusions secondary to other diseases. IL-8 levels were higher in empyema fluid than in parapneumonic effusions (p = 0.01). There was a significant correlation between IL-8 levels and the total numbers of neutrophils in empyema fluids (r = 0.80). Chemotactic activity for neutrophils was elevated in empyema fluid and the addition of IL-8 neutralizing serum decreased bioactivity by 32.22%. Malignant pleural effusions had the highest levels of MCP-1 (12.0 +/- 3.7 ng/ml) when compared with others. Cytology-positive pleural fluids (n = 10) had a higher level of MCP-1 than cytology-negative effusions (p = < 0.05). Malignant pleural fluid MCP-1 levels correlated (r = 0.70) with the absolute number of monocytes in the pleural fluid. Neutralization of monocyte chemotactic activity of malignant pleural fluid by specific neutralizing serum caused a 70.3% inhibition of bioactivity. Immunohistochemical staining of malignant pleural fluid localized antigenic MCP-1 to malignant cells. We conclude that both IL-8 and MCP-1 play major but not exclusive roles in the recruitment of neutrophils and monocytes from the vascular compartment to the pleural space.

Topics: Chemokine CCL2; Chemotactic Factors; Cytokines; Empyema; Heart Failure; Humans; Immunohistochemistry; Interleukin-8; Pleural Effusion; Pleural Effusion, Malignant; Pleurisy; Pneumonia; Tuberculosis, Pulmonary

IL-8 belongs to the family of chemotactic cytokines and may play an important role in the inflammatory response. In the current studies, a murine mAb (DM/C7) to human rIL-8 was found to have protective effects in inflammatory lung injury in rats. DM/C7 was nonreactive with the rat cytokine-induced neutrophil chemoattractant peptide. In vivo, DM/C7 blocked the glycogen-induced accumulation of neutrophils in rats and was highly protective against lung and dermal vascular injury after deposition of IgG immune complexes. The latter model of injury has recently been shown to be E-selectin dependent. The protective effects of DM/C7 correlated with reduced tissue accumulation of neutrophils, as measured by myeloperoxidase content. DM/C7 reacted with an epitope expressed by TNF-alpha-stimulated rat pulmonary artery endothelial cells and with the pulmonary vascular endothelium after intrapulmonary deposition of IgG immune complexes. In the model of IgG immune complex-induced lung injury, the protective effects of DM/C7 were abolished by prior absorption of the antibody with human rIL-8. Polyclonal antibody to cytokine-induced neutrophil chemoattractant peptide failed to protect against IgG immune complex-induced vascular injury even though this antibody blocked the in vitro chemotactic activity of cytokine-induced neutrophil chemoattractant. In the model of rapidly developing lung injury due to systemic activation of C after infusion of cobra venom factor, DM/C7 was not protective. As well, in the neutrophil-independent model of IgA immune complex-induced lung injury, treatment with DM/C7 was not protective. These data indicate that in inflammatory lung injury that is linked to E-selectin-dependent recruitment of neutrophils in rats, antibody to human IL-8 also blocks recruitment of neutrophils and thereby affords protection against lung injury. The data suggest the presence of an IL-8-like product in this model of lung injury.

Topics: Animals; Antibodies, Monoclonal; Antigen-Antibody Complex; Elapid Venoms; Humans; Immunoglobulin G; Immunohistochemistry; Interleukin-8; Lung; Male; Peroxidase; Pneumonia; Pulmonary Artery; Rats; Tumor Necrosis Factor-alpha

There is ample experimental evidence that polymorphonuclear neutrophils (PMN) play a critical role in the pathogenesis of the adult respiratory distress syndrome (ARDS). Since interleukin-8 (IL-8) is a strong chemotactic factor for PMN, we measured IL-8 levels in plasma and bronchoalveolar lavage (BAL) fluid of 18 patients, 12 with ARDS and 6 with severe pneumonia uncomplicated by ARDS, all of whom had an increased number of PMN in BAL fluid. Seven healthy subjects served as controls. We found elevated levels of IL-8 in the alveolar spaces of all patients tested. Elevated BAL IL-8 levels were related to a fatal outcome and the presence of shock and correlated with a general clinical severity index (simplified acute physiological score). BAL fluid levels of IL-8 were significantly higher in patients with ARDS than in patients with pneumonia. In plasma, IL-8 levels were increased similarly in all patients and did not correlate with survival or the presence of shock. The BAL fluid-to-plasma ratio of IL-8 was significantly greater than that of tumor necrosis factor alpha, indicating higher local production of IL-8. Moreover, the presence of a primed subpopulation of blood PMN with respect to H2O2 production indicates that IL-8 may contribute to the neutrophil-mediated process in the pathogenesis of ARDS and pneumonia.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Humans; Hydrogen Peroxide; Interleukin-8; Middle Aged; Neutrophils; Pneumonia; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Inhalation of grain dusts can cause symptoms of both acute and chronic bronchitis, which has been associated with a neutrophilic inflammatory response in the lung. Since this influx of neutrophils may potentially result in bronchial injury, mechanisms of neutrophil recruitment to grain dust were examined. Sterile, aqueous grain dust extracts were prepared from settled dusts of grain sorghum, corn, oats, and soybeans. The extracts were evaluated for their ability to directly attract human neutrophils using a blindwell neutrophil chemotaxis assay. Each extract was found to possess significant chemotactic activity compared to control (p less than 0.01). To evaluate if the dusts could attract neutrophils indirectly by activating humoral inflammatory mechanisms, the grain dust extracts were evaluated for their ability to activate the complement system. When incubated with normal human serum, each of the grain dusts caused cleavage of the complement proteins C3 and properdin factor B (PFB). Importantly, the grain dust extracts lead to the generation of C5a, a potent neutrophil chemoattractant generated by complement activation. Since activation of the alveolar macrophage to release chemotactic activity represents an additional indirect mechanism of neutrophil recruitment, an extract from grain sorghum dust was evaluated for its ability to stimulate guinea pig and human alveolar macrophages to release neutrophil chemotactic activity. The results demonstrate that supernatants obtained from alveolar macrophages cultured in the presence of grain sorghum dust extract possessed increased chemotactic activity compared to controls (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biomechanical Phenomena; Chemotactic Factors; Chemotaxis, Leukocyte; Complement Activation; Dust; Edible Grain; Humans; Interleukin-8; Lung; Macrophages; Neutrophils; Pneumonia; Pulmonary Alveoli