interleukin-8 and Respiratory-Distress-Syndrome

With the development of new techniques to easily obtain lower respiratory tract specimens, bronchoalveolar lavage fluid and other lung fluids are gaining importance in pulmonary disease diagnosis. We aimed to review and summarize lung fluid biomarkers associated with acute respiratory distress syndrome diagnosis and mortality.. After searching PubMed, Embase, Web of Science, and the Cochrane Library for articles published prior to January 11, 2018, we performed a meta-analysis on biomarkers for acute respiratory distress syndrome diagnosis in at-risk patients and those related to disease mortality. From the included studies, we then extracted the mean and standard deviation of the biomarker concentrations measured in the lung fluid, acute respiratory distress syndrome etiologies, sample size, demographic variables, diagnostic criteria, mortality, and protocol for obtaining the lung fluid. The effect size was measured by the ratio of means, which was then synthesized by the inverse-variance method using its natural logarithm form and transformed to obtain a pooled ratio and 95% confidence interval.. In total, 1156 articles were identified, and 49 studies were included. Increases in total phospholipases A2 activity, total protein, albumin, plasminogen activator inhibitor-1, soluble receptor for advanced glycation end products, and platelet activating factor-acetyl choline were most strongly associated with acute respiratory distress syndrome diagnosis. As for biomarkers associated with acute respiratory distress syndrome mortality, interleukin-1β, interleukin-6, interleukin-8, Kerbs von Lungren-6, and plasminogen activator inhibitor-1 were significantly increased in the lung fluid of patients who died. Decreased levels of Club cell protein and matrix metalloproteinases-9 were associated with increased odds for acute respiratory distress syndrome diagnosis, whereas decreased levels of Club cell protein and interleukin-2 were associated with increased odds for acute respiratory distress syndrome mortality.. This meta-analysis provides a ranking system for lung fluid biomarkers, according to their association with diagnosis or mortality of acute respiratory distress syndrome. The performance of biomarkers among studies shown in this article may help to improve acute respiratory distress syndrome diagnosis and outcome prediction.

Topics: Antigens, Human Platelet; Biomarkers; Bronchoalveolar Lavage Fluid; Hepatocyte Growth Factor; Humans; Interleukin-8; Lung; Plasminogen Activator Inhibitor 1; Platelet Activating Factor; Receptor for Advanced Glycation End Products; Respiratory Distress Syndrome

The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30-40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.

Topics: Angiopoietin-2; Antigens, CD; Biomarkers; Cadherins; Carbon Dioxide; Glucocorticoids; High-Frequency Ventilation; Humans; Interleukin-8; Positive-Pressure Respiration; Quality of Life; Radiography; Respiration, Artificial; Respiratory Distress Syndrome; Vasodilator Agents; Ventilator-Induced Lung Injury; von Willebrand Factor

Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury, characterized by increased pulmonary capillary endothelial cells and alveolar epithelial cells permeability leading to respiratory failure in the absence of cardiac failure. Despite recent advances in treatments, the overall mortality because of ARDS remains high. Biomarkers may help to diagnose, predict the severity, development, and outcome of ARDS in order to improve patient care and decrease morbidity and mortality. This review will focus on soluble receptor for advanced glycation end-products, soluble tumor necrosis factor-receptor 1, Interluken-6 (IL-6), IL-8, and plasminogen activator inhibitor-1, which have a greater potential based on recent studies.

Topics: Acute Lung Injury; Alveolar Epithelial Cells; Biomarkers; Humans; Interleukin-6; Interleukin-8; Plasminogen Activator Inhibitor 1; Receptor for Advanced Glycation End Products; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome

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; 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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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The article provides an overview of efforts to identify and validate biomarkers in acute respiratory distress syndrome (ARDS) and a discussion of the challenges confronting researchers in this area.. Although various putative biomarkers have been investigated in ARDS, the data have been largely disappointing and the 'troponin' of ARDS remains elusive. Establishing a relationship between measurable biological processes and clinical outcomes is vital to advancing clinical trials in ARDS and expanding our arsenal of treatments for this complex syndrome.. This article summarizes the current status of ARDS biomarker research and provides a framework for future investigation.

Topics: Biomarkers; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Male; Mucin-1; Plasminogen Activator Inhibitor 1; Receptor for Advanced Glycation End Products; Research; Respiration, Artificial; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Ventilator-Induced Lung Injury; Vesicular Transport Proteins; von Willebrand Factor

The acute respiratory distress syndrome (ARDS) is a life-threatening lung condition resulting from direct and indirect insults to the lung. It is characterized by disruption of the endothelial-epithelial barrier, alveolar damage, pulmonary edema, and respiratory failure. A key feature of ARDS is the accumulation of neutrophils in the lung microvasculature, interstitium, and alveolar space. Despite a clear association between neutrophil influx into the lung and disease severity, there is some debate as to whether neutrophils directly contribute to disease pathogenesis. The primary function of neutrophils is to provide immediate host defense against pathogenic microorganisms. Neutrophils release numerous antimicrobial factors such as reactive oxygen species, proteinases, and neutrophil extracellular traps. However, these factors are also toxic to host cells and can result in bystander tissue damage. The excessive accumulation of neutrophils in ARDS may therefore contribute to disease progression. Central to neutrophil recruitment is the release of chemokines, including the archetypal neutrophil chemoattractant IL-8, from resident pulmonary cells. However, the chemokine network in the inflamed lung is complex and may involve several other chemokines, including CXCL10, CCL2, and CCL7. This review will therefore focus on the experimental and clinical evidence supporting neutrophils as key players in ARDS and the chemokines involved in recruiting them into the lung.

Topics: Animals; Chemokines; Humans; Interleukin-8; Lung; Neutrophil Infiltration; Neutrophils; Peptide Hydrolases; Respiratory Distress Syndrome

ALI/ARDS (acute lung injury/acute respiratory distress syndrome) is a severe inflammatory lung disease associated with very high mortality. Importantly, no effective therapy has been developed to date for ALI/ARDS. Neutrophils have been implicated in the pathogenesis of ALI/ARDS, and IL-8 (interleukin-8) has been identified as the main chemotactic factor for neutrophils in lung fluids of patients with ALI/ARDS. Significantly, studies from our laboratory have revealed the presence of anti-IL-8 autoantibody:IL-8 immune complexes in lung fluids from patients with ALI/ARDS. Autoantibodies to several cytokines, including IL-8, have been found in human plasma and other tissues. The function of anticytokine autoantibodies is far from clear; however, in some instances, it has been suggested that such autoantibodies may contribute to the pathogenesis of variety of human diseases. In addition, many of these autoantibodies can form immune complexes with target cytokines. Furthermore, immune complexes consisting of anti-IL-8 autoantibodies and IL-8 are very stable due to the high affinity of autoantibodies against IL-8. These complexes are present in various human tissues, including the lung, as they have been detected in lung fluids from patients with ALI/ARDS. In this review, the significance of the latter findings are explored, and the possible involvement of anti-IL-8 autoantibody:IL-8 immune complexes in pathogenesis of ALI/ARDS is discussed.

Topics: Antigen-Antibody Complex; Autoantibodies; Humans; Inflammation Mediators; Interleukin-8; Receptors, Immunologic; Respiratory Distress Syndrome

Clinical acute lung injury (ALI) is a major cause of acute respiratory failure in critically ill patients. There is considerable experimental and clinical evidence that pro- and anti-inflammatory cytokines play a major role in the pathogenesis of inflammatory-induced lung injury from sepsis, pneumonia, aspiration, and shock. A recent multi-center clinical trial found that a lung-protective ventilatory strategy reduces mortality by 22% in patients with ALI. Interestingly, this protective ventilatory strategy was associated with a marked reduction in the number of neutrophils and the concentration of pro-inflammatory cytokines released into the airspaces of the injured lung. Further research is needed to establish the contribution of cytokines to both the pathogenesis and resolution of ALI.

Topics: Animals; Chemokines; Chemotactic Factors; Clinical Trials as Topic; Cytokines; Edema; Enzyme-Linked Immunosorbent Assay; HMGB1 Protein; Humans; Inflammation; Interleukin-1; Interleukin-10; Interleukin-8; Ligands; Lung; Lung Injury; Macrophage Migration-Inhibitory Factors; Models, Biological; Multicenter Studies as Topic; Neutrophils; Respiratory Distress Syndrome; Time Factors

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

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

Neutrophil recruitment is one of the hallmarks of acute inflammation. A potent neutrophil chemotactic and activating factor, interleukin-8 (IL-8), has been demonstrated to be elevated in body fluids in various human diseases and experimental animal models. Recent investigations on animal disease models using blocking antibodies to IL-8 have revealed the essential involvement of IL-8 in acute inflammation. We previously reported that the administration of a neutralizing antibody against IL-8 prevented the neutrophil infiltration and neutrophil-mediated tissue injury in several animal studies. In addition, we have recently demonstrated that anti-IL-8 treatment is also effective in prevention of two models that are very relevant to clinical situations: cerebral reperfusion injury and endotoxemia-induced acute respiratory distress syndrome-like lung injury. These results further support the hypothesis that IL-8 has a pivotal role and is a novel target for therapeutic intervention in neutrophil-mediated injury.

Topics: Animals; Brain; Brain Diseases; Humans; Interleukin-8; Reperfusion Injury; Respiratory Distress Syndrome

Epithelial neutrophil-activating protein 78 (ENA-78) is a member of the CXC chemokines and acts as a potent chemoattractant and activator of neutrophil function. On stimulation in vitro, ENA-78 is highly expressed in many cell types. ENA-78 protein levels are strongly elevated in synovial fluid and blood of patients with rheumatoid arthritis. By in situ hybridization and immunofluorescence staining, ENA-78 has been recognized as a major CXC chemokine expressed in epithelial cells of the intestinal mucosa of patients with Crohn's disease, ulcerative colitis, and acute appendicitis. A high expression of ENA-78 and interleukin-8 (IL-8) was also observed in the exocrine tissue of patients with chronic pancreatitis (CP). It is interesting to note that expression of IP-10, MIP-1alpha, and MCP-1 is high in healthy pancreatic tissue but low in tissue of patients with CP, suggesting a mutually exclusive expression of the ELR-CXC vs. non-ELR-CXC/CC chemokines. High-resolution studies of intracellular chemokines has revealed specific immunoreactivity for ENA-78 associated with the endoplasmic reticulum of many cell types. In contrast, GROalpha immunoreactivity was exclusively localized in the nucleus. Despite their common effects on neutrophil functions, the differential intracellular localization of ENA-78 and GROalpha suggests additional roles for these two chemokines in normal cell biology.

Topics: Arthritis, Rheumatoid; Chemokine CXCL5; Chemokines, CXC; Chronic Disease; Humans; Inflammatory Bowel Diseases; Interleukin-8; Monocytes; Pancreatitis; Respiratory Distress Syndrome

Fibrosis is a pathological process characterized by the replacement of normal tissue by mesenchymal cells and the extracellular matrix produced by these cells. The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in the area of derangement. The same sequence of events occurs in wound healing with normal granulation tissue and scar formation, but, while normal scar formation is very localized and transient, in contrast, in fibrosis, the repair process is exaggerated and usually widespread and can be chronic. Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair. The evaluation of three human fibrotic lung diseases, two diffuse [idiopathic pulmonary fibrosis (IPF), and the adult respiratory distress syndrome (ARDS)], and one focal (tumor stroma in lung cancer), has shown that several cytokines participate to the local injury and inflammatory reaction [interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha)], while other cytokines are involved in tissue repair and fibrosis [platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF)]. A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches.

Topics: Cytokines; Humans; Interleukin-1; Interleukin-8; Molecular Weight; Platelet-Derived Growth Factor; Pulmonary Fibrosis; Respiratory Distress Syndrome; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Wound Healing

The recruitment of leukocyte populations to an area of inflammation is one of the most fundamental processes of immune reactivity, yet a number of the mechanisms which are important to this process are not clearly understood. Investigations directed at understanding the mechanisms of leukocyte elicitation have centered around classical chemotactic factors such as C5a and fMLP, however, these known agents have demonstrated little specificity for recruiting particular leukocyte populations. Recent advances in this field have been made with the discovery of a novel supergene family of chemotactic cytokines or chemokines. These cytokines are important as they possess a high degree of specificity for the recruitment of specific subpopulations of leukocytes.

Topics: Adult; Chemotaxis, Leukocyte; Cytokines; Humans; Inflammation; Interleukin-8; Lung Diseases; Multigene Family; Pulmonary Fibrosis; Respiratory Distress Syndrome

Time relationships of physiologic patterns that are relevant to the pathogenesis of adult respiratory distress syndrome (ARDS) have not been well studied. The purpose of this review is to summarize the temporal relationship of blood volume, hemodynamics, and oxygen transport patterns occurring in postoperative patients before and after ARDS in order to develop a more complete mechanistic evaluation of its pathophysiology and to propose more rational therapeutic strategies. The data indicate that hypovolemia, reduced or uneven blood flow, inadequate delivery of oxygen, and insufficient consumption of oxygen precede the appearance of ARDS and are the primary precipitating physiologic events. This is contrary to conventional thinking which emphasizes capillary leak and fluid overload as the primary problems. The conventional approach also ignores events antecedent to ARDS that produce hypoxia of the lung tissue, result in pulmonary vasoconstriction, and increased pulmonary venous admixture (shunt). Therapy to prevent or rapidly treat these antecedent events has been shown to prevent or attenuate postoperative and posttraumatic ARDS. Various mediators such as interleukin (IL)-1, IL-6, and IL-8 and tumor necrosis factor as measured by plasma concentrations do not precede diagnostic criteria of ARDS, but may accelerate and augment the disorder as it is occurring.

Topics: Blood Volume; Capillary Permeability; Clinical Trials as Topic; Female; Fluid Therapy; Hemodynamics; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Male; Oxygen Consumption; Postoperative Complications; Precipitating Factors; Prospective Studies; Pulmonary Edema; Respiratory Distress Syndrome; Shock; Survival Rate; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Congenital heart disease (CHD) after cardiopulmonary bypass can cause systemic inflammation, and its degree is closely related to the incidence of acute respiratory distress syndrome (ARDS). The purpose of this study was to determine the effectiveness of high-frequency oscillatory ventilation (HFOV) combined with volume guarantee (VG) in reducing systemic inflammation in infants with ARDS after cardiopulmonary bypass for congenital heart surgery.. A randomized controlled trial.. Single-center study in a tertiary teaching hospital.. A total of 58 infants with ARDS after congenital heart surgery were eligible and were randomized to the HFOV (n = 29) or the HFOV-VG (n = 29) between January 2020 and January 2021.. Tracheal aspirate samples for the measurement of interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) were obtained on days one, two, and three of HFOV or HFOV-VG ventilation.. The authors found a significantly increasing trend in the HFOV group mean values of IL-6, IL-8, and TNF-α (p < 0.05 on days two and three v day one), and IL-6, IL-8, and TNF-α levels were significantly higher on day three in the HFOV group versus the HFOV+VG group (p < 0.05). In addition, the incidences of hypocapnia and hypercapnia in infants supported with HFOV-VG were significantly lower (p < 0.05). Furthermore, the postoperative mechanical ventilation duration in the HFOV-VG group also was shorter than that in the HFOV group (p < 0.05).. Compared with HFOV alone, HFOV-VG reduced proinflammatory systemic reactions after congenital cardiac surgery, decreased the incidences of hypercapnia and hypocapnia, and shortened the postoperative mechanical ventilation duration.

Topics: High-Frequency Ventilation; Humans; Hypercapnia; Hypocapnia; Infant; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-6; Interleukin-8; Lung; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Tumor Necrosis Factor-alpha

Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15).. Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1β, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints.. Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1β, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients.. In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic.. ECSA-2020-009; Elaine Galwey Research Bursary.

Topics: alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; COVID-19; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Respiratory Distress Syndrome

This study aims to determine the feasibility of using oligodeoxynucleotides with unmethylated cytosine-guanine dinucleotide sequences (CpG ODN) as an immunity protection strategy for a mouse model of acute respiratory distress syndrome (ARDS). This is a prospective laboratory animal investigation. Twenty-week-old BALB/c mice in Animal research laboratory were randomized into groups. An ARDS model was induced in mice using lipopolysaccharides (LPSs). CpG ODN was intranasally and transrectally immunized before or after the 3rd and 7th days of establishing the ARDS model. Mice were euthanized on Day 7 after the second immunization. Then, retroorbital bleeding was carried out and the chest was rapidly opened to collect the trachea and tissues from both lungs for testing. CpG ODN significantly improved the pathologic impairment in mice lung, especially after the intranasal administration of 50 μg. This resulted in the least severe lung tissue injury. Furthermore, interleukin-6 (IL-6) and IL-8 concentrations were lower, which was second to mice treated with the rectal administration of 20 µg CpG ODN. In contrast, the nasal and rectal administration of CpG ODN in BALB/c mice before LPS immunization did not appear to exhibit any significant protective effects. The intranasal administration of CpG ODN may be a potential treatment approach to ARDS. More studies are needed to further determine the protective mechanism of CpG ODN.

Topics: Administration, Intranasal; Animals; CpG Islands; Disease Models, Animal; Female; Immunity, Mucosal; Interleukin-6; Interleukin-8; Lung; Lung Injury; Male; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides; Prospective Studies; Protective Agents; Respiratory Distress Syndrome

Mortality prediction in ARDS is important for prognostication and risk stratification. However, no prediction models have been independently validated. A combination of two biomarkers with age and APACHE III was superior in predicting mortality in the NHLBI ARDSNet ALVEOLI trial. We validated this prediction tool in two clinical trials and an observational cohort.. The validation cohorts included 849 patients from the NHLBI ARDSNet Fluid and Catheter Treatment Trial (FACTT), 144 patients from a clinical trial of sivelestat for ARDS (STRIVE), and 545 ARDS patients from the VALID observational cohort study. To evaluate the performance of the prediction model, the area under the receiver operating characteristic curve (AUC), model discrimination, and calibration were assessed, and recalibration methods were applied.. The biomarker/clinical prediction model performed well in all cohorts. Performance was better in the clinical trials with an AUC of 0.74 (95% CI 0.70-0.79) in FACTT, compared to 0.72 (95% CI 0.67-0.77) in VALID, a more heterogeneous observational cohort. The AUC was 0.73 (95% CI 0.70-0.76) when FACTT and VALID were combined.. We validated a mortality prediction model for ARDS that includes age, APACHE III, surfactant protein D, and interleukin-8 in a variety of clinical settings. Although the model performance as measured by AUC was lower than in the original model derivation cohort, the biomarker/clinical model still performed well and may be useful for risk assessment for clinical trial enrollment, an issue of increasing importance as ARDS mortality declines, and better methods are needed for selection of the most severely ill patients for inclusion.

Topics: Acute Lung Injury; Adult; Aged; APACHE; Biomarkers; Cohort Studies; Female; Hospital Mortality; Humans; Interleukin-8; Male; Middle Aged; Pulmonary Surfactant-Associated Protein D; Reproducibility of Results; Respiration, Artificial; Respiratory Distress Syndrome; ROC Curve

Platelets play an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). Animal and observational studies have shown aspirin's antiplatelet and immunomodulatory effects may be beneficial in ARDS.. To test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS.. Healthy volunteers were randomised to receive placebo or aspirin 75  or 1200 mg (1:1:1) for seven days prior to lipopolysaccharide (LPS) inhalation, in a double-blind, placebo-controlled, allocation-concealed study. Bronchoalveolar lavage (BAL) was performed 6 hours after inhaling 50 µg of LPS. The primary outcome measure was BAL IL-8. Secondary outcome measures included markers of alveolar inflammation (BAL neutrophils, cytokines, neutrophil proteases), alveolar epithelial cell injury, systemic inflammation (neutrophils and plasma C-reactive protein (CRP)) and platelet activation (thromboxane B2, TXB2). Human lungs, perfused and ventilated ex vivo (EVLP) were randomised to placebo or 24 mg aspirin and injured with LPS. BAL was carried out 4 hours later. Inflammation was assessed by BAL differential cell counts and histological changes.. In the healthy volunteer (n=33) model, data for the aspirin groups were combined. Aspirin did not reduce BAL IL-8. However, aspirin reduced pulmonary neutrophilia and tissue damaging neutrophil proteases (Matrix Metalloproteinase (MMP)-8/-9), reduced BAL concentrations of tumour necrosis factor α and reduced systemic and pulmonary TXB2. There was no difference between high-dose and low-dose aspirin. In the EVLP model, aspirin reduced BAL neutrophilia and alveolar injury as measured by histological damage.. These are the first prospective human data indicating that aspirin inhibits pulmonary neutrophilic inflammation, at both low and high doses. Further clinical studies are indicated to assess the role of aspirin in the prevention and treatment of ARDS.. NCT01659307 Results.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biomarkers; Bronchoalveolar Lavage; C-Reactive Protein; Cytokines; Double-Blind Method; Female; Humans; Inflammation; Inhalation; Interleukin-8; Lipopolysaccharides; Male; Neutrophils; Prospective Studies; Respiratory Distress Syndrome; Treatment Outcome; Volunteers

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

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; 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Ventilation with low tidal volume (VT) is well recognized as a protective approach to patients with acute respiratory distress syndrome (ARDS), but the optimal level of positive end-expiratory pressure (PEEP) remains uncertain. This study aims to evaluate two protective ventilatory strategies sequentially applied in patients with early ARDS.. In this prospective cohort study, fifteen patients were ventilated during 24 h with positive end-expiratory pressure (PEEP) adjusted according to the ARDSnet low-PEEP table (ARDSnet-24 h). During the next 24 h, nine patients with PaO2/FIO2 ratio below 350 mmHg were ventilated with PEEP titrated according to the Open Lung Concept protocol (ARDSnet + OLC). In the other six patients, regardless of their PaO2/FIO2 ratio, the ARDSnet remained for a further 24 h (ARDSnet-48 h). Ventilatory variables, arterial blood-gas and cytokine were obtained at baseline, 24 and 48 h. Additionally, whole-lung-computed tomography was acquired at 24 and 48 h.. A sustained improvement in PaO2/FIO2 ratio (P = 0.008) with a decrease in collapsed regions (P = 0.008) was observed in the ARDSnet + OLC group compared with the ARDSnet-24 h group. A reduction in IL-6 in plasma (P < 0.02) was observed throughout the protocol in the ARDSnet + OLC group. Compared with the ARDSnet-48 h group, the ARDSnet + OLC presented smaller amounts of collapsed areas (P = 0.018) without significant differences in hyperinflated regions and in driving and plateau pressures.. In this set of patients with early ARDS, mechanical ventilation with an individually tailored PEEP sustained improved pulmonary function with better aeration, without significant increase in hyperinflated areas".. Brazilian Clinical Trials Registry (ReBec). RBR-5zm9pr. 04th November 2015.

Topics: Adult; Aged; Aged, 80 and over; Blood Gas Analysis; Female; Humans; Interleukin-6; Interleukin-8; Lung; Male; Middle Aged; Positive-Pressure Respiration; Prospective Studies; Protective Factors; Pulmonary Atelectasis; Respiratory Distress Syndrome; Tomography, Spiral Computed; Young Adult

ARDS is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (eg, nonpulmonary sepsis); however, this hypothesis has not been well studied in humans.. We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single-center study of 100 patients with ARDS and severe sepsis and in a secondary analysis of 853 patients with ARDS drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts.. In both studies, patients with direct ARDS had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2) than those with indirect ARDS. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, patients with direct ARDS also had lower levels of von Willebrand factor antigen and IL-6 and IL-8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS.. Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct and indirect ARDS, respectively.

Topics: Adult; Aged; Angiopoietin-2; Biomarkers; Cohort Studies; Comorbidity; Endothelium; Female; Humans; Interleukin-6; Interleukin-8; Lung; Male; Middle Aged; Phenotype; Prognosis; Pulmonary Surfactant-Associated Protein D; Respiratory Distress Syndrome; Respiratory Mucosa; Sepsis; von Willebrand Factor

There are no current pharmacological therapies for the prevention or treatment of acute respiratory distress syndrome. Early dysregulated inflammation likely plays a role in acute respiratory distress syndrome development and possibly acute respiratory distress syndrome outcomes. p38 mitogen-activated protein kinase is central to the regulation of multiple inflammatory mediators implicated in acute organ dysfunction and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. In preclinical models, p38 inhibitors reduce lung injury following pancreatitis and burn injury.. We conducted a phase IIa, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and tolerability of dilmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in patients at risk for developing acute respiratory distress syndrome admitted with an Injury Severity Score more than 16, excluding head trauma. Enrolled patients received 4- or 24-hour IV dilmapimod infusions at different doses or placebo, daily for 3 days, in four separate cohorts.. Multicenter randomized clinical trial of large, academic trauma centers.. Seventy-seven patients were enrolled. Although adverse events were common in this critically ill population, dilmapimod was well tolerated, with no clinically relevant safety findings. Pharmacokinetic models indicated that the higher dose of 10 mg given as continuous infusion over 24 hours had the most favorable plasma concentration profile. Likewise, measures of soluble inflammatory markers including interleukin-6, C-reactive peptide, interleukin-8, and soluble tumor necrosis factor receptor 1 were most different between this dosing arm and placebo. Although the study was not specifically designed with acute respiratory distress syndrome as an outcome, the number of patients who developed acute respiratory distress syndrome was small (2/77).. The novel p38 mitogen-activated protein kinase inhibitor dilmapimod appears well tolerated and may merit further evaluation for prevention of acute respiratory distress syndrome and other organ injury in larger clinical trials. Furthermore, results of this early-phase trial may aid in design of future studies aimed at prevention of acute respiratory distress syndrome and other organ injury.

Topics: Adult; C-Reactive Protein; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hospital Mortality; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Male; Middle Aged; p38 Mitogen-Activated Protein Kinases; Pyridones; Pyrimidines; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome; Trauma Severity Indices; Wounds and Injuries

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

Lung volume recruitment maneuver (LVRM) may improve gas exchange but inflating the lungs to nearly vital capacity may cause further lung injuries. Our aim was to determine the potent inflammatory cytokine response following lung volume recruitment (LVRM) with high frequency oscillator ventilation (HFOV) in pediatric acute respiratory distress syndrome (ARDS).. We prospectively recruited pediatric patients (age >1 month - <15 year old) with a diagnosis of ARDS within 72 hrs of PICU admission. They underwent the LVRM protocol combined with HFOV. Any enrolled subject who had a 20% improvement in PaO2/FiO2 (PF ratio) 1 hr after the LVRM we classified as a responder. Baseline clinical data were recorded. Blood was also drawn at baseline, 1 & 24 hrs after LVRM and kept for further sICAM-1, IL-6 & IL-8 analysis.. Eighteen children with ARDS were enrolled. Their mean age was at 6.8 +/- 6.1 years (mean +/- SD). The initial oxygen index (iOI) was at 26.8 +/- 17.8 (11.5-84.9). There was no significant differences in sICAM-1, IL-6 and IL-8 levels at baseline; (34 +/- 17.5, 121.7 +/- 115.15, 601.5 +/- 675 pg/ml); 1 hr (39.6 +/- 28.7, 99.8 +/- 75.5, 617.4 +/- 692.5 pg/ml) and at 24 hrs (44.23 +/- 34.4, 109.4 +/- 63.9, 737.6 +/- 922.3 pg/ml) following LVRMs, respectively. However, there was significant difference in the elevation of sICAM-1 levels (%change) from baseline in responders (-1.8 +/- 12.2%) vs. non-responders (47.65 +/- 43.5%) at 1 hr. Additionally, sICAM-1 levels were also significantly higher at baseline, 1 hr and 24 hrs in non-survivors as compared with survivors.. There was no significant elevation of potent inflammatory cytokines that may indicate further lung injuries in the majority of our patients. However, there was significant elevation of sICAM-1 levels in non-responders and in those who did not survive that may indicate more lung injuries in these individuals.

Topics: Adolescent; Child; Child, Preschool; Cytokines; Female; High-Frequency Ventilation; Humans; Infant; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Lung; Lung Injury; Male; Oxygen; Partial Pressure; Prospective Studies; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Tidal Volume

Post-operative pulmonary complications such as systemic inflammatory response syndrome (SIRS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are strongly associated with morbidity and mortality after esophagectomy. Post-operative administration of sivelestat sodium hydrate (sivelestat), a selective inhibitor of neutrophil elastase (NE), has been shown to improve the post-operative clinical course after esophagectomy. This study aimed to evaluate the effect of prophylactic administration of sivelestat on bronchial inflammatory responses. We randomized 24 patients into two groups. One group received 0.2 mg/kg/h sivelestat from the induction of anesthesia to post-operative day 1 (sivelestat group) and the other group received the same amount of physiological saline (control group). Bronchial alveolar epithelial lining fluid (ELF) samples were obtained from both groups at the induction of anesthesia and at the end of surgery. The serum and ELF levels of interleukin (IL)-6 and IL-8 were measured by enzyme-linked immunosorbent assay, and NE activity was spectrophotometrically determined using the same samples. Although IL-6 levels in the ELF significantly increased at the end of surgery compared with the pre-operative levels in both groups, the IL-8 levels and NE activity did not significantly increase at the end of the surgery compared to the corresponding pre-operative values in the sivelestat group. Moreover, IL-8 levels and NE activity in the ELF were significantly reduced at the end of surgery in the sivelestat group compared with corresponding values in the control group. The durations of ALI and ARDS were apparently shorter in the sivelestat group and the duration of SIRS was significantly shorter in the sivelestat group compared to the control group. We demonstrated that prophylactic use of sivelestat mitigated bronchial inflammation by suppressing NE activity and IL-8 levels in the ELF and shortened the duration of SIRS after transthoracic esophagectomy.

Topics: Acute Lung Injury; Aged; Bronchitis; Esophagectomy; Female; Glycine; Humans; Interleukin-6; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Postoperative Complications; Premedication; Respiratory Distress Syndrome; Respiratory Function Tests; Serine Proteinase Inhibitors; Sulfonamides; Systemic Inflammatory Response Syndrome; Treatment Outcome

Tidal volume and plateau pressure minimisation are the standard components of a protective lung ventilation strategy for patients with acute respiratory distress syndrome (ARDS). Open lung strategies, including higher positive end-expiratory pressure (PEEP) and recruitment manoeuvres to date have not proven efficacious. This study examines the effectiveness and safety of a novel open lung strategy, which includes permissive hypercapnia, staircase recruitment manoeuvres (SRM) and low airway pressure with PEEP titration.. Twenty ARDS patients were randomised to treatment or ARDSnet control ventilation strategies. The treatment group received SRM with decremental PEEP titration and targeted plateau pressure < 30 cm H2O. Gas exchange and lung compliance were measured daily for 7 days and plasma cytokines in the first 24 hours and on days 1, 3, 5 and 7 (mean ± SE). Duration of ventilation, ICU stay and hospital stay (median and interquartile range) and hospital survival were determined.. There were significant overall differences between groups when considering plasma IL-8 and TNF-α. For plasma IL-8, the control group was 41% higher than the treatment group over the seven-day period (ratio 1.41 (1.11 to 1.79), P = 0.01), while for TNF-α the control group was 20% higher over the seven-day period (ratio 1.20 (1.01 to 1.42) P = 0.05). PaO2/FIO2 (204 ± 9 versus 165 ± 9 mmHg, P = 0.005) and static lung compliance (49.1 ± 2.9 versus 33.7 ± 2.7 mls/cm H2O, P < 0.001) were higher in the treatment group than the control group over seven days. There was no difference in duration of ventilation (180 (87 to 298) versus 341 (131 to 351) hrs, P = 0.13), duration of ICU stay (9.9 (5.6 to 14.8) versus 16.0 (8.1 to 19.3) days, P = 0.19) and duration of hospital stay (17.9 (13.7 to 34.5) versus 24.7 (20.5 to 39.8) days, P = 0.16) between the treatment and control groups.. This open lung strategy was associated with greater amelioration in some systemic cytokines, improved oxygenation and lung compliance over seven days. A larger trial powered to examine clinically-meaningful outcomes is warranted.. ACTRN12607000465459.

Topics: Aged; Female; Humans; Hypercapnia; Interleukin-8; Lung Compliance; Male; Middle Aged; Oxygen; Pilot Projects; Positive-Pressure Respiration; Pressure; Respiratory Distress Syndrome; Tidal Volume; Treatment Outcome; Tumor Necrosis Factor-alpha

In the pathophysiology of acute respiratory distress syndrome (ARDS), the increase in capillary and alveolar permeability caused by various humoral mediators and resultant pulmonary interstitial edema play major roles. In this study, the efficacy of continuous hemodiafiltration using a cytokine-adsorbing hemofilter with a membrane made of polymethylmethacrylate (PMMA-CHDF) in the treatment of ARDS patients was investigated.. Fifty-one patients with a diagnosis of ARDS complicated by renal failure and without prior steroid therapy were enrolled in this study. Changes in respiratory index (RI), positive end-expiratory pressure, central venous pressure (CVP) and blood levels of TNFalpha, IL-6 and IL-8 before/after blood purification for 3 days as well as the cumulative water balance during the 3-day treatment and 28-day cumulative survival rate were compared between 2 patient groups. One group underwent PMMA-CHDF and the other intermittent hemodialysis (IHD) without water removal for elimination of metabolites and continuous hemofiltration (CHF) for fluid management.. Blood purification for 3 days significantly decreased blood levels of cytokines and successfully removed water without changing CVP in the PMMA-CHDF group, but not in the IHD+CHF group. Significant correlations between changes in blood levels of cytokines (IL-6 and IL-8) and changes in RI were demonstrated in the PMMA-CHDF group. The 28-day cumulative survival rate in the PMMA-CHDF group (68.8%) was significantly higher than that in the IHD+CHF group (36.8%).. Cytokine removal therapy with PMMA-CHDF is expected to be useful as a new therapeutic modality in ARDS patients for non-renal indications.

Topics: Cytokines; Hemodiafiltration; Humans; Immunomodulation; Interleukin-6; Interleukin-8; Membranes, Artificial; Polymethyl Methacrylate; Renal Insufficiency; Respiratory Distress Syndrome; Survival Rate; Tumor Necrosis Factor-alpha

A prolonged period of one-lung ventilation(OLV) is required during thoracic surgery and this may activate cytokine release and cause lung inflammatory response. The lung protective ventilatory strategy has reduced lung and systemic cytokine release and achieved remarkable curative effect in patients with acute respiratory distress syndrome (ARDS). This study was to investigate the effect of the lung protective ventilatory strategy on proinflammatory cytokine release during OLV in patients underwent thoracic surgery.. Forty patients underwent esophagectomy were randomly divided into conventional ventilation (CV) group (n=20) and protective ventilation (PV) group (n=20). In CV group, all patients received two-lung ventilation (TLV) and OLV with a tidal volume (VT) of 10 mL/kg and an inspiration/expiration ratio (I/E) of 1:1.5. In PV group, all patients received TLV with a VT of 10 mL/kg and an I/E ratio of 1:1.5, and received OLV with a VT of 5-6 mL/kg and an I/E ratio of 1:1, along with positive end-expiratory pressure (PEEP) preset at 3-5 cm H2O. Blood samples of 3 mL were extracted at three time courses, which were after tracheal intubation (T1), 120 min after OLV (T2) and 24 h after operation (T3), to analyze concentrations of interleukin (IL)-6 and IL-8 in the two groups. Values of airway peak pressure (Ppeak), airway plateau pressure (Pplat), and airway resistance(Raw)were also recorded using side stream spirometry.. In CV group, concentrations of IL-6 and IL-8 at T2 [(269.4+/-57.2) ng/L, (180.8+/-35.0) ng/L] and T3[(335.8+/-98.7) ng/L,(178.5+/-18.3) ng/L] were significantly increased as compared with those at T1 [(17.0+/-5.4) ng/L,(18.2+/-2.8) ng/L](P<0.05). In PV group, concentrations of IL-6 and IL-8 at T2 [(209.3+/-55.7) ng/L], (115.3+/-71.5) ng/L] and T3 [(278.2+/-100.8) ng/L,(124.2+/-40.1) ng/L] were significantly increased as compared with those at T1[(20.0+/-7.1) ng/L,(15.3+/-3.6) ng/L] (P<0.05). Concentrations of IL-6 and IL-8 at T2 and T3 were significantly higher in CV group than in PV group (P<0.05). Ppeak, Pplat and Raw at T2 were significantly higher in CV group [(33.6+/-4.6 cmH2O,(21.5+/-3.1) cmH2O, (26.3+/-2.1) cmH2O.L(-1).S(-1)] than in PV group [(26.7+/-3.5) cmH2O, (12.4+/-2.1) cmH2O, (18.3+/-2.3) cmH2O.L(-1).S(-1)](P<0.05).. Concentrations of IL-6 and IL-8 are increased during and after OLV in thoracic surgery. The lung protective ventilatory strategy can reduce the airway pressure and airway resistance during OLV, decrease the release of IL-6 and IL-8, and inhibit lung inflammatory responses during OLV and postoperatively.

Topics: Adult; Aged; Airway Resistance; Esophageal Neoplasms; Esophagectomy; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Positive-Pressure Respiration; Pulmonary Ventilation; Respiratory Distress Syndrome; Tidal Volume

To determine whether inhaled steroid administration after cardiopulmonary bypass will attenuate pulmonary inflammation and improve lung compliance and oxygenation.. Randomized, prospective, double-blind, placebo-controlled clinical trial.. Children's Hospital of Michigan, intensive care unit.. Thirty-two children <2 yrs of age with congenital heart disease requiring cardiopulmonary bypass.. Participants were randomly assigned to one of two groups. Group 1 (n = 16) received an inhaled steroid, Budesonide (0.25 mg/2 mL), and group 2 (n = 16) received an inhaled placebo (2 mL of inhaled 0.9% saline). The nebulizations were given at the end of cardiopulmonary bypass, 6 hrs after cardiopulmonary bypass, and 12 hrs after cardiopulmonary bypass. Two hours after each nebulization, bronchoalveolar lavage for interleukin-6 and interleukin-8 was collected.. The concentrations of interleukin-6 and interleukin-8 in the bronchoalveolar lavage increased in both groups after cardiopulmonary bypass. Interleukin-6 peaked 2 hrs after cardiopulmonary bypass and was decreasing by 14 hrs after cardiopulmonary bypass. However, administration of corticosteroid did not affect the production of interleukin-6 when compared with the placebo group (378 +/- 728 vs. 287 +/- 583 pg/mL pre-cardiopulmonary bypass, 1662 +/- 1410 vs. 1584 +/- 1645 pg/mL at the end of cardiopulmonary bypass, 2601 +/- 3132 vs. 3677 +/- 4935 pg/mL 2 hrs after cardiopulmonary bypass, and 1792 +/- 3100 vs. 1283 +/- 1344 pg/mL 14 hrs after cardiopulmonary bypass; p > .05). Likewise, interleukin-8 in the lavage fluid was similar in both the placebo and steroid groups at all time points (570 +/- 764 vs. 990 +/- 1147 pg/mL pre-cardiopulmonary bypass, 1647 +/- 1232 vs. 1394 +/- 1079 pg/mL at the end of cardiopulmonary bypass, 1581 +/- 802 vs. 1523 +/- 852 pg/mL 2 hrs after cardiopulmonary bypass, and 1652 +/- 1069 pg/mL vs. 1808 +/- 281 pg/mL 14 hrs after cardiopulmonary bypass; p > .05). Lung compliance and oxygenation were similar in both groups.. Cardiopulmonary bypass is associated with a pulmonary inflammatory response. Inhaled corticosteroid did not affect the pulmonary inflammatory response as measured by interleukin-6 and interleukin-8 concentrations in the lung lavage after cardiopulmonary bypass. Pulmonary mechanics and oxygenation were not improved by the use of inhaled corticosteroid.

Topics: Administration, Inhalation; Bronchoalveolar Lavage Fluid; Budesonide; Cardiopulmonary Bypass; Child; Double-Blind Method; Female; Glucocorticoids; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Lung; Lung Compliance; Male; Prospective Studies; Respiratory Distress Syndrome

We evaluated the effect of sivelestat sodium (SiV), a novel synthesized polymorphonuclear (PMN) elastase inhibitor, on acute lung injury (ALI) caused by cardiopulmonary bypass (CPB).. Fourteen patients who underwent cardiopulmonary surgery using CPB, followed by the development of both systemic inflammatory response syndrome (SIRS) and ALI, were treated with either 0.2 mg/kg per hour SiV (SiV group, n = 7) or saline (control group, n = 7) for 4 days from the time of arrival in the intensive care unit.. The SiV group had a significantly lower ratio of serum PMN elastase and interleukin (IL)-8, a significantly lower ratio of the respiratory index, and a significantly higher ratio of PaO(2)/FiO(2) after 24 h of treatment than the control group.. Sivelestat sodium suppressed the production of PMN elastase and IL-8, resulting in improved respiratory function in patients with ALI caused by CPB.

Topics: Acute Disease; Aged; Cardiopulmonary Bypass; Female; Glycine; Humans; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Perfusion; Respiratory Distress Syndrome; Serine Proteinase Inhibitors; Sulfonamides; Systemic Inflammatory Response Syndrome

To explore better ventilation strategies above lower-tidal-volume (LTV) strategy to protect lung function and improve outcome in acute respiratory distress syndrome (ARDS).. Thirty ARDS patients were enrolled in Department of Critical Care Medicine of Peking Union Medical College Hospital from July, 2004 to June, 2005. They were randomly allocated into two groups, LTV group and individual ventilation (IV) group. Patients received 6 ml/kg tidal volume (V(T)) and high positive end-expiratory pressure (PEEP) in LTV group. In IV group, static pressure-volume (P-V) curve was measured daily, and PEEP and V(T) were set based on P-V variation, and the open-lung potential was evaluated before recruitment maneuvers. The clinical effect, the degree of lung injury and other outcome indicators in two groups were assessed.. The mortality rate in 28 days of IV group (35.7%) was lower than that of LVT group (57.2%, chi(2) = 1.265, P > 0.05). The serum surfactant-associated protein D (SP-D) expression in the third and the seventh day of IV group [154 (91 - 217), 149 (91 - 206) mg/L] were higher than those before enrollment [140 (80 - 200) mg/L]; and the IL-8 expression in the third and the seventh day of IV group [179 (122 - 236), 210 (100 - 321) ng/L] were higher than those before enrollment [210 (132 - 289) ng/L]; but all showed no significant difference [chi(2) = 1.265, Z = 1.079, 1.741, -0.879, 0.471, respectively, all P > 0.05]. The free-ICU days in 28 days and free-organ-dysfunction days of IV group [11 (5 - 16) d, 13 (6 - 18) d] were significantly higher than that of LTV group [3 (0 - 8) d, 3 (0 - 7) d, Z = -2.277, -2.372 respectively, all P < 0.05]. The PEEP, V(T), partial pressure of carbon dioxide in arterial blood (PaCO2), the plateau pressure (Pplat) of initial 3 days after enrollment in IV group [(11 +/- 2) cm H2O (1 cm H2O = 0.098 kPa), (511 +/- 66) ml, (37 +/- 5) mm Hg (1 mm Hg = 0.133 kPa), (21 +/- 5) cm H2O] were significant different with those of LTV group [(16 +/- 3) cm H2O, (407 +/- 58) ml, (47 +/- 8) mm Hg, (26 +/- 4) cm H2O, t = -8.019, 6.501, -4.311, -4.823, all P < 0.01].. Compared with LTV and high PEEP therapy, IV strategies are feasible for decreasing PEEP and Pplat, increasing tidal compliance and V(T), and avoiding CO2 retention. It also increased free-ICU days and free-organ-dysfunction days.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Interleukin-8; Male; Middle Aged; Pulmonary Surfactant-Associated Protein D; Respiration, Artificial; Respiratory Distress Syndrome

To evaluate the association between interleukin-6, interleukin-8, and interleukin-10 and clinical outcomes including mortality in patients with acute lung injury and to determine whether lower tidal volume ventilation was associated with a decrease in plasma cytokines in patients with acute lung injury.. Multiple-center, randomized trial.. Intensive care units in ten university centers.. The study included 861 patients enrolled in the National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial of lower tidal volumes compared with traditional tidal volumes for acute lung injury.. Patients were randomized to a 6 mL/kg or a 12 mL/kg tidal volume strategy that has been previously described.. Baseline plasma levels of interleukin-6, interleukin-8, and interleukin-10 were each associated with an increased risk of death in both logistic regression analyses controlling for ventilator group (odds ratio 1.63 per log-10 increment, 95% confidence interval 1.33-1.98; odds ratio 2.33 per log-10 increment, 95% confidence interval 1.79-3.03; odds ratio 2.02 per log-10 increment, 95% confidence interval 1.47-2.76, respectively) and multivariate analyses controlling for ventilation strategy, Acute Physiology and Chronic Health Evaluation III score, Pao2/Fio2 ratio, creatinine, platelet count, and vasopressor use (odds ratio 1.63 per log-10 increment, 95% confidence interval 0.93-1.49; odds ratio 1.73 per log-10 increment, 95% confidence interval 1.29-2.34; odds ratio 1.23 per log-10 increment, 95% confidence interval 0.86-1.76, respectively). Interleukin-6 and interleukin-8 levels were also associated with a significant decrease in ventilator free and organ failure free days. Patients with sepsis had the highest cytokine levels and the greatest risk of death per cytokine elevation. By day 3, the 6 mL/kg strategy was associated with a greater decrease in interleukin-6 and interleukin-8 levels. There was a 26% reduction in interleukin-6 (95% confidence interval, 12-37%) and a 12% reduction in interleukin-8 (95% confidence interval, 1-23%) in the 6 mL/kg group compared with the 12 mL/kg group.. In patients with acute lung injury, plasma interleukin-6 and interleukin-8 levels are associated with morbidity and mortality. The severity of inflammation varies with clinical risk factor, suggesting that clinical risk factor should be considered when both developing and testing therapeutic interventions. Low tidal volume ventilation is associated with a more rapid attenuation of the inflammatory response.

Topics: Adult; Aged; APACHE; Critical Care; Female; Hospital Mortality; Hospitals, University; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Lung Injury; Male; Middle Aged; Positive-Pressure Respiration; Prognosis; Respiratory Distress Syndrome; Survival Rate; Systemic Inflammatory Response Syndrome; Tidal Volume

Despite recent advances in the prospective identification of the patient with sepsis who may benefit from anti-inflammatory or antithrombotic therapies, successful treatment regimens have been fairly modest. We have explored whether determination of several proinflammatory cytokine or mediator concentrations can complement physiologic scoring systems to identify patients with severe sepsis who will survive or expire within 28 days. The design of the study included an exploratory analysis performed in conjunction with a prospective, randomized, double-blind, placebo-controlled, multicenter, clinical trial and involved 33 academic institutions in the United States. One hundred twenty-four patients with severe sepsis with or without septic shock were included in this analysis. Blood samples were obtained at baseline and on days 1 through 4, and were evaluated for proinflammatory and anti-inflammatory cytokine concentrations, as well as for procalcitonin and total protein C levels. Baseline concentrations and changes in the concentrations of these mediators were evaluated in relationship to the Acute Physiology and Chronic Health Evaluation (APACHE) II and multiple organ dysfunction (MOD) scores, and 28-day all-cause mortality. Using univariate logistic regression analyses, APACHE II and MOD scores, age (but not gender), and baseline plasma interleukin (IL)-6 and soluble tumor necrosis factor receptor (sTNFR) 1 (log transformed) concentrations were all predictive of increased 28-day all-cause mortality (P < 0.01). Baseline total protein C, IL-8, IL-10, TNF-alpha, and procalcitonin concentrations, and the change in plasma cytokine concentrations from baseline over the initial 4 days were not useful in predicting outcome. Selected baseline proinflammatory cytokine concentrations and APACHE II score were correlated (P < 0.01). IL-6 concentration is a strong candidate for predicting clinical outcome in patients with severe sepsis alone, or when combined with the APACHE II or MOD scores. The potential usefulness of the combination of cytokine measurements and prognostic scores to identify patients who may benefit from treatment with anti-inflammatory or antithrombotic therapies should be further evaluated.

Topics: Aged; Calcitonin; Calcitonin Gene-Related Peptide; Cytokines; Double-Blind Method; Female; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Placebos; Prognosis; Protein C; Protein Precursors; Receptors, Tumor Necrosis Factor; Regression Analysis; Respiratory Distress Syndrome; Risk; Sepsis; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

The objective of this study was to clarify the efficacy and mechanism of action of direct hemoperfusion with an immobilized polymyxin B fiber column (DHP-PMX) in patients with acute lung injury or acute respiratory distress syndrome caused by sepsis.. Thirty-six patients with sepsis were included. In each patient a thermodilution catheter was inserted, and the oxygen delivery index and oxygen consumption index were measured. DHP-PMX was performed in patients with a normal oxygen delivery index and oxygen consumption index (> 500 ml/minute per m2 and > 120 ml/minute per m2, respectively). The Acute Physiology and Chronic Health Evaluation II score was used as an index of the severity of sepsis, and survival was assessed after 1 month. The humoral mediators measured were the chemokine IL-8, plasminogen activator inhibitor-1, and neutrophil elastase (NE). These mediators were measured before DHP-PMX treatment, and at 24, 48, and 78 hours after the start of treatment. The arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2) ratio was measured before DHP-PMX treatment and at 24, 48, 72, 92, and 120 hours after the start of treatment.. All patients remained alive after 1 month. Before DHP-PMX treatment, the Acute Physiology and Chronic Health Evaluation II score was 24 +/- 2.0, the IL-8 level was 54 +/- 15.8 pg/ml, plasminogen activator inhibitor-1 was 133 +/- 28.1 ng/ml, and NE was 418 +/- 72.1 mug/l. These three humoral mediators began to decrease from 24 hours after DHP-PMX treatment, and the decline became significant from 48 hours onward. The PaO2/FiO2 ratio was 244 +/- 26.3 before DHP-PMX treatment but improved significantly from 96 hours onward. There were significant negative correlations between the PaO2/FiO2 ratio and blood levels of NE and IL-8.. The mechanism of action of DHP-PMX is still not fully understood, but we report the following findings. The mean blood levels of plasminogen activator inhibitor-1, NE, and IL-8 were significantly decreased from 48 hours after DHP-PMX treatment. The mean PaO2/FiO2 ratio was significantly improved from 96 hours after DHP-PMX treatment. Improvement in the PaO2/FiO2 ratio appeared to be related to the decreases in blood NE and IL-8 levels.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Biomarkers; Endothelial Cells; Female; Hemoperfusion; Humans; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Oxygen; Plasminogen Activator Inhibitor 1; Polymyxin B; Respiratory Distress Syndrome; Sepsis; Time Factors; Treatment Outcome

We closely followed the pulmonary function of 150 consecutive high-risk breast cancer patients who underwent standard induction CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) chemotherapy, followed by randomization to either standard-dose CPB (cyclophosphamide, cisplatin, bischloroethylnitrosourea [BCNU]) chemotherapy (SDC) or to high-dose CPB chemotherapy (HDC) with autologous bone marrow transplantation (ABMT) and peripheral blood progenitor cell support (PBPCS). Previously, we have described a delayed pulmonary toxicity syndrome (DPTS) which characterizes the pulmonary dysfunction after HDC and ABMT in this patient population. However, little is known concerning the role induction chemotherapy plays in its development. We found that after three cycles of induction CAF, the mean diffusing capacity of the lungs for carbon monoxide (DL(CO)) significantly decreased by 12.6%. Additionally, in patients receiving HDC, the mean DL(CO) further decreased to a nadir of 55.2 +/- 14.1% which was significantly lower than those receiving SDC (nadir: 80.7 +/- 12.3%). DPTS occurred in 72% of patients receiving HDC as compared with only 4% of patients receiving SDC. All individuals diagnosed with DPTS were treated with prednisone and the 2-yr follow-up of pulmonary function revealed a gradual improvement in mean DL(CO) such that there were no differences between HDC and SDC groups at the end of the study. No mortality was attributable to pulmonary toxicity in either group. After induction chemotherapy, but before HDC, bronchoalveolar lavage (BAL) demonstrated significant elevations in interleukin-6 (IL-6), IL-8, neutrophils, and lymphocytes. We conclude that induction CAF produces asymptomatic pulmonary dysfunction and inflammation which may prime the lungs for further injury by HDC and predispose to the development of DPTS. Fortunately, in this specific ABMT patient population, the early and judicious use of prednisone appears to improve pulmonary function in patients who develop DPTS.

Topics: Adenocarcinoma; Adult; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Bronchoalveolar Lavage Fluid; Bronchoscopy; Dose-Response Relationship, Drug; Female; Glucocorticoids; Humans; Interleukin-6; Interleukin-8; Lung; Lymphocytes; Neutrophils; Prednisone; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome; Respiratory Function Tests; Retrospective Studies; Transplantation, Autologous

To investigate the effect of ventilation with 100% oxygen on lung injury associated with surgery involving cardiopulmonary bypass (CPB).. A prospective randomized study.. University hospital.. Thirty patients undergoing coronary artery bypass graft surgery with CPB.. Patients were randomized to receive 100% oxygen (Oxygen group) or 50% oxygen (Air group) throughout surgery. During CPB, patients' lungs in the Air group were flushed with air and in the Oxygen group with 100% oxygen.. Lung injury was evaluated by arterial oxygen tension-inspired oxygen concentration (PaO2-FIO2) ratio and cytokine levels (tumor necrosis factor-alpha and interleukin-8) in blood and bronchoalveolar lavage fluid measured before and after CPB. The lowest PaO2-FIO2 value was observed after 40 minutes following the completion of CPB in both groups. PaO2-FIO2 values 6 hours after CPB were not different from baseline in the Air group but remained lower (359+/-63 mmHg and 298+/-78 mmHg; p = 0.013) in the Oxygen group. Blood cytokine levels rose during surgery in both groups. Bronchoalveolar lavage levels of interleukin-8 did not change, whereas tumor necrosis factor-alpha increased only in the Oxygen group (p = 0.035).. A significant decrease of oxygenation was observed in the early post-CPB period in both groups of patients, with delay in recovery in patients treated with 100% oxygen. A larger increase of the proinflammatory cytokines was found in patients treated with 100% oxygen. High oxygen concentrations during surgery with CPB should be used only when specifically required.

Topics: Bronchoalveolar Lavage Fluid; Cardiopulmonary Bypass; Humans; Interleukin-8; Oxygen; Prospective Studies; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

The interaction between activated neutrophils and pulmonary endothelium is thought to contribute to the pathogenesis of the adult respiratory distress syndrome (ARDS), but its relation to ARDS severity, which may support a pathogenetic role, is unclear. Therefore, circulating inflammatory mediators, including the neutrophil chemoattractant and activator interleukin 8 (IL-8), the acute phase cytokine IL-6, and the neutrophil product elastase complexed to alpha 1-antitrypsin (alpha 1-AT), were measured prospectively, together with gas exchange, ventilatory and radiographic variables, in 13 mechanically ventilated patients with ARDS, mostly owing to sepsis, at admission into the intensive care unit. Measurements were repeated in the eight improving patients at the time that positive end-expiratory pressure could be reduced to 0 cm H2O. From the gas exchange, ventilatory and radiographic abnormalities, a lung injury score (LIS) was calculated. For pooled data, the LIS and the arterial PO2/inspiratory O2 fraction, the oxygenation ratio, correlated with plasma levels of IL-8 (rs = 0.60, P < 0.01 and rs = -0.65, P < 0.005, respectively), with levels of IL-6 (rs = 0.60, P < 0.01, and rs = -0.68, P < 0.005, respectively), and the oxygenation ratio related to elastase-alpha 1-AT (rs = -0.70, P < 0.005). Levels of IL-8 and IL-6 interrelated (rs = 0.61, P < 0.01) and related to the elastase complexes (rs = 0.45, P < 0.05). Hence, our data support a role of cytokine-induced activation of neutrophils in the clinical severity of ARDS.

Topics: Adult; Aged; Female; Humans; Inflammation Mediators; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Pancreatic Elastase; Predictive Value of Tests; Prospective Studies; Respiratory Distress Syndrome

We studied methods for diagnosing the acute respiratory distress syndrome (ARDS) based on its characteristic abnormalities. A gamma-ray external counting method with Tc-99m human serum albumin revealed that pulmonary microvascular permeability was abnormally high in patients with ARDS. With this method, ARDS could be distinguished from cardiogenic pulmonary edema. Levels of interleukin-8 in bronchoalveolar fluid from patients with septic ARDS, reexpansion pulmonary edema, and inhalation burn injury were abnormally high. In 21 patients with acute lung injury, 15 of whom had ARDS, plasma concentrations of three inflammatory markers were measured: thiobarbituric acid reactive material which reflects cell membrane lipid peroxidation; 7S collagen, a component of basement membrane; and the soluble form of P-selectin, an adhesion molecule. Levels of all three were abnormally high in patients with ARDS, and correlated with the degree of lung injury and with the outcome in these patients. We conclude that these measurements in plasma or bronchoalveolar lavage fluid may enable us to assess the severity of ARDS.

Topics: Biomarkers; Bronchoalveolar Lavage Fluid; Capillary Permeability; Cell Adhesion Molecules; Humans; Interleukin-8; Lipid Peroxidation; P-Selectin; Respiratory Distress Syndrome

Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths confined to Black/African American (AA) patients in some areas. However, targeted studies on this vulnerable population are scarce. Here, we applied multiomics single-cell analyses of immune profiles from matching airways and blood samples of Black/AA patients during acute SARS-CoV-2 infection. Transcriptional reprogramming of infiltrating IFITM2+/S100A12+ mature neutrophils, likely recruited via the IL-8/CXCR2 axis, leads to persistent and self-sustaining pulmonary neutrophilia with advanced features of acute respiratory distress syndrome (ARDS) despite low viral load in the airways. In addition, exacerbated neutrophil production of IL-8, IL-1β, IL-6, and CCL3/4, along with elevated levels of neutrophil elastase and myeloperoxidase, were the hallmarks of transcriptionally active and pathogenic airway neutrophilia. Although our analysis was limited to Black/AA patients and was not designed as a comparative study across different ethnicities, we present an unprecedented in-depth analysis of the immunopathology that leads to acute respiratory distress syndrome in a well-defined patient population disproportionally affected by severe COVID-19.

Topics: COVID-19; Humans; Interleukin-8; Lung; Membrane Proteins; Neutrophils; Respiratory Distress Syndrome; SARS-CoV-2; Viral Load

Toxic epidermal necrolysis (TEN) is a fatal cutaneous adverse reaction that occasionally affects multiple organs. Acute respiratory distress syndrome (ARDS) is a rare complication that can cause rapid and potentially fatal pulmonary dysfunction. However, the mechanisms underlying TEN-induced ARDS remain unknown. This retrospective single-center study aimed to identify potential biomarkers for predicting ARDS onset in TEN patients. Pre-treatment serum samples were collected from 16 TEN patients and 16 healthy controls (HCs). The serum levels of cytokines/chemokines were determined using the Luminex Assay Human Premixed Multi-analyte kit. The expression levels of cytokines and chemokines in the skin were examined via immunohistochemistry. The serum levels of C-C motif chemokine ligand 2 (CCL2), interleukin (IL)-6, and IL-8 were significantly higher in TEN patients with ARDS than in those without ARDS and in HCs, whereas those of CCL2 and IL-8 were not significantly different between TEN patients without ARDS and HCs. There was no significant difference in CCL2 and IL-8 expression in the skin between TEN patients with and without ARDS. Interestingly, there were no significant differences in the cytokine/chemokine levels between TEN and other organ damage, other than ARDS and TEN without any organ damage. We further analyzed the changes in cytokine/chemokine levels before and after treatment in two TEN patients with ARDS. CCL2, IL-6, and IL-8 levels decreased after systemic treatment compared to their baseline levels before treatment at an early stage. These results suggest that IL-8 and CCL2 may be involved in the pathogenesis of TEN-induced ARDS and have potential application as predictive markers for ARDS onset.

Topics: Biomarkers; Chemokines; Cytokines; Humans; Interleukin-6; Interleukin-8; Ligands; Respiratory Distress Syndrome; Retrospective Studies; Stevens-Johnson Syndrome

As the COVID-19 pandemic strains healthcare systems worldwide, finding predictive markers of severe courses remains urgent. Most research so far was limited to selective questions hindering general assumptions for short- and long-term outcome.. In this prospective single-center biomarker study, 47 blood- and 21 bronchoalveolar lavage (BAL) samples were collected from 47 COVID-19 intensive care unit (ICU) patients upon admission. Expression of inflammatory markers toll-like receptor 3 (TLR3), heme oxygenase-1 (HO-1), interleukin (IL)-6, IL-8, leukocyte counts, procalcitonin (PCT) and carboxyhemoglobin (CO-Hb) was compared to clinical course. Clinical assessment comprised acute local organ damage, acute systemic damage, mortality and outcome after 6 months.. PCT correlated with acute systemic damage and was the best predictor for quality of life (QoL) after 6 months (r = - 0.4647, p = 0.0338). Systemic TLR3 negatively correlated with impaired lung function (ECMO/ECLS: r = - 0.3810, p = 0.0107) and neurological short- (RASS mean: r = 0.4474, p = 0.0023) and long-term outcome (mRS after 6 m: r = - 0.3184, p = 0.0352). Systemic IL-8 correlated with impaired lung function (ECMO/ECLS: r = 0.3784, p = 0.0161) and neurological involvement (RASS mean: r = - 0.5132, p = 0.0007). IL-6 in BAL correlated better to the clinical course than systemic IL-6. Using three multivariate regression models, we describe prediction models for local and systemic damage as well as QoL. CO-Hb mean and max were associated with higher mortality.. Our predictive models using the combination of Charlson Comorbidity Index, sex, procalcitonin, systemic TLR3 expression and IL-6 and IL-8 in BAL were able to describe a broad range of clinically relevant outcomes in patients with severe COVID-19-associated ARDS. Using these models might proof useful in risk stratification and predicting disease course in the future. Trial registration The trial was registered with the German Clinical Trials Register (Trial-ID DRKS00021522, registered 22/04/2020).

Topics: COVID-19; Disease Progression; Humans; Inflammation; Interleukin-6; Interleukin-8; Pandemics; Procalcitonin; Prospective Studies; Quality of Life; Respiratory Distress Syndrome; Toll-Like Receptor 3

There is a need for research exploring the temporal trends of nonpulmonary organ dysfunction (NPOD) and biomarkers in order to identify unique predictive or prognostic phenotypes. We examined the associations between the number and trajectories of NPODs and plasma biomarkers of early and late inflammatory cascade activation, specifically plasma interleukin-1 receptor antagonist (IL-1ra) and interleukin-8 (IL-8), respectively, in the setting of acute respiratory failure (ARF).. Secondary analysis of the Randomized Evaluation for Sedation Titration for Respiratory Failure clinical trial and Biomarkers in Acute Lung Injury (BALI) ancillary study.. Multicenter.. Intubated pediatric patients with ARF.. NPODs were evaluated against plasma IL-1ra and IL-8 levels on individual days (1 to 4 d after intubation) and longitudinally across days.. Within the BALI cohort, 432 patients had at least one value for IL-1ra or IL-8 within days 0 through 5. 36.6% had a primary diagnosis of pneumonia, 18.5% had a primary diagnosis of sepsis and 8.1% died. Multivariable logistic regression models showed that increasing levels of both plasma IL-1ra and IL-8 were statistically significantly associated with increasing numbers of NPODs (IL-1ra: days 1-3; IL-8: days 1-4), independent of sepsis diagnosis, severity of oxygenation defect, age, and race/ethnicity. Longitudinal trajectory analysis identified four distinct NPOD trajectories and seven distinct plasma IL-1ra and IL-8 trajectories. Multivariable ordinal logistic regression revealed that specific IL-1ra and IL-8 trajectory groups were associated with greater NPOD trajectory group ( p = 0.004 and p < 0.0001, respectively), independent of severity of oxygenation defect, age, sepsis diagnosis, and race/ethnicity.. Both the inflammatory biomarkers and number of NPODs exhibit distinct trajectories over time with strong associations with one another. These biomarkers and their trajectory patterns may be useful in evaluating the severity of multiple organ dysfunction syndrome in critically ill children and identifying those phenotypes with time-sensitive, treatable traits.

Topics: Biomarkers; Child; Cytokines; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-8; Respiratory Distress Syndrome; Respiratory Insufficiency; Sepsis

Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct "high-risk" patients not captured by prior LCA classifications.. Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar's test and then tested the correlation between IL-18 and LCA biomarkers using Pearson's exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup.. Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients.. Six hundred eighty-three patients in SAILS and 511 patients in HARP-2.. None.. We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17-0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8-6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2-3.8; p = 0.009).. Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts.

Topics: Biomarkers; Cytokines; Humans; Interleukin-18; Interleukin-8; Latent Class Analysis; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome; Retrospective Studies

Acute respiratory distress syndrome (ARDS) subphenotypes differ in outcomes and treatment responses. Subphenotypes in high-flow nasal oxygen (HFNO)-treated ARDS patients have not been investigated.. To identify biological subphenotypes in HFNO-treated ARDS patients.. Secondary analysis of a prospective multicenter observational study including ARDS patients supported with HFNO. Plasma inflammation markers (interleukin [IL]-6, IL-8, and IL-33 and soluble suppression of tumorigenicity-2 [sST2]) and lung epithelial (receptor for advanced glycation end products [RAGE] and surfactant protein D [SP-D]) and endothelial (angiopoietin-2 [Ang-2]) injury were measured. These biomarkers and bicarbonate were used in K-means cluster analysis to identify subphenotypes. Logistic regression was performed on biomarker combinations to predict clustering. We chose the model with the best AUROC and the lowest number of variables. This model was used to describe the HAIS (High-flow ARDS Inflammatory Subphenotype) score.. Among 41 HFNO patients, two subphenotypes were identified. Hyperinflammatory subphenotype (n = 17) showed higher biomarker levels than hypoinflammatory (n = 24). Despite similar baseline characteristics, the hyperinflammatory subphenotype had higher 60-day mortality (47 vs 8.3% p = 0.014) and longer ICU length of stay (22.0 days [18.0-30.0] vs 39.5 [25.5-60.0], p = 0.034). The HAIS score, based on IL-8 and sST2, accurately distinguished subphenotypes (AUROC 0.96 [95%CI: 0.90-1.00]). A HAIS score ≥ 7.45 was predictor of hyperinflammatory subphenotype.. ARDS patients treated with HFNO exhibit two biological subphenotypes that have similar clinical characteristics, but hyperinflammatory patients have worse outcomes. The HAIS score may identify patients with hyperinflammatory subphenotype and might be used for enrichment strategies in future clinical trials.

Topics: Biomarkers; Humans; Interleukin-8; Oxygen; Prospective Studies; Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a life-threatening disease caused by the induction of inflammatory cytokines and chemokines in the lungs. There is a dearth of drug applications that can be used to prevent cytokine storms in ARDS treatment. This study was designed to investigate the effects of tocilizumab and dexamethasone on oxidative stress, antioxidant parameters, and cytokine storms in acute lung injury caused by oleic acid in rats.. Adult male rats were divided into five groups: the CN (healthy rats, n = 6), OA (oleic acid administration, n = 6), OA + TCZ-2 (oleic acid and tocilizumab at 2 mg/kg, n = 6), OA + TCZ-4 (oleic acid and tocilizumab at 4 mg/kg, n = 6), and OA + DEX-10 (oleic acid and dexamethasone at 10 mg/kg, n = 6) groups. All animals were euthanized after treatment for histopathological, immunohistochemical, biochemical, PCR, and SEM analyses.. Expressions of TNF-α, IL-1β, IL-6, and IL-8 cytokines in rats with acute lung injury induced by oleic acid were downregulated in the TCZ and DEX groups compared to the OA group (P < 0.05). The MDA level in lung tissues was statistically lower in the OA + TCZ-4 group compared to the OA group. It was further determined that SOD, GSH, and CAT levels were decreased in the OA group and increased in the TCZ and DEX groups (P < 0.05). Histopathological findings such as thickening of the alveoli, hyperemia, and peribronchial cell infiltration were found to be similar when lung tissues of the TCZ and DEX groups were compared to the control group. With SEM imaging of the lung tissues, it was found that the alveolar lining layer had become indistinct in the OA, OA + TCZ-2, and OA + TCZ-4 groups.. In this model of acute lung injury caused by oleic acid, tocilizumab and dexamethasone were effective in preventing cytokine storms by downregulating the expression of proinflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-8. Against the downregulation of antioxidant parameters such as SOD and GSH in the lung tissues caused by oleic acid, tocilizumab and dexamethasone upregulated them and showed protective effects against cell damage.

Topics: Acute Lung Injury; Animals; Antibodies, Monoclonal, Humanized; Antioxidants; Cytokine Release Syndrome; Cytokines; Dexamethasone; Down-Regulation; Interleukin-6; Interleukin-8; Lung; Male; Oleic Acid; Rats; Respiratory Distress Syndrome; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Up-Regulation

Lymphopenia and the neutrophil/lymphocyte ratio may have prognostic value in COVID-19 severity.. We investigated neutrophil subsets and functions in blood and bronchoalveolar lavage (BAL) of COVID-19 patients on the basis of patients' clinical characteristics.. We used a multiparametric cytometry profiling based to mature and immature neutrophil markers in 146 critical or severe COVID-19 patients.. The Discovery study (38 patients, first pandemic wave) showed that 80% of Intensive Care Unit (ICU) patients develop strong myelemia with CD10. LOX-1-expressing ImNs may help identifying COVID-19 patients at high risk of severity and thrombosis complications.

Topics: Adult; Aged; B7-H1 Antigen; Bronchoalveolar Lavage Fluid; COVID-19; Critical Illness; Female; Humans; Interleukin-3 Receptor alpha Subunit; Interleukin-8; Male; Middle Aged; Neutrophils; Respiratory Distress Syndrome; SARS-CoV-2; Scavenger Receptors, Class E; Thrombosis

The hyper-inflammatory response is thought to be a major cause of acute respiratory distress syndrome (ARDS) in patients with COVID-19. Although multiple cytokines are reportedly associated with disease severity, the key mediators of SARS-CoV-2 induced cytokine storm and their predictive values have not been fully elucidated. The present study analyzed maximal and early (within 10 days after disease onset) concentrations of 12-plex cytokines in plasma. We found consistently elevated plasma levels of IL-6, IL-8 and IL-5 in patients who were deceased compared with those who had mild/moderate or severe disease. The early plasma concentrations of IFN-a and IL-2 positively correlated with the length of the disease course. Moreover, correlation network analysis showed that IL-6, IL-8, and IL-5 located at the center of an inter-correlated cytokine network. These findings suggested that IL-8, IL-6, IL-5 might play central roles in cytokine storms associated with COVID-19 and that the early detection of multiple plasma cytokines might help to predict the prognosis of this disease.

Topics: Aged; Correlation of Data; COVID-19; Cytokine Release Syndrome; Cytokines; Female; Humans; Interferon-alpha; Interleukin-2; Interleukin-5; Interleukin-6; Interleukin-8; Male; Middle Aged; Prognosis; Respiratory Distress Syndrome; Retrospective Studies; SARS-CoV-2; Severity of Illness Index

Transcription co-activator p300/CBP, a histone acetyltransferase, has a central role in tumours, inflammation and neurodegenerative diseases. We investigated the effect of p300/CBP and its association with various IL-17-related indicators and prognosis in patients with acute respiratory distress syndrome (ARDS).. We enrolled 45 adult ARDS patients who were followed for 28 days and 22 healthy controls. The mRNA expression of p300, CBP, RORγt and Foxp3 and the plasma levels of several cytokines were measured.. The mRNA levels of p300, CBP and RORγt, and plasma concentration of IL-17, IL-6, were higher in acute ARDS patients (P < 0.05) compared with controls, and the mean levels of p300, CBP and IL-6 in non-survivors were higher than in survivors (P < 0.05). The expression of p300 was associated with the level of RORγt, IL-17 and disease prognosis.. The levels of p300, RORγt mRNA and plasma concentration of IL-6 and IL-17 in acute ARDS patients were increased compared with controls. Increased p300/CBP expression may be an independent risk factor for 28-day mortality in ARDS.

Topics: Adult; E1A-Associated p300 Protein; Humans; Interleukin-17; Interleukin-8; p300-CBP Transcription Factors; Prognosis; Respiratory Distress Syndrome; RNA, Messenger; Transcription Factors

The 2015 definition for pediatric acute respiratory distress syndrome did not require the presence of bilateral infiltrates. We tested the hypothesis that pediatric patients meeting oxygenation criteria for pediatric acute respiratory distress syndrome but without bilateral infiltrates would have different inflammatory biomarker levels and clinical outcomes than those with bilateral infiltrates.. Secondary analysis of a prospective cohort study.. Twenty-two PICUs.. Four-hundred forty-six patients age 2 weeks to 17 years intubated for respiratory failure with oxygenation index greater than or equal to 4 or oxygenation saturation index greater than or equal to 5 on the day of intubation or the day after.. None.. Patients with bilateral infiltrates, either on the day of intubation or within the following 2 days, were compared with children who never developed bilateral infiltrates. Two analyses were performed to test 1) whether bilateral infiltrates are associated with elevated interleukin-1 receptor antagonist or interleukin-8 and 2) whether bilateral infiltrates are associated with worse clinical outcomes. Patients with bilateral infiltrates more often had a primary diagnosis of pneumonia (41% vs 28%; p = 0.02) and less often asthma (8% vs 23%; p < 0.01). After controlling for age, gender, and primary diagnosis, interleukin-1 receptor antagonist was higher on study days 1 and 2 in patients with bilateral infiltrates. There was no difference in interleukin-8 levels. After adjusting for age, gender, Pediatric Risk of Mortality score, and severity of oxygenation defect, presence of bilateral infiltrates was associated with longer duration of mechanical ventilation in survivors (hazard ratio, 0.64; 95% CI, 0.49-0.82; p < 0.01); this association was independent of primary diagnosis. Overall mortality was 9%; mortality was higher in those without bilateral infiltrates (14% vs 8%; p = 0.04).. Children meeting pediatric acute respiratory distress syndrome oxygenation criteria with bilateral infiltrates on chest radiograph experience a more intense early inflammatory response. Bilateral infiltrates are associated with longer time on the ventilator independent of oxygenation defect severity.

Topics: Adolescent; Asthma; Biomarkers; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Inflammation Mediators; Intensive Care Units, Pediatric; Interleukin-8; Intubation, Intratracheal; Male; Prospective Studies; Receptors, Interleukin-1; Respiration, Artificial; Respiratory Distress Syndrome; Risk Factors; Severity of Illness Index

Topics: Adult; Betacoronavirus; Chemotaxis, Leukocyte; Colchicine; Coronavirus Infections; COVID-19; Dapsone; Humans; Interleukin-8; Neutrophils; Olanzapine; Pandemics; Pneumonia, Viral; Respiratory Distress Syndrome; SARS-CoV-2

In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, China)

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Animals; Asymptomatic Infections; Betacoronavirus; China; Cohort Studies; Coronavirus Infections; COVID-19; Critical Illness; Disease Progression; Evolution, Molecular; Female; Genetic Variation; Genome, Viral; Hospitalization; Host-Pathogen Interactions; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Pandemics; Phylogeny; Pneumonia, Viral; Respiratory Distress Syndrome; SARS-CoV-2; T-Lymphocytes; Time Factors; Treatment Outcome; Virulence; Virus Shedding; Young Adult; Zoonoses

To investigate the changes in the concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and 8-iso-prostaglandin F2α (8-isoPGF2α) in exhaled breath condensate (EBC) in patients undergoing cardiac valve replacement under cardiopulmonary bypass (CPB) and its relationship with postoperative acute respiratory distress syndrome (ARDS).A prospective, case-control study was performed on 55 patients undergoing elective cardiac valve replacement under cardiopulmonary bypass, between November 2017 and May 2019. According to the diagnosis of postoperative ARDS, the patients were divided into ARDS group and control group. We compared the clinical characteristics, outcomes, respiratory mechanics, oxygenation parameters, and mediators in the 2 groups immediately after tracheal intubation (T1), at the end of CPB (T2), and 2 hours (T3) and 6 hours (T4) after CPB, and calculated the receiver operating characteristic curve (ROC), sensitivity, and specificity of the corresponding mediators.ARDS occurred in 29 patients after CPB. The ARDS group exhibited prolonged postoperative ventilator support, time to extubation, length of stay in the ICU, and postoperative length of stay. The peak airway pressure (Ppeak) and plat airway pressure (Pplat) at T4 were higher in the ARDS group compared with the control group. The alveolar-arterial oxygen partial pressure [P(A-a)O2] and respiratory index (RI) were higher and PaO2/FiO2 was lower in the ARDS group at T2-4 compared with the control group. The levels of EBC and serum mediators in the ARDS group were significantly higher at T2-4 compared with those in the control group. All the mediators in EBC were correlated significantly with those in the serum in the ARDS group (r = 0.7314, 0.898, 0.8386, 0.792) and control group (r = 0.6093, 0.8524, r = 0.7828, r = 0.6575) (P < .001). Meanwhile, the area under the curve (AUC) of IL-8 in EBC was significantly lower at T2 and the AUC of IL-6 in EBC was significantly higher at T4 than in serum (P < .05). In addition, all of the mediators in EBC had a certain accuracy in diagnose of postoperative ARDS.EBC analysis could be used to predict the high incidence of ARDS after cardiac valve replacement under CPB.

Topics: Adult; Aged; Aged, 80 and over; Cardiopulmonary Bypass; Case-Control Studies; Exhalation; Female; Heart Valve Prosthesis Implantation; Humans; Interleukin-6; Interleukin-8; Length of Stay; Male; Middle Aged; Postoperative Period; Prospective Studies; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Topics: Age Factors; Area Under Curve; Bicarbonates; Bilirubin; Biomarkers, Tumor; Blood Pressure; Carbon Dioxide; Creatinine; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Latent Class Analysis; Leukocyte Count; Machine Learning; Mortality; Oxygen; Partial Pressure; Phenotype; Plasminogen Activator Inhibitor 1; Platelet Count; Prognosis; Protein C; Pulmonary Ventilation; Randomized Controlled Trials as Topic; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome; Serum Albumin; Tidal Volume; Vasoconstrictor Agents; Vital Signs

BACKGROUNDElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare with those observed in critically ill patients with acute respiratory distress syndrome (ARDS) or sepsis due to other causes.METHODSWe used a Luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1β, IL-1RA, IL-6, IL-8, IL-18, and TNF-α) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTSFifteen hospitalized COVID-19 patients, 9 of whom were critically ill, were compared with critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1β, IL-1RA, IL-6, IL-8, IL-18, and TNF-α between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONLevels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDINGFunding was received from NHLBI K23 HL125663 (AJR); The Bill and Melinda Gates Foundation OPP1113682 (AJR and CAB); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687 NIH/NIAID U19AI057229-16; Stanford Maternal Child Health Research Institute; and Chan Zuckerberg Biohub (CAB).

Topics: Adult; Aged; Case-Control Studies; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Cytokines; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-18; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Middle Aged; Pandemics; Pneumonia, Viral; Respiratory Distress Syndrome; Sepsis; Severity of Illness Index; Tumor Necrosis Factor-alpha

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

Endogenous tissue mediators inducing lung inflammation in the context of ventilator-induced lung injury (VILI) and acute respiratory distress syndrome (ARDS) are ill-defined.. To test whether mitochondrial alarmins are released during VILI, and are associated with lung inflammation.. Release of mitochondrial DNA, adenosine triphosphate (ATP), and formyl-Met-Leu-Phe (fMLP) peptide-dependent neutrophil chemotaxis were measured in conditioned supernatants from human alveolar type II-like (A549) epithelial cells submitted to cyclic stretch in vitro. Similar measurements were performed in bronchoalveolar lavage fluids from rabbits submitted to an injurious ventilatory regimen, and from patients with ARDS.. Mitochondrial DNA was released by A549 cells during cell stretching, and was found elevated in BAL fluids from rabbits during VILI, and from ARDS patients. Cyclic stretch-induced interleukin-8 (IL-8) of A549 cells could be inhibited by Toll-like receptor 9 (TLR9) blockade. ATP concentrations were increased in conditioned supernatants from A549 cells, and in rabbit BAL fluids during VILI. Neutrophil chemotaxis induced by A549 cells conditioned supernatants was essentially dependent on fMLP rather than IL-8. A synergy between cyclic stretch-induced alarmins and lipopolysaccharide (LPS) was found in monocyte-derived macrophages in the production of IL-1ß.. Mitochondrial alarmins are released during cyclic stretch of human epithelial cells, as well as in BAL fluids from rabbits ventilated with an injurious ventilatory regimen, and found in BAL fluids from ARDS patients, particularly in those with high alveolar inflammation. These alarmins are likely to represent the proximal endogenous mediators of VILI and ARDS, released by injured pulmonary cells.

Topics: A549 Cells; Alarmins; Animals; Bronchoalveolar Lavage Fluid; Culture Media, Conditioned; DNA, Mitochondrial; Humans; Interleukin-8; Macrophages; Male; Mitochondria; Neutrophil Infiltration; Oligoribonucleotides, Antisense; Rabbits; Respiratory Distress Syndrome; Stress, Physiological; Toll-Like Receptor 9; Ventilator-Induced Lung Injury

There is a compelling unmet medical need for biomarker-based models to risk-stratify patients with acute respiratory distress syndrome. Effective stratification would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new interventions. Our objective was to develop a prognostic, biomarker-based model for predicting mortality in adult patients with acute respiratory distress syndrome.. This is a secondary analysis using a cohort of 252 mechanically ventilated subjects with the diagnosis of acute respiratory distress syndrome. Survival to day 7 with both day 0 (first day of presentation) and day 7 sample availability was required. Blood was collected for biomarker measurements at first presentation to the intensive care unit and on the seventh day. Biomarkers included cytokine-chemokines, dual-functioning cytozymes, and vascular injury markers. Logistic regression, latent class analysis, and classification and regression tree analysis were used to identify the plasma biomarkers most predictive of 28-day ARDS mortality.. From eight biologically relevant biomarker candidates, six demonstrated an enhanced capacity to predict mortality at day 0. Latent-class analysis identified two biomarker-based phenotypes. Phenotype A exhibited significantly higher plasma levels of angiopoietin-2, macrophage migration inhibitory factor, interleukin-8, interleukin-1 receptor antagonist, interleukin-6, and extracellular nicotinamide phosphoribosyltransferase (eNAMPT) compared to phenotype B. Mortality at 28 days was significantly higher for phenotype A compared to phenotype B (32% vs 19%, p = 0.04).. An adult biomarker-based risk model reliably identifies ARDS subjects at risk of death within 28 days of hospitalization.

Topics: Adult; APACHE; Biomarkers; Cytokines; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Interleukin-6; Interleukin-8; Intramolecular Oxidoreductases; Latent Class Analysis; Logistic Models; Macrophage Migration-Inhibitory Factors; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Peptide Fragments; Respiratory Distress Syndrome; Risk Assessment; Sphingosine-1-Phosphate Receptors; Vesicular Transport Proteins

This study aims to explore whether positive end-expiratory pressure (PEEP) guided by esophageal pressure is better than the acute respiratory distress syndrome network (ARDSNet) during the treatment of traumatic acute respiratory distress syndrome (ARDS) patients.. The use of the oxygenation method of inhaled oxygen concentration titration PEEP is suggested.. This study takes traumatic ARDS patients as the research object. The data of 23 patients were included in this study. The patients were randomly divided into two groups: the esophageal pressure titration PEEP group (n= 12), and the ARDSNet (PEEP-FiO2 table) titration PEEP group (n= 11). All patients were given mechanical ventilation, and changes in oxygenation index, respiratory mechanics, hemodynamics and inflammatory reaction index were recorded when titrating the best PEEP with the two methods on the current day of grouping and after grouping for 24, 48 and 72 hours.. The PEEP titration value in the esophageal pressure group was 12 ± 4 cm H2O, and this value was significantly higher than the PEEP titration value in the ARDSNet group (8 ± 3 cm H2O) (P< 0.05). The end-expiratory transpulmonary pressure of titrating the best PEEP with the esophageal pressure method and ARDSNet method is 0.5 ± 0.7 cm H2O vs.-1.1 ± 3.3 cm H2O (P< 0.05). When titrating the best PEEP with the esophageal pressure method, lung tissue compliance, end-expiratory transpulmonary pressure and the oxygenation index are higher than those obtained through the ARDSNet method (P< 0.05). (2) In the esophageal pressure group, with the extension of treatment time, high-sensitivity C reactive protein (hs-CRP) and procalcitonin (PCT) exhibited a trend of significant decrease (P< 0.05). In the ARDSNet group, with the extension of treatment time, PCT also exhibited a significant decrease (P< 0.05), while the decrease in hs-CRP was not significant (P> 0.05). After comparing these two treatment groups at each monitoring time point, we found that the difference in hs-CRP and PCT was not statistically significant (P> 0.05). During the 72-hour treatment of interleukin-6 (IL-6) and interleukin-8 (IL-8), we found that these two were significantly lower in the esophageal pressure group than in the ARDSNet group (P< 0.05).. The PEEP selection of mechanical ventilation of patients with traumatic ARDS guided by transpulmonary pressure and calculated by measuring intrapleural pressure can realize the individual adjustment of PEEP, identify ARDS patients benefiting from high PEEP, and provide a PEEP setting that can better meet the needs of traumatic patients.

Topics: Adult; C-Reactive Protein; Esophagus; Female; Humans; Interleukin-6; Interleukin-8; Male; Oxygen; Positive-Pressure Respiration; Procalcitonin; Respiratory Distress Syndrome; Wounds and Injuries

The association of plasma interleukin-8 (IL-8), or IL-8 genetic variants, with pediatric acute respiratory distress syndrome (PARDS) in children with acute respiratory failure at risk for PARDS has not been examined. The purpose of this study was to examine the association of early and sequential measurement of plasma IL-8 and/or its genetic variants with development of PARDS and other clinical outcomes in mechanically ventilated children with acute respiratory failure.. This was a prospective cohort study of children 2 weeks to 17 years of age with acute airways and/or parenchymal lung disease done in 22 pediatric intensive care units participating in the multi-center clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). Plasma IL-8 levels were measured within 24 h of consent and 24 and 48 h later. DNA was purified from whole blood, and IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, were genotyped.. Five hundred forty-nine patients were enrolled; 480 had blood sampling. Plasma IL-8 levels ranged widely from 4 to 7373 pg/mL. Highest IL-8 levels were observed on the day of intubation with subsequent tapering. Levels of IL-8 varied significantly across primary diagnoses with the highest levels occurring in patients with sepsis and the lowest levels in those with asthma. Plasma IL-8 was strongly correlated with oxygenation defect and severity of illness. IL-8 was consistently higher in PARDS patients compared to those without PARDS; levels were 4-12 fold higher in non-survivors compared to survivors. On multivariable analysis, IL-8 was independently associated with death, duration of mechanical ventilation, and PICU length of stay on all days measured, but was not associated with PARDS development. There was no association between the IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, and PARDS development or plasma IL-8 level.. When measured sequentially, plasma IL-8 was robustly associated with multiple, relevant clinical outcomes including mortality, but was not associated with PARDS development. The wide range of plasma IL-8 levels exhibited in this cohort suggests that further study into the heterogeneity of this patient population and its impact on individual responses to PARDS treatment is warranted.

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Cohort Studies; Female; Humans; Infant; Infant, Newborn; Interleukin-8; Logistic Models; Male; Odds Ratio; Pediatrics; Prospective Studies; Respiratory Distress Syndrome; Respiratory Insufficiency; Risk Factors

Topics: Child; Humans; Interleukin-8; Prospective Studies; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Respiratory Insufficiency

Receptor for advanced glycation end products (RAGE) is implicated in inflammatory responses in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), but its role in pulmonary edema formation remains unclear, especially in infection-related ARDS mainly caused by pneumonia or sepsis. In this study, we investigated the role of RAGE in alveolar fluid regulation by using RAGE gene knockout (RAGE) mice in a murine ALI model induced by lipopolysaccharide (LPS), and by comparing soluble RAGE (sRAGE) levels in serum and bronchial alveolar lavage fluid between ARDS patients and control subjects. We found that RAGE knockout significantly improved alveolar fluid clearance and reduced pulmonary vascular albumin leakage upon LPS challenge. Furthermore, LPS-induced substantial decrease in lung expression of sodium-potassium ATPase (Na,K-ATPase), epithelial sodium channel, and zonula occluden-1 (ZO-1) were fully or partially restored by the deletion of RAGE. In addition to this, LPS-induced lung leukocyte infiltration and inflammatory cytokine and chemokine release were all attenuated in RAGE mice as compared to wide-type mice. In infection-related ARDS patients, both serum and bronchial alveolar lavage fluid levels of the sRAGE were much higher than those in control subjects, and they were positively correlated with pulmonary vascular permeability and levels of interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-2. Taken together, we provided the first direct evidence for the essential role of RAGE in regulating lung fluid balance in infection-related ARDS/ALI. The underlying mechanisms may involve the downregulation of both ion-channel and tight junction proteins mediated by RAGE signaling in bacterial endotoxin-induced lung injury.

Topics: Animals; Chemokine CXCL2; Glycation End Products, Advanced; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Male; Mice; Receptor for Advanced Glycation End Products; Respiratory Distress Syndrome

Patients who develop ARDS from medical or traumatic causes typically present after the inciting event has already occurred. Postoperative ARDS is unique in that the inciting insult potentially responsible for ARDS is known ahead of time, which provides an opportunity to study the early pathophysiology of ARDS. The objective of this study was to better understand the early pathophysiology of postoperative ARDS through a temporal analysis of key biomarkers of interest.. We performed a case-control study of adults undergoing elective thoracic, aortic vascular, or cardiac surgery, which placed them at increased risk of developing postoperative ARDS. Biomarkers were measured at baseline, 2 h, and 6 h after the key intraoperative event believed to be responsible for ARDS.. Of the 467 subjects enrolled, 26 developed ARDS and were matched to non-ARDS controls 1:2 based on age, sex, surgical procedure, and surgical lung injury prediction score. Patients with ARDS were more likely to have lower preoperative albumin (. Our study supported the hypothesis that dysregulated coagulation, inflammation, and epithelial injury are pathophysiologic features of early postoperative ARDS. Interleukin-8, plasminogen activator-1, and surfactant protein-D may help predict development of postoperative ARDS.

Topics: Aged; Aorta; Biomarkers; Cardiac Surgical Procedures; Case-Control Studies; Elective Surgical Procedures; Female; Humans; Interleukin-8; Male; Middle Aged; Operative Time; Plasminogen Activator Inhibitor 1; Postoperative Complications; Postoperative Period; Preoperative Period; Pulmonary Surfactant-Associated Protein D; Respiratory Distress Syndrome; Serum Albumin; Severity of Illness Index; Vascular Surgical Procedures

Inhalation injury commonly accompanies thermal injury, increasing the likelihood of mortality and multiple organ dysfunction (MOD). Large animal models have given important insight into the pathophysiology of this injury; however recapitulating late MOD has remained difficult. The current report describes experiments using a smoke inhalation and burn model, with follow-up of ambulatory swine for 14days with bronchoscopy, CT scanning, and bronchoalveolar lavage fluid (BALF)/blood collection. Clinically, animals cleared airway damage in the first several days after-injury. This was mirrored with erythematous airways on day 2 after-injury, which resolved by the end of the experiment, as did parenchymal damage seen on CT. An initial rise in the protein content of BALF immediately after-injury was followed by a dramatic increase in the concentration of leukocytes. Circulating neutrophils increased while lymphocytes decreased; both correlated with cell counts in BALF. IL8 levels in BALF increased 30-fold and remained elevated throughout the experiment. IL1ra increased circulation immediately after-injury, and afterwards in BALF. Other cytokines (TNFα, IL12) transiently increased in BALF (and decreased in circulation) on day 2. Taken together, these results display a remarkable capability for the lungs to recover in the absence of intubation, with further evidence of the role of cytokines such as IL8 and IL1ra. The possible exacerbating effects of clinical practices such as ventilation and bronchoscopies should be considered.

Topics: Animals; Bronchoalveolar Lavage Fluid; Bronchoscopy; Burns; Cytokines; Disease Models, Animal; Female; Interleukin 1 Receptor Antagonist Protein; Interleukin-12; Interleukin-8; Lung; Recovery of Function; Respiration, Artificial; Respiratory Distress Syndrome; Smoke Inhalation Injury; Sus scrofa; Swine; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha; Wound Healing

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterised by pulmonary oedema, respiratory failure and severe inflammation. ARDS is further characterised by the recruitment of neutrophils into the lung interstitium and alveolar space.. The factors that regulate neutrophil infiltration into the inflamed lung and our understanding of the pathomechanisms in ARDS remain incomplete. This study aimed at determining the role of the chemokine (C-C motif) ligand (CCL)2 and CCL7 in ARDS.. CCL2 and CCL7 protein levels were measured in bronchoalveolar lavage (BAL) fluid obtained from lipopolysaccharide(LPS)-challenged human volunteers and two separate cohorts of patients with ARDS. Neutrophil chemotaxis to ARDS BAL fluid was evaluated and the contribution of each was assessed and compared with chemokine (C-X-C motif) ligand 8 (CXCL8). Chemokine receptor expression on neutrophils from blood or BAL fluid of patients with ARDS was analysed by flow cytometry.. CCL2 and CCL7 were significantly elevated in BAL fluid recovered from LPS-challenged volunteers and patients with ARDS. BAL fluid from patients with ARDS was highly chemotactic for human neutrophils and neutralising either CCL2 or CCL7 attenuated the neutrophil chemotactic response. Moreover, CCL2 and CCL7 synergised with CXCL8 to promote neutrophil migration. Furthermore, neutrophils isolated from the blood or BAL fluid differentially regulated the cell surface expression of chemokine (C-X-C motif) receptor 1 and C-C chemokine receptor type 2 during ARDS.. This study highlights important inflammatory chemokines involved in regulating neutrophil migration, which may have potential value as therapeutic targets for the treatment of ARDS.

Topics: Adult; Antibodies, Neutralizing; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Chemokine CCL7; Chemotaxis, Leukocyte; Healthy Volunteers; Humans; Interleukin-8; Lipopolysaccharides; Membrane Proteins; Neutrophils; Receptors, CCR2; Receptors, Interleukin-8A; Respiratory Distress Syndrome; Young Adult

Interleukin-17A is a proinflammatory cytokine known to play a role in host defense and pathologic inflammation in murine models of lung injury. The relationship between interleukin-17A and inflammation in human lung injury is unknown. Our primary objective was to determine whether interleukin-17A levels are associated with alveolar measures of inflammation and injury in patients with acute respiratory distress syndrome. Our secondary objective was to test whether interleukin-17A levels are associated with acute respiratory distress syndrome-related outcomes.. Observational study.. Six North American medical centers.. We studied two groups of patients with acute respiratory distress syndrome: 1) patients previously enrolled in a placebo-controlled clinical trial of omega-3 fatty acids performed at five North American medical centers (n = 86, acute respiratory distress syndrome 1), and 2) patients with systemic inflammatory response syndrome admitted to an ICU who developed acute respiratory distress syndrome (n = 140, acute respiratory distress syndrome 2). In acute respiratory distress syndrome 1, we used paired serum and bronchoalveolar lavage fluid samples obtained within 48 hours of acute respiratory distress syndrome onset, whereas in acute respiratory distress syndrome 2, we used plasma obtained within the first 24 hours of ICU admission.. None.. We measured circulating interleukin-17A in acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2. We also measured interleukin-17A, neutrophil counts, and total protein in bronchoalveolar lavage fluid from acute respiratory distress syndrome 1. We found that bronchoalveolar lavage interleukin-17A was strongly associated with higher bronchoalveolar lavage percent neutrophils (p < 0.001) and bronchoalveolar lavage total protein (p < 0.01) in acute respiratory distress syndrome1. In both acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2, elevated interleukin-17A was associated with higher Sequential Organ Failure Assessment scores (p < 0.05).. Elevated circulating and alveolar levels of interleukin-17A are associated with increased percentage of alveolar neutrophils, alveolar permeability, and organ dysfunction in acute respiratory distress syndrome.

Topics: Acute Lung Injury; Aged; Bronchoalveolar Lavage Fluid; Cytokines; Female; Humans; Inflammation; Intensive Care Units; Interleukin-17; Interleukin-8; Leukocyte Count; Male; Middle Aged; Neutrophils; Organ Dysfunction Scores; Pulmonary Alveoli; Respiratory Distress Syndrome; Sepsis; Treatment Outcome

Immunocompromised patients who develop sepsis while neutropenic are at high risk for morbidity and mortality; however, it is unknown if neutropenic sepsis is associated with distinct clinical and biological characteristics.. We conducted a prospective cohort study of patients admitted to the medical intensive care unit of an academic medical center with severe sepsis. Patients were followed for the development of acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and mortality. Plasma proteins, representing the host inflammatory response, anti-inflammatory response, and endothelial leak were measured in 30 % of subjects. Clinical characteristics and plasma protein concentrations of patients with neutropenia at enrollment were compared to patients without neutropenia.. Of 797 subjects enrolled, 103 (13 %) were neutropenic at ICU admission. The neutropenic subjects were more often in shock, admitted from the hospital ward, had higher APACHE III scores, and more likely bacteremic. Neutropenia was an independent risk factor for AKI (RR 1.28; 95 % CI 1.04, 1.57; p = 0.03), but not ARDS (RR 0.90; 95 % CI 0.70, 1.17; p = 0.42) or 30-day mortality (RR 1.05; 95 % CI 0.85, 1.31; p = 0.65). Neutropenic subjects had higher plasma interleukin (IL)-6 (457 vs. 249 pg/ml; p = 0.03), IL-8 (581 vs. 94 pg/ml; p <0.001), and granulocyte colony-stimulating factor (G-CSF) (3624 vs. 99 pg/ml; p <0.001). Angiopoietin-2 and IL-1 receptor antagonist concentrations did not differ between groups.. Neutropenic sepsis is associated with a higher AKI risk and concentrations of inflammatory mediators IL-6, IL-8, and G-CSF relative to non-neutropenic patients. These differences may have implications for future therapies targeting neutropenic sepsis.

Topics: Acute Kidney Injury; Adult; Aged; Angiopoietin-2; APACHE; Biomarkers; Chi-Square Distribution; Cohort Studies; Critical Illness; Female; Granulocyte Colony-Stimulating Factor; Humans; Intensive Care Units; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Neutropenia; Pennsylvania; Prospective Studies; Receptors, Interleukin-1; Respiratory Distress Syndrome; Sepsis

Patients with severe traumatic brain injury (TBI) are at risk of the development of acute respiratory distress syndrome (ARDS). TBI and ARDS pathophysiologic mechanisms are known to independently involve significant inflammatory responses. The literature on the association between plasma inflammatory cytokines and ARDS in patients with TBI is sparse.. The study was a secondary analysis of the safety of a randomized trial of erythropoietin and transfusion threshold in patients with severe TBI. Inflammatory markers within the first 24 hours after injury were compared in patients who developed ARDS and patients without ARDS, using Cox proportional hazards models.. There were 200 patients enrolled in the study. The majority of plasma and cerebrospinal fluid (CSF) cytokine levels were obtained within 6 hours. Plasma proinflammatory markers IL-6 and IL-8 and anti-inflammatory marker IL-10 were associated with the development of ARDS (adjusted hazard ratio (HR) = 1.55, confidence interval (CI) = 1.14, 2.11, P = 0.005 for IL-6; adjusted HR = 1.32, CI = 1.10, 1.59, P = 0.003 for IL-8).. Plasma markers of IL-6, IL-8, and IL-10 are associated with ARDS in patients with severe TBI.. NCT00313716 registered 4/2006.

Topics: Adolescent; Adult; Biomarkers; Brain Injuries, Traumatic; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Respiratory Distress Syndrome

Several biological markers of lung injury are predictors of morbidity and mortality in patients with acute respiratory distress syndrome (ARDS). Some lung-protective ventilation strategies, such as low tidal volume, are associated with a significant decrease in plasma biomarker levels compared to the high tidal volume ventilation strategy. The primary objective of this study was to test whether the institution of high-frequency percussive ventilation (HFPV) to patients with respiratory distress after smoke inhalation injury influenced initial biomarker levels of lung injury (just before and after using percussive ventilation).. A prospective observational cohort study was conducted in the intensive care unit of the Brussels Burn Center. Fifteen intubated, mechanically ventilated patients with minor burns and ARDS following smoke inhalation were enrolled in our study. Physiologic data and serum samples were collected before intubation and at four different time points within the first 48h after intubation to measure the concentration of interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF alpha). The differences in biomarker levels before and after starting HFPV were analyzed using repeated measure analysis of variance and a paired t test with correction for multiple comparisons.. Before starting HFPV under endotracheal intubation, all biological markers (IL-6, IL-8, and TNF alpha) were elevated in the spontaneously breathing patients with acute lung injury (ALI). After intubation and institution of a positive pressure ventilation with HFPV (tidal volume 5.6-6.6ml/kg per ideal body weight), none of the biological markers were increased significantly at either an early (3±2h) or a later point in time. However, the levels of IL-8 had decreased significantly after intubation at a later point in time. During the post-intubation period, the PaO2/FiO2 (partial pressure of arterial oxygen/fraction of the inspired oxygen) ratio increased significantly and the plateau airway pressure decreased significantly.. Levels of IL-6, IL-8, and TNF alpha are elevated in spontaneously ventilating patients with minor burns and ARDS following smoke exposition prior to endotracheal intubation. The institution of HFPV with percussive positive pressure ventilation enhances blood oxygenation and could not further increase the initial levels of these biological markers of lung injury after smoke inhalation injury.

Topics: Adult; Biomarkers; Burn Units; Burns; Cohort Studies; Female; High-Frequency Ventilation; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Positive-Pressure Respiration; Prospective Studies; Respiratory Distress Syndrome; Smoke Inhalation Injury; Tidal Volume; Tumor Necrosis Factor-alpha; Ventilator-Induced Lung Injury; Young Adult

To evaluate the predictive value of 6 different biomarkers in the development of multiple-organ failure (MOF) and mortality in a contemporary prospective cohort of acute respiratory distress syndrome (ARDS).. Patients with ARDS admitted to a tertiary referral center during an 8-month period were included. Plasma sample collection of 6 different biomarkers on days 1, 3, and 5 after ARDS onset was performed (von Willebrand factor, thrombin-antithrombin III complex, plasminogen activator inhibitor 1, interleukin 8, receptor for advanced glycation end-products, and club cell secretory protein). Main outcomes included hospital mortality and development of MOF. Logistic regression models for MOF and mortality prediction were created including biomarkers levels and clinical predictors.. One hundred patients were included in the study. Do-not-resuscitate status and McCabe score were independently associated with increased mortality. None of the 6 biomarkers measured at the time of ARDS diagnosis predicted hospital mortality. After adjustment for important clinical characteristics, elevated day-1 interleukin 8 levels were associated with the development of MOF.. Addition of biomarkers did not improve mortality prediction in this cohort of ARDS. Association between elevated interleukin 8 levels and progression of organ failures suggests an important role of exaggerated inflammatory response in the development of MOF.

Topics: Aged; Antithrombin III; APACHE; Biomarkers; Female; Hospital Mortality; Humans; Interleukin-8; Male; Middle Aged; Multiple Organ Failure; Peptide Hydrolases; Phospholipase A2 Inhibitors; Plasminogen Activator Inhibitor 1; Prospective Studies; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Respiratory Distress Syndrome; Resuscitation Orders; Uteroglobin; von Willebrand Factor

Oxidative stress and inflammatory responses are thought to be involved in the pathogenesis of ARDS, which is one of the most serious complications of orthotopic liver transplantation (OLT). The collection of exhaled breath condensate (EBC) is a noninvasive method for obtaining clinical samples from the lungs. However, the changes of mediators of inflammation and oxidative stress in EBC remain unclear. Therefore, the aim of this study was to investigate the changes of mediators in EBC from OLT subjects and the relations between these mediators and ARDS.. The levels of mediators of oxidative stress (superoxide dismutase [SOD], malondialdehyde [MDA], H2O2, NO, and 8-iso-prostaglandin F2α) and of inflammatory factors (tumor necrosis factor-α[TNF-α], interleukin [IL]-8, and IL-10) were measured in EBC and serum samples collected from 28 subjects before OLT surgery and at 2 and 4 h after the anhepatic phase. The diagnostic value for ARDS until the 3 days following transplantation was evaluated.. Eighteen subjects developed ARDS after OLT. The concentrations of TNF-α, IL-8, MDA, NO, H2O2, and 8-iso-prostaglandin F2α were much higher in the ARDS group than in the control group, whereas the levels of IL-10 and SOD were lower in the ARDS group than in the control group. The serum levels of mediators of oxidative stress or inflammation were closely related to EBC levels. Receiver operating characteristic analysis showed that areas under the curves for MDA, NO, H2O2, 8-iso-prostaglandin F2α, TNF-α, IL-8, SOD, and IL-10 were 0.88, 0.88, 0.78, 0.84, 0.84, 0.94, 0.81, and 0.84 at 2 h after graft reperfusion and 0.98, 0.88, 0.92, 0.79, 0.95, 0.83, 0.88, and 0.97 at 4 h after graft reperfusion.. EBC analysis is a noninvasive method for detecting mediators of inflammation and oxidative stress from the lungs. This method could be used to predict the higher incidence of ARDS induced by OLT.

Topics: Aged; Breath Tests; Exhalation; Female; Humans; Hydrogen Peroxide; Inflammation Mediators; Interleukin-10; Interleukin-8; Liver Transplantation; Male; Malondialdehyde; Middle Aged; Nitric Oxide; Oxidative Stress; Postoperative Complications; Postoperative Period; Prostaglandins; Respiratory Distress Syndrome; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Hyperinflation (HI) is performed following open endotracheal suctioning (OES), whose goals include: to stimulate a cough, recover oxygenation and improve compliance. However, it may also induce unintended consequences, including: lung stress and strain, failure to maintain high distending pressure, and subsequently cycling recruitment and derecruitment. Here, our aim was to investigate the effects of hyperinflation after repeated OES on sequential alteration of arterial oxygenation and lung injury profile using a saline lavage-induced surfactant depleted ARDS rabbit model.. Briefly, 30 Japanese White Rabbits were anesthetized and ventilated in pressure-controlled setting with a tidal volume of 6-8 ml/kg. Animals were divided into four groups, i.e.; Control, ARDS, OES, and HI. Saline-lavage-induced lung injury was induced except for Control group. Thereafter, rabbits were ventilated with positive-end expiratory pressure (PEEP) at 10 cm H2O. The ARDS group received ventilation with the same PEEP without derecruitment. As intervention, OES and HI were performed in ARDS animals. OES was performed for 15 seconds at 150 mm Hg, whereas HI was performed with PEEP at 0 cm H2O and peak inspiratory pressure at +5 cm H2O for a minute. Total duration of the experiment was for 3 hours. OES and HI were performed every 15 minutes from beginning of the protocol.. PaO2 was maintained at about 400 mm Hg in both control and ARDS groups for the duration of this study, while in both OES and HI groups, PaO2 decreased continuously up to 3 hours, dropped to a mean (±SD) of 226 ± 28.9 and 97.0 ± 30.7 mmHg at 3 h, respectively. HI group had the lowest PaO2 in the present investigation. Histological lung injury score was the highest in HI group than other three groups. Pulmonary TNF-α and IL-8 levels were the highest in HI group compared to other groups, but without significant alterations at circulatory level in all the experimental groups.. We show in the present study that hyperinflation following repeated OES deteriorate arterial oxygenation and the severity of lung injury in a rabbit model of ARDS undergoing mechanical ventilation.

Topics: Analysis of Variance; Animals; Carbon Dioxide; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Interleukin-8; Lung Injury; Male; Oxygen; Partial Pressure; Positive-Pressure Respiration; Rabbits; Random Allocation; Respiratory Distress Syndrome; Suction; Tumor Necrosis Factor-alpha

Acute respiratory distress syndrome (ARDS) is a serious clinical problem that has a 30-50% mortality rate. Budesonide has been used to reduce lung injury. This study aims to investigate the effects of nebulized budesonide on endotoxin-induced ARDS in a rabbit model. Twenty-four rabbits were randomized into three groups. Rabbits in the control and budesonide groups were injected with endotoxin. Thereafter, budesonide or saline was instilled, ventilated for four hours, and recovered spontaneous respiratory. Peak pressure, compliance, and PaO2/FiO2 were monitored for 4 h. After seven days, PaO2/FiO2 ratios were measured. Wet-to-dry weight ratios, total protein, neutrophil elastase, white blood cells, and percentage of neutrophils in BALF were evaluated. TNF-α, IL-1β, IL-8, and IL-10 in BALF were detected. Lung histopathologic injury and seven-day survival rate of the three groups were recorded. Peak pressure was downregulated, but compliance and PaO2/FiO2 were upregulated by budesonide. PaO2/FiO2 ratios significantly increased due to budesonide. Wet-to-dry weight ratios, total protein, neutrophil elastase, white blood cells and percentage of neutrophils in BALF decreased in the budesonide group. TNF-α, IL-1β, and IL-8 levels decreased in BALF, while IL-10 levels increased in the budesonide group. Lung injuries were reduced and survival rate was upregulated by budesonide. Budesonide effectively ameliorated respiratory function, attenuated endotoxin-induced lung injury, and improved the seven-day survival rate.

Topics: Administration, Inhalation; Animals; Budesonide; Endotoxins; Glucocorticoids; Interleukin-10; Interleukin-1beta; Interleukin-8; Lung; Male; Rabbits; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Outcomes and risk factors associated with new-onset atrial fibrillation (AF) during acute respiratory distress syndrome (ARDS) are unclear. We investigated mortality and risk factors associated with new-onset AF during ARDS.. We obtained data from the ARDS Network Albuterol for Treatment of Acute Lung Injury trial, which prospectively identified new-onset AF among patients with ARDS as an adverse event. We determined Acute Physiology and Chronic Health Evaluation III-adjusted associations between new-onset AF and 90-day mortality. We also examined associations between new-onset AF and markers of inflammation (interleukin 6 and interleukin 8), myocardial injury (troponin I), autonomic activation (epinephrine), and atrial stretch (central venous pressure) as well as other clinical characteristics.. Of 282 patients (mean age, 51.6 years; 45% women; 77% white) enrolled in Albuterol for Treatment of Acute Lung Injury, 28 (10%) developed new-onset AF during the study. We did not identify associations between new-onset AF and baseline central venous pressure, plasma levels of troponin I, epinephrine, interleukin 6, or interleukin 8. New-onset AF during ARDS was associated with increased 90-day mortality (new-onset AF, 43% vs no new-onset AF, 19%; Acute Physiology and Chronic Health Evaluation-adjusted odds ratio, 3.09 [95% confidence interval, 1.24-7.72]; P = .02).. New-onset AF during ARDS is associated with increased mortality; however, its mechanisms require further study.

Topics: Aged; Albuterol; Atrial Fibrillation; Biomarkers; Bronchodilator Agents; Female; Hospital Mortality; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Odds Ratio; Prognosis; Prospective Studies; Respiratory Distress Syndrome; Risk Factors

Acute respiratory distress syndrome (ARDS) is a contemporary term incorporating the historic 'acute lung injury' and the colloquial term 'shock lung'. ARDS remains a serious and enigmatic human disease, causing significant mortality. The mechanisms involved at the alveolar cell/capillary endothelial interface have been explored but to date we lack clarity on the role of intracellular calcium ([Ca(2+)]i) fluxes across this interface. To explore the mechanisms of Ca(2+) induced inflammatory reaction in epithelial cells and pulmonary microvascular endothelial cells (HMVEC) located at the two sides of blood-air barrier, lung epithelial A549 and HMVEC cells were treated with LPS. Our results demonstrated that LPS evoked the increase of [Ca(2+)]i, TNF-α and IL-8 in both cells types. The [Ca(2+)]i increases involved intracellular but not extracellular Ca(2+) sources in A549, but both intracellular and extracellular Ca(2+) sources in HMVEC cells. The effects of LPS on both cells types were completely inhibited by the combination of LPS and CaSR-targeted siRNA. Furthermore, LPS-inhibited cell proliferations were significantly reversed by the combined treatment. Therefore, LPS induced different mechanisms of [Ca(2+)]i increase during the activation of CaSR in A549 and HMVEC cells, which translates into functional outputs related to ARDS.

Topics: Calcium; Cell Line; Cell Proliferation; Endothelial Cells; Endothelium, Vascular; Epithelial Cells; Gene Expression; Humans; Interleukin-8; Lipopolysaccharides; Lung; Models, Biological; Receptors, Calcium-Sensing; Respiratory Distress Syndrome; RNA, Small Interfering; Signal Transduction; Tumor Necrosis Factor-alpha

Acute respiratory distress syndrome (ARDS) remains a high morbidity and mortality disease entity in critically ill patients, despite decades of numerous investigations into its pathogenesis. To obtain global protein expression changes in acute lung injury (ALI) lung tissues, we employed a high-throughput proteomics method to identify key components which may be involved in the pathogenesis of ALI. In the present study, we analyzed lung tissue proteomes of Pseudomonas aeruginosa-induced ALI rats and identified eighteen proteins whose expression levels changed more than twofold as compared to normal controls. In particular, we found that PRDX1 expression in culture medium was elevated by a lipopolysaccharide (LPS) challenge in airway epithelial cells in vitro. Furthermore, overexpression of PRDX1 increased the expression of proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α), whereas knockdown of PRDX1 led to downregulated expression of cytokines induced by LPS. In conclusion, our findings provide a global alteration in the proteome of lung tissues in the ALI rat model and indicate that PRDX1 may play a critical role in the pathogenesis of ARDS by promoting inflammation and represent a novel strategy for the development of new therapies against ALI.

Topics: Acute Lung Injury; Animals; Cell Line; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Male; Peroxiredoxins; Proteomics; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Recent studies suggest a role for distal airway injury in acute respiratory distress syndrome (ARDS). The epithelium lining the small airways secretes a large number of molecules such as surfactant components and inflammatory mediators. There is little information on how these small airway secretory functions are altered in ARDS.. We studied the lungs of 31 patients with ARDS (Pao(2)/fraction of inspired oxygen ≤200, 45 ± 14 years, 16 men) and 11 controls (52 ± 16 years, 7 men) submitted to autopsy and quantified the expression of interleukin (IL) 6, IL-8, surfactant proteins (SP) A and SP-B in the epithelium of small airways using immunohistochemistry and image analysis. In addition, an index of airway epithelial apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine-triphosphatase nick-end labeling assay, caspase 3, and Fas/Fas ligand expression. The density of inflammatory cells expressing IL-6 and IL-8 within the small airway walls was also quantified.. Acute respiratory distress syndrome airways showed an increase in the epithelial expression of IL-8 (P = .006) and an increased density of inflammatory cells expressing IL-6 (P = .004) and IL-8 (P < .001) compared with controls. There were no differences in SP-A and SP-B epithelium expression or in epithelial apoptosis index between ARDS and controls.. Distal airways are involved in ARDS lung inflammation and show a high expression of proinflammatory interleukins in both airway epithelial and inflammatory cells. Apoptosis may not be a major mechanism of airway epithelial cell death in ARDS.

Topics: Acute-Phase Proteins; Apoptosis; Case-Control Studies; Cytokines; Female; Humans; Immunohistochemistry; Interleukin-6; Interleukin-8; Male; Middle Aged; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Proteins; Respiratory Distress Syndrome; Respiratory Mucosa; Retrospective Studies

Alveolar IL-8 has been reported to early identify patients at-risk to develop ARDS. However, it remains unknown how alveolar IL-8 is related to pulmonary and systemic inflammation in patients predisposed for ARDS. We studied 24 patients 2-6h after multiple trauma. Patients with IL-8 >200 pg/ml in bronchoalveolar lavage (BAL) were assigned to the group at high risk for ARDS (H, n = 8) and patients with BAL IL-8 <200 pg/ml to the group at low risk for ARDS (L, n = 16). ARDS developed within 24h after trauma in 5 patients at high and at least after 1 week in 2 patients at low risk for ARDS (p = 0.003). High-risk patients had also increased BAL IL-6, TNF-α, IL-1β, IL-10 and IL-1ra levels (p<0.05). BAL neutrophil counts did not differ between patient groups (H vs. L, 12% (3-73%) vs. 6% (2-32%), p = 0.1) but correlated significantly with BAL IL-8, IL-6 and IL-1ra. High-risk patients had increased plasma levels of pro- but not anti-inflammatory mediators. The enhanced alveolar and systemic inflammation associated with alveolar IL-8 release should be considered to identify high-risk patients for pulmonary complications after multiple trauma to adjust surgical and other treatment strategies to the individual risk profile.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Disease Susceptibility; Enzyme-Linked Immunosorbent Assay; Female; Hospital Mortality; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-8; Leukocyte Count; Male; Middle Aged; Multiple Trauma; Predictive Value of Tests; Prognosis; Prospective Studies; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha; Young Adult

Pulmonary complications together with surgical complications are the most frequent causes for morbidity and mortality after thoracoabdominal esophagectomy. The con-tinuous improvement of surgical techniques has led to a decrease in surgical complications, whereas up to 30% of the patients develop postoperative pulmonary complications such as acute lung injury (ALI) or even the more severe acute respiratory distress syndrome (ARDS), which are characterized by an acute inflammation in the lung parenchyma and the airspace. Evidence from several studies indicates that a complex network of inflammatory cytokines and mediators play a key role in mediation, amplification, and perpetuation of the process of lung injury and that the thoracotomy itself is a risk factor for developing ALI or ARDS. In this trial, the cytokine levels of IL6, IL8 and IL10 were measured and compared in 30 patients who had undergone an extended radical thoracoabdominal esophagectomy for esophageal cancer, via anterolateral thoracotomy (n=17) or posterolateral thoracotomy (n=13). Patients of both groups were similar in terms of age, sex and preoperative pulmonary function as well as in the anesthetic procedures they have undergone. All patients displayed significantly increased serum levels of IL6 and IL8 after thoracoabdominal esophagectomy. However, patients who were subjected to an anterolateral thoracotomy were reported with significantly higher serum levels of IL6 and IL8 compared to patients who had received a posterolateral thoracotomy. Thus, the choice of the thoracotomy method during the thoracoabdominal esophagectomy and the resultant cytokine levels may contribute to the occurrence of postoperative pulmonary complications and may have an impact on the extent and severity of the surgical stress.

Topics: Adult; Aged; Cytokines; Enzyme-Linked Immunosorbent Assay; Esophageal Neoplasms; Esophagectomy; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Neoplasm Staging; Postoperative Complications; Respiratory Distress Syndrome; Thoracotomy

Prostaglandin E(2) (PGE(2)) is a bioactive prostanoid implicated in the inflammatory processes of acute lung injury/acute respiratory distress syndrome. This study investigated whether PGE(2) can induce production of interleukin (IL)-8, the major chemokine for neutrophil activation, from human pulmonary microvascular endothelial cells (HPMVECs). PGE(2) significantly enhanced IL-8 protein production with increases in IL-8 mRNA expression and intracellular cAMP levels. HPMVECs expressed only EP4 receptor mRNA. The PGE(2) effects were mimicked by a selective EP4 receptor agonist, ONO-AE1-329, and inhibited by a selective EP4 receptor antagonist, ONO-AE3-208, or a protein kinase A inhibitor, Rp-adenosine 3',5'-cyclic monophosphorothioate triethylamine salt. The specific agonist for EP1, EP2, or EP3 receptor did not induce IL-8 production. PGE(2)-induced IL-8 production was accompanied by p38 phosphorylation and was significantly inhibited by a p38 inhibitor, SB-203580, but not by an ERK1/2 inhibitor, U-0126, or a JNK inhibitor, SP-600125. Additionally, PGE(2) increased cyclooxygenase-2 expression with no change in constitutive cyclooxygenase-1 expression, suggesting possible involvement of an autocrine or paracrine manner. In conclusion, PGE(2) enhances IL-8 production via EP4 receptor coupled to G(s) protein in HPMVECs. Activation of the cAMP/protein kinase A pathway, followed by p38 activation, is essential for these mechanisms. Because neutrophils play a critical role in the inflammation of acute lung injury/acute respiratory distress syndrome, IL-8 released from the pulmonary microvasculature in response to PGE(2) may contribute to pathophysiology of this disease.

Topics: Acute Lung Injury; Anthracenes; Butadienes; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Endothelial Cells; Humans; Imidazoles; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lung; MAP Kinase Signaling System; Methyl Ethers; Microvessels; Naphthalenes; Neutrophils; Nitriles; p38 Mitogen-Activated Protein Kinases; Phenylbutyrates; Pyridines; Receptors, Prostaglandin E, EP4 Subtype; Respiratory Distress Syndrome; RNA, Messenger; Thionucleotides

Fibroblast migration is an initiating step in fibroproliferation; its involvement during acute lung injury and acute respiratory distress syndrome remains poorly understood. The aims of this study were: 1) to determine whether bronchoalveolar lavage fluids from patients with acute lung injury/acute respiratory distress syndrome modulate lung fibroblast migration; 2) to assess lung fibroblast migration's clinical relevance; and 3) to evaluate the role of the platelet-derived growth factor pathway in this effect.. Prospective cohort study.. Three intensive care units of a large tertiary referral center.. Ninety-three ventilated patients requiring bronchoalveolar lavage fluids were enrolled (48 with acute respiratory distress syndrome, 33 with acute lung injury, and 12 ventilated patients without acute lung injury/acute respiratory distress syndrome).. After bronchoalveolar lavage fluids collection during standard care, the patients were followed up for 28 days and clinical outcomes were recorded. Migration assays were performed by using a Transwell model; bronchoalveolar lavage fluids platelet-derived growth factor and soluble platelet-derived growth factor receptor-α were characterized by Western blot and measured by ELISA.. Most of the bronchoalveolar lavage fluids inhibited basal fibroblast migration. Bronchoalveolar lavage fluids chemotactic index increased with severity of lung injury (28% in patients without acute lung injury/acute respiratory distress syndrome and with acute lung injury vs. 91% in acute respiratory distress syndrome patients; p = .016). In acute lung injury/acute respiratory distress syndrome patients, inhibition of basal fibroblast migration by bronchoalveolar lavage fluids below 52% was independently associated with a lower 28-day mortality (odds ratio [95% confidence interval] 0.313 [0.10-0.98], p = .046). Platelet-derived growth factor-related peptides and soluble platelet-derived growth factor-Rα were detected in all bronchoalveolar lavage fluids from acute lung injury/acute respiratory distress syndrome patients. The effect of bronchoalveolar lavage fluids stimulating migration was inhibited by a specific platelet-derived growth factor receptor inhibitor (AG1296). Bronchoalveolar lavage fluids inhibiting migration reversed the effect of rh-platelet-derived growth factor-BB and reduced by 40% the binding of 125I-platelet-derived growth factor-BB to fibroblast cell surface in favor of a role for platelet-derived growth factor-sRα.. : Together, our results suggest that during acute lung injury, fibroblast migration is modulated by bronchoalveolar lavage fluids through a platelet-derived growth factor/platelet-derived growth factor-sRα balance. Migration is associated with clinical severity and patient 28-day mortality.

Topics: Acute Lung Injury; Aged; Blotting, Western; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cell Line; Cell Movement; Enzyme Inhibitors; Female; Fibroblasts; Humans; Intensive Care Units; Interleukin-8; Male; Middle Aged; Multiple Organ Failure; Multivariate Analysis; Neutrophils; Platelet-Derived Growth Factor; Prospective Studies; Receptors, Platelet-Derived Growth Factor; Respiration, Artificial; Respiratory Distress Syndrome; Severity of Illness Index; Tyrphostins

Despite the technique of cardiopulmonary bypass (CPB) improved the development of modern cardiac surgery, many factors during CPB have been reported to induce acute respiratory distress syndrome (ARDS). The present study was to investigate which pro-inflammatory factors involved in the early phase of ARDS. Ten patients underwent valve replacement surgery with or without ARDS were enrolled for analysis of pulmonary function and inflammatory factors release including white blood cell (WBC), neutrophils, CD11b, CD18, interleukin (IL)-8 and tumor necrosis factor-α (TNF-α). The results demonstrated that the ratio of arterial oxygen tension/fraction of inspire oxygen (PaO(2)/FiO(2)) was greatly reduced in ARDS patients, but only the release of TNF-α was significantly increased, which was reversely correlated to the values of PaO(2)/FiO(2). Also, the count of neutrophils adhesive to pulmonary endothelial cells was significantly increased in ARDS patients. Therefore, we concluded that TNF-α was quickly up-regulated and involved in the pathogenesis of CPB-induced ARDS via guiding primed neutrophils to pulmonary interstitium.

Topics: Adolescent; Adult; Aged; Cardiopulmonary Bypass; Female; Flow Cytometry; Humans; Interleukin-8; Leukocyte Count; Linear Models; Male; Middle Aged; Neutrophils; Respiratory Distress Syndrome; Respiratory Function Tests; Tumor Necrosis Factor-alpha; Up-Regulation

Interleukin-8 (IL-8) is a central chemokine in acute respiratory distress syndrome (ARDS), and the IL-8 gene contains a functional single nucleotide polymorphism (SNP) -251A/T in its promoter region. We hypothesized that IL-8 -251A/T SNP is associated with PaO(2)/FiO(2) in critically ill patients.. We conducted genetic-association studies in intensive care units at academic teaching centres using a derivation septic shock cohort (vasopressin and septic shock trial (VASST), n = 467) and a validation post-cardiopulmonary bypass surgery cohort (CPB, n = 739) of Caucasian patients. Patients in both cohorts were genotyped for IL-8 -251A/T. The primary outcome variable in both cohorts was the fraction of patients who had a PaO(2) /FiO(2) < 200. IL-8 mRNA expression was measured in genotyped lymphoblastoid cells in vitro.. The frequency of the patients with PaO(2)/FiO(2) <200 was significantly greater in patients who had the AA genotype of -251A/T than in patients who had the AT or TT genotypes in both VASST (AA = 60.8% vs AT and TT = 53.8% and 48.0%, P = 0.038) and the CPB cohort (AA = 37.0% vs AT and TT = 27.0% and 26.0%, P = 0.039). Patients having the AA genotype had a higher probability to remain on mechanical ventilation (P = 0.047) in the first 14 days. Lymphoblastoid cells having the AA genotype had significantly higher IL-8 mRNA expression than cells having the AT or TT genotype (P = 0.022).. Critically ill Caucasian patients who had the AA genotype of IL-8 -251A/T had an increased risk of PaO(2)/FiO(2) <200. The AA genotype was associated with greater IL-8 mRNA expression than the AT or TT genotypes.

Topics: Aged; Cardiopulmonary Bypass; Cells, Cultured; Cohort Studies; Critical Illness; Female; Gene Frequency; Genetic Association Studies; Genotype; Humans; Intensive Care Units; Interleukin-8; Male; Middle Aged; Oxygen; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Respiration, Artificial; Respiratory Distress Syndrome; Severity of Illness Index; Shock, Septic

The level of active urokinase (uPA) is decreased in lung fluids of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) whereas α(2)-macroglobulin (α(2)-M), a plasma proteinase inhibitor, is a major component of these fluids. Since there have been reports describing the ability of α(2)-M to form complexes with uPA in vitro, we hypothesized that α(2)-M may interact with uPA in the lung to modulate its biological activity. Pulmonary edema fluids and lung tissues from patients with ALI/ARDS were evaluated for the presence of uPA associated with α(2)-M. Complexes between α(2)-M and uPA were detected in alveolar edema fluids as well as in lungs of patients with ALI/ARDS where they were located mainly in close proximity to epithelial cells. While uPA bound to α(2)-M retains its amidolytic activity towards low-molecular-weight substrates, it is not inhibited by its main physiological inhibitor, plasminogen activator inhibitor 1. We also investigated the functional consequences of formation of complexes between uPA and α(2)-M in vitro. We found that when α(2)-M:uPA complexes were added to cultures of human bronchial epithelial cells (BEAS-2B), activation of nuclear factor-κB as well as production of interleukin-6 and -8 was substantially suppressed compared with the addition of uPA alone. Our findings indicate for the first time that the function of uPA in patients with ALI/ARDS may be modulated by α(2)-M and that the effects may include the regulation of the fibrinolytic and signaling activities of uPA.

Topics: Acute Lung Injury; alpha-Macroglobulins; Cell Line; Epithelial Cells; Humans; Interleukin-6; Interleukin-8; NF-kappa B; Pulmonary Edema; Respiratory Distress Syndrome; Signal Transduction; Urokinase-Type Plasminogen Activator

Setting and strategies of mechanical ventilation with positive end-expiratory pressure (PEEP) in acute lung injury (ALI) remains controversial. This study compares the effects between lung-protective mechanical ventilation according to the Acute Respiratory Distress Syndrome Network recommendations (ARDSnet) and the open lung approach (OLA) on pulmonary function and inflammatory response.. Eighteen juvenile pigs were anaesthetized, mechanically ventilated, and instrumented. ALI was induced by surfactant washout. Animals were randomly assigned to mechanical ventilation according to the ARDSnet protocol or the OLA (n=9 per group). Gas exchange, haemodynamics, pulmonary blood flow (PBF) distribution, and respiratory mechanics were measured at intervals and the lungs were removed after 6 h of mechanical ventilation for further analysis.. PEEP and mean airway pressure were higher in the OLA than in the ARDSnet group [15 cmH(2)O, range 14-18 cmH(2)O, compared with 12 cmH(2)O; 20.5 (sd 2.3) compared with 18 (1.4) cmH(2)O by the end of the experiment, respectively], and OLA was associated with improved oxygenation compared with the ARDSnet group after 6 h. OLA showed more alveolar overdistension, especially in gravitationally non-dependent regions, while the ARDSnet group was associated with more intra-alveolar haemorrhage. Inflammatory mediators and markers of lung parenchymal stress did not differ significantly between groups. The PBF shifted from ventral to dorsal during OLA compared with ARDSnet protocol [-0.02 (-0.09 to -0.01) compared with -0.08 (-0.12 to -0.06), dorsal-ventral gradients after 6 h, respectively].. According to the OLA, mechanical ventilation improved oxygenation and redistributed pulmonary perfusion when compared with the ARDSnet protocol, without differences in lung inflammatory response.

Topics: Acute Lung Injury; Animals; Female; Interleukin-6; Interleukin-8; Lung; Positive-Pressure Respiration; Pulmonary Circulation; Pulmonary Gas Exchange; Respiration, Artificial; Respiratory Distress Syndrome; RNA, Messenger; Stress, Mechanical; Swine

Acute respiratory distress syndrome (ARDS) is a poorly understood condition with greater than 30% mortality. Massive recruitment of neutrophils to the lung occurs in the initial stages of the ARDS. Significant variability in the severity and duration of ARDS-associated pulmonary inflammation could be linked to heterogeneity in the inflammatory capacity of neutrophils. Interferon-stimulated genes (ISGs) are a broad gene family induced by Type I interferons. While ISGs are central to anti-viral immunity, the potential exists for these genes to evoke extensive modification in cellular response in other clinical settings. In this prospective study, we sought to determine if ISG expression in circulating neutrophils from ARDS patients is associated with changes in neutrophil function. Circulating neutrophil RNA was isolated, and hierarchical clustering ranked patients' expression of three ISGs. Neutrophil response to pathogenic bacteria was compared between normal and high ISG-expressing neutrophils. High neutrophil ISG expression was found in 25 of 95 (26%) of ARDS patients and was associated with reduced migration toward interleukin-8, and altered responses to Staphylococcus aureus, but not Pseudomonas aeruginosa, which included decreased p38 MAP kinase phosphorylation, superoxide anion release, interleukin-8 release, and a shift from necrotic to apoptotic cell death. These alterations in response were reflected in a decreased capacity to kill S. aureus, but not P. aeruginosa. Therefore, the ISG expression signature is associated with an altered circulating neutrophil response phenotype in ARDS that may predispose a large subgroup of patients to increased risk of specific bacterial infections.

Topics: Adult; Aged; Aged, 80 and over; Cell Death; Cell Movement; Cell Separation; Cohort Studies; Female; Gene Expression Regulation; Humans; Interferons; Interleukin-8; Male; Microbial Viability; Middle Aged; Neutrophils; p38 Mitogen-Activated Protein Kinases; Respiratory Distress Syndrome; Species Specificity; Staphylococcus aureus; Superoxides; Viruses; Young Adult

To explore the pathophysiology of acute lung injury in children.. Prospective cohort study.. Regional University Hospital, pediatric intensive care unit.. Children without a preexisting lung injury who developed acute lung injury and were intubated were eligible for the study. Children without lung injury and intubated for minor surgical procedures acted as controls.. Bronchoalveolar lavage fluid and blood were collected on days 1 to 4, weekly, and immediately before extubation during acute lung injury. Molecular species compositions of phosphatidylcholine were determined by electrospray ionization mass spectrometry of lipid extracts of bronchoalveolar lavage fluid supernatants. Surfactant proteins A, B, and D and interleukin-8 were measured in bronchoalveolar lavage fluid and plasma by enzyme-linked immunosorbent assay and Western blotting.. Eighteen children with acute lung injury were enrolled in the study and compared with eight controls. In children with acute lung injury, there were significant changes in the bronchoalveolar lavage fluid phosphatidylcholine species. Bronchoalveolar lavage fluid dipalmitoyl phosphatidylcholine (PC 16:0/16:0) and palmitoyl-myristoyl phosphatidylcholine (PC 16:0/14:0) significantly deceased during acute lung injury (p < .001 and p < .001, respectively), whereas oleoyl-linoleoyl PC (18:1/18:2), palmitoyl-linoleoyl PC (16:0/18:2) and stearoyl-linoleoyl PC (18:0/18:2) characteristic of plasma PC were significantly increased (p < .05, p < .02, and p < .05 respectively), as well as palmitoyl-oleoyl PC (16:0/18:1), and stearoyl-arachidonoyl PC (18:0/20:4) which are characteristic of cell membranes (p < .02, and p < .02, respectively). There were no significant changes to bronchoalveolar lavage fluid, surfactant protein A or B levels compared with controls during acute lung injury, whereas bronchoalveolar lavage fluid, surfactant protein D, and interleukin-8 levels significantly increased (p < .05 and p < .02, respectively). In plasma during acute lung injury, there were significant increases in surfactant proteins A, B, and D, and interleukin-8 (p < .001, p < .001, p < .05, and p < .001, respectively).. Changes to the phosphatidylcholine profile, surfactant proteins, and inflammatory markers of bronchoalveolar lavage fluid and plasma in children with acute lung injury are consistent with an alveolar/blood leakage and inflammatory cell membrane degradation products. These changes are due to alveolar capillary membrane damage and cellular infiltration.

Topics: Acute Lung Injury; Biomarkers; Bronchoalveolar Lavage Fluid; Child; Child, Preschool; Cohort Studies; Female; Humans; Inflammation; Intensive Care Units, Pediatric; Interleukin-8; Intubation, Intratracheal; Lipoproteins; Male; Phospholipids; Prospective Studies; Pulmonary Surfactants; Respiratory Distress Syndrome

Although fibroblasts are key cells in the lung repair/fibrosis process, their characteristics are poorly studied in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The aims of our study were to: 1) determine the biological behaviour of alveolar fibroblasts during ALI; and 2) to evaluate the clinical relevance of positive alveolar fibroblast culture from patients with ALI/ARDS. Cells were cultured from bronchoalveolar lavage (BAL) obtained from 68 critically ill, ventilated patients: ALI n = 17; ARDS n = 31; and ventilated controls n = 20. Patients were followed for 28 days and clinical data was recorded. We studied proliferation, migration and collagen-1 synthesis capacities of fibroblasts. Cells expressing fibroblast markers were cultured from BAL obtained in six (35%) ALI patients and six (19%) ARDS patients, but never from ventilated controls. Alveolar fibroblasts exhibited a persistent activated phenotype with enhanced migratory and collagen-1 production capacities, with hyporesponsiveness to prostaglandin E(2) compared to normal lung fibroblasts (p< or =0.04). Positive fibroblast culture was associated with both an increased collagen-1 concentration and monocyte/macrophage percentage in BAL fluid (p< or =0.01), and with a reduced duration of mechanical ventilation (p<0.001). We conclude that activated alveolar fibroblasts can be cultured either in ALI or ARDS and that their presence might reflect the initiation of the organising phase of ALI.

Topics: Acute Lung Injury; Adult; Aged; Biomarkers; Bronchoalveolar Lavage Fluid; Cell Division; Cell Movement; Cells, Cultured; Chemokine CCL2; Collagen Type I; Female; Fetal Proteins; Fibroblasts; Humans; Interleukin-8; Male; Middle Aged; Peptide Fragments; Procollagen; Pulmonary Alveoli; Respiratory Distress Syndrome; Transforming Growth Factor beta1

As one of the most important endogenous chemotactic factors for neutrophils, the chemokine CXCL8 (IL-8) is involved in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by massive neutrophil infiltration in the lung. Since neutralization of CXCL8 with polyclonal antibody has been shown to reduce the severity of ALI/ARDS in animal models, we explored the potential of humanized anti-CXCL8 antibody as a preventive or therapeutic agent for ALI. We used a 'two-hit' protocol to induce ALI in rabbits that showed extensive edema in the alveolar lumina, marked infiltration of neutrophils in the lung tissue, fibrin deposition in alveolar space, and destruction of pulmonary architecture, culminating in severe hypoxemia. Concomitant challenge with endotoxin after priming with oleic acid (OA) induced a marked elevation of CXCL8 level in bronchoalveolar lavage fluid. Treatment of the rabbits with a humanized anti-CXCL8 antibody prevented neutrophil infiltration in the lung in association with alleviated ALI syndrome. Our results indicate a promising future for utilization of humanized anti-CXCL8 antibody in the prevention and treatment of ALI and ARDS in human.

Topics: Acute Lung Injury; Animals; Antibodies, Monoclonal; Bronchoalveolar Lavage; Capillary Permeability; Edema; Endotoxins; Female; Fibrin; Hypoxia; Interleukin-1; Interleukin-8; Lung; Male; Mice; Neutrophils; Oleic Acid; Rabbits; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

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

Serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), a detector of acute inflammatory response to microbial products and a good marker for diagnosing sepsis and pneumonia, has not yet been described as a predictor for infection or a prognostic factor in patients with acute respiratory distress syndrome (ARDS).. This prospective observational cohort study enrolled 63 ventilated adult patients with ARDS; 50 as septic and 13 as non-septic, and followed them for 28 days in intensive care units at a university hospital in Taiwan. Serial serum sTREM-1 levels and cytokines, such as interleukin (IL)-1, IL-8, and tumor necrosis factor-α, on days 1, 3, 5, 7 and 14 were measured by an enzyme-linked immunosorbent assay. The association between biomarkers and clinical infectious diagnosis/outcome in ARDS was explored.. Serum sTREM-1 and cytokine levels could not differentiate septic from non-septic ARDS. Serum log sTREM-1 and inflammatory cytokine levels were correlated positively (r = 0.325 for IL-1β; r = 0.247 for IL-8; r = 0.480 for tumor necrosis factor-α). As prognostic factors, higher serum sTREM-1 level on day 1 and increasing levels over time, especially in the first 5 days, were independent predictors of mortality on day 28, using a multivariate Cox regression model. Serum sTREM-1 levels remained stable or even increased in the non-surviving patients, but decreased in the survivors.. Serum sTREM-1 level might not be a reliable marker for infection in ARDS patients. However, as an inflammatory marker, initial serum sTREM-1 level and its trend over time, especially in the first 5 days, could be predictive of short-term mortality. A progressive decline in serum sTREM-1 levels during follow-up indicates a favorable outcome, whereas persistently elevated sTREM-1 indicates a poor prognosis and should lead to a re-evaluation of therapy.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Hospitals, University; Humans; Intensive Care Units; Interleukin-1; Interleukin-8; Male; Membrane Glycoproteins; Middle Aged; Pneumonia, Bacterial; Proportional Hazards Models; Prospective Studies; Receptors, Immunologic; Respiratory Distress Syndrome; Sepsis; Taiwan; Time Factors; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

Our previous studies revealed that the presence in lung fluids of anti-IL-8 autoantibody:IL-8 immune complexes is an important prognostic indicator for the development and outcome of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Anti-IL-8:IL-8 complexes purified from lung edema fluids trigger chemotaxis of neutrophils, induce activation of these cells, and regulate their apoptosis, all via IgG receptor, FcgammaRIIa. Importantly, increased levels of FcgammaRIIa are present in lungs of patients with ARDS, where FcgammaRIIa is partially associated with anti-IL-8:IL-8 complexes. In the current study, we demonstrate the ability of anti-IL-8:IL-8 complexes to promote an inflammatory phenotype of human umbilical vein endothelial cells via interaction with FcgammaRIIa. Human umbilical vein endothelial cells cultured in the presence of the complexes become activated, as shown by increased phosphorylation of ERK, JNK, and Akt, and augmented nuclear translocation of NF-kappaB. Anti-IL-8:IL-8 complexes also up-regulate expression of intracellular adhesion molecule (ICAM)-1 on the cell surface. Furthermore, we detected increased levels of ICAM-1 on lung endothelial cells from mice in which lung injury was induced by generating immune complexes in alveolar spaces. On the other hand, ICAM-1 expression was unchanged in lungs of gamma chain-deficient mice, lacking receptors that interact with immune complexes. Moreover, in lung tissues from patients with ARDS, anti-IL-8:IL-8 complexes were associated with endothelial cells that expressed higher levels of ICAM-1. Our current findings implicate that anti-chemokine autoantibody:chemokine immune complexes, such as IL-8:IL-8 complexes, may contribute to pathogenesis of lung inflammation by inducing activation of endothelial cells through engagement of IgG receptors.

Topics: Animals; Antigen-Antibody Complex; Antigens, CD34; Autoantibodies; Cells, Cultured; Endothelial Cells; Extracellular Signal-Regulated MAP Kinases; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lung; Mice; Mice, Inbred BALB C; Mice, Knockout; Proto-Oncogene Proteins c-akt; Receptors, IgG; Respiratory Distress Syndrome; Signal Transduction; Transcription Factor RelA

We examined the possible role of hydrogen sulfide (H2S) in the pathogenesis of oleic acid (OA)-induced acute lung injury (ALI) and its regulatory effects on the inflammatory response. Compared to control rats, the OA-treated rats had decreased partial pressure of oxygen in the arterial blood (PaO2) levels, an increased pulmonary wet/dry weight (W/D) ratio, increased index of quantitative assessment (IQA) score and increased frequency of polymorphonuclear (PMN) cells in the lung 2, 4 or 6 h after OA injection (0.1 ml/kg, intravenous injection). In addition, significantly increased IL-6, IL-8 and IL-10 levels together with decreased H2S levels were observed in the plasma and lung tissue of OA-treated rats compared to controls. Administration of the H2S donor sodium hydrosulfide (NaHS, 56 micromol/L, intraperitoneal injection) into OA-treated rats increased the PaO2 level, reduced the lung W/D ratio and infiltration of PMN cells, and alleviated the degree of ALI (measured by the IQA score). In addition, NaHS decreased IL-6 and IL-8 levels but increased IL-10 levels in the plasma and lung tissues, suggesting that H2S may regulate the inflammatory response during ALI via regulation of IL-6, IL-8 and IL-10. Thus, the down-regulation of endogenous H2S production might be involved in the pathogenesis of OA-induced ALI in rats.

Topics: Animals; Body Weight; Bronchoalveolar Lavage Fluid; Cell Differentiation; Hydrogen Sulfide; Interleukin-10; Interleukin-6; Interleukin-8; Leukocytes; Male; Oleic Acid; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome

Variable ventilation is superior to control mode ventilation in a number of circumstances. The nature of the breathing file used to deliver the variable rate and tidal volume has not been formally examined.. We compared two different noise files in a randomized prospective trial of variable ventilation. Pigs were anesthetized, intubated, and mechanically ventilated. Oleic acid was infused to introduce lung injury. The animals were ventilated at a tidal volume of 7 mL x kg(-1), in variable mode, with either physiologically-derived noise (variability file - 1,587 breath intervals-obtained from a spontaneously breathing volunteer; n = 10) or a variability file of identical length derived from computer- generated white noise (n = 10).. The physiologically-derived noise had a power law alpha-exponent of -0.27 and a Hölder exponent of -0.38, indicative of auto-correlated noise. The computer-generated noise had an alpha-exponent of -0.52 and a Hölder exponent of -0.49, indicative of white noise. Both files showed multifractal characteristics. There were no differences between groups, at any time period, for PaO2, PaCO2, and static or dynamic respiratory system compliance. No differences were observed between groups for wet:dry lung weight ratios or for interleukin-8 in bronchoalveolar lavage fluid.. This study demonstrates that the nature of the variability files, chosen to drive the variable ventilator, had no effect on indices of gas exchange or respiratory mechanics in this model. A considerable overlap of the multifractal files existed. The potential to drive a variable ventilator using algorithm-derived files with multifractal characteristics, thereby eliminating the requirement to use physiologically-derived signals, is discussed.

Topics: Algorithms; Anesthesia; Animals; Blood Pressure; Body Temperature; Carbon Dioxide; Cardiac Output; Enzyme-Linked Immunosorbent Assay; Heart Rate; Humans; Interleukin-8; Lung Diseases; Oleic Acid; Organ Size; Oxygen; Pulmonary Circulation; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Mechanics; Signal Processing, Computer-Assisted; Swine; Tidal Volume; Vascular Resistance

A 75-year-old previously healthy man presented for elective resection of rectal cancer under general anesthesia. Six days before the operation, he had a high-grade fever, and elevated leukocyte count and C-reactive protein concentration, but this was resolved by an intravenous antibiotic. His condition was well controlled before the operation. Soon after the operation started, severe hypoxemia emerged, with low arterial pressure. Fiberoptic bronchoscopy demonstrated a massive amount of plasma-like edema fluid; the total amount of suctioned fluid was approximately 800 ml at the end of the surgery. This acute pulmonary edema appeared to be due to increased permeability rather than pulmonary congestion as indicated by chest radiography, pulmonary artery occlusion pressure, echocardiogram, and the protein-rich edema fluid. Elevated concentrations of the proinflammatory cytokines, interleukin (IL)-6 and IL-8, in both plasma and the pulmonary edema fluid, suggested a possible role of systemic and pulmonary inflammation in the development of this acute pulmonary capillary leak. According to the "two-hit" hypothesis, the bacterial infection preceding the operation may have primed the immune cells, and the following surgical stress may have then triggered rapid progression of acute respiratory distress syndrome. We should keep in mind that, especially following sepsis, sudden massive pulmonary capillary leak can occur during elective surgery, even though the patient's condition is well controlled.

Topics: Aged; Anesthesia, General; Capillary Leak Syndrome; Elective Surgical Procedures; Humans; Hypoxia; Interleukin-6; Interleukin-8; Lung Diseases; Male; Radiography; Respiratory Distress Syndrome; Treatment Outcome

The aim of this study was to compare the effects of conventional ventilation, lateral (non-injured lung-dependent) position, asynchronous and synchronous independent lung ventilation on inflammatory markers in an animal model of unilateral lung acid injury.. Twenty-eight dogs underwent unilateral endobronchial instillation with hydrochloric acid and randomly received (n = 7 in each group) conventional ventilation in the supine (group I) or lateral position (group II), and independent lung ventilation in asynchronous (group III) or synchronous (group IV) modes. Arterial blood gases and serum cytokine levels were assessed at baseline, and 5 min and 4 h after mechanical ventilation. At the end of the study, cytokine levels were measured in individual lung lavage fluid. In three animals per group, differential lung perfusion was detected using a dual-head gamma camera.. Unilateral acid injury alone worsened oxygenation as determined by the ratio of PaO(2) to fraction of inspired oxygen (PaO(2)/FiO(2)) and increased serum cytokine levels. Mean oxygenation (SD) was significantly preserved in group II, 338 (26); group III, 396 (28); and group IV, 395 (22) compared with group I, 173 (18) (all P < 0.01). Serum IL-8, left-lung lavage IL-8 and matrix metalloproteinase-9 levels were significantly lower in groups II-IV (all P < 0.05). Only group I showed significantly different left and right lung lavage fluid cytokine levels. Groups III and IV showed slightly decreased left lung perfusion. Cytokine levels and oxygenation were similar in groups III and IV.. In this model of unilateral lung acid injury, lateral position and independent lung ventilation preserved oxygenation and attenuated the inflammatory response in serum and injured lung BAL fluid.

Topics: Animals; Bronchoalveolar Lavage; Disease Models, Animal; Dogs; Hydrochloric Acid; Interleukin-10; Interleukin-8; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Posture; Respiration, Artificial; Respiratory Distress Syndrome

Acute lung injury (ALI) is a major cause of acute respiratory failure with high mortality despite lung-protective ventilation. Prior work has shown disordered inflammation and coagulation in ALI, with strong correlations between biomarker abnormalities and worse clinical outcomes. We measured plasma markers of inflammation, coagulation and fibrinolysis simultaneously to assess whether these markers remain predictive in the era of lung-protective ventilation.. Plasma samples and ventilator data were prospectively collected from 50 patients with early ALI. Plasma biomarkers of inflammation (IL-6, IL-8, intercellular adhesion molecule 1), of coagulation (thrombomodulin, protein C) and of fibrinolysis (plasminogen activator inhibitor 1) were measured by ELISA. Biomarker levels were compared between survivors (n = 29) and non-survivors (n = 21) using Mann-Whitney analysis.. The tidal volume for the study group was 6.6 +/- 1.1 ml/kg predicted body weight and the plateau pressure was 25 +/- 7 cmH2O (mean +/- standard deviation), consistent with lung-protective ventilation. All markers except IL-6 were significantly different between survivors and nonsurvivors. Nonsurvivors had more abnormal values. Three biomarkers - IL-8, intercellular adhesion molecule 1 and protein C - remained significantly different by multivariate analysis that included age, gender, Simplified Acute Physiology Score II and all biomarkers that were significant on bivariate analysis. Higher levels of IL-8 and intercellular adhesion molecule 1 were independently predictive of worse outcomes (odds ratio = 2.0 and 5.8, respectively; P = 0.04 for both). Lower levels of protein C were independently associated with an increased risk of death (odds ratio = 0.5), a result that nearly reached statistical significance (P = 0.06).. Despite lung-protective ventilation, abnormalities in plasma levels of markers of inflammation, coagulation and fibrinolysis predict mortality in ALI patients, indicating more severe activation of these biologic pathways in nonsurvivors.

Topics: APACHE; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Logistic Models; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Predictive Value of Tests; Prospective Studies; Protein C; Respiration, Artificial; Respiratory Distress Syndrome; Statistics, Nonparametric; Survival Rate; Thrombomodulin; Tidal Volume

Mechanical ventilation (MV) and lipopolysaccharide (LPS) synergistically increase inflammation and lung injury. The goal of this study was to determine whether blockade of CD14 or Toll-like receptor 4 (TLR4) would reduce inflammation caused by LPS and MV. Rabbits were pretreated with anti-TLR4 or anti-CD14 monoclonal antibodies, followed by endobronchial LPS and MV. Blockade of TLR4 reduced the number of neutrophils and the amount of CXCL8 in bronchoalveolar lavage fluid. In contrast, blockade of CD14 did not significantly decrease the number of neutrophils or the amount of CXCL8. These data show that TLR4 blockade reduces pulmonary inflammation caused by the combination of LPS and Mechanical ventilation.

Topics: Animals; Antibodies, Blocking; Antibodies, Monoclonal; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Escherichia coli; Female; Interleukin-8; Lipopolysaccharide Receptors; Lipopolysaccharides; Lung; Neutrophils; Rabbits; Respiration, Artificial; Respiratory Distress Syndrome; Specific Pathogen-Free Organisms; Toll-Like Receptor 4

Markers of inflammation, coagulation, and fibrinolysis predict an adverse outcome in patients with sepsis. These markers also seem predictive of an adverse outcome in patients with localized infection and inflammation, such as in acute lung injury. Whether this is entirely related to the disease or is also due to ventilation strategies that may be harmful for the lungs, however, is not clear. In the present issue of Critical Care, McClintock and colleagues demonstrate that these biomarkers retain their predictive effect even if lung-protective ventilation strategies are applied. Besides being biomarkers that predict outcome in patients with acute lung injury, their activation of inflammation and coagulation seems also to play a pivotal role in the pathogenesis of acute lung injury, and may thereby represent an interesting novel target for therapeutic intervention.

Topics: APACHE; Biomarkers; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Predictive Value of Tests; Protein C; Respiration, Artificial; Respiratory Distress Syndrome; Survival Rate; Thrombomodulin; Tidal Volume

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

Neutrophil elastase probably contributes to the development of acute lung injury after cardiopulmonary bypass (CPB) in patients with infection or shock. We evaluated whether pretreatment with sivelestat sodium hydrate, a neutrophil elastase inhibitor (EI), can prevent acute lung injury caused by CPB.. Rabbits were assigned four groups: CPB for 60 minutes, control CPB group; low-dose lipopolysaccharide (LPS) administration without CPB, LPS group; CPB after lipopolysaccharide administration, LPS+CPB group; or preparation with continuous infusion of sivelestat and CPBs after lipopolysaccharide administration, EI group. Blood samples to determine blood gas concentration, plasma elastase activity, and plasma interleukin-8 levels were obtained. Histopathologic examinations of the lung were performed.. The decreased arterial oxygen pressure at the end of CPB was observed in the LPS+CPB group only, but was suppressed in the EI group (p < 0.01). Elastase activity was markedly elevated at 120 minutes after CPB, and interleukin-8 levels were markedly elevated at 180 minutes in the LPS+CPB group but were much lower (p < 0.05) in the EI group. Histopathology demonstrated accumulation of polymorphonuclear neutrophils in bronchoalveolar areas in the LPS+CPB group (p < 0.01). Pulmonary myeloperoxidase activity was significantly lower in the LPS+CPB group than in the other groups (p < 0.01). These changes were minimal in the EI group.. The combination of low dose LPS+60 minutes of CPB, but neither intervention alone, produced evidence of acute lung injury in a rabbit model. This did not occur when the animals were pretreated with sivelestat.

Topics: Animals; Cardiopulmonary Bypass; Glycine; Interleukin-8; Leukocyte Elastase; Lipopolysaccharides; Neutrophils; Peroxidase; Rabbits; Respiratory Distress Syndrome; Sulfonamides

Although all-trans retinoic acid (ATRA) can treat acute promyelocytic leukemia (APL), it also causes retinoic acid syndrome with presentations similar to acute respiratory distress syndrome. We investigated the role of interleukin (IL)-8 and growth-regulated oncogene (GRO)-alpha in the chemotactic transmigration of ATRA-treated NB4 (ATRA-NB4) APL cells toward A549 alveolar epithelial cells.. An in vitro human cell culture study.. University hospital research laboratories.. NB4 and A549 cells.. NB4 and A549 cells were separately cultured with ATRA and/or dexamethasone for 1-3 days. NB4 or ATRA-NB4 cells were then placed in an upper insert and co-incubated with A549 cells or their conditioned medium located in a lower plate.. ATRA stimulated NB4 cells to transmigrate toward the A549 cells in a time- and dose-dependent manner. Replacement of A459 condition medium by its original medium abrogated this transmigration. Only A549 cells constitutively secreted GRO-alpha, and both A549 and NB4 cells constitutively secreted IL-8, which was enhanced by ATRA. Exogenous administration of IL-8 or GRO-alpha also promoted the ATRA-NB4 transmigration. The binding assay demonstrated that ATRA-NB4 cells bound IL-8, but not GRO-alpha, more avidly. Pretreatment with antibodies directed against IL-8 and GRO-alpha receptors reduced ATRA-NB4 transmigration by about 60%. Dexamethasone did not suppress their IL-8 secretion and transmigration in ATRA-NB4 cells, but when applied to A549 cells, IL-8 secretion was suppressed but not GRO-alpha secretion, and there was attenuation of ATRA-NB4 transmigration.. IL-8 and GRO-alpha secreted from alveolar epithelial cells play an important role in the cell-cell interaction involved in the chemotactic transmigration of ATRA-treated APL cells toward alveolar epithelial cells.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Chemokine CXCL1; Chemokines, CXC; Chemotaxis, Leukocyte; Epithelial Cells; Flow Cytometry; Humans; In Vitro Techniques; Interleukin-8; Leukemia, Promyelocytic, Acute; Pulmonary Alveoli; Respiratory Distress Syndrome; Tretinoin

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

The purpose of this study was to characterize the effects of doubling minute ventilation (either by doubling ventilator frequency [Freq] or tidal volume [V T]) and of normal minute ventilation prolonged to 12-fold duration, synchronously at biophysical, biochemical/cellular, histological, and transcriptional levels in a model of mild lung injury. A prospective, randomized study was performed on adolescent New-Zealand white rabbits. The rabbits were randomly assigned to one of the following groups: control (normal minute ventilation for 0.5 hours); 1 x V T, 12-fold prolongation at normal V T (normal minute ventilation for 6 hours [12 x 0.5 hours]); 2 x Freq at normal V T (double minute ventilation for 6 hours); and 2 x V T at normal Freq (double minute ventilation for 6 hours). Normocapnia was maintained throughout the experiment. At the biophysical level, gas exchange (alveolar-arterial O2-tension difference [ AaDO2]) deteriorated by 23, 51, and 95%, and respiratory compliance decreased by 6.0, 18.4, and 26% in the 1 x V T, 2 x Freq, and 2 x V T group, respectively, during 6 hours of ventilation. Concomitantly, at the biochemical-cellular level, interleukin-8 (IL-8) in the bronchoalveolar lavage fluid increased 44-fold, 150-fold, and 275-fold ( P = 0.02), respectively. The white blood cell count decreased significantly in all three intervention groups. At the histological level, the influx of leukocytes as well as the tissue water content increased in proportion to the degree of injury. At the transcriptional level, lung IL-8 mRNA expression increased 11-fold in the 2 x V T group ( P = 0.002), 9-fold ( P = 0.02) in the 2 x Freq group, and 4-fold in the 1 x V T group as compared with control. Not only doubling V T, but also doubling Freq at normal V T injures the lung significantly, although to a lesser extent. A concept of weighted risk for increases of V T and Freq is proposed.

Topics: Animals; Bronchoalveolar Lavage Fluid; Carbon Dioxide; Interleukin-8; Prospective Studies; Pulmonary Gas Exchange; Rabbits; Random Allocation; Respiration, Artificial; Respiratory Distress Syndrome; RNA, Messenger; Tidal Volume; Time Factors; Transcription, Genetic

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Chemokine CXCL1; Chemokines, CXC; Chemotaxis, Leukocyte; Epithelial Cells; Flow Cytometry; Humans; In Vitro Techniques; Interleukin-8; Leukemia, Promyelocytic, Acute; Pulmonary Alveoli; Respiratory Distress Syndrome; Syndrome; Tretinoin

Interleukin-8 (IL-8) is regarded as one of the most important mediators in the pathogenesis of Adult Respiratory Distress Syndrome (ARDS). However, knowledge regarding the influence of genetic variations within the IL-8 gene either on the development of ARDS or on IL-8 production in the traumatic setting is sparse.. In this prospective cohort study, patients were included if the following criteria were fulfilled: Injury Severity Score (ISS) >16, age 18-60 years and a survival >48 h after injury. Systemic IL-8 concentrations and the polymorphisms (IL-8-251A/T) were determined. Patients were separated according to the development of ARDS (group +ARDS vs. group -ARDS) and the genotypes of the IL-8-251A/T polymorphism (genotypes A/A, A/T and T/T).. Group +ARDS demonstrated significantly higher IL-8 plasma concentrations from day 3 until the end of the observation period compared to group -ARDS. In addition, duration of mechanical ventilation and length of stay in the ICU were significantly longer in this group. Furthermore, a significant association between the IL-8-251A allele and IL-8 production (day 4-8) was observed. Genotype A/A showed a significantly longer duration of mechanical ventilation compared to genotype T/T. A trend towards an association between the IL-8-251A allele and an increased incidence of posttraumatic ARDS was observed (p=0.08).. This data reaffirms a central role of IL-8 in the pathogenesis of ARDS. Furthermore, it points towards a genetic predisposition for posttraumatic IL-8 synthesis which might also be associated with the development of posttraumatic ARDS.

Topics: Adult; Female; Humans; Interleukin-8; Male; Middle Aged; Multiple Trauma; Polymorphism, Single Nucleotide; Respiratory Distress Syndrome

Anti-interleukin 8 autoantibody:interleukin 8 (anti-IL-8 autoantibody:IL-8) complexes are present in lung fluids of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS), and levels of these complexes correlate with progression to and the outcome of ARDS. Fc gammaRIIa, an immunoglobulin G (IgG) receptor, mediates proinflammatory activity of the complexes.. To evaluate lung tissues from patients with ARDS for presence of anti-IL-8 autoantibody:IL-8 complexes and to establish whether the complexes associate with Fc gammaRIIa.. Lung tissue sections from 3 patients with ARDS and sections of normal lung tissues from 3 patients were stained with antibodies against IL-8 and IgG to detect immune complexes and with antibody against Fc gammaRIIa. In some experiments, sections were blocked with anti-Fc gamma RIIa antibody before staining. Samples were analyzed using confocal microscopy.. Interleukin 8 costained with IgG and Fc gammaRIIa in lung tissues from patients with ARDS but not in control tissues, suggesting that anti-IL-8 autoantibody:IL-8 complexes are deposited in lungs of patients with ARDS via Fc gammaRIIa. Further, colocalization between IL-8 and Fc gammaRIIa could be blocked by anti-Fc gammaRIIa.. Our data demonstrate that anti-IL-8 autoantibody:IL-8 complexes are present in lung tissues of patients with ARDS, and are attached to Fc gammaRIIa.

Topics: Antigen-Antibody Complex; Autoantibodies; Case-Control Studies; Humans; Interleukin-8; Lung; Microscopy, Confocal; Receptors, IgG; Respiratory Distress Syndrome

Acute lung injury (ALI) makes up a spectrum of disease that is commonly defined as "acute non-cardiogenic edematous lung injury". It may contribute to morbidity and mortality in the critically ill patient in the intensive care unit. ALI was induced by oleic acid in rabbits. During the experiment, blood samples were taken from cervical artery and subjected to blood-gas analysis at different time points after oleic acid injection. Shortly after the rabbits were killed at 3 hour after iv OA injection, bronchoalveolar lavage fluid (BALF) was colleted, and the concentrations of protein, platelet-activating factor (PAF), intercellular adhesion molecule-1 (ICAM-1), interleukin 8 (IL-8) in BALF were then measured by ELISA. The ratio of wet to dry weight (W/D) of left lung was calculated to assess alveolar edema. Lung tissue was fixed in formaldehyde and stained with HE, and examined under a light microscope. The OA-induced elevation of arterial blood oxygen pressure was inhibited, as well as PAF, ICAM-1, IL-8 in BALF in rupatadine group. Furthermore, rupatadine also decreased the concentration of protein in BALF and inhibited the increase of the W/D weight ratio significantly. Light microscopic findings showed that the damage in rupatadine groups was far less severe than that in OA model group. Pretreatment with rupatadine has a beneficial effect on acute lung injury induced by oleic acid in rabbits. The ultimate reduction of inflammatory factors was involved, at least in part, in the mechanism of action of rupatadine effects.

Topics: Animals; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Cyproheptadine; Enzyme-Linked Immunosorbent Assay; Intercellular Adhesion Molecule-1; Interleukin-8; Lung; Male; Oleic Acid; Platelet Activating Factor; Protective Agents; Rabbits; Random Allocation; Respiratory Distress Syndrome

Secondary abdominal compartment syndrome (ACS) is a lethal complication after resuscitation from burn shock, even after abdominal decompression (AD) is performed. This study investigated increased susceptibility to multiple organ dysfunction syndrome (MODS) in extensively burned patients with ACS.. Patients admitted to our burn unit between 2002 and 2005 with burns affecting 40% or more of the total body surface area without severe inhalation injury were analyzed. Hemodynamic parameters, blood gas analysis, and intrabladder pressure as intra-abdominal pressure were recorded. Serum interleukin (IL)-8 and IL-6 concentrations were measured in 20 of these patients. Lung injury score and Sequential Organ Failure Assessment scores were serially determined.. Fourteen of 38 patients developed intra-abdominal hypertension in 22.9 +/- 8.9 hours postburn. Hemodynamic parameters in these 14 patients, including peak intra-abdominal pressure (46.6 +/- 11.2 to 19.8 +/- 9.9 cm H2O), peak inspiratory pressure (51.4 +/- 10.5 to 31.8 +/- 7.0 cm H2O), and abdominal perfusion pressure (51.3 +/- 18.3 to 73.9 +/- 13.6 mm Hg), were improved immediately after AD. Despite AD, lung injury score and Sequential Organ Failure Assessment scores increased significantly 2 and 3 days postburn in patients who required AD. Plasma concentration of IL-8 was elevated in intra-abdominal hypertension patients 3 days postburn.. Intra-abdominal hypertension induced acute lung injury and MODS with IL-8 elevation, even though AD improved hemodynamic parameters in extensively burned patients.

Topics: Abdominal Cavity; Burns; Compartment Syndromes; Decompression, Surgical; Humans; Interleukin-8; Multiple Organ Failure; Respiratory Distress Syndrome

In patients with acute respiratory distress syndrome (ARDS), a focal distribution of loss of aeration in lung computed tomography predicts low potential for alveolar recruitment and susceptibility to alveolar hyperinflation with high levels of positive end-expiratory pressure (PEEP).. We tested the hypothesis that, in this cohort of patients, the table-based PEEP setting criteria of the National Heart, Lung, and Blood Institute's ARDS Network (ARDSnet) low tidal volume ventilatory protocol could induce tidal alveolar hyperinflation.. In 15 patients, physiologic parameters and plasma inflammatory mediators were measured during two ventilatory strategies, applied randomly: the ARDSnet and the stress index strategy. The latter used the same ARDSnet ventilatory pattern except for the PEEP level, which was adjusted based on the stress index, a monitoring tool intended to quantify tidal alveolar hyperinflation and/or recruiting/derecruiting that occurs during constant-flow ventilation, on a breath-by-breath basis.. In all patients, the stress index revealed alveolar hyperinflation during application of the ARDSnet strategy, and consequently, PEEP was significantly decreased (P < 0.01) to normalize the stress index value. Static lung elastance (P = 0.01), plasma concentrations of interleukin-6 (P < 0.01), interleukin-8 (P = 0.031), and soluble tumor necrosis factor receptor I (P = 0.013) were significantly lower during the stress index as compared with the ARDSnet strategy-guided ventilation.. Alveolar hyperinflation in patients with focal ARDS ventilated with the ARDSnet protocol is attenuated by a physiologic approach to PEEP setting based on the stress index measurement.

Topics: Adult; Aged; Aged, 80 and over; Cardiac Output; Cohort Studies; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Positive-Pressure Respiration; Pulmonary Alveoli; Pulmonary Gas Exchange; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome; Respiratory Mechanics; Tidal Volume; Vascular Resistance

OBJECTIVES AND SUMMARY BACKGROUND: Low tidal volume ventilation (LTV) has improved survival with acute respiratory distress syndrome (ARDS) by reducing lung stretch associated with volutrauma and barotrauma. Additional strategies to reduce lung stretch include arteriovenous carbon dioxide removal (AVCO2R), and high frequency percussive ventilation (HFPV). We performed a prospective, randomized study comparing these techniques in our clinically relevant LD100 sheep model of ARDS to compare survival, pathology, and inflammation between the 3 ventilator methods.. Adult sheep (n = 61) received smoke inhalation (48 breaths) and a 40% third-degree burn. After ARDS developed (Pao2/FiO2 <200), animals were randomized. In experiment 1, animals were killed at 48 hours after randomization. Hemodynamics, pulmonary function, injury scores, myeloperoxidase (MPO) in lung tissues and neutrophils, IL-8 in lung tissues, and apoptosis were evaluated. In experiment 2, the end point was survival to 72 hours after onset of ARDS or end-of-life criteria with extension of the same studies performed in experiment 1.. There were no differences in hemodynamics, but minute ventilation was lower in the AVCO2R group and Paco2 for the HFPV and AVCO2R animals remained lower than LTV. Airway obstruction and injury scores were not different among the 3 ventilation strategies. In experiment 1, lung tissue MPO and IL-8 were not different among the ventilation strategies. However, in experiment 2, lung tissue MPO was significantly lower for AVCO2R-treated animals (AVCO2R < HFPV < LTV). TUNEL staining showed little DNA breakage in neutrophils from experiment 1, but significantly increased breakage in all 3 ventilator strategies in experiment 2. In contrast, AVCO2R tissue neutrophils showed significant apoptosis at 72 hours post-ARDS criteria as measured by nuclear condensation (P < 0.001). Survival 72 hours post-ARDS criteria was highest for AVCO2R (71%) compared with HFPV (55%) and LTV (33%) (AVCO2R vs. LTV, P = 0.05).. Significantly more animals survived AVCO2R than LTV. In experiment 2, Lung MPO was significantly lower for AVCO2R, compared with LTV (P < 0.05). This finding taken together with the TUNEL and neutrophil apoptosis results, suggested that disposition of neutrophils 72 hours post-ARDS criteria was different among the ventilatory strategies with neutrophils from AVCO2R-treated animals removed chiefly through apoptosis, but in the cases of HFPV and LTV, dying by necrosis in lung tissue.

Topics: Analysis of Variance; Animals; Apoptosis; Burns, Inhalation; Carbon Dioxide; Disease Models, Animal; In Situ Nick-End Labeling; Interleukin-8; Prospective Studies; Pulmonary Gas Exchange; Random Allocation; Respiration, Artificial; Respiratory Distress Syndrome; Sheep, Domestic; Smoke Inhalation Injury; Survival Rate; Tidal Volume

Overdistention of the lung tissue during mechanical ventilation may initiate ventilator-induced lung injury (VILI). Release of cytokines, including IL-8, may be responsible for VILI, although the mechanisms remain unclear. This study aimed to determine whether stretch-induced IL-8 production is dependent on degradation of IkappaB (IkappaB) and the resulting Rel A translocation into the nucleus.. A549 cells were exposed to cyclic stretch of varying amplitude, frequency and duration before the mRNA and protein level of IL-8 were measured. To observe the role of Rel A and IkappaB of nuclear factor kappaB, A549 cells were exposed to cyclic stretch for 5 min to 1 h. Real-time PCR and ELISA respectively were performed to detect mRNA and IL-8 protein. Rel A and IkappaBalpha were assessed by Western blot. Further confirmation was sought using a nuclear factor kappaB inhibitor (PDTC) before mechanical stretch.. A549 cells exposed to cyclic stretch produced IL-8 in a time- and strain-dependent manner, but there was no observed effect related to stretch frequency. Activation of Rel A and IkappaBalpha was detected 10 min after the initiation of stretch, peaked at 15 min and returned to baseline within 1 h. IL-8 production was partially inhibited by the presence of PDTC.. Cyclic mechanical stretch can activate Rel A translocation and IkappaBalpha degradation, thus inducing the secretion of IL-8 in alveolar epithelial type II cells. Pharmacological inhibition of Rel A and IkappaBalpha inhibits IL-8 mRNA and protein levels, suggesting novel approaches to prevent VILI.

Topics: Antioxidants; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; I-kappa B Proteins; Interleukin-8; NF-kappa B; Proline; Pulmonary Alveoli; Respiratory Distress Syndrome; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stress, Mechanical; Thiocarbamates

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

Acute endotoxemia is characterized by an enhanced inflammatory response. Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to decrease TNF-alpha levels and to down-regulate neutrophil activation, likely because of increases in intracellular cyclic AMP. Its effects on lipopolysaccharide (LPS) induced lung injury, more specifically on tissue neutrophil infiltration and degranulation, adhesion molecule expression, and transcriptional factor activation, have not been fully investigated. We postulated that PTX treatment in acute endotoxemia downregulates the inflammatory response and may decrease lung injury.. Male Sprague-Dawley rats were randomized into three groups: Sham (saline i.v.), LPS (5 mg/kg i.v.), and PTX + LPS (25 mg/kg and 5 mg/kg i.v., respectively; concomitant injection). After 4 hours, bronchoalveolar lavage fluid (BAL), plasma, and lungs were sampled. BAL IL-8 (ELISA), BAL MMP-2, plasma MMP-9, and BAL MMP-9 (Zymography) were measured. Lung histology (H&E), in addition to lung MPO, ICAM-1, and NF-kappaB expression evaluated by immunohistochemistry were analyzed. Lung NF-kappaB DNA binding was evaluated by electrophoretic mobility shift assay.. PTX treatment decreased BAL IL-8 levels, BAL MMP-2, and plasma MMP-9 activity. Lung neutrophil infiltration (MPO), ICAM-1 expression and NF-kappaB activation were decreased by PTX. In addition, PTX treatment caused a marked attenuation of LPS-induced lung injury.. Phosphodiesterase inhibition by PTX attenuates LPS-induced end-organ injury. In addition, proinflammatory cytokine production is also downregulated, likely because of the marked attenuation of NF-kappaB DNA binding and activation.

Topics: Animals; Disease Models, Animal; Endotoxemia; Escherichia coli Infections; Intercellular Adhesion Molecule-1; Interleukin-8; Lipopolysaccharides; Lung; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; NF-kappa B; Pentoxifylline; Peroxidase; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome

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

Acute lung injury (ALI) and its extreme manifestation the acute respiratory distress syndrome (ARDS) complicate a wide variety of serious medical and surgical conditions. Thioredoxin is a small ubiquitous thiol protein with redox/inflammation modulatory properties relevant to the pathogenesis of ALI. We therefore investigated whether thioredoxin is raised extracellulary in patients with ALI and whether the extent of any increase is dependent upon the nature of the precipitating insult.. Bronchoalveolar lavage (BAL) fluid and plasma samples were collected from patients with ALI (n=30) and healthy controls (n=18, plasma; n=14, BAL fluid). Lung tissue was harvested from a separate group of patients and controls (n=10). Thioredoxin was measured by ELISA in fluids and by immunohistochemistry in tissue. Interleukin (IL)-8 levels were determined by ELISA. Disease severity was assessed as APACHE II and SOFA scores.. BAL fluid levels of thioredoxin were higher in patients with ALI than in controls (median 61.6 ng/ml (IQR 34.9-132.9) v 16.0 ng/ml (IQR 8.9-25.1), p<0.0001); plasma levels were also significantly higher. When compared with controls, sections of wax embedded lung tissue from patients with ALI showed greater positive staining for thioredoxin in alveolar macrophages and type II epithelial cells. BAL fluid levels of thioredoxin correlated with IL-8 levels in BAL fluid but not with severity of illness scores or mortality. BAL fluid levels of thioredoxin, IL-8, and neutrophils were significantly greater in patients with ALI of pulmonary origin.. Extracellular thioredoxin levels are raised in patients with ALI, particularly of pulmonary origin, and have a significant positive association with IL-8. Extracellular thioredoxin levels could provide a useful indication of inflammation in ALI.

Topics: Acute Disease; Adult; Autopsy; Biopsy; Bronchitis; Bronchoalveolar Lavage Fluid; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunohistochemistry; Interleukin-8; Male; Middle Aged; Respiratory Distress Syndrome; Thioredoxins

Proinflammatory cytokines play an important role in ventilator-induced lung injury (VILI). High-mobility group box-1 (HMGB1) is a macrophage-derived proinflammatory cytokine that can cause lung injury.. This study tested the hypothesis that HMGB1 is released in intact lungs ventilated with large Vt. A second objective was to identify the source of HMGB1. A third objective was to examine the effects of blocking HMGB1 on the subsequent development of VILI.. Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained from rabbits mechanically ventilated for 4 h with a small (8 ml/kg) versus a large (30 ml/kg) Vt. BALF was also obtained from rabbits with intratracheal instillation of anti-HMGB1 antibody before the initiation of large Vt ventilation.. The concentrations of HMGB1 in BALF were fivefold higher in the large than in the small Vt group. Immunohistochemistry and immunofluorescence studies revealed expression of HMGB1 in the cytoplasm of macrophages and neutrophils in lungs ventilated with large Vt. Blocking HMGB1 improved oxygenation, limited microvascular permeability and neutrophil influx into the alveolar lumen, and decreased concentrations of tumor necrosis factor-alpha in BALF.. These observations suggest that HMGB1 could be one of the deteriorating factors in the development of VILI.

Topics: Bronchoalveolar Lavage Fluid; Cell Membrane Permeability; HMGB1 Protein; Humans; Immunohistochemistry; Interleukin-8; Lung; Macrophages; Neutrophils; Respiration, Artificial; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Cardiopulmonary bypass may cause lung injury that does not respond to traditional therapies. Total liquid ventilation has been developed as an alternative ventilatory strategy for severe lung injury. The aim of this study is to investigate the effect of total liquid ventilation on lung injury in piglets after cardiopulmonary bypass.. After exposure to 60 minutes of cardiac arrest and weaning from cardiopulmonary bypass, 12 piglets (4.2 +/- 0.3 kg) were randomly treated with conventional gas ventilation (control group) or total liquid ventilation (study group) for 240 minutes. Samples for blood gas analysis were collected before, and at 30-minute intervals after, cardiopulmonary bypass. The degree of lung injury was quantified by histologic examination. The inflammatory cells and the levels of interleukin-6, interleukin-8, and myeloperoxidase in bronchoalveolar lavage were analyzed.. Neutrophil and macrophage count in bronchoalveolar lavage were significantly decreased in the study group (52.4 +/- 6.82 vs 0.46 +/- 0.11 10(4)/mL; 58.33 +/- 0.88 vs 4.37 +/- 0.90 10(5)/mL; p < 0.001, respectively). The inflammation score and the total lung injury score were also reduced in the study group (4.39 +/- 1.14 vs 2.61 +/- 1.09; 11.06 +/- 1.66 vs 6.94 +/- 1.43; p < 0.05, respectively). The concentrations of interleukin-6 and myeloperoxidase in bronchoalveolar lavage were significantly reduced in the study group (81.32 +/- 15.23 vs 53.55 +/- 15.48 pg/mL, 75.00 +/- 9.19 vs 50.00 +/- 7.37 u/mL; p < 0.05, respectively), whereas the interleukin-8 levels were similar between both groups (551.63 +/- 119.34 vs 563.68 +/- 137.14 pg/mL, p > 0.05).. Total liquid ventilation with FC-77 (3M, St. Paul, MN) reduces biochemical and histologic lung injury in piglets after cardiopulmonary bypass.

Topics: Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Cardiopulmonary Bypass; Cell Count; Fluorocarbons; Inflammation; Interleukin-6; Interleukin-8; Liquid Ventilation; Macrophages, Alveolar; Neutrophils; Peroxidase; Postoperative Complications; Pulmonary Gas Exchange; Random Allocation; Respiratory Distress Syndrome; Swine; Swine, Miniature

To explore the acting mechanism of viscera purging method (VP) in purging Fu-organs and benefiting Fei from integral, cellular and molecular levels.. Forty SD rats were equally divided into four groups randomly: the normal group, the model group, the unhitch group and the VP group. Except those in the normal group were untreated, rats were established to intestinal obstruction model by incomplete ligation of the rectum in vitro. The ligation was relieved 48 h after operation in the unhitch group and the VP group, and the animals were fed continuously on routine. Meanwhile, Dachengqi Decoction (DD) 2 ml was given twice a day to the VP group for 2 days. Finally, the serum interleukin 8 (IL-8) and mRNA expression of tumor necrosis factor-alpha (TNF-alpha) in the lung tissue were detected by radioimmunoassay and RT-PCR respectively. Besides, the number of pulmonary alveolar macrophages (PAM) in the bronchial alveolus lavage fluid (BALF) was counted and their death rate calculated.. Compared with the normal control, the serum IL-8 content in lung tissue in the model rats were remarkably higher (P < 0.01); however, the VP group showed the lowest level of IL-8 content and the highest was shown in the model group. Number of PAM in BALF was higher and its death rate was lower in the VP group than that in the unhitch groups (both P< 0.05). The expression of TNF-alpha mRNA was sinificantly higher as compared with that in the normal group, and lowered after administration of DD.. Viscera purging method could protect the injured lung tissue to some extent.

Topics: Animals; Drugs, Chinese Herbal; Female; Interleukin-8; Intestinal Obstruction; Lung; Male; Medicine, Chinese Traditional; Phytotherapy; Plant Extracts; Random Allocation; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; RNA, Messenger; Tumor Necrosis Factor-alpha

Topics: Biomarkers; Critical Care; Cytokines; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Lung; Lung Injury; Prognosis; Respiration, Artificial; Respiratory Distress Syndrome; Tidal Volume

To evaluate the differential effects of physical properties of combinational perfluorochemical liquids (PFC) during partial liquid ventilation (PLV) on inflammatory indexes in the injured lung.. : Interventional laboratory study.. Academic medical research laboratory.. Seventeen saline lavage-injured juvenile rabbits.. Rabbits were anesthetized, ventilated, saline lavage-injured, and randomized into groups: group 1 (conventional mechanical ventilation alone-no PFC), group 2 (PLV: lowest viscosity, highest vapor pressure), group 3 (PLV: mid-viscosity, mid-vapor pressure), group 4 (PLV: highest viscosity, lowest vapor pressure).. Arterial blood chemistry and pulmonary mechanics were monitored throughout the protocol. Following 4 hrs, lung tissue was harvested for interleukin-8, myeloperoxidase, and histologic analyses. Oxygenation (Pao2), ventilation (ventilation efficiency index), and respiratory compliance were not significantly different between groups before or following injury. Pao2 increased significantly following treatment in groups 3 and 4. Oxygenation index was significantly lower and respiratory compliance and ventilation efficiency index were significantly higher for group 4 following 4 hrs than all other groups. Total lung tissue interleukin-8 was significantly lower in groups 3 and 4 than groups 1 and 2, and lung myeloperoxidase was significantly lower in all PLV-treated groups than CMV alone. Histologic examination showed increased recruitment of the dependent lung in groups 3 and 4, with significantly greater lung expansion index, than groups 1 and 2.. PLV, with a single dose of higher viscosity and lower vapor pressure PFC, resulted in significantly improved gas exchange and lung mechanics with significant reduction in lung inflammation compared with conventional mechanical ventilation alone and PLV with lower viscosity and higher vapor pressure liquid. Since PFC evaporative loss and redistribution are minimized by lower VP and higher viscosity, these data suggest that greater mechanoprotection and cytoprotection of the lung are conferred during PLV with PFC liquids that remain distributed throughout the entire lung for a longer duration.

Topics: Animals; Fluorocarbons; Interleukin-8; Liquid Ventilation; Peroxidase; Rabbits; Respiratory Distress Syndrome; Structure-Activity Relationship

Acute lung injury is a common complication in patients with extensive burns in which the burned area exceeds 30% of the total body surface area (TBSA). This study was undertaken to evaluate the effect of Ligustrazine on burn-induced lung injury as well as the release of interleukin-8 (IL-8) in rats to characterize the role of Ligustrazine and IL-8 in lung injury after burn trauma. Sprague-dawley rats were divided into three groups: (1) sham group, rats who underwent sham burn; (2) control group, rats given third-degree burns over 30% TBSA and lactated Ringer solution for resuscitation; and (3) Ligustrazine group, rats given burn injury and lactated Ringer's solution with Ligustrazine inside for resuscitation. Pulmonary injury was assessed at 24 h by pulmonary capillary permeability determined with fluorescein isothiocyanate-labeled albumin and lung histologic analysis, and lung myeloperoxidase (MPO) activity as well as lung wet/dry weight ratio. The IL-8 levels were measured in serum by enzyme-linked immunosorbent assay. These studies showed that burn trauma results in increased pulmonary leakage permeability and lung wet/dry ratio, elevated serum IL-8 levels and MPO activity, and worsened histologic condition. Ligustrazine inhibited these changes, prevented burn-mediated lung injury, and the production of IL-8. This will likely provide further evidence for ligustrazine as a therapeutic strategy in burn-induced lung injury.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Burns; Capillary Permeability; Interleukin-8; Lung; Male; Models, Animal; Peroxidase; Pyrazines; Random Allocation; Rats; Rats, Wistar; Respiratory Distress Syndrome

Studies in vitro reveal that endothelin-1 (ET-1) activates the alpha isoform of protein kinase C (PKC-alpha) in cultures of endothelial cells, thereby deranging cellular integrity. Sepsis and endotoxemia are associated with increased plasma concentrations of ET-1 that induce acute lung injury (ALI). We recently reported that non-selective ET-1 receptor blockade attenuates ALI in sheep by reducing the endotoxin-induced increase in extravascular lung water index (EVLWI). The aim of this study was to find out whether this attenuation is associated with reduced translocation of PKC-alpha from the cytosolic to the membrane fraction of lung tissue homogenate.. Seventeen awake, instrumented sheep were randomly assigned to a sham-operated group (n = 3), a lipopolysaccharide (LPS) group (n = 7) receiving an intravenous infusion of Escherichia coli 15 ng/kg per min for 24 hours, and a tezosentan group (n = 7) subjected to LPS and, from 4 hours, an intravenous injection of tezosentan 3 mg/kg followed by infusion at 1 mg/kg per hour for the reminder of the experiment. Pulmonary micro-occlusion pressure (Pmo), EVLWI, plasma concentrations of ET-1, tumor necrosis factor-a (TNF-a), and interleukin-8 (IL-8) were determined every 4 hours. Western blotting was used to assess PKC-alpha.. In non-treated sheep a positive correlation was found between the plasma concentration of ET-1 and Pmo in the late phase of endotoxemia (12 to 24 hours). A positive correlation was also noticed between Pmo and EVLWI in the LPS and the LPS plus tezosentan groups, although the latter was significantly reduced in comparison with LPS alone. In both endotoxemic groups, plasma concentrations of ET-1, TNF-alpha, and IL-8 increased. In the LPS group, the cytosolic fraction of PKC-alpha decreased by 75% whereas the membrane fraction increased by 40% in comparison with the sham-operated animals. Tezosentan completely prevented the changes in PKC-alpha in both the cytosolic and the membrane fractions, concomitantly causing a further increase in the plasma concentrations of ET-1, TNF-alpha, and IL-8.. In endotoxemic sheep, ET-1 receptor blockade alleviates lung injury as assessed by a decrease in EVLWI paralleled by a reduction in Pmo and the prevention of activation of PKC-alpha.

Topics: Animals; Endothelin A Receptor Antagonists; Endothelin-1; Endotoxemia; Enzyme Activation; Escherichia coli Infections; Interleukin-8; Protein Kinase C; Pyridines; Respiratory Distress Syndrome; Sheep; Tetrazoles; Tumor Necrosis Factor-alpha; Vasodilator Agents

Neutrophil migration into the lung is a critical, but poorly understood step in the pathogenesis of post-traumatic, acute respiratory distress syndrome (ARDS). We investigated changes in interleukin-8 (IL-8) mediated neutrophil migration and associated changes in receptor expression, of the IL-8 receptors CXCR1, the integrins CD11b/CD18 and platelet endothelial cell adhesion molecule-1 (PECAM-1) in patients sustaining major trauma.. Eleven patients with major trauma, injury severity score (ISS), median 22 (range 18-41), were followed prospectively. Eleven normal volunteers were used as controls. Blood samples were obtained within 4+/-2 h of injury, at 24 h, day 3 and day 5. Neutrophils migration was assessed by an in vitro IL-8 assay and neutrophil surface receptor expression by FACS analysis.. IL-8 mediated neutrophil migration was significantly increased on admission following major trauma and remained elevated for 3 days (p<0.05). This was associated with up-regulation of CXCR1 (p<0.01) and down-regulation of PECAM-1 (p<0.05). CD11b and CD18 although initially unchanged, became down-regulated on day 3 (p<0.05).. These data show that major trauma primes circulating neutrophils for increased migration in response to IL-8. This response is sustained for 72 h and is associated with changes in neutrophil surface receptor expression.

Topics: Adult; Aged; Cell Movement; Female; Humans; Interleukin-8; Male; Middle Aged; Neutrophil Infiltration; Neutrophils; Receptors, Cell Surface; Respiratory Distress Syndrome; Wounds, Nonpenetrating

To explore the possible mechanism of heme oxygenase-1 (HO-1) induction for its protective effects on acute respiratory distress syndrome (ARDS).. The production of HO-1 was induced by hemoglobin (Hb) injection into oleic acid (OA) induced ARDS rats. Western blot and RT-PCR techniques were used to observe the induction of HO-1 in vivo. Both the levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) in serum and bronchoalveolar lavage fluid (BALF) were measured by enzyme linked immunosorbent assay (ELISA). Combined with blood gas analysis and other indexes, the effect of HO-1 on ARDS could be clearly manifested.. The expression of HO-1 mRNA was increased significantly 16 h after Hb injection, and the protein expression of HO-1 was also obviously increased 24 h later (P < 0.01). The levels of TNF-alpha and IL-8 in both serum and BALF were significantly lower in Hb + OA group than in OA group (P < 0.01). Arterial blood PaO(2), oxygen saturation, and oxygenated index in Hb + OA group [(56.28 +/- 6.71) mm Hg, (79.53 +/- 5.82)%, and (258.81 +/- 29.37) mm Hg respectively] were higher than in OA group [(35.08 +/- 4.59) mm Hg, (55.80 +/- 12.76)%, and (167.86 +/- 21.94) mm Hg]. Lung wet and dry weight, and pathological changes were also improved.. The production of HO-1 was successfully induced by hemoglobin in vivo. Protective effects of HO-1 on ARDS might be related to the decreasing in inflammatory factors, such as TNF-alpha and IL-8.

Topics: Animals; Blotting, Western; Bronchoalveolar Lavage Fluid; Enzyme-Linked Immunosorbent Assay; Heme Oxygenase-1; Hemoglobins; Interleukin-8; Male; Oleic Acid; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reduc

Topics: Animals; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Inflammation; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Leukocyte Elastase; Lung; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesenteric Artery, Superior; Models, Chemical; Oxygen; Peptide Hydrolases; Pulmonary Edema; Respiratory Distress Syndrome; Sepsis; Swine; Tetracycline; Tetracyclines; Time Factors

To determine granulocyte colony-stimulating factor (G-CSF), epithelial neutrophil-activating peptide (ENA)-78, and interleukin (IL)-8 in BAL fluid (BALF), epithelial lining fluid (ELF), and serum for establishing the concentration gradient of G-CSF, ENA-78, and IL-8 between the blood and the alveolar space in ARDS and acute lung injury (ALI); and to evaluate the relationship of G-CSF, IL-8, and ENA-78 to pulmonary neutrophilia and severity of lung injury.. Prospective study.. An adult trauma/surgical ICU.. Nineteen patients with ARDS and 10 patients with ALI.. None.. BAL and blood sampling simultaneously within 12 h and 24 h after onset of ARDS/ALI; G-CSF was detected in BALF in 18 of 19 patients with ARDS, in 7 of 10 patients with ALI, and in all serum samples. G-CSF in BALF and serum was significantly higher in ARDS than in ALI. ENA-78 was detected in BALF in 14 of 19 patients with ARDS, in 8 of 10 patients with ALI, and in serum of all patients. Levels in BALF and serum were not different between ARDS and ALI. IL-8 was detected in all patients; concentrations in BALF in ARDS were significantly higher than in ALI. Concentrations of G-CSF, ENA-78, and IL-8 in ELF were significantly higher than in serum. G-CSF in BALF and serum and IL-8 in BALF correlated positively with pulmonary neutrophilia. G-CSF in serum and IL-8 in BALF correlated negatively with PaO(2)/fraction of inspired oxygen (FIO(2)) ratio. However, ENA-78 did not show a correlation with neutrophil count or with PaO(2)/FIO(2) ratio.. G-CSF may be pathophysiologically important for accumulation and activation of neutrophils in ARDS. Local G-CSF production is the likely driving force for neutrophils rather than elevation of circulating levels. In comparison to ENA-78, IL-8 seems to be the predominant neutrophil chemoattractant in the early phase of ARDS.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Chemokine CXCL5; Chemokines, CXC; Extravascular Lung Water; Female; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-8; Male; Middle Aged; Prospective Studies; Pulmonary Alveoli; Respiratory Distress Syndrome

A significant fraction of IL-8 in lung fluids from patients with the acute lung injury (ALI) is associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 complexes), and lung fluid concentrations of these complexes correlate with development and outcome of ALI. In this study, we examined whether anti-IL-8:IL-8 complexes exhibit proinflammatory activity in vitro. These complexes were purified from pulmonary edema fluid samples obtained from patients with ALI. First, we found that IL-8 bound to the autoantibody retained its ability to trigger chemotaxis of neutrophils, whereas control antibody did not have significant chemotactic activity. Next, we examined the ability of anti-IL-8:IL-8 complexes to induce neutrophil activation, i.e., neutrophil respiratory burst and degranulation. Anti-IL-8:IL-8 complexes triggered superoxide and myeloperoxidase release from human neutrophils, and in contrast, the control antibody had no effect. We also demonstrated that IgG receptor, FcgammaRIIa, is the receptor involved in cellular activation mediated by these complexes. Blockade of FcgammaRIIa completely reverses activity of the complexes with the exception of chemotaxis. Both FcgammaRIIa and IL-8 receptors mediate chemotactic activity of anti-IL-8:IL-8 complexes, with FcgammaRIIa being, however, a predominant receptor. Furthermore, activity of the complexes is partially dependent on the activation of the mitogen-activated protein kinases, i.e., ERK and p38, important components of the FcgammaRIIa signaling cascade. Anti-IL-8:IL-8 complexes may therefore be involved in the pathogenesis of lung inflammation in clinical acute lung injury.

Topics: Antigen-Antibody Complex; Antigens, CD; Autoantibodies; Blotting, Western; Chemotaxis; Extravascular Lung Water; Humans; In Vitro Techniques; Interleukin-8; Neutrophil Activation; Neutrophils; Pulmonary Alveoli; Pulmonary Edema; Receptors, IgG; Respiratory Distress Syndrome; Signal Transduction

Acute lung injury induced by lung overstretch is associated with neutrophil influx, but the pathogenic role of neutrophils in overstretch-induced lung injury remains unclear.. To assess the contribution of neutrophils, we compared the effects of noninjurious large tidal volume (Vt) ventilation on lungs in normal and neutrophil-depleted animals.. Research animal laboratory.. Twenty-six male Japanese white rabbits.. Animals were mechanically ventilated for 4 hrs with one of the three following protocols: large Vt (20 mL/kg), small Vt (8 mL/kg), and large Vt (20 mL/kg) with neutrophil depletion achieved by a single dose of vinblastine injection (0.75 mg/kg) intravenously 4 days before the experiment.. Large Vt ventilation produced alveolar neutrophil influx compared with low Vt (p =.002) without evidence of edema or increased epithelial permeability. The neutrophil influx was accompanied by increases in interleukin-8 in bronchoalveolar lavage fluid (p =.04). Immunohistochemistry of large Vt lungs showed increased interleukin-8 staining in bronchial epithelial cells, alveolar epithelium, alveolar macrophages, and smooth muscles of pulmonary vessels. Neutrophil depletion attenuated the interleukin-8 increase in the lung. Large Vt did not increase plasma interleukin-8 or tumor necrosis factor-alpha in plasma and bronchoalveolar lavage fluid. No expression of p-selectin or intercellular adhesion molecule-1 was observed.. Cyclic overstretching of normal rabbit lungs with noninjurious large Vt produced neutrophil influx and interleukin-8 increase in bronchoalveolar lavage fluid. Production of pulmonary interleukin-8 by lung overstretch might require the interaction between resident lung cells and migrated neutrophils. This study suggests that large Vt ventilation potentiates the predisposed, subclinical lung injury, such as nosocomial pneumonia or aspiration of gastric contents.

Topics: Animals; Interleukin-8; Neutrophils; Pulmonary Stretch Receptors; Rabbits; Respiration, Artificial; Respiratory Distress Syndrome

To investigate the role of apoptosis of pulmonary cells in aspiration induced lung injury in patients with severe brain injury with or without aspiration-induced lung injury.. The Glasgow scale (GCS) of 11 dead patients with severe closed brain injury was 3-8. There 11 cases were divided into aspiration-induced lung injury (AILI) and non-aspiration-induced lung injury (NAILI) groups. The plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) were measured, and the ratio of apoptosis in lung tissue cells was also determined.. The plasma levels of TNF-alpha and IL-8 in NAILI and AILI groups were (2.17+/-0.41)nug/L vs. (3.14+/-0.28)nug/L and (0.42+/-0.05)nug/L vs. (0.91+/-0.08) nug/L (P<0.05) respectively. Lung tissue cell apoptosis ratio was significantly higher in AILI group than NAILI group (P<0.01).. TNF-alpha and IL-8 may induce apoptosis in lung tissues through different signaling pathway. During the early phase of aspiration-induced lung injury complicating severe closed brain injury, apoptosis in cells of lung tissue may play a role in the pathogenes.

Topics: Adult; Apoptosis; Autopsy; Brain Injuries; Female; Humans; In Situ Nick-End Labeling; Interleukin-8; Lung; Male; Pneumonia, Aspiration; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Ventilator-induced lung injury (VILI) is characterized by release of inflammatory cytokines, but the mechanisms are not well understood. We hypothesized that stretch-induced cytokine production is dependent on oxidant release and is regulated by intracellular glutathione (GSH) inhibition of nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) binding.. Type 2-like alveolar epithelial cells (A549) were exposed to cyclic stretch at 15% strain for 4 h at 20 cycles/min with or without N-acetylcysteine (NAC) or glutathione monoethylester (GSH-e) to increase intracellular GSH, or buthionine sulfoximine (BSO), to deplete intracellular GSH.. Cyclic stretch initially caused a decline in intracellular GSH and a rise in the levels of isoprostane, a marker of oxidant injury. This was followed by a significant increase in intracellular GSH and a decrease in isoprostane. Stretch-induced IL-8 and IL-6 production were significantly inhibited when intracellular GSH was further increased by NAC or GSH-e (P < 0.0001). Stretch-induced IL-8 and IL-6 production were augmented when intracellular GSH was depleted by BSO (P < 0.0001). NAC blocked stretch-induced NF-kappa B and AP-1 binding and inhibited IL-8 mRNA expression.. We conclude that oxidant release may play a role in lung cell stretch-induced cytokine release, and antioxidants, which increase intracellular GSH, may protect lung cells against stretch-induced injury.

Topics: Acetylcysteine; Antioxidants; Blotting, Northern; Buthionine Sulfoximine; Cells, Cultured; Cytokines; Epithelial Cells; Glutathione; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Isoprostanes; Lipid Peroxidation; NF-kappa B; Oxidative Stress; Pulmonary Alveoli; Respiratory Distress Syndrome; Stress, Mechanical; Transcription Factor AP-1

To establish of acute respiratory distress syndrome (ARDS) model in canine after inhalation of perfluoroisobutylene (PFIB), and to observe the progressing of lung injury, and to study the mechanisms of injury.. A device of inhalation of PFIB for canine was made. The concentration of PFIB was 0.30 - 0.32 mg/L. Serum IL-6 and IL-8 were dynamically measured. Clinical manifestations, pathology of organs in canine were observed.. (1) During inhalation, the concentration of PFIB remained stable; (2) After inhalation, blood arterial oxygen partial pressure fell gradually, and eventually met the criteria for diagnosing ARDS; (3) The level of IL-8 in serum rises significantly after inhalation (P < 0.05), whereas that of IL-6 was not obviously altered (P > 0.05); (4) Within 6 hours after inhalation, no abnormality in canine was observed, but afterwards symptoms gradually appeared, and typical breath of ARDS, such as high frequency and lower level could be seen in later phase; (5) Pathological examination showed severe congestion, edema and atelectasis in most part of both lungs, and signs of anoxia in other organs.. (1) The device designed is capable of ensuring control of inhalation of PFIB; (2) Exposure to PFIB for 30 mins, canines all met the criteria for diagnosing ARDS 22 hours after inhalation, therefore the modeling is successful; (3) PFIB specifically damages the lung by causing excessive inflammation.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Dogs; Female; Fluorocarbons; Interleukin-6; Interleukin-8; Lung; Male; Random Allocation; Respiratory Distress Syndrome

alpha-Defensins, antimicrobial peptides localized in neutrophils, participate in tissue damage through their cytotoxic effects in neutrophil-mediated pulmonary diseases. Neutrophils play an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). We measured alpha-defensins levels in plasma and bronchoalveolar lavage fluid (BALF) of ARDS patients to assess the kinetics of alpha-defensins in ARDS. Plasma alpha-defensins levels were higher in ARDS patients than in control subjects, and BALF levels were also higher in ARDS patients than in control subjects. In ARDS, BALF alpha-defensins levels correlated with those of interleukin (IL)-8, and plasma alpha-defensins levels also correlated with Lung Injury Score. Peripheral neutrophil alpha-defensins contents were higher in ARDS than the control. IL-8 dose-dependently stimulated alpha-defensins release from cultured neutrophils and these levels were higher in ARDS than the control. Reverse-phase high performance liquid chromatography showed high plasma levels of pro-defensins, precursors of alpha-defensins from the bone marrow in ARDS, although alpha-defensins in peripheral and BALF neutrophils were mature type. In conclusion, high plasma alpha-defensins in ARDS patients result from the release of pro-defensins from bone marrow, rather than mature alpha-defensins from neutrophils that accumulate in the alveolar space. The alpha-defensins contents of peripheral neutrophils in ARDS are higher and easier to release than control.

Topics: Aged; alpha-Defensins; Bone Marrow; Bronchoalveolar Lavage Fluid; Chromatography, High Pressure Liquid; Enzyme-Linked Immunosorbent Assay; Female; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-8; Kinetics; Lung Injury; Male; Middle Aged; Neutrophils; Respiratory Distress Syndrome

Topics: Adolescent; Adult; Female; Humans; Interleukin-8; Male; Middle Aged; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha; Wounds and Injuries; Young Adult

Blockade of tissue factor before lethal sepsis prevents acute lung injury and renal failure in baboons, indicating that activation of coagulation by tissue factor is an early event in the pathogenesis of acute lung injury and organ dysfunction. We hypothesized that blockade of tissue factor would also attenuate these injuries in established sepsis by prevention of further fibrin deposition and inflammation. Twelve male baboons received heat-killed Escherichia coli intravenously followed 12 hours later by live E. coli infusion. Six animals were treated 2 hours after the live bacteria with site-inactivated Factor VIIa, a competitive tissue factor inhibitor, and six animals were vehicle-treated sepsis control subjects. Animals were ventilated and monitored for 48 hours. Physiologic and hematologic parameters were measured every 6 hours, and pathologic evaluation was performed after 48 hours. Animals treated with site inactivated Factor VIIa had less severe lung injury, with preserved gas exchange, better lung compliance and histology scores, and decreased lung wet/dry weight. In treated animals, urine output was higher, metabolic acidosis was attenuated, and renal tubular architecture was protected. Coagulopathy was attenuated, and plasma interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-1 levels were significantly lower in the treated animals. These results show that blockade of coagulation attenuates acute lung and renal injury in established Gram-negative sepsis accompanied by antiinflammatory effects of therapy.

Topics: Acute Kidney Injury; Animals; Antigens, CD; Cytokines; Disease Models, Animal; Drug Monitoring; Escherichia coli Infections; Factor VIIa; Hemodynamics; Inflammation; Interleukin-6; Interleukin-8; Lung Compliance; Male; Papio; Pulmonary Gas Exchange; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome; Sepsis; Severity of Illness Index; Thromboplastin

Neutrophil infiltration of the lung is characteristic of early posttraumatic acute respiratory distress syndrome (ARDS). This study examines the ability of neutrophils isolated (over the first 24 hrs) from the peripheral blood of patients admitted after major trauma to migrate in response to interleukin-8. Interleukin-8 is elevated in the lung within 2 hrs of major trauma in patients who later develop ARDS, and thus it plays a central role in the recruitment of neutrophils to the lung and their subsequent activation. We hypothesized that enhanced interleukin-8-mediated neutrophil migratory activity in the early postinjury phase, before the development of ARDS, may be a crucial factor in the etiology of ARDS.. Prospective observational study.. University Hospital Wales, the Royal Gwent Hospital, and East Glamorgan General Hospital. Laboratory work was conducted at the Institute of Nephrology.. Adult blunt trauma victims with Injury Severity Score > or = 18.. Neutrophils were isolated from citrated blood from 17 adult blunt major trauma patients at admission (0 hrs) and 8 and 24 hrs later. Identical samples were obtained from normal laboratory volunteers (n = 9). The neutrophil count in each specimen was measured, and the number of neutrophils migrating across porous tissue culture inserts in response to defined concentrations of interleukin-8 (0, 10, 30, and 100 ng/mL) was quantitated by peroxidase assay. Neutrophil counts in the whole blood specimens obtained from those later developing ARDS were elevated significantly at admission and declined rapidly throughout the next 24 hrs. Significantly greater numbers of trauma patients' neutrophils migrated to concentrations of interleukin-8 (30 and 100 ng/mL) at each time point when compared with normal volunteers (Mann-Whitney U test, p <.05). Neutrophils isolated from major trauma patients exhibited an enhanced migratory response to high concentrations of interleukin-8 throughout the first 24 hrs of admission, in contrast to the normal physiologic attenuation of migration seen in neutrophils isolated from normal laboratory volunteers.. These data indicate that major blunt trauma enhances the migratory capacity of circulating neutrophils. This is manifest within 2 hrs of admission and may be attributable to alteration in interleukin-8 receptor expression, affinity, or downstream signaling. In patients who later develop ARDS, initially elevated circulating neutrophil counts decrease rapidly, over the same time course. Early enhanced neutrophil migratory activity coupled with elevated pulmonary concentrations of interleukin-8 may be central to the establishment of the neutrophil infiltration that is characteristic of ARDS.

Topics: Acute Disease; Adult; Cell Movement; Humans; Interleukin-8; Leukocyte Count; Neutrophil Infiltration; Neutrophils; Prospective Studies; Respiratory Distress Syndrome; Risk Factors; Time Factors; Trauma Severity Indices; Wales; Wounds, Nonpenetrating

To test the hypothesis that elevated concentrations of interleukin-8 associated with anti-interleukin-8 autoantibodies (anti-interleukin-8:interleukin-8 complexes) are found in patients at risk for acute respiratory distress syndrome who developed the disease.. Measurement of anti-interleukin-8:interleukin-8 complex concentrations in previously collected bronchoalveolar lavage fluids. These fluids were obtained from patients at risk for acute respiratory distress syndrome who subsequently either recovered or developed acute respiratory distress syndrome.. A unique population of patients at risk for acute respiratory distress syndrome was studied. There were 26 patients at risk for acute respiratory distress syndrome who were divided into three groups. Group I patients had high interleukin-8 concentrations and developed acute respiratory distress syndrome, group II had high interleukin-8 concentrations and did not develop acute respiratory distress syndrome, and group III had low interleukin-8 concentrations and did not develop acute respiratory distress syndrome. These patients were selected to test the hypothesis that presence of elevated concentrations of anti-interleukin-8:interleukin-8 complexes differentiates patients at risk for acute respiratory distress syndrome who developed acute respiratory distress syndrome from patients who did not.. Bronchoalveolar lavage fluid concentrations of interleukin-8 associated with the anti-interleukin-8 autoantibodies were significantly different between groups (p <.03). The amount of interleukin-8 bound to the anti-interleukin-8 autoantibody was higher in group I than in group II and group III.. Bronchoalveolar lavage fluid concentration of anti-interleukin-8:interleukin-8 complexes may serve as a marker of disease progression in patients at risk for acute respiratory distress syndrome.

Topics: Antigen-Antibody Complex; Autoantibodies; Biomarkers; Bronchoalveolar Lavage Fluid; Humans; Interleukin-8; Intestinal Perforation; Multiple Trauma; Pancreatitis; Respiratory Distress Syndrome; Risk Factors

In bronchoalveolar lavage (BAL) fluid from ventilated patients, cytotoxic oxidant activity is correlated with neutrophil activation. The aim of the present study was to investigate the hypothesis that BAL fluid induces activation of the transcription nuclear factor-kappaB (NF-kappaB) in human alveolar cells, in correlation with inflammatory mediators. We measured endotoxin, inflammatory cytokines [interleukin-1beta (IL-1beta), IL-8], nitrated proteins and the activity of myeloperoxidase (MPO) in BAL fluid from ventilated patients developing bronchopneumonia ( n =19 samples) or with acute respiratory distress syndrome (ARDS) ( n =14), and from ARDS/infection-free patients ( n =11). We also exposed alveolar cells to the BAL fluid or to human MPO, H(2)O(2) or HOCl, and tested nuclear extracts for the activation of NF-kappaB. IL-1beta, IL-8, nitrated protein, MPO and endotoxin levels were significantly higher in BAL fluid from patients with bronchopneumonia than in that from the ARDS and ARDS/infection-free groups. A correlation was observed between IL-8 and MPO values ( r =0.82). The level of NF-kappaB activity induced by the BAL fluid was correlated with levels of IL-1beta ( P <0.001), IL-8 ( P <0.005) and MPO ( P <0.002), and with the neutrophil count ( P <0.002), and was higher for BAL fluid from the bronchopneumonia group. NF-kappaB activation by MPO was also demonstrated. The activation of NF-kappaB by BAL fluid, especially that from bronchopneumonia patients, suggests that a similar phenomenon may occur in vivo, leading to potential amplification of the inflammatory reaction.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bronchoalveolar Lavage Fluid; Bronchopneumonia; Cell Line; Endotoxins; Female; Humans; Interleukin-1; Interleukin-8; Leukocyte Count; Male; Middle Aged; Neutrophils; NF-kappa B; Peroxidase; Pulmonary Alveoli; Respiratory Distress Syndrome

The systemic inflammatory response syndrome (SIRS), which may develop following cardiopulmonary bypass (CPB), can cause postoperative complications that contribute to the morbidity and mortality associated with open-heart surgery. Inflammatory mediators such as cytokines, are thought to play an important role in SIRS. Zero Balance Ultrafiltration (Z-BUF) is thought to reduce the quantity of inflammatory mediators associated with CPB and may attenuate the adverse effects of bypass. Following ethics committee approval, both an unfiltered experimental group and Z-BUF treatment group consisting of Yorkshire pigs (41 +/- 19 kg) were anesthetized, ventilated, instrumented, cannulated and placed on CPB for 60 minutes. Following CPB, an infusion of low-dose endotoxin (1 microg/kg) was administered I.V. and the animals were monitored for 3.5 hours. The Z-BUF treatment group (n = 5) received high-volume Z-BUF (122 ml/kg +/- 41) and the unfiltered experimental group (n = 5) did not. Hemodynamics, blood gases, and pulmonary functions were measured before, during, and after CPB. Following euthanasia, the middle lobe of the lung was prepared for histological analysis. Necropsy of the lung sample was weighed before and after dehydration to evaluate lung water content. During the experimental time course, plasma samples were evaluated for Interleukin-8 (IL-8) concentrations. Arterial PO2's (mmHg) in the unfiltered experimental group showed a significant reduction at 3.5 hours post CPB when compared to baseline while the Z-BUF treatment group PaO2 did not significantly change. There was a significant difference in the PaO2 between the unfiltered experimental and Z-BUF group at the final 3.5 hour time point (78 +/- 32 vs. 188 +/- 92 mmHg respectively). Pulmonary compliance (ml/cmH2O) was significantly reduced in both the unfiltered experimental and Z-BUF treatment groups with the unfiltered experimental group being the most significant. Lung wet/dry ratios were established and results found the unfiltered experimental group ratio significantly greater than that of the Z-BUF treatment group. Morphometric analysis of histologic lung sections confirmed pulmonary injury in the unfiltered experimental group and protection in the Z-BUF treatment group. This study suggests that Z-BUF provides higher arterial PO2's and lung compliances while reducing pulmonary edema and lung injury in a porcine model of PPS.

Topics: Animals; Cardiopulmonary Bypass; Electrolytes; Extravascular Lung Water; Hemodynamics; Interleukin-8; Models, Animal; Respiratory Distress Syndrome; Respiratory Function Tests; Swine; Ultrafiltration; United States

The formation of alpha(2)-macroglobulin (alpha(2)-M)/interleukin-8 (IL-8) complexes may influence the biological activity of IL-8 and the quantitative assessment of IL-8 activity. Therefore, in this study, concentrations of free IL-8 and IL-8 complexes with alpha(2)-M were measured in pulmonary edema fluid samples from patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and compared with control patients with hydrostatic pulmonary edema. Patients with ALI/ARDS had significantly higher concentrations of alpha(2)-M (P < 0.01) as well as alpha(2)-M/IL-8 complexes (P < 0.05). Because a substantial amount of IL-8 is complexed to alpha(2)-M, standard assays of free IL-8 may significantly underestimate the concentration of biologically active IL-8 in the distal air spaces of patients with ALI/ARDS. Furthermore, IL-8 bound to alpha(2)-M retained its biological activity, and this fraction of IL-8 was protected from proteolytic degradation. Thus complex formation may modulate the acute inflammatory process in the lung.

Topics: Acute Disease; alpha-Macroglobulins; Extravascular Lung Water; Humans; In Vitro Techniques; Interleukin-8; Macrophages, Alveolar; Neutrophils; Pancreatic Elastase; Pulmonary Edema; Respiratory Distress Syndrome

Systemic inflammation triggered by insults like sepsis and acute pancreatitis may play a role in development of indirect acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Because little is known about the course of systemic inflammation on the days preceding diagnosis of ARDS, we prospectively monitored immune inflammatory status in 52 patients at risk and we assessed the presence of ALI and ARDS on day 7 after admission to the intensive care unit. On admission, serum interleukin (IL) 8, IL-6, and soluble IL-2 receptor concentrations were significantly higher in patients with subsequent ALI (n = 18) than in patients without ALI (n = 30). During a 4-day follow-up, IL-8 and IL-6 levels of ALI patients remained high and those of non-ALI patients decreased. None of the markers discriminated ARDS patients (n = 9) from non-ARDS ALI patients (n = 9). Among 11 patients with acute pancreatitis, ALI patients had significantly higher IL-8, IL-6, and phagocyte CD11b expression levels than did non-ALI patients, whereas among 14 patients with massive transfusion, respective findings in ALI and non-ALI patients were comparable. Results give credence to the view that systemic inflammation plays a role in development of ALI triggered by pancreatitis, but not in that by massive transfusion. This finding, if confirmed in studies with sufficient statistical power, suggests that the patients with massive transfusion do not necessarily benefit from novel biotherapies aimed at altering the course of systemic inflammation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Critical Care; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung Injury; Male; Middle Aged; Pancreatitis; Prospective Studies; Receptors, Interleukin-2; Respiratory Distress Syndrome; Transfusion Reaction

Topics: Dyspnea; Gene Expression; Granulocyte Colony-Stimulating Factor; HLA-B Antigens; HLA-B51 Antigen; HLA-B52 Antigen; Humans; Interleukin-8; Respiratory Distress Syndrome; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Respiratory disturbance caused by ARDS has been reported during administration of granulocyte-colony stimulating factor. The clinical features of such respiratory distress were investigated in this study.. Retrospective case review.. A 1,100-bed university teaching hospital.. Five patients who had dyspnea caused by ARDS develop after chemotherapy or bone marrow transplantation (BMT) at our hospital.. None.. Levels of cytokines, human leukocyte antigen (HLA) typing, and the clinical course were analyzed to clarify common features. All five patients possessed HLA-B51 or HLA-B52, and all had fever and an enhanced inflammatory response at the time of the WBC nadir. The tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 levels increased when respiratory distress syndrome occurred.. If patients with HLA-B51 or HLA-B52 have infection develop at the time of WBC nadir after chemotherapy or BMT, ARDS may occur in association with elevation of TNF-alpha and IL-8 during WBC recovery.

Topics: Adult; Antineoplastic Agents; Bone Marrow Transplantation; Female; Granulocyte Colony-Stimulating Factor; HLA-B Antigens; HLA-B51 Antigen; HLA-B52 Antigen; Humans; Interleukin-8; Leukocyte Count; Male; Middle Aged; Recombinant Proteins; Respiratory Distress Syndrome; Retrospective Studies; Tumor Necrosis Factor-alpha

Increased levels of interleukin 8 (IL-8) are found in bronchoalveolar lavage (BAL) fluids from patients with the acute respiratory distress syndrome (ARDS). However, IL-8 is not an efficient predictor of the course of ARDS. Our prior studies demonstrated that IL-8 present in lung fluids from patients with ARDS is associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 complexes). These data led us to hypothesize that the complexes might better predict the development of acute lung injury. Accordingly, we measured concentrations of free and complexed IL-8 in BAL fluids from 19 patients at risk and 45 with established ARDS on Days 1, 3, 7, 14, and 21 after the onset of ARDS. The concentrations of anti-IL-8:IL-8 complexes in patients with ARDS on Day 1 were significantly higher than in patients at risk (p < 0.05). There was a significant association between anti-IL-8:IL-8 complex concentrations and the onset of ARDS (p = 0.03). Similarly, anti-IL-8:IL-8 complex concentrations were significantly higher in patients on Day 1 of ARDS who later died (p < 0.05), and the association between high anti-IL-8: IL-8 complex concentrations and the probability of dying was significant (p = 0.03). The presence of anti-IL-8:IL-8 complexes in BAL fluids of patients with ARDS is an important prognostic indicator for the development and outcome of ARDS.

Topics: Adolescent; Adult; Aged; Antigen-Antibody Complex; Autoantibodies; Bronchoalveolar Lavage Fluid; Female; Hospital Mortality; Humans; Interleukin-8; Lung; Male; Middle Aged; Prognosis; Respiratory Distress Syndrome; Survival Rate

Serum concentrations of catecholamines are high in patients with sepsis or acute respiratory distress syndrome (ARDS). Because chemokines mediate the recruitment of neutrophils into inflammatory sites, we addressed the question of whether dopamine (DA) is able to influence chemokine production in endothelial cells under basal and proinflammatory conditions. To this end, lung microvascular endothelial cells (LMVEC) were stimulated or not for 24 h with the bacterial toxins lipopolysaccharide (LPS) (1 microg/ml) or lipoteichonic acid (LTA) (10 microg/ml) in the presence or absence of various concentrations of DA (1-100 microg/ml). Whereas under basal and stimulatory conditions, the addition of DA to endothelial cells dose-dependently increased IL-8 production, the production of ENA-78 and Gro-alpha was significantly inhibited (P < 0.01). This effect could still be demonstrated when the cells were stimulated for up to 3 h with LPS before DA administration. Similar findings were detected for the mRNA expression of these chemokines. The influence of DA on chemokine production was not receptor mediated and could be prevented by antioxidants or radical scavengers. Moreover, addition of H(2)O(2) to endothelial cells gave results similar to those observed with DA stimulation, suggesting a pivotal role for reactive oxygen species in DA-mediated modulation of chemokine production in endothelial cells. Our data thus demonstrate that DA administration results in the induction of oxidative stress, with profound effects on endothelial chemokine production.

Topics: Cardiotonic Agents; Cell Polarity; Chemokine CXCL1; Chemokine CXCL5; Chemokines; Chemokines, CXC; Chemotactic Factors; Dopamine; Endothelium, Vascular; Gene Expression; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Lipopolysaccharides; Lung; Microcirculation; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Respiratory Distress Syndrome; Teichoic Acids

The acute respiratory distress syndrome (ARDS) represents a form of severe acute inflammatory lung disease. We have previously demonstrated significantly raised interleukin-8 (IL-8) levels in the lungs of at-risk patients that progress to ARDS, and identified the alveolar macrophage as an important source of this chemokine. We wished to extend this study in a well-defined group of patients with major trauma, and to investigate potential mechanisms for rapid intrapulmonary IL-8 generation.. Patients with major trauma underwent bronchoalveolar lavage (BAL) and IL-8 levels were measured in BAL fluid by ELISA. Human macrophages were derived from peripheral blood monocytes from healthy volunteers. Rabbit alveolar macrophages were obtained from ex-vivo lavage of healthy rabbit lungs. Macrophages were culture under normoxic or hypoxic (PO2 26 mmHg) conditions. IL-8 and other proinflammatory mediator expression was measured by ELISA, northern blotting or multi-probe RNase protection assay.. In patients with major trauma, IL-8 levels were significantly higher in patients that progressed to ARDS compared to those that did not (n = 56, P = 0.0001). High IL-8 levels negatively correlated with PaO2/FiO2 (r = -0.56, P < 0.001). In human monocyte derived macrophages hypoxia rapidly upregulated IL-8 protein (within 2 hours) and mRNA expression (within 30 mins). Acute hypoxia also increased rabbit alveolar macrophage IL-8 expression. Hypoxia increased DNA binding activity of AP-1 and C/EBP but not NF-kappaB. Hypoxia induced HIF-1 expression, but cobaltous ions and desferrioxamine did not mimic hypoxic IL-8 induction. Hypoxia downregulated a range of other proinflammatory mediators, including MCP-1 and TNF-alpha. Both the pattern of cytokine expression and transcription factor activation by hypoxia was different to that seen with endotoxin.. Rapidly raised intrapulmonary IL-8 levels are associated with ARDS progression in patients with major trauma. Acute hypoxia, a clinically relevant stimulus, rapidly and selectively upregulates IL-8 in macrophages associated with a novel pattern of transcription factor activation. Acute hypoxia may represent one of potentially several proinflammatory stimuli responsible for rapid intrapulmonary IL-8 generation in patients at-risk of ARDS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Blotting, Northern; Bronchoalveolar Lavage Fluid; Cells, Cultured; DNA Primers; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoblotting; Interleukin-8; Macrophages; Male; Middle Aged; NF-kappa B; Nuclear Proteins; Rabbits; Respiratory Distress Syndrome; Reverse Transcriptase Polymerase Chain Reaction; RNA; Transcription Factor AP-1; Transcription Factors

Glucocorticoids are the most potent and widely used anti-inflammatory agents, but they are not particularly effective against early phase of acute respiratory distress syndrome. We investigated whether methylprednisolone, a synthetic glucocorticoid, could inhibit increase of phospholipase A(2) activity in the lung and lead to protection against a model of acute respiratory distress syndrome in rabbits. Infusion of oleic acid (0.1 ml/kg/h, i.v. for 2 h) provoked pulmonary hemorrhage and edema, protein leakage and massive neutrophil infiltration, resulted in severe hypoxemia and impaired lung compliance, accompanying the increase of phospholipase A(2) activity and interleukin-8, and degradation of surfactant in the bronchoalveolar lavage fluid. Infusion of methylprednisolone (60 mg/kg/h, i.v. for 30 min before the oleic acid and then 0.5 mg/kg/h, i.v. for 6 h) did not improve the above described lung injury induced by oleic acid, nor did it suppress phospholipase A(2) activity and degradation of surfactant in bronchoalveolar lavage fluid, while it strongly reduced interleukin-8 levels in both plasma and bronchoalveolar lavage fluid. We conclude that methylprednisolone did not attenuate oleic acid-induced acute lung injury and this can be explained partly by its failure to reduce the increase of phospholipase A(2) activity and the surfactant degradation in the lung, which might also account for its clinical ineffectiveness against early acute respiratory distress syndrome.

Topics: Animals; Bronchoalveolar Lavage Fluid; Capillary Permeability; Eicosanoids; Interleukin-8; Lung; Male; Methylprednisolone; Oleic Acid; Phospholipases A; Pulmonary Surfactants; Rabbits; Respiratory Distress Syndrome

To compare the evolution of plasma concentrations of leukotriene (LT) B4, LTC4, LTD4, and interleukin (IL)-8 in patients with acute respiratory distress syndrome (ARDS) and in patients at risk of ARDS and to assess the value of these mediators in predicting mortality rate from ARDS.. A case-control study comparing ARDS patients and patients at risk of ARDS as well as survivors and nonsurvivors with ARDS.. Hospital intensive care unit, laboratory, and department of hematology.. Twenty-one patients with ARDS and 14 patients at risk of ARDS.. Arterial blood samples were collected on days 0, 1, and 5 after admission to the intensive care unit.. LTs were extracted, separated by high-pressure liquid chromatography and quantified by enzyme immunoassay. IL-8 was analyzed by ELISA. Plasma concentrations of LTB4 and LTC4 plus LTD4 were significantly higher in ARDS patients than in patients at risk of ARDS during the first 24 hrs. Concentrations of IL-8 were also higher in ARDS patients than in patients at risk throughout the study, although the differences between the two groups were only significant on day 5. Only the plasma concentration of LTB4 on day 1 was a marker of ARDS (72.2% sensitivity, 84.6% specificity). A logistic regression analysis showed that LTB4 and IL-8, on day 1, were markers of mortality rate in patients with ARDS (70.0% sensitivity, 87.5% specificity).. LTs are elevated during the early phases of ARDS, whereas IL-8 increases throughout the study. The evaluation of LTB4 and IL-8 may be useful prognostic indices in patients with early phase ARDS after admission to the intensive care unit.

Topics: Biomarkers; Case-Control Studies; Chromatography, High Pressure Liquid; Critical Care; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Leukotrienes; Logistic Models; Male; Middle Aged; Odds Ratio; Predictive Value of Tests; Prognosis; Respiratory Distress Syndrome; Risk Factors

Reexpansion of a collapsed lung induces increased microvascular permeability leading to reexpansion pulmonary edema (REPE). This study was designed to prove the hypothesis that local overproduction of interleukin-8 (IL-8) induces inflammatory cell accumulation which leads to the induction of REPE. Initially, we examined the detailed characteristics of a rabbit model of REPE in association with IL-8 production and its mRNA expression. The lung tissue to plasma ratio of radiolabeled albumin (T/P ratio), the lung wet to dry ratio, and bronchoalveolar lavage (BAL) neutrophil counts were significantly increased in the reexpanded lung. IL-8 concentrations and mRNA expression were significantly increased in the reexpanded lung homogenate. Immunohistochemically, alveolar macrophages (AMs) and epithelial cells in the reexpanded lung and AMs in the collapsed lung were positive for IL-8. Second, we examined the effect of pretreatment with a specific monoclonal anti-IL-8 antibody (Ab) or control IgG on the development of REPE. The T/P ratio and BAL neutrophil counts were conspicuously decreased by pretreatment with anti-IL-8 Ab, but not with control IgG. On a histopathological study, lung injury and leukocyte infiltration were attenuated by the pretreatment with anti-IL-8 Ab. In conclusion, IL-8 production is enhanced in the reexpanded lung, and contributes to the development of REPE. The pretreatment with anti-IL-8 antibody may be useful as a novel protective therapy for this disease.

Topics: Animals; Antibodies, Monoclonal; Bronchoalveolar Lavage Fluid; Interleukin-8; Lung; Male; Neutrophils; Pulmonary Atelectasis; Pulmonary Edema; Rabbits; Respiratory Distress Syndrome

Activated neutrophils play a major role in the pathogenesis of acute respiratory distress syndrome (ARDS), and persistence of pulmonary neutrophilia is related to poor survival. Interleukin (IL)-8 is implicated in recruiting neutrophils to the lungs but it has been postulated that granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), which can promote the survival of neutrophils by delaying apoptosis, may prolong the inflammatory response. The aim of this study was to investigate the levels of GM-CSF and G-CSF in the lungs of patients with ARDS and determine their relationship relative to IL-8 with levels of neutrophils and clinical outcome. The lungs of 31 patients with ARDS were sampled by means of bronchoalveolar lavage (BAL) and assays of the three cytokines were conducted via enzyme-linked immunosorbent assay. GM-CSF, G-CSF and IL-8 were all increased in the patients compared to healthy controls but concentrations of GM-CSF were much lower than those of G-CSF and IL-8 (GM-CSF

Topics: Adolescent; Adult; Aged; Bronchoalveolar Lavage Fluid; Disease Progression; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Male; Middle Aged; Neutrophil Infiltration; Respiratory Distress Syndrome; Severity of Illness Index

Bleomycin (BLM) has proven effective for the treatment of cancers, but the most serious dose-limiting side-effect is the development of pulmonary toxicity. Although the precise mechanism in the pathogenesis of BLM-induced lung injury has not been determined, oxygen radicals and neutrophils are indicated to play a key role in it. Interleukin-8 (IL-8) is thought to be an important mediator of the pathogenesis of acute lung injury.. The IL-8 production from bronchial epithelial cell line, BEAS-2B cells was measured by enzyme-linked immunosorbent assays for IL-8.. The concentrations of IL-8 were reportedly elevated in BLM-induced lung injury, suggesting the involvement of IL-8 in the pathogenesis of BLM-induced lung injury. In the present study, we showed that BLM induced the expression of IL-8 protein and mRNA in BEAS-2B cells, and N-acetyl-L-cysteine (NAC) inhibited IL-8 expression. In addition, the structurally unrelated antioxidant, pyrrolidine dithiocarbamate (PDTC) also effectively inhibited BLM-induced IL-8 production.. These results suggest that anti-oxidant-sensitive mechanism might be involved in the inhibition of IL-8 secretion by BLM-stimulated bronchial epithelial cells and that NAC might be useful for the treatment of BLM-induced lung injury.

Topics: Acetylcysteine; Antimetabolites, Antineoplastic; Antioxidants; Bleomycin; Bronchi; Cell Line; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Free Radical Scavengers; Humans; Interleukin-8; Pyrrolidines; Respiratory Distress Syndrome; Respiratory Mucosa; Thiocarbamates

To determine the concentrations of proinflammatory mediators, collagenases, and procollagen type III peptides in undiluted pulmonary edema fluids and in plasma obtained in patients with early acute respiratory distress syndrome (ARDS) and in control patients with hydrostatic lung edema; and to assess the relationship between these inflammatory and profibrotic markers.. A prospective, clinical study with measurements of inflammatory markers in pulmonary edema fluids and in paired plasma samples.. A medical intensive care unit.. Patients intubated with lung permeability (n = 23) and hydrostatic (n = 8) pulmonary edema were prospectively enrolled in the study. The severity of the disease at the time of intubation was assessed, using the Simplified Acute Physiological Score (SAPS) II and the Lung Injury Score (LIS).. Plasma and undiluted edema fluids were obtained at the time of intubation with pulmonary edema requiring mechanical ventilation; and in some patients, a second edema fluid sample was collected a few hours later.. Proinflammatory activity, dependent on the presence of bioactive proinflammatory cytokines, interleukin (IL)-8, and neutrophil matrix metalloproteinase (MMP)-9 were significantly increased in ARDS fluids compared with plasma or control fluids from patients with congestive heart failure. In contrast, MMP-2, originating from lung cells other than phagocytes, was slightly increased in ARDS edema fluids compared with plasma, but similar to levels found in hydrostatic edema fluids. Proinflammatory activity was undetectable in plasma from ARDS patients. Levels of procollagen peptide III, a marker of collagen synthesis, were increased in permeability edema fluids compared with hydrostatic edema fluids or plasma, confirming that alveolar collagen synthesis begins very early and in parallel with acute inflammation in ARDS. Control patients with hydrostatic edema had similar SAPS II and LIS scores compared with ARDS patients.. These results strongly support the conclusion that during the early phase of ARDS, the lung is the site of an intense inflammatory process with sequential activation of cytokines, chemokines, and secretion of proteases, as well as concomitant collagen synthesis. The inflammation is mostly limited to the lung, with low levels of inflammatory mediators in the systemic circulation. Unlike clinical scoring systems (SAPS II and LIS), inflammatory markers differentiate patients with permeability and hydrostatic pulmonary edema.

Topics: Adult; Aged; Biomarkers; Body Fluids; Collagenases; Fibrosis; Heart Failure; Humans; Inflammation Mediators; Interleukin-8; Matrix Metalloproteinase 9; Middle Aged; Peptide Fragments; Procollagen; Prospective Studies; Pulmonary Alveoli; Pulmonary Edema; Random Allocation; Respiratory Distress Syndrome; Time Factors

To establish and monitor a rabbit model of graded severity of acute pancreatitis to test the hypothesis that interleukin-8 (IL-8) and the adhesion molecule complex CD11b/CD18 are involved in the development of systemic complications in severe acute pancreatitis.. Acute pancreatitis induction in rabbits by duct ligation with or without infusion of 5.0% or 0.5% chenodeoxycholic acid or 0.9% saline. Control animals underwent laparotomy. The animals were monitored biochemically, histologically and immunohistochemically.. Increased serum levels of IL-8, tumour necrosis factor alpha (TNF-alpha), amylase and lipase were found in the chenodeoxycholic acid groups when compared with the saline, duct-ligated or control groups. Leukopenia, hypocalcaemia, and hyperglycaemia were marked in the 5.0% chenodeoxycholic acid group as compared to the saline, duct-ligated and control groups. Histologically, the 5.0% chenodeoxycholic acid group manifested a significant degree of pancreatic necrosis and neutrophil infiltration. The lungs of these animals showed acute lung injury and a significant up-regulation of CD11b/CD18. IL-8 was produced in pancreatic acinar and ductal cells. A significantly large output of ascitic fluid was seen in the 5.0% chenodeoxycholic acid group.. The rabbit models of acute pancreatitis are reliable in that enzymatic and histological evidence of acute pancreatitis with or without systemic complications developed. IL-8 is produced locally in pancreatic acinar and ductal cells and significantly increased in peripheral blood during severe but not mild pancreatitis. The expression of the adhesion molecule complex CD11b/CB18 is significantly increased in lung tissue during severe acute pancreatitis with acute lung injury. IL-8 and CD11b/CB18 are involved in the pathogenesis of severe acute pancreatitis but not of mild oedematous pancreatitis.

Topics: Acute Disease; Amylases; Animals; Ascites; CD11 Antigens; CD18 Antigens; Chenodeoxycholic Acid; Cholagogues and Choleretics; Disease Models, Animal; Hyperglycemia; Hypocalcemia; Interleukin-8; Laparotomy; Leukopenia; Ligation; Lipase; Necrosis; Neutrophils; Pancreas; Pancreatic Ducts; Pancreatitis; Rabbits; Respiratory Distress Syndrome; Sodium Chloride; Tumor Necrosis Factor-alpha; Up-Regulation

Topics: Autoantibodies; Bronchoalveolar Lavage Fluid; Humans; Interleukin-8; Respiratory Distress Syndrome

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; Enzyme Activation; Interleukin-8; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Pulmonary Alveoli; Respiration, Artificial; Respiratory Distress Syndrome

Topics: Cells, Cultured; Humans; In Vitro Techniques; Interleukin-8; Macrophages, Alveolar; Monocytes; Respiration, Artificial; Respiratory Distress Syndrome; Stress, Mechanical

Proinflammatory cytokines like TNF-alpha and IL-8 have been thought to play a pivotal role in the propagation of severe acute pancreatitis (AP) and the development of its systemic complications, particularly acute lung injury.. To investigate the effects of pretreatment with hydrocortisone on the production of cytokines and the occurrence of acute lung injury in rabbits with AP.. AP was induced in 17 rabbits by infusion of 5% chenodeoxycholic acid into the pancreatic duct, followed by ductal ligation. The rabbits were allocated to pretreatment with subcutaneous and intravenous hydrocortisone (25 mg/kg, respectively; n = 7) or 0.9% saline (n = 10) 30 min before induction of AP. Rabbits were observed for 12 h. Serum amylase, lipase, TNF-alpha, IL-8, glucose, calcium and leukocyte count were measured every 3 h. At the end of the experimental period, ascitic fluid was collected and tissue specimens from the pancreas, lungs and kidney were obtained.. Hydrocortisone pretreatment improved survival from 40 to 100%. Serum TNF-alpha and IL-8 were lower in the hydrocortisone group than in the control group at 6 h (p = 0.006 and p < 0.001, respectively). Hydrocortisone abolished leukopenia (p < 0. 001), hyperamylasemia (p = 0.05), the occurrence of acute lung injury and reduced the volume of ascites.. Our findings suggest a role for TNF-alpha and IL-8 in mediating the progress of AP from a local disease into a systemic illness. Hydrocortisone should be tested experimentally after the induction of AP and clinically as a prophylactic measure to avoid severe AP induced by endoscopic retrograde cholangiopancreaticography.

Topics: Acute Disease; Amylases; Animals; Blood Glucose; Calcium; Female; Hydrocortisone; Interleukin-8; Leukocyte Count; Lipase; Male; Pancreatitis; Premedication; Rabbits; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Trauma and adult respiratory distress syndrome (ARDS) are associated with increased CXC chemokine (CXC) activity. CXCs such as interleukin (IL)-8 activate polymorphonuclear neutrophils (PMNs) in the lung by means of calcium signals ([Ca2+]i). We studied CXC effects on PMN [Ca2+]i in ARDS and trauma.. Isolated PMNs were loaded with Fura-2 dye. Normal PMNs were incubated in ARDS plasma or volunteer plasma, with or without blocking antibodies to IL-8, growth-related oncogene alpha (GRO-alpha), or both (n = 6 pairs), and then stimulated with 1 to 10 nmol/L IL-8. PMNs from trauma patients or volunteers (n = 10 pairs) were stimulated with GRO-alpha, or with sequential GRO-alpha/IL-8. [Ca2+]i was measured with spectrofluorometry.. [Ca2+]i responses to IL-8 were higher after being incubated in ARDS plasma than in volunteer plasma (251 +/- 33 vs 218 +/- 33 nmol/L, P = .03). Blockade of GRO-alpha or IL-8 reversed ARDS plasma effects. After GRO-alpha/IL-8, PMNs from trauma patients demonstrated more Ca2+ store release than did PMNs from volunteers (235 +/- 13 vs 170 +/- 10 nmol/L, P < .01). Conversely, PMNs from trauma patients lost receptor-operated Ca2+ influex to GRO-alpha.. In traumatic ARDS, plasma CXCs prime PMNs for higher [Ca2+]i flux, making PMN activation more likely. IL-8 and GRO-alpha interact to modulate these PMN [Ca2+]i responses.

Topics: Adult; Calcium Signaling; Chemokine CXCL1; Chemokines, CXC; Chemotactic Factors; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Male; Neutrophils; Respiratory Distress Syndrome; Wounds and Injuries

Group IIA secretory phospholipase A(2) (sPLA(2)) has been implicated in a variety of inflammatory diseases including acute lung injury (ALI); however, the role of sPLA(2) in this disorder remains unclear. The aim of the present investigation was to examine the role of this enzyme in a model of ALI induced by oleic acid (OA) in rabbits by testing human group IIA phospholipase A(2) (PLA(2)) inhibitor, S-5920/LY315920Na. Experimental groups consisted of a saline control group (n = 8), an OA control group (n = 10) infused intravenously with OA (0.1 ml/kg/h for 2 h), and three groups given OA + S-5920/LY315920Na (three different doses, n = 8, respectively). Infusion of OA provoked pulmonary hemorrhage and edema formation, protein leakage, and massive neutrophil infiltration, resulting in severe hypoxemia and impaired lung compliance. PLA(2) activity was detected in the bronchoalveolar lavage fluid (BALF), but not plasma, which correlated well with severity of lung injury in this model. Pretreatment with S-5920/LY315920Na diminished the OA-induced PLA(2) activity in the BALF and dose-dependently attenuated the previously described lung injury induced by OA, accompanied by protection against lung surfactant degradation and production of thromboxane A(2) (TXA(2)) and leukotriene B(4) (LTB(4)). S-5920/LY315920Na also inhibited the OA-induced production of interleukin-8 (IL-8), both in plasma and BALF. Thus, sPLA(2) appears to play a key role in OA-induced lung injury, suggesting that the group IIA PLA(2) inhibitor may be a promising agent for patients with acute respiratory distress syndrome (ARDS).

Topics: Acetates; Animals; Bronchoalveolar Lavage Fluid; Capillary Permeability; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extravascular Lung Water; Group II Phospholipases A2; Indoles; Interleukin-8; Keto Acids; Leukotriene B4; Lung; Lung Compliance; Male; Oleic Acid; Oxygen; Phospholipases A; Phospholipids; Pulmonary Edema; Rabbits; Respiratory Distress Syndrome; Thromboxane A2

Although prior studies have shown that smoke inhalation causes lung endothelial injury and formation of pulmonary edema, there is no information about the effect of smoke inhalation on the function of the alveolar epithelial barrier. Therefore, the primary objective of this study was to determine the effect of smoke-induced lung injury on the alveolar epithelial barrier in a rabbit experimental model. The second objective was to investigate whether pretreatment with a monoclonal anti-interleukin (IL)-8 antibody prevented alveolar epithelial barrier injury after smoke inhalation. Anesthetized rabbits were tracheotomized and were insufflated with cooled smoke generated from burning cotton cloth (75 breaths). In some experiments, anti-IL-8 antibody or an irrelevant antibody (2 mg/¿g) was given intravenously 5 min before insufflation of cotton smoke. Smoke inhalation caused a significant increase in the alveolar epithelial permeability to protein and a 40% reduction in the fluid transport capacity of the alveolar epithelium. Pretreatment with anti-IL-8 antibody, but not with an irrelevant-isotype antibody, significantly reduced the smoke-mediated increase in bidirectional transport of protein across the alveolar epithelium, and restored alveolar liquid clearance to a normal level. The results of the study show that smoke inhalation causes injury to both the alveolar epithelial barrier and the lung endothelium, and that IL-8 is an important mediator of this injury.

Topics: Animals; Antibodies; Biological Transport, Active; Capillary Permeability; Endothelium; Hemodynamics; Interleukin-8; Lung; Permeability; Proteins; Pulmonary Alveoli; Rabbits; Respiratory Distress Syndrome; Respiratory Mucosa; Smoke Inhalation Injury

Although prior experimental work has demonstrated that anti-interleukin-8 (anti-IL-8) therapy reduces lung endothelial injury after acid instillation, there is no information regarding the effect of anti-IL-8 on the function of the alveolar epithelial barrier after acid-induced lung injury. Therefore, the primary objective of this study was to determine the effect of acid-induced lung injury on the function of the alveolar epithelium, and secondly to determine whether pretreatment with anti-IL-8 attenuates acid-induced injury to the lung epithelial barrier. Hydrochloric acid (pH = 1.5 in 1/3 normal saline) was instilled into the lungs of anesthetized, ventilated rabbits. Anti-IL-8 monoclonal antibody (2 mg/kg) or saline was given intravenously 5 min before acid instillation. Acid instillation into the distal airspaces caused an increase in the alveolar epithelial permeability to protein and an approximately 50% reduction in net alveolar fluid clearance. Because a decrease in net alveolar fluid clearance could be due to lung endothelial injury and increased fluid flux from the blood into the airspaces, additional experiments were carried out in which pulmonary blood flow was eliminated. In the absence of pulmonary blood flow, acid instillation led to a 50% decrease in net alveolar fluid clearance. Pretreatment with anti-IL-8 antibody significantly reduced the acid-mediated increase in bi-directional transport of protein across the alveolar epithelium and restored alveolar fluid clearance to normal. The results indicate that acid instillation causes injury to the alveolar epithelial barrier that can be distinguished from the injury to the lung endothelium. Furthermore, pretreatment with anti-IL-8 therapy prevents acid-induced alveolar epithelial injury, a finding of potential clinical importance.

Topics: Animals; Antibodies, Monoclonal; Biological Transport, Active; Capillary Permeability; Extravascular Lung Water; Hemodynamics; Hydrochloric Acid; Interleukin-8; Lung; Male; Permeability; Pneumonia, Aspiration; Proteins; Pulmonary Alveoli; Rabbits; Recombinant Proteins; Respiratory Distress Syndrome; Respiratory Mucosa

In the process of developing a model of Escherichia coli endotoxin-induced acute lung injury and shock in specific pathogen-free pigs, the effects of pretreatment with metyrapone (a cortisol-synthesis inhibitor) were examined. Metyrapone was administered 1.5 h before start of endotoxin infusion at t = 0 h (MET-ETOX group, n = 6). At the end of the experiments (t = 4 h) a bronchoalveolar lavage (BAL) was performed. Control animals received only endotoxin (CON-ETOX group, n = 6) or metyrapone (MET-CON group, n = 4). The following results are presented as means +/- SEM. It was found that metyrapone successfully blocked endogenous cortisol synthesis (plasma cortisol levels were 41.0 +/- 5.9 nM in MET-ETOX vs. 339.0 +/- 37.7 nM in CON-ETOX at t = 4 h, P <0.01). At t = 4 h the MET-ETOX animals had substantially increased systemic hypotension compared to the CON-ETOX group (mean arterial pressure 26.7 +/- 4.3 vs. 77.7 +/- 12.2 mmHg, P <0.01), decreased dynamic lung compliance (10.9 +/- 0.7 vs. 13.7 +/- 0.6 ml/cmH2O, P <0.01), increased percentage of BAL neutrophils (28.4 +/- 6.5 vs. 6.6 +/-1.8, P <0.01), pulmonary edema (BAL total protein 0.82 +/- 0.21 vs. 0.42 +/- 0.09 mg/mL, P <0.05), elevated levels of interleukin-8 (1924 +/- 275 vs. 324 +/- 131 pg/mL, P <0.01) and acidosis (pH 7.11 +/- 0.03 vs. 7.23 +/- 0.06, P <0.05). The MET-ETOX group also showed an increased pulmonary hypertension between 2 and 3 h after start of endotoxin infusion and a trend toward significantly increased levels of plasma interleukin-8 (P = 0.052). Arterial pCO2, pO2/FiO2, plasma endothelin-1, plasma TNFalpha, and blood leukocytes were not markedly influenced by the plasma cortisol levels. Nitric oxide production did not seem to be altered by endotoxin infusion in this model, in contrast to other animal studies; this discrepancy could be thought to be due to endotoxin-dosage differences or species differences. It is concluded that if endogenous cortisol production is blocked by metyrapone, the reactions occurring as a result of the endotoxin-induced acute lung injury and shock are greatly enhanced and that therefore pretreatment with metyrapone might be an important addition to this model with specific pathogen-free pigs.

Topics: Acid-Base Imbalance; Animals; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endothelin-1; Endotoxins; Female; Hydrocortisone; Hypotension; Interleukin-8; Leukocytes; Male; Metyrapone; Neutrophils; Nitric Oxide; Nitrites; Peroxidase; Proteins; Pulmonary Edema; Respiratory Distress Syndrome; Respiratory Function Tests; Shock; Specific Pathogen-Free Organisms; Swine; Tumor Necrosis Factor-alpha

Adult respiratory distress syndrome-like respiratory disorders are a serious, but uncommon, complication of bone marrow transplantation.. We measured various cytokines in 2 patients with respiratory disorders and 11 patients without respiratory problems after allogeneic bone marrow transplantation.. The patients with respiratory disorders had elevated levels of interferon-gamma and interleukin-2 in the aplastic phase, and elevation of tumor necrosis factor-alpha, intercellular adhesion molecule-1, and interleukin-8 at the time of leukocyte recovery. Both patients with respiratory disorders developed fever during the aplastic phase, whereas none of the patients without fever had respiratory disorders. Among patients who had fever during the aplastic phase but no respiratory disorders, there was no elevation of cytokines from the aplastic phase to the recovery phase.. Respiratory disorders may occur after bone marrow transplantation when an inflammatory response during the aplastic phase stimulates cytokines that cause vascular endothelial damage and increases the levels of chemokines and adhesive molecules along with elevation of the leukocyte count.

Topics: Adult; Bone Marrow Transplantation; Female; Granulocyte Colony-Stimulating Factor; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Respiratory Distress Syndrome; Transplantation, Homologous; Tumor Necrosis Factor-alpha

Neutrophil (PMN) priming and subsequent responses to the IL-8 presented on pulmonary endothelial surfaces may be crucial determinants of the development of adult respiratory distress syndrome after injury. Elevated plasma ELR+ C-X-C chemokine (CXC) levels might contribute to PMN priming after trauma, but the role of CXCs in priming circulating PMNs is unstudied. We evaluated the interactions of IL-8 and GRO-alpha in priming human PMN calcium fluxes [Ca2+]i within circulatory environments. At physiologic concentrations, GRO-alpha primes PMN for IL-8 mediated [Ca2+]i mobilization, whereas IL-8 abolishes GRO-alpha responses. Repeated GRO-alpha exposures further enhance IL-8 responses. PMN priming for IL-8 responses in normal plasma was CXCR2 dependent. CXCR2 was more responsive than CXCR1 to low levels of IL-8, together suggesting that CXCR2 is the important CXC receptor at circulating (i.e., low) agonist concentrations. CXCR1 stimulation down-regulated CXCR2 surface expression, whereas CXCR2 stimulation upregulated CXCR1 expression. GRO-alpha/ CXCR2 signaling enhanced post-receptor IL-8 initiated PMN [Ca2+]i influx as well as efflux. Sufficient stimulation of the CXCR1 terminated this cooperative relationship by downregulating surface expression of CXCR2. This study is the first to report that at physiologic concentrations, C-X-C chemokines can act on circulating human PMNs as an integrated system where CXCR2 agonists, rather than cross-desensitizing CXCR1, act to enhance signaling of IL-8 at CXCR1 both by receptor and post-receptor mechanisms. Such CXCR2 mediated priming of CXCR1/ IL-8 interaction may enhance PMN attack on the lung after injury.

Topics: Adult; Antigens, CD; Calcium; Calcium Signaling; Chemokine CXCL1; Chemokines, CXC; Chemotactic Factors; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Neutrophils; Receptors, Chemokine; Receptors, Interleukin; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Respiratory Distress Syndrome

Viridans streptococci are a heterogeneous group of Gram-positive bacteria that are normal inhabitants of the mouth, upper gastrointestinal tract and oropharynx. These organisms are typically thought of as of low virulence, classically as the cause of infective endocarditis, although recently they have been implicated in serious infections in other settings. In particular, viridans group streptococci have been described as responsible for the alpha-streptococcal shock syndrome in neutropenic patients. The mechanism by which viridans streptococci cause bacteraemia associated with adult respiratory distress syndrome (ARDS) in these patients has not been elucidated. Using enzyme-linked immunosorbent assays, we compared the ability of cell-free bacterial supernatants derived from commensal and clinical strains of viridans streptococci to induce the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-alpha), tumour necrosis factor beta (TNF-beta) and interleukin 8 (IL-8) from human peripheral blood mononuclear cells (PBMC) in vitro. Supernatants of clinical isolates induced significantly more TNF-beta (P < 0.002) and IL-8 (P < 0.001) than did supernatants from commensal strains. The increased production of IL-8 by the clinical strains may be of importance in view of the role of IL-8 in the pathogenesis of the acute respiratory distress syndrome (ARDS), one of the principal clinical features of the alpha-streptococcal shock syndrome.

Topics: Adult; Cells, Cultured; Humans; Interleukin-8; Leukocytes, Mononuclear; Lymphotoxin-alpha; Mitogens; Respiratory Distress Syndrome; Streptococcus; Tumor Necrosis Factor-alpha

The acute respiratory distress syndrome (ARDS) is a frequent complication of severe sepsis and a major cause of death in patients with hematologic malignancy during chemotherapy-induced leukocytopenia. Inflammatory mediators are important modulators of host response to injury and have been found to be increased in the bronchoalveolar lavage (BAL) fluid of nonleukocytopenic patients with ARDS. Since inflammatory cytokines in plasma of nonleukocytopenic patients seem to be efficient predictors of the course of ARDS, we examined this hypothesis in leukocytopenic patients with septic shock-induced ARDS.. Prospective, observational study.. Intensive care unit (ICU) of a university hospital.. Nineteen patients with leukocytopenia (white blood cell count of <1/nL) following cytoreductive chemotherapy for malignant disorders and severe sepsis with shock-induced ARDS (Murray score of >2.5).. BAL and plasma sampling and ICU management.. The proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 were measured in the BAL aspirates and in plasma samples, both obtained within 18 hrs after onset of ARDS. Hemodynamic and oxygen metabolism data were measured immediately before plasma samples were taken and BAL was performed. Of the 19 patients studied, nine patients responded to ICU treatment (e.g., mechanical ventilation as indicated by PaO2/FIO2, FIO2, shunt volume, and course of pulmonary infiltrates), whereas ten patients did not respond. BAL cytokine concentrations were significantly increased in nonresponders in comparison with responding patients (TNF-alpha, p = .021; IL-6, p = .008; IL-8, p = .019). In contrast, we did not observe any differences between the groups in terms of plasma cytokine concentrations.. Determination of cytokine concentrations in BAL samples may be useful for evaluation of severity and course of ARDS in leukocytopenic patients, whereas measurement of plasma cytokines is not helpful.

Topics: Adult; Aged; Biomarkers; Bronchoalveolar Lavage Fluid; Critical Care; Cytokines; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Interleukin-6; Interleukin-8; Leukopenia; Male; Middle Aged; Prospective Studies; Respiratory Distress Syndrome; Shock, Septic; Tumor Necrosis Factor-alpha

Topics: Adult; Biomarkers; Bronchoalveolar Lavage Fluid; Cardiovascular Surgical Procedures; Female; Humans; Interleukin-8; Male; Myocardial Ischemia; Respiratory Distress Syndrome; Sensitivity and Specificity; Tumor Necrosis Factor-alpha

To evaluate the role of interleukin 8 (IL-8) in the regulation of neutrophil (PMN) apoptosis in normal plasma and plasma from patients with early, fulminant acute respiratory distress syndrome (ARDS).. Experimental study using cultured human PMNs.. University hospital, level I trauma center.. Plasma was obtained from 6 patients with early, fulminant posttraumatic ARDS (mean Injury Severity Score, 26). All samples were drawn within 24 hours after injury. Plasma was also taken from 13 healthy control subjects. These controls were also used as sources of PMNs.. Effect of early, fulminant ARDS and normal plasma on spontaneous apoptosis, CD16, and CD11-b expression in PMNs in vitro; levels of IL-8 in plasma; correlation of extracellular IL-8 concentration with rate of PMN apoptosis; and effect of IL-8 blockade on PMN apoptosis, CD16, and CD11-b expression in ARDS and normal plasma.. Plasma from patients with early, fulminant ARDS inhibited spontaneous PMN apoptosis at 24 hours (35%+/-5% vs 54%+/-5%; P=.01). Neither CD16 nor CD1l-b differed significantly between the 2 groups. The mean plasma level of IL-8 in patients with early, fulminant ARDS was 359+/-161 pg/mL vs 3.0+/-0.4 pg/mL in healthy controls (P<.05). Interleukin 8 inhibited apoptosis in plasma-free medium at low doses (1-50 pg/mL) but had no significant effect at higher doses (100-5000 pg/mL) (P<.05). Interleukin 8 blockade with monoclonal antibody suppressed apoptosis in normal plasma (28%+/-5% with monoclonal antibody vs 51%+/-5% without monoclonal antibody; P=.008) but not in plasma from patients with early, fulminant ARDS (29%+/-5% with monoclonal antibody vs 34%+/-6% without monoclonal antibody; P=.67). It had no effect on CD16 or CD11-b expression in either plasma.. Plasma from patients with early, fulminant ARDS contains soluble factors that inhibit PMN apoptosis in vitro. Low levels of IL-8 inhibit PMN apoptosis in normal plasma. Although plasma levels of IL-8 are markedly elevated in early, fulminant ARDS, IL-8 is not directly responsible for the antiapoptotic effect of plasma from patients with early, fulminant ARDS.

Topics: Apoptosis; Case-Control Studies; CD11 Antigens; Cells, Cultured; Humans; Injury Severity Score; Interleukin-8; Neutrophil Activation; Neutrophils; Receptors, IgG; Respiratory Distress Syndrome; Time Factors; Wounds and Injuries

Chemokines are a family of cytokines regulating the migration and functions of leukocytes in a cell-type specific manner. A prototype of C-X-C chemokines, interleukin-8 (IL-8), chemoattracts and activates neutrophils in vitro, and IL-8 concentrations in body fluids are markedly increased in several neutrophil-mediated acute inflammation. Moreover, we previously reported that the administration of a neutralizing antibody to IL-8 prevented neutrophil-mediated tissue injury, as well as neutrophil infiltration, in several animal disease models. These observations implicate IL-8 as a major mediator of neutrophil-mediated tissue injury. Furthermore, we recently showed that an anti-IL-8 antibody effectively prevented two models that are very relevant to clinical situations; endotoxemia-induced acute respiratory distress syndrome (ARDS)-like lung injury and cerebral reperfusion injury. These results raise the possibility that IL-8 is a novel target for therapeutic intervention in neutrophil-mediated acute inflammation.

Topics: Animals; Antibodies, Monoclonal; Brain Ischemia; Chemokines; Endotoxemia; Female; Immunization, Passive; Inflammation; Interleukin-8; Macrophages; Mice; Neutrophils; Rabbits; Reactive Oxygen Species; Reperfusion Injury; Respiratory Distress Syndrome

To study the protective effect of removing circulatory TNF by immunoadsorption on endotoxin-induced acute lung injury in rabbits.. New Zealand white rabbits injected with lethal dose of endotoxin underwent hemoperfusion with immunoadsorbent. TNF and IL-8 levels in BALF were measured, the number of leukocytes and percentage of PMN in BALF were analyzed and the ratio of wet lung to body weight and pulmonary microvascular permeability index were also studied. In addition, the survival rate was observed.. Treatment with immunoadsorption markedly attenuated the pulmonary microvascular permeability increased by endotoxin and improved the survival rate.. Immunoadsorption to remove circulating TNF is an effective way to protect rabbits against endotoxin-induced acute lung injury.

Topics: Animals; Bronchoalveolar Lavage Fluid; Female; Hemoperfusion; Immunosorbent Techniques; Interleukin-8; Lipopolysaccharides; Male; Rabbits; Random Allocation; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

alpha 2-Macroglobulin (alpha 2m) is a major plasma proteinase inhibitor, as well as a carrier and regulator of the function of many cytokines. IL-8 is a potent neutrophil attractant and activator, and it plays an important role in the pathogenesis of adult respiratory distress syndrome (ARDS). The concentration of both IL-8 and alpha 2m is increased in lung fluids from patients with ARDS. Therefore, interaction of IL-8 with human alpha 2m was studied. Mixtures of native and methylamine-treated alpha 2m (fast alpha 2m) with 125I-labeled IL-8 were analyzed using nonreducing gel electrophoresis. 125I-labeled IL-8 exclusively bound to fast alpha 2m, and the binding could be inhibited by unlabeled IL-8. Analysis of the IL-8-alpha 2m interaction using SDS-PAGE gels indicated that the binding was mainly noncovalent. The affinity of the binding of alpha 2m to IL-8 was measured using an equilibrium dialysis technique, and Kd was 30 nM. Bioassays revealed that fast alpha 2m did not affect IL-8-induced neutrophil degranulation or chemotaxis. However, it protected IL-8 from proteolytic degradation. In addition, IL-8 complexed to alpha 2m was detected in lung fluids from patients with ARDS. alpha 2m may therefore modulate IL-8 function in the lung.

Topics: alpha-Macroglobulins; Antigens, CD; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Drug Interactions; Endopeptidases; Humans; Hydrolysis; Interleukin-8; Low Density Lipoprotein Receptor-Related Protein-1; Microdialysis; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Protein Binding; Receptors, Immunologic; Receptors, Interleukin; Receptors, Interleukin-8A; Respiratory Distress Syndrome

The influence of cytokines on the inflammatory response in surgery has recently been the subject of investigations. We measured tumor necrotic factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), interleukin 8 (IL-8), and granulocyte elastase (GEL) in 26 patients undergoing elective cardiac operations using cardiopulmonary bypass (CPB), preoperatively, immediately after CPB, and on post-operative days (PODs) 1, 3, and 6. To evaluate the effect of these cytokines on pulmonary function, the patients were divided according to whether the oxygenation index (OI) on POD 1 was > 250 or < 250, into groups A and B, respectively. TNF-alpha and IL-1 beta were undetectable and there were no significant differences in the preoperative IL-6, IL-8, and GEL levels. However, immediately following CPB, the mean IL-6, IL-8 and GEL levels in both groups were significantly higher than the preoperative levels (P < 0.01). Moreover, all these levels were significantly higher in group B than in group A, at 162 +/- 150 pg/ml vs 64 +/- 53 pg/ml (P < 0.05) for IL-6; 53 +/- pg/ ml vs 22 +/- 20 pg/ml (P < 0.01) for IL-8; and 2477 +/- 1642 mg/ l vs 1397 +/- 774 mg/l (P < 0.01) for GEL. The IL-6 levels returned to the preoperative values in both groups on POD 1; however, the GEL levels remained significantly higher in group B than in group A postoperatively, at 616 +/- 326 mg/l vs 378 +/- 70 mg/l on POD 1, and at 292 +/- 70 mg/l vs 218 +/- 62 mg/ l on POD 3 (P < 0.05). Thus high levels of cytokines such as IL-6, IL-8, and GEL may be detrimental to respiratory function.

Topics: Adult; Aged; Cardiopulmonary Bypass; Cytokines; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

We have herein established an endotoxemia-induced acute respiratory distress syndrome (ARDS)-like lung injury administered a sublethal dose of lipopolysaccharide (LPS) intravenously 36 hours after the intratracheal instillation of heat-killed Streptococcus pyogenes (OK-432). At 36 hours after OK-432 priming, a mild infiltration into the lungs, consisting of a small number of neutrophils and macrophages, was observed without destruction of pulmonary architecture. A subsequent challenge with a sublethal dose of LPS induced pathologic changes characteristic of ARDS--such as extensive edema in alveolar lumina, marked infiltration composed of a large number of neutrophils and a few macrophages, fibrin deposit in alveolar space, and destruction of pulmonary architecture--resulting in severe hypoxemia. Concomitantly, LPS challenge after priming with OK-432 induced a marked elevation of IL-8 levels in serum and bronchoalveolar lavage fluid with local IL-8 production in lungs, as revealed by immunohistochemical analysis. An anti-IL-8 antibody treatment almost completely prevented pulmonary edema, destruction of pulmonary architecture, and impairment in gas exchange as well as neutrophil infiltration in lungs; there was also a significant reduction in the rate of acute lethality. These results provide evidence that IL-8 has a pivotal role in the induction of ARDS associated with endotoxemia, probably by recruiting and activating neutrophils locally.

Topics: Animals; Antibodies, Monoclonal; Biomarkers; Edema; Endotoxemia; Female; Humans; Immunoglobulin G; Immunoglobulin kappa-Chains; Interleukin-8; Lipopolysaccharides; Lung; Mice; Neutrophils; Peroxidase; Pulmonary Alveoli; Rabbits; Respiratory Distress Syndrome

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 development of acute respiratory distress syndrome (ARDS) during acute pancreatitis is associated with interleukin (IL)-1 and tumor necrosis factor (TNF) gene expression within the pulmonary parenchyma. Although activated pancreatic enzymes have been thought to mediate pancreatitis-induced ARDS, they are not capable of inducing cytokine production in vitro. We hypothesized that IL-1 and TNF production in the lungs is essential to the development of ARDS and is induced by a mediator released from the inflamed pancreas.. Pancreatic ascites was obtained from rats after induction of bile-salt pancreatitis, cultured, and assayed for IL-1, TNF, IL-6, IL-8, IL-10, interferon-gamma, and endotoxin. Sterile, cytokine-free ascites or saline (control) was subsequently administered intravenously (20 ml/kg) to healthy rats and to IL-1 R1 or TNF R1 knockout mice.. Animals administered intravenous ascites had a 30-fold rise in pulmonary IL-1 and TNF mRNA, as well as increased alveolar leukocytes and protein. Knockout animals devoid of active IL-1 or TNF receptors failed to develop increased alveolar protein or leukocytes.. A component of pancreatic ascites other than activated enzymes, bacteria, or inflammatory cytokines is capable of inducing ARDS in healthy animals. The mechanism appears to be directly attributable to the activity of pulmonary IL-1 and TNF.

Topics: Acute Disease; Animals; Antigens, CD; Ascites; Bile Acids and Salts; Biological Factors; Cells, Cultured; Cytokines; Interferon-gamma; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Lung; Male; Mice; Mice, Knockout; Pancreatitis; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-1; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

The authors sought to evaluate the pathogenetic and prognostic role of a procoagulant and hypofibrinolytic state in the adult respiratory distress syndrome (ARDS). Twenty-two consecutive patients admitted to the intensive care unit (ICU) for respiratory monitoring (n = 2) or mechanical ventilation (n = 20) were studied, of whom 13 had ARDS and 9 were at risk for the syndrome. Plasma levels of thrombin-antithrombin III complexes (TAT), the plasmin-alpha2-antiplasmin complexes (PAP), tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1) were measured within 48 h after admission, together with respiratory variables allowing computation of the lung injury score (LIS), and pulmonary microvascular permeability [67Gallium-transferrin pulmonary leak index (PLI)], as measures of pulmonary dysfunction. Blood was also sampled 6-hourly until 2 days after admission. The LIS and PLI were higher in ARDS than at risk patients, in the presence of similar systemic morbidity and mortality. TAT complexes were elevated in a minority of patients of both groups, whereas the PAP, tPA and PAI levels were elevated above normal in the majority of ARDS and at risk patients, but groups did not differ. Neither circulating coagulation nor fibrinolysis variables correlated to either LIS or PLI. Furthermore, the course of haemostatic variables did not relate to outcome. These data indicate that systemic activation of coagulation and impaired fibrinolysis do not play a major role in ARDS development and outcome in patients with acute lung injury.

Topics: Adult; Aged; Aged, 80 and over; Blood Coagulation; Data Interpretation, Statistical; Female; Fibrinolysin; Fibrinolysis; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged; Partial Thromboplastin Time; Plasminogen; Plasminogen Activator Inhibitor 1; Prothrombin Time; Respiratory Distress Syndrome; Risk Factors; Tissue Plasminogen Activator

The purpose of this study was to assess the phenotypic and functional characteristics of pulmonary microvascular endothelial cells (MVEC) in the acute respiratory distress syndrome (ARDS). Pulmonary MVEC were isolated from the lungs of five patients who developed ARDS, and from four patients who had undergone a lobectomy for lung carcinoma, as controls. Adhesion molecules and other surface molecules were quantitated on these cells by flow cytometry and the cytokines IL-6 and IL-8 were measured in the supernatants by ELISA. The constitutive expression of intercellular adhesion molecule and, to a lesser extent, vascular adhesion molecule-1, was significantly increased on MVEC isolated from all ARDS patients, as compared with control MVEC. CD14 and TNF receptor p75 were also increased on the surface of MVEC isolated from most patients with ARDS. The expression of ELAM-1 and TNF receptor p55 (TNF-R1) was not significant on the surface of either ARDS-derived or control pulmonary MVEC. The constitutive ability of ARDS-derived MVEC to secrete IL-6 and IL-8 was markedly enhanced as compared with control MVEC. Upon in vitro restimulation by TNF, pulmonary MVEC from ARDS patients showed lower ICAM-1 upregulation, but similar IL-6 and IL-8 production capacity, when compared with control MVEC. Selective differences were found in cell adhesion molecules and TNF receptor p75 expression on pulmonary MVEC isolated from patients with ARDS. These pulmonary MVEC spontaneously overexpress some adhesion molecules and produce greater amounts of the pro- and anti-inflammatory cytokines IL-8 and IL-6. These findings suggest that ICAM-1 and TNF receptor p75 may have a particular involvement in the pathogenesis of acute lung injury, and that the endothelium may be an important source of cytokines detected in broncho-alveolar lavage during this syndrome. It is tempting to hypothesize that the differences observed result from either a genetic predisposition to ARDS based on MVEC phenotype or to a long-lived MVEC phenotypic change induced by ARDS. By allowing the monitoring of phenotypic and functional parameters, cultures of pulmonary MVEC isolated from ARDS patients may thus represent a useful system to analyze further the mechanisms of acute lung injury and to evaluate the efficacy of drugs, including inhibitors of cytokines and of adhesion molecules.

Topics: Adult; Animals; E-Selectin; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Lipopolysaccharide Receptors; Lipopolysaccharides; Lung; Male; Mice; Middle Aged; Phenotype; Receptors, Tumor Necrosis Factor; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

It was recently demonstrated that nitric oxide (NO) inhalation improves arterial oxygenation in patients with the adult respiratory distress syndrome (ARDS). However, the potential adverse reaction of NO on inflammatory cells and mediators in the lung has not yet been investigated. In this study, we evaluated the impact of NO inhalation on lung polymorphonuclear neutrophil (PMN) activation and proinflammatory cytokine release, both of which are involved in the pathophysiology of ARDS. Two groups of patients with ARDS of similar etiologies were compared; one received NO (n=9) and the other did not (n=5). After 4 d of NO inhalation (18 ppm), PMN form bronchoalveolar lavage (BAL) showed a reduction in both spontaneous H2O2 production (p<0.05) and beta 2 integrin CD11b/CD18 expression (p<0.05). Moreover, the high levels of IL8 and IL-6 decreased in BAL fluid supernatants after NO inhalation (p<0.05). In the NO-untreated group of patients with ARDS, neither PMN activation nor levels of IL-8 and IL-6 in BAL fluid changed significantly on Day 4. These results suggest that NO inhalation might reduce lung inflammation in ARDS, as reflected by PMN activation status and IL-8/IL-6 release.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Bronchoalveolar Lavage Fluid; CD18 Antigens; Cytokines; Female; Gene Expression Regulation; Humans; Hydrogen Peroxide; Interleukin-6; Interleukin-8; Macrophage-1 Antigen; Male; Middle Aged; Neutrophil Activation; Neutrophils; Nitric Oxide; Oxygen; Pulmonary Alveoli; Respiratory Distress Syndrome; Respiratory System Agents

Topics: Alzheimer Disease; Animals; Asthma; Chemokine CCL11; Chemokine CCL2; Chemokines; Chemokines, CC; Chemotactic Factors, Eosinophil; Chemotaxis, Leukocyte; Cytokines; Humans; Inflammation; Interleukin-8; Monocytes; Neoplasms; Neutrophils; Respiratory Distress Syndrome

We studied paired bronchoalveolar lavage (BAL) in patients with sepsis-associated acute respiratory distress syndrome (ARDS). Patients were evaluated at one institution and underwent bronchoscopy with BAL within 48 h of the onset of ARDS. Patients were restudied with bronchoscopy and BAL after 4 d of treatment. Fifty-eight patients were initially studied, with 44 patients having follow-up bronchoscopy after 4 d. The overall 30-d survival for the ARDS group was 60%. In the initial lavage, there was no difference in the neutrophils between the survivors and nonsurvivors (survivors: 59 [0-98]%; Median [Range]; nonsurvivors: 55 [0-92]%). The follow-up lavage demonstrated a significant drop in the neutrophils for the survivors (36 [4-89]%, p < 0.002) which was not seen for the nonsurvivors (70 [26-95]%). Initial IL-8 concentrations in the BAL fluid were not significantly different between the two groups. In the follow-up lavage, there was a significant fall for the IL-8 concentrations for the survivors but not the nonsurvivors. We conclude that neutrophil influx in ARDS may rapidly resolve within a week of the onset of ARDS. The resolution of neutrophils was associated with a good prognosis.

Topics: Acute Disease; Adult; Aged; Bronchoalveolar Lavage Fluid; Bronchoscopy; Female; Humans; Interleukin-8; Lung; Male; Middle Aged; Prognosis; Respiratory Distress Syndrome; Sepsis; Survival Rate

To determine the relation between 1) intra-alveolar concentrations of the proinflammatory cytokines (tumor necrosis factor, interleukin-1 beta, and interleukin-8) and the anti-inflammatory cytokines (interleukin-10 and interleukin-1 receptor antagonist) in patients with early adult respiratory distress syndrome (ARDS) and 2) subsequent patient mortality rates.. Prospective cohort study.. University medical center.. 28 consecutive patients in whom ARDS was prospectively identified during hospitalization and 9 ventilated controls.. Concentrations of proinflammatory cytokines and anti-inflammatory cytokines in bronchoalveolar lavage fluid.. The concentrations of proinflammatory and anti-inflammatory cytokines within the alveolar air spaces were significantly elevated in patients with ARDS compared with controls (P = 0.01 for tumor necrosis factor [median, 90 pg/mL (range, 0 to 2500 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 118 pg/mL) for controls]; P = 0.001 for interleukin-1 beta [median, 179 pg/mL (range, 0 to 2200 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 80 pg/mL) for controls]; P = 0.0001 for interleukin-8 [median, 628 pg/mL (range, 0 to 4700 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 278 pg/mL) for controls]; P = 0.0005 for interleukin-10 [median, 100 pg/mL (range, 0 to 1600 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 50 pg/mL) for controls], and P = 0.002 for interleukin-1 receptor antagonist [median, 820 pg/mL (range, 0 to 18,900 pg/mL) for patients with ARDS; median, 50 pg/mL (range, 0 to 240 pg/mL) for controls]). A highly significant correlation was found between low concentrations of anti-inflammatory cytokines and subsequent patient mortality rates (P = 0.003 for interleukin-10 [median, 120 pg/mL (range, 30 to 1600 pg/mL) for survivors; median, 40 pg/mL (range, 0 to 110 pg/mL) for nonsurvivors]; P = 0.008 for interleukin-1 receptor antagonist [median, 1600 pg/mL (range, 80 to 18,900 pg/mL) for survivors; median, 90 pg/mL (range, 0 to 3400 pg/mL) for nonsurvivors. No significant correlation was found between the concentrations of the proinflammatory cytokines and mortality rates.. Low concentrations of the anti-inflammatory cytokines interleukin-10 and interleukin-1 receptor antagonist in bronchoalveolar lavage fluid obtained from patients with early ARDS are closely associated with poor prognosis. These findings support the hypothesis that failure to mount a localized intrapulmonary anti-inflammatory response early in the pathogenesis of ARDS contributes to more severe organ injury and worse prognosis. Our findings suggest that augmenting anti-inflammatory cytokine defenses would be a beneficial therapeutic approach to patients with ARDS and other inflammatory diseases.

Topics: Adult; Aged; Aged, 80 and over; Bronchoalveolar Lavage Fluid; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Prospective Studies; Receptors, Interleukin; Receptors, Interleukin-1; Receptors, Interleukin-10; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

We examined the effect of the antioxidant lazaroid U-74389F on acute lung injury induced in rabbits by phorbol myristate acetate (PMA). Thirty minutes after receiving either U-74389F (15 mg.kg-1 i.v.) or U-74389F vehicle, rabbits (n = 60) were given PMA (60 micrograms.kg-1 i.v.). PMA vehicle injected rabbits (n = 20) served as controls. Over a 5 h period after PMA or PMA vehicle injection, we measured arterial pH, arterial oxygen tension (Pa,O2), arterial carbon dioxide tension (Pa,CO2), and the plasma concentration of the neutrophil chemoattractant interleukin-8 (IL-8). At postmortem, lungs were inspected for macroscopic injury and examined histologically. Malondialdehyde levels were assayed in lung tissue as an index of lipid peroxidation. In bronchoalveolar lavage (BAL), total and differential cell counts, protein and IL-8 concentrations were measured. Compared to normal controls, rabbits challenged with PMA alone developed arterial acidosis, hypercapnia and hypoxaemia, accompanied by significant rise in plasma IL-8 concentration. U-74389F pretreated animals did not develop significant arterial blood gas abnormalities and had significantly lower IL-8 concentration in plasma. U-74389F did not prevent PMA-induced lipid peroxidation. However, macroscopic signs of lung injury and the degree of alveolar haemorrhage and protein extravasation were significantly less severe in pretreated rabbits than in those given PMA alone. In addition, U-74389F significantly reduced IL-8 concentration and neutrophil number in BAL. By histological assessment, 80% of lung neutrophils were localized in alveolar spaces of animals receiving PMA alone. Conversely, in U-74389F pretreated animals, 75% of neutrophils were distributed within extra-alveolar blood vessels and alveolar septa. We conclude that lazaroid U-74389F attenuates lung injury in rabbits given PMA by preventing neutrophil migration into pulmonary alveoli. This effect may, in part, be related to downregulation of IL-8 production.

Topics: Animals; Antioxidants; Bronchoalveolar Lavage Fluid; Cell Count; Dimethyl Sulfoxide; Interleukin-8; Lung; Malondialdehyde; Neutrophils; Pregnatrienes; Proteins; Rabbits; Respiratory Distress Syndrome; Respiratory Function Tests; Tetradecanoylphorbol Acetate

A 75-year-old man was admitted to the hospital due to acute onset of a dry cough and dyspnea on exertion. Arterial blood gas analysis showed hypoxemia (PaO2 = 63 Torr) on room air. Chest radiography and computed tomography showed diffuse bilateral infiltrates. Adult respiratory distress syndrome was diagnosed from the findings described above and from the lack of evidence of left heart failure. Diffuse alveolar damage was confirmed at autopsy. During the course of his illness, the patient underwent bronchoalveolar lavage five times. The recovered fluid had high concentrations of interleukin-8 (IL-8), with a maximum of 6260 pg/ml and a minimum of 190 pg/ml, and these values correlated with the number of polymorphonuclear cells in the fluid. Levels of leukotriene B4, another chemotactic factor for PMN, in the lavage fluid were not high. We conclude that IL-8 was a major chemoattractant for PMN in the alveoli of this patient.

Topics: Aged; Bronchoalveolar Lavage Fluid; Fatal Outcome; Humans; Interleukin-8; Leukocyte Count; Leukotriene B4; Male; Neutrophils; Pulmonary Alveoli; Respiratory Distress Syndrome

To test the hypothesis that significantly higher concentrations of interleukin-8 (IL-8) are found in the pulmonary edema fluid and plasma of patients with a septic vs. a nonseptic etiology of acute respiratory distress syndrome (ARDS).. Prospective measurement of IL-8 concentrations in previously collected edema fluid and plasma.. Adult intensive care units at a university medical center.. There were 27 patients with ARDS (16 patients with a septic etiology and nine patients with a nonseptic etiology) plus eight control patients with hydrostatic pulmonary edema.. IL-8 was present in the pulmonary edema fluid of all patients with ARDS, but the median IL-8 concentration was higher in the edema fluid of patients with ARDS associated with sepsis (84.2 ng/mL, n = 16) compared with the ARDS patients without sepsis (14.8 ng/mL, n = 11) (p < .05). In patients with cardiogenic edema, IL-8 concentration (5.0 ng/mL,n = 8, p < .05) was significantly lower than those values in patients with ARDS. Median plasma concentration of IL-8 was increased in septic individuals (1.3 ng/mL), but these concentrations were not significantly higher than in patients with a nonseptic etiology of ARDS (0.35 ng/mL) (p = .14) or those patients with cardiac failure (0.21 ng/mL).. The high concentrations of IL-8 in pulmonary edema fluid, coupled with the relatively low concentrations of IL-8 in the plasma, suggest that the lung was the primary source of IL-8 in the patients with ARDS. The markedly increased concentrations of IL-8 in the pulmonary edema fluid of patients with ARDS from sepsis suggests that this group of patients may be particularly suitable for potential trials directed at inhibiting the activity of this important chemokine.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Humans; Intensive Care Units; Interleukin-8; Lung; Middle Aged; Prospective Studies; Pulmonary Edema; Respiratory Distress Syndrome; Sepsis

IL-8 is a potent neutrophil attractant and activator. IL-8 has been reported to be involved in the pathogenesis of several diseases, including rheumatoid arthritis, sepsis, psoriasis, and the adult respiratory distress syndrome (ARDS). Our previous studies demonstrated that high concentrations of IL-8 were present in alveolar fluids from patients with ARDS and were associated with increased mortality. In this study we report that a major portion of IL-8 in bronchoalveolar fluids from patients with ARDS is associated with anti-IL-8 autoantibody (anti-IL-8:IL-8 complexes). Free autoantibodies that recognize IL-8 were also detected in these fluids. Next, we examined the properties of anti-IL-8 autoantibodies present in lung fluids from ARDS patients and compared them with autoantibodies from normal plasma and arthritic synovial fluids. The anti-IL-8 autoantibody was polyclonal, and IgG3 and IgG4 were the primary IgG subclasses. Anti-IL-8:IL-8 complexes consisted of one IgG and one IL-8 molecule. In addition, anti-IL-8 autoantibody bound IL-8 with a high affinity (approximately 10(-12) M) and inhibited IL-8 interaction with its specific receptors on neutrophils. The results suggest that anti-IL-8 autoantibodies may regulate IL-8 activity.

Topics: Antibody Specificity; Autoantibodies; Blood Chemical Analysis; Bronchoalveolar Lavage Fluid; Chromatography, Gel; Humans; Interleukin-8; Respiratory Distress Syndrome; Synovial Fluid

To determine the relationship between airspace cytokines and cellular inflammatory responses in patients with the acute respiratory distress syndrome (ARDS), we performed bronchoalveolar lavage (BAL) in 82 prospectively identified, mechanically ventilated patients on Days 3, 7, 14, and/or 21 after the onset of ARDS. We studied the relationships between bronchoalveolar lavage fluid (BALF) cell populations and the concentrations of two potent neutrophil (PMN) chemoattractants, interleukin-8 (IL-8) and epithelial cell-derived neutrophil activator-78 (ENA-78); two potent monocyte chemoattractants, monocyte chemotactic peptide-1 (MCP-1) and macrophage inflammatory peptide-1 alpha (MIP-1 alpha); and the early response cytokine interleukin-1 beta (IL-1 beta) and its naturally occurring antagonist, IL-1 receptor antagonist protein (IRAP). We found that all of these cytokines were significantly increased regardless of the duration of ARDS. IL-8 and ENA-78 were the cytokines most strongly and consistently correlated with PMN concentrations in the lung fluids of patients with ARDS, and the correlations were independent of the other cytokines or coexisting lung infection. None of the cytokines tested correlated with macrophage concentrations. MCP-1 was directly correlated with lung injury score on Days 7, 14, and 21. Although neither IL-8 nor ENA-78 was associated with outcome, levels of IL-1 beta measured on Day 7 were associated with an increased risk of death (odds ratio [OR] = 2.8; 95% confidence interval [CI] = 1.1 to 7.4). These data demonstrate potential molecular mechanisms of the persistent inflammatory process in the lungs of patients with ARDS.

Topics: Adolescent; Adult; Aged; Bronchoalveolar Lavage Fluid; Chemokine CXCL5; Chemokines, CXC; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intensive Care Units; Interleukin-8; Male; Middle Aged; Neutrophils; Predictive Value of Tests; Respiration, Artificial; Respiratory Distress Syndrome

We report a case with adult respiratory distress syndrome (ARDS) associated with increased levels of squamous cell carcinoma-related antigen (SCC) in the serum and bronchoalveolar lavage fluid (BALF). ARDS was likely induced by ibuprofen, based on the presence of pancytopenia and a weakly positive drug lymphocyte stimulating test (DLST). High serum and BALF levels of interleukin (IL)-8, neutrophil elastase as well as SCC were detected. Corticosteroid therapy resulted in clinical improvement, resolution of pulmonary infiltrates on chest roentgenogram and normalization of serum and BALF levels of IL-8, neutrophil elastase and SCC.

Topics: Antigens, Neoplasm; Biomarkers; Bronchoalveolar Lavage Fluid; Humans; Ibuprofen; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Pancreatic Elastase; Pancytopenia; Pulmonary Edema; Respiratory Distress Syndrome; Serpins

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

Topics: Humans; Interleukin-8; Respiratory Distress Syndrome

Neutrophils are reported to be a major factor in the pathogenesis of the adult respiratory distress syndrome (ARDS). We measured serial levels of circulatory interleukin (IL)-8 and neutrophil elastase in 16 patients with ARDS at the onset, on day 3 and on day 7 and studied the relationship of these levels to the clinical course. Circulatory IL-8 levels of all the patients at the onset were significantly elevated compared with controls, mean +/- SE, 30.0 +/- 6.7 pg/ml and 3.3 +/- 0.3 pg/ ml, respectively. There was a significant correlation between IL-8 and neutrophil elastase levels at the onset (r = 0.65, p < 0.01). In nonsurvivors circulatory IL-8 levels were significantly higher than those of survivors throughout the study. There were significant differences in oxygenation, as reflected by PaO2/FIO2 ratios, between survivors and nonsurvivors at day 7, mean +/- SE, 208.5 +/- 21.9 and 113.5 +/- 9.6, respectively. In conclusion, we have shown that the level of circulatory IL-8 is elevated in patients with ARDS, and sustained high levels of circulatory IL-8 might be correlated with a poor outcome.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Prognosis; Respiratory Distress Syndrome; Survivors

We measured the levels of defensins, antimicrobial peptides, and cytotoxic peptides in azurophil granules of neutrophils in plasma, and in bronchoalveolar lavage fluid (BALF) from patients with the acute respiratory distress syndrome (ARDS). High levels of plasma defensins were observed in samples from patients with ARDS. Samples of BALF from patients with ARDS also had more neutrophils and higher concentrations of defensins than did samples from healthy volunteers and from patients with idiopathic pulmonary fibrosis or diffuse panbronchiolitis. In addition, the concentration of interleukin (IL)-8 in BALF was higher in patients with ARDS than in other subjects. A significant correlation was found between the concentration of defensins and that of IL-8 in BALF from patients with ARDS. These findings suggest that the lung injury in ARDS is caused by defensins released by neutrophils that accumulate in the lungs.

Topics: Aged; Blood Proteins; Bronchoalveolar Lavage Fluid; Defensins; Female; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Respiratory Distress Syndrome

Pulmonary diffusion capacity (DLCO) is reduced 2 h after various types of exercise, such as rowing, treadmill running, arm cranking and marathon running. The decrease in DLCO may involve alterations in the alveolar-capillary membrane as well as depletion of the central blood volume. We hypothesized that the reduction in DLCO might also be influenced by oxygen free radicals, acute phase proteins and endotoxin, which are also involved in the adult respiratory distress syndrome (ARDS). Ten competitive male oarsmen performed a 6 min 'all-out' ergometer row. Single breath DLCO was determined before and 2 h after rowing and venous blood samples were also obtained during the row. Absolute DLCO decreased by 11% (range 0-20%) 2 h after rowing, whereas the concentration of endotoxin did not change significantly and interleukin (IL)-1-alpha, IL-8 and tumour necrosis factor (TNF)-alpha were below the levels of detection before, during and 2 h after rowing. Oxygen free radicals were evaluated by oxidative modification of amino acids and DNA. Corrected for creatinine in urine voided 3 h post-exercise, the DNA repair product 8-oxo-7,8-dehydro-2-deoxyguanosine (8-oxodG) did not change significantly. The ratio of fluorescence due to dityrosine to that due to tryptophan in plasma proteins increased after exercise. This might reflect an effect of oxygen free radicals, but it might also indicate an altered relative composition of plasma proteins. These results suggest that the reduced pulmonary diffusion capacity following exercise is unrelated to factors typically associated with ARDS.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute-Phase Proteins; Adult; Blood Proteins; Blood Volume; Capillaries; Creatinine; Deoxyguanosine; Endotoxins; Exercise Test; Free Radicals; Humans; Interleukin-1; Interleukin-8; Male; Physical Exertion; Pulmonary Alveoli; Pulmonary Diffusing Capacity; Reactive Oxygen Species; Respiratory Distress Syndrome; Running; Tryptophan; Tumor Necrosis Factor-alpha; Tyrosine

Polymorphonuclear leukocytes (PMN) are the predominant inflammatory cells recruited in acute lung injury. This study compares the concentration of interleukin-8 (IL-8) to those of GRO alpha, both of which are CXC chemokines, in bronchoalveolar lavage fluid (BALF) in three acute pathologic states: bacterial pneumonia (BPN); adult respiratory distress syndrome (ARDS); and Pneumocystis carinii pneumonia (PCP). Levels of both IL-8 and GRO alpha were below 5 pg/ml in 16 nonsmoking volunteers who served as controls. Despite more than twice as many neutrophils in the BALF of the BPN group (n = 12) than in the group with ARDS (n = 13), both groups had similar levels of IL-8, of 569 +/- 120 pg/ml and 507 +/- 96 pg/ml, respectively. The GRO alpha concentrations in the BPN and ARDS patients were respectively 3.3 and 3.4 times those of IL-8, reaching 1,870 +/- 314 pg/ml for the BPN and 1,699 +/- 377 for the ARDS patients. In the PCP group (n = 48, 45 human immunodeficiency virus [HIV]-positive, 3 HIV-negative), GRO alpha levels (897 +/- 172 pg/ml) were sevenfold higher than IL-8 levels (123 +/- 40 pg/ml). In all pathologic states there was a good correlation between GRO alpha and IL-8 (r = 0.53, p = 0.0001). GRO alpha or IL-8 both correlate with the absolute neutrophil number/ml when all groups were studied together (r = 0.52, p = 0.0001). Only in the PCP and ARDS groups did IL-8 correlate with the PMN number.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Bronchoalveolar Lavage Fluid; Bronchopneumonia; Chemokine CXCL1; Chemokines; Chemokines, CXC; Chemotactic Factors; Chemotaxis, Leukocyte; Growth Substances; HIV-1; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Male; Neutrophils; Pneumonia, Bacterial; Pneumonia, Pneumocystis; Respiratory Distress Syndrome; Statistics, Nonparametric

We determined the plasma concentrations of interleukin 8 (IL-8), polymorphonuclear leukocyte elastase (PMNE), and endotoxin in patients with septic shock in order to investigate the role of IL-8 and PMNE in the development of septic shock, especially in septic adult respiratory distress syndrome (ARDS). The IL-8 concentration in patients with septic shock was 6.28 +/- 9.00 ng/mL (mean +/- SD, n = 29), which was significantly higher (P < 0.0001) than the concentration in septic patients without shock (0.35 +/- 0.35 ng/mL, n = 40). There was a significant correlation between the IL-8 concentration and the PMNE concentration at the onset of septic shock (r = 0.6916, P < 0.0001). The IL-8 concentration was also significantly correlated with the endotoxin concentration (r = 0.5584, P = 0.0016). There was a significant negative correlation (r = -0.8237, P < 0.0001) between the serum PMNE concentration and the oxygenation index (PaO2/FiO2) at the onset of septic shock. These results indicate that IL-8 and PMNE are produced in large quantities when septic shock occurs, and may play a role in the development of septic ARDS.

Topics: Adult; Endotoxins; Humans; Interleukin-2; Interleukin-8; Kinetics; Leukocyte Elastase; Male; Middle Aged; Oxygen; Pancreatic Elastase; Reference Values; Respiratory Distress Syndrome; Shock, Septic

Inflammatory cytokines have been related to the development of adult respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction syndrome (MODS). We tested the hypothesis that unfavorable outcome in patients with ARDS is related to the presence of a persistent inflammatory response. For this purpose, we evaluated the behavior of inflammatory cytokines during progression of ARDS and the relationship of plasma inflammatory cytokines with clinical variables and outcome.. We prospectively studied 27 consecutive patients with severe medical ARDS. Plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukins (ILs) 1 beta, 2, 4, 6, and 8 were measured (enzyme-linked immunosorbent assay [ELISA] method) on days 1, 2, 3, 5, 7, 10, and 12 of ARDS and every third day thereafter while patients were receiving mechanical ventilation. Subgroups of patients were identified based on outcome, cause of ARDS, presence or absence of sepsis, shock, and MODS at the time ARDS developed. Subgroups were compared for levels of plasma inflammatory cytokines on day 1 of ARDS and over time.. Of the 27 patients, 13 survived ICU admission and 14 died (a mortality rate of 52%). Overall mortality was higher in patients with sepsis (86 vs 38%, p < 0.02). The mean initial plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 were significantly higher in nonsurvivors (p < 0.0001) and in those patients with sepsis (p < 0.0001). Plasma levels of IL-1 beta (p < 0.01) and IL-6 (p = 0.03) were more strongly associated with patient outcome than cause of ARDS (p = 0.8), lung injury score (LIS), APACHE II score, sepsis (p = 0.16), shock, or MODS score. Plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 remained significantly elevated over time (p < 0.0001) in those who died. Although it was the best early predictor of death (p < 0.001), plasma IL-2 > 200 pg/mL lost its usefulness after the first 48 h. A plasma IL-1 beta or IL-6 level > 400 pg/mL on any day in the first week of ARDS was associated with a low likelihood of survival.. Our findings indicate that unfavorable outcome in acute lung injury is related to the degree of inflammatory response at the onset and during the course of ARDS. Patients with higher plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 on day 1 of ARDS had persistent elevation of these inflammatory cytokines over time and died. Survivors had lesser elevations of plasma inflammatory cytokines on day 1 of ARDS and a rapid reduction over time. Plasma IL-1 beta and IL-6 levels were consistent and efficient predictors of outcome.

Topics: Adult; Female; Humans; Interleukin-1; Interleukin-2; Interleukin-4; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Prognosis; Prospective Studies; Respiratory Distress Syndrome; Sensitivity and Specificity; Survival Rate; Time Factors; Tumor Necrosis Factor-alpha

Aortic surgery results in ischemia/reperfusion of the lower body. This may liberate inflammatory mediators that activate neutrophils, and may result in lung microvascular changes with increased permeability and respiratory failure. We studied circulating inflammatory mediators and the pulmonary leak index (PLI) of 67Ga, a measure of transvascular transferrin transport and permeability, in patients scheduled for elective aortic and peripheral vascular surgery, before and after surgery. Aortic surgery patients in Groups 1 (n = 10) and 2 (n = 7) were studied before and at a median of 2.5 and 21.0 h after surgery, respectively. A control Group 3 (n = 6) was studied before and at a median of 2.9 h after peripheral vascular surgery. The PLI (median) increased from a median of 9.1 (range, 6.6 to 14.7) before to a median of 23.4 (range, 18.7 to 86.4) x 10(-3)/min after surgery in Group 1 but not in the other groups (p < 0.001). The postoperative increase in circulating neutrophils and elastase-alpha 1-antitrypsin, a marker of neutrophil activation, was similar among the groups. Plasma levels of activated complement 3a and tumor necrosis factor (TNF-alpha) did not change in any of the groups. In contrast, plasma levels of interleukin-8 (IL-8) increased in Group 1 from < 3 (range, < 3 to 37) before to 324 (range, 36 to 868) pg/ml after surgery, but did not change in the other groups (p < 0.005). The decrease in plasma levels of angiotensin converting enzyme (ACE) was greater in Group 1 than in the other groups (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aortic Diseases; Capillary Permeability; Citrates; Citric Acid; Erythrocytes; Female; Gallium Radioisotopes; Humans; Inflammation Mediators; Interleukin-8; Lung; Male; Middle Aged; Neutrophil Activation; Peptidyl-Dipeptidase A; Peripheral Vascular Diseases; Postoperative Complications; Radionuclide Imaging; Reperfusion Injury; Respiratory Distress Syndrome; Sodium Pertechnetate Tc 99m

To better understand the pathogenesis of acute respiratory distress syndrome (ARDS), we analyzed bronchoalveolar lavage fluid (BALF) from patients with ARDS (n = 89, survival rate = 56.2%), who were admitted to our intensive care units over the past 7 years. ARDS was diagnosed when the lung injury score proposed by Murray et al was greater than 2.5. The BALF had very high centrations of albumin, a marker of permeability edema, along with remarkably high neutrophil counts, percent neutrophils, neutrophil-elastase, and interleukin-8, markers of neutrophil-related lung injury. In addition, the level of IL-8 in BALF was higher in non-survivors than in survivors. Levels of thrombin-antithrombin complex fibrin degenerative product and soluble thrombomodulin (recently recognized as a natural anticoagulant combined with vascular endothelial cells) were very high in BALF from patients with ARDS. Moreover, the level of soluble thrombomodulin in BALF was higher in non-survivors than in survivors. There were significant relationships between these neutrophil-related markers and markers of abnormal coagulation. The results of the BALF analysis suggest that accumulation and activation of neutrophils can affect thrombomodulin on vascular endothelial cells, which can activate thrombin and cause the coagulopathy seen in ARDS.

Topics: Adult; Aged; Albumins; Biomarkers; Bronchoalveolar Lavage Fluid; Capillary Permeability; Female; Humans; Interleukin-8; Leukocyte Count; Leukocyte Elastase; Lung; Male; Middle Aged; Neutrophils; Respiratory Distress Syndrome

To elucidate the relationship between active oxygen and interleukin 8 (IL-8) in patients with septic adult respiratory distress syndrome (ARDS), we determined the serum levels of alpha-tocopherol, which has an antioxidant action, and IL-8 in seven patients with this disease. Serum alpha-tocopherol and IL-8 levels determined at the time of diagnosis of septic ARDS were 0.97 +/- 0.36 mg/dl and 0.98 +/- 0.99 ng/ml, respectively. A significant correlation was found between serum alpha-tocopherol level and IL-8 level (r = -0.758, p = 0.0473). These findings suggest that IL-8 activates neutrophils, which produce active oxygen.

Topics: Adolescent; Adult; Aged; Bacteremia; Chromatography, High Pressure Liquid; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Male; Middle Aged; Reactive Oxygen Species; Respiratory Distress Syndrome; Vitamin E

Topics: Chemokine CCL2; Chemokine CCL4; Chemokine CXCL5; Chemokines, CXC; Chemotactic Factors; Cytokines; Humans; Interleukin-8; Macrophage Inflammatory Proteins; Monokines; Respiratory Distress Syndrome

The adult respiratory distress syndrome (ARDS) is a frequent complication after severe accidental trauma. This study examines the hypothesis that increased systemic concentrations of proinflammatory cytokines, endotoxin, or complement fragments may predict the development of ARDS.. Prospective, observational study.. Two Level I university trauma centers.. Fifteen severely injured patients (Injury Severity Score of > or = 25).. Standard emergency department, operating room, and intensive care unit management.. Plasma samples were obtained at 4-hr intervals from the time of injury and were assayed for concentrations of endotoxin, tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, IL-8, and complement fragments C3a and C4a. Hemodynamic and oxygen metabolism variables also were measured at 4-hr intervals after injury. Seven patients developed ARDS and eight patients did not. The PaO2/FIO2 ratio was significantly decreased in the patients with ARDS compared with non-ARDS patients as early as 4 hrs postinjury, and remained significantly decreased throughout the initial 24 hrs after severe accidental injury. Plasma IL-8, IL-6, C3a, and C4a concentrations were markedly increased starting in the immediate postinjury period in both ARDS and non-ARDS patients, but no significant differences were found between the two groups until 16 hrs after injury when plasma IL-8, C3a, and C4a concentrations became significantly higher in the ARDS group. Neither the ARDS nor non-ARDS patients showed the presence of circulating IL-1 beta, TNF-alpha, or endotoxin at any postinjury time point.. These results demonstrate that measurements of plasma concentrations of proinflammatory cytokines, endotoxin, or complement fragments are not helpful in predicting the development of ARDS after severe accidental injury.

Topics: Adult; Blood Gas Analysis; Complement C3a; Complement C4a; Craniocerebral Trauma; Endotoxins; Enzyme-Linked Immunosorbent Assay; Female; Hemodynamics; Humans; Injury Severity Score; Interleukin-1; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Middle Aged; Oxygen Consumption; Peptide Fragments; Predictive Value of Tests; Prognosis; Prospective Studies; Radioimmunoassay; Respiratory Distress Syndrome; Risk Factors; Survival Rate; Time Factors; Tumor Necrosis Factor-alpha

Neutrophils have been implicated in the pathogenesis of the adult respiratory distress syndrome (ARDS). We have measured concentrations of the neutrophil attractant interleukin-8 in blood and bronchoalveolar lavage fluid (BAL) from patients at risk of ARDS. We studied 29 patients from three groups at risk of developing ARDS: multiple trauma (n = 16), perforated bowel (n = 6), and pancreatitis (n = 7). ARDS developed in 7 of these patients. Interleukin-8 in BAL and blood samples taken on initial hospital presentation was measured by a sandwich enzyme-linked immunosorbent assay. The mean BAL interleukin-8 concentration was significantly higher for the patients who subsequently progressed to ARDS than for the non-ARDS group (3.06 [SE 2.64] vs 0.053 [0.010] ng/mL, p = 0.0006). There was no difference between the groups in plasma interleukin-8 (6.23 [2.60] vs 5.12 [2.22] ng/mL, p = 0.31). Immunocytochemistry suggested that the alveolar macrophage is an important source of interleukin-8 at this early stage in ARDS development. This study provides evidence of a relation between the presence of interleukin-8 in early BAL samples and the development of ARDS. The early appearance of interleukin-8 in BAL of patients at risk of ARDS may be an important prognostic indicator for the development of the disorder and reinforces the likely importance of neutrophils and the effects of their accumulation and activation in the pathogenesis of many cases of ARDS.

Topics: Adolescent; Adult; Aged; Bronchoalveolar Lavage Fluid; Humans; Interleukin-8; Intestinal Perforation; Middle Aged; Multiple Trauma; Pancreatitis; Prognosis; Respiratory Distress Syndrome; Risk Factors

Topics: Bronchoalveolar Lavage Fluid; Humans; Interleukin-8; Prognosis; Respiratory Distress Syndrome

Topics: Animals; Humans; Interleukin-8; Mice; Respiratory Distress Syndrome

Topics: Bronchoalveolar Lavage Fluid; Humans; Interleukin-8; Respiratory Distress Syndrome; Risk Factors

Topics: Adhesiveness; Age Factors; Animals; Antibodies, Monoclonal; Antigens, CD; CD11 Antigens; CD18 Antigens; Cell Adhesion Molecules; Cell Movement; Disease Models, Animal; Endothelium; Humans; Infant, Newborn; Inflammation; Interleukin-8; Multiple Organ Failure; Neutrophils; Platelet Activating Factor; Receptors, Leukocyte-Adhesion; Reperfusion Injury; Respiratory Distress Syndrome

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

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Humans; Immunity, Cellular; Interleukin-8; Middle Aged; Respiratory Distress Syndrome

To determine the effects of accidental injury of varying severity on interleukin (IL)-1 alpha, IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), and endotoxin release.. Prospective, multi-unit, longitudinal study.. Emergency Departments and intensive care units of two university hospitals.. Trauma patients after mild, moderate, and severe injury (Injury Severity Score of < or = 10, 11 to 24, and > or = 25, respectively).. None.. Plasma cytokine and endotoxin concentrations were measured over a 5-day period, starting within 2 hrs of accidental injury. An enzyme-linked immunosorbent assay was used to determine plasma concentrations of IL-1 alpha, IL-6, IL-8, and TNF-alpha. Plasma endotoxin concentrations were measured using a chromogenic limulus amebocyte assay. Preresuscitation samples obtained immediately on arrival in the Emergency Department, and within 2 hrs of injury, demonstrated significant increases of IL-6 and IL-8 concentrations in the severe injury group, in contrast to minimal increases seen after mild or moderate injury. Analysis of serial postresuscitation samples demonstrated rapid increases in IL-6 and IL-8 concentrations within 12 hrs of injury. IL-6 and IL-8 remained increased for 24 hrs after injury, then decreased markedly from their peak values during the next 24 hrs. Increased circulating concentrations of these cytokines continued to be present for > 5 days in the severely injured patients. IL-6 and IL-8 concentrations were only minimally increased in patients 8 and 24 hrs after moderate injury. Endotoxin and IL-1 alpha were not found in any samples, including those samples obtained serially from severely injured patients. No patient at any time point had TNF-alpha concentrations of > 35 pg/mL.. These results demonstrate that severe injury produces rapid, large increases in circulating concentrations of IL-6 and IL-8 that may contribute to the frequent development of the adult respiratory distress syndrome and multiple organ system failure in this clinical setting.

Topics: Adult; Endotoxins; Enzyme-Linked Immunosorbent Assay; Female; Humans; Injury Severity Score; Interleukin-1; Interleukin-6; Interleukin-8; Limulus Test; Longitudinal Studies; Male; Multiple Organ Failure; Multiple Trauma; Prospective Studies; Respiratory Distress Syndrome; Resuscitation; Time Factors; Tumor Necrosis Factor-alpha

A plasma lipopolysaccharide (LPS)-binding protein (LBP) has been shown to regulate the response of rabbit peritoneal macrophages and human blood monocytes to endotoxin (LPS). We investigated whether LBP is present in lung fluids and the effects of LBP on the response of lung macrophages to LPS. Immunoreactive LBP was detectable in the lavage fluids of patients with the adult respiratory distress syndrome by immunoprecipitation followed by Western blotting, and also by specific immunoassay. In rabbits, the LBP appeared to originate outside of the lungs, inasmuch as mRNA transcripts for LBP were identified in total cellular RNA from liver, but not from lung homogenates or alveolar macrophages. Purified LBP enhanced the response of human and rabbit alveolar macrophages to both smooth form LPS (Escherichia coli O111B:4) and rough form LPS (Salmonella minnesota Re595). In the presence of LBP and LPS, the onset of tumor necrosis factor-alpha (TNF alpha) production occurred earlier and at an LPS threshold dose that was as much as 1,000-fold lower for both types of LPS. In rabbit alveolar macrophages treated with LBP and LPS, TNF alpha mRNA appeared earlier, reached higher levels, and had a prolonged half-life as compared with LPS treatment alone. Neither LPS nor LPS and LBP affected pHi or [Cai++] in alveolar macrophages. Specific monoclonal antibodies to CD14, a receptor that binds LPS/LBP complexes, inhibited TNF alpha production by human alveolar macrophages stimulated with LPS alone or with LPS/LBP complexes, indicating the importance of CD14 in mediating the effects of LPS on alveolar macrophages. Thus, immunoreactive LBP accumulates in lung lavage fluids in patients with lung injury and enhances LPS-stimulated TNF alpha gene expression in alveolar macrophages by a pathway that depends on the CD14 receptor. LBP may play an important role in augmenting TNF alpha expression by alveolar macrophages within the lungs.

Topics: Acute-Phase Proteins; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Bronchoalveolar Lavage Fluid; Calcium; Carrier Proteins; Gene Expression; Humans; Hydrogen-Ion Concentration; Interleukin-8; Lipopolysaccharide Receptors; Lipopolysaccharides; Macrophages, Alveolar; Membrane Glycoproteins; Permeability; Rabbits; Respiratory Distress Syndrome; RNA, Messenger; Tumor Necrosis Factor-alpha

A sensitive and specific radioimmunoassay was used to measure interleukin 8 (IL-8) in bronchoalveolar lavage fluids from control subjects, patients with the adult respiratory distress syndrome (ARDS) and patients undergoing coronary bypass surgery, a risk factor for developing ARDS. Concentrations of IL-8, albumin, total protein and numbers of neutrophils were higher in both patient groups than in controls. Levels of IL-8 were significantly correlated with the influx of neutrophils, plasma protein extravasation and with the PaO2/FiO2 ratio. These data suggest that IL-8 may mediate the recruitment of neutrophils from the vascular compartment into the alveolar space and may therefore be an important determinant in neutrophil-mediated lung injury. Since increased levels of IL-8 were also found in BAL fluid from patients at risk in whom ARDS did not develop, other factors are likely to be involved and IL-8, as well as other markers of inflammation, are of little prognostic use.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Coronary Artery Bypass; Female; Humans; Interleukin-8; Male; Middle Aged; Postoperative Complications; Radioimmunoassay; Respiratory Distress Syndrome; Risk Factors; Sensitivity and Specificity

The adult respiratory distress syndrome (ARDS) is characterized by increased neutrophils within the airspaces of the lungs. In order to determine if neutrophil activating protein (NAP)-1/interleukin-8 (NAP-1/IL-8) could be an important cause of neutrophil influx and activation in ARDS, we examined fluid, which was either directly aspirated or lavaged with saline from the lungs of patients with ARDS. NAP-1/IL-8 was present in significantly higher concentrations in the fluids of patients with ARDS compared with control subjects. There was a significant correlation between the percentage of neutrophils in the lavage fluids and the NAP-1/IL-8 concentration (r2 = 0.74). Furthermore, the NAP-1/IL-8 concentration of the pulmonary edema fluid was equivalent to the optimal concentration required to induce neutrophil chemotaxis in vitro. Although not all of the chemotactic activity of the edema fluid was removed by an anti-NAP-1/IL-8 affinity column, the data established that NAP-1/IL-8 is an important neutrophil chemotaxin in the airspaces of patients with ARDS. In addition, those patients with very high concentrations of NAP-1/IL-8 in their bronchoalveolar lavage fluids had a higher mortality rate than those patients with lower concentrations of NAP-1/IL-8. The correlation between NAP-1/IL-8 concentration and mortality is not paralleled by total protein concentration and mortality.

Topics: Adolescent; Adult; Aged; Bronchoalveolar Lavage Fluid; Evaluation Studies as Topic; Humans; Interleukin-8; Leukocyte Count; Middle Aged; Neutrophils; Proteins; Respiratory Distress Syndrome; San Francisco; Suction; Survival Analysis; Texas; Washington

Because of its neutrophil-activating properties, interleukin-8 (IL-8) may play an important role in the pathophysiology of sepsis. We measured circulating IL-8 levels in 47 patients with clinical sepsis. Levels on admission were elevated in 42 of the 47 patients (89%) and were comparable in patients with gram-positive or gram-negative infections. Patients with shock had significantly higher IL-8 levels than normotensive patients (P = 0.0014, Wilcoxon-Mann-Whitney test), whereas no differences in IL-8 levels were found between patients with or without adult respiratory distress syndrome. Patients who died had higher IL-8 levels on admission than the patients who survived. The largest differences in IL-8 levels between survivors and nonsurvivors was found when only patients with positive cultures were considered (P = 0.0342). IL-8 levels appeared to correlate significantly with lactate levels and inversely with leukocyte and platelet numbers and mean arterial pressure. In addition, the IL-8 level in the sepsis patients was found to correlate significantly with levels of IL-6, elastase-alpha 1-antitrypsin, and C3a. Serial observations revealed that in most patients IL-8 levels decreased, irrespective of the outcome. Thus, our results demonstrate that IL-8 levels are increased in most patients with sepsis and correlate with some important clinical, biochemical, and inflammatory parameters. These findings suggest a role for IL-8 in the pathophysiology of sepsis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; alpha 1-Antitrypsin; Bacteremia; Blood Pressure; Complement C3a; Enzyme-Linked Immunosorbent Assay; Factor XII; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Interleukin-6; Interleukin-8; Lactates; Lactic Acid; Lactoferrin; Leukocyte Elastase; Middle Aged; Pancreatic Elastase; Prekallikrein; Respiratory Distress Syndrome; Shock, Septic

Topics: Animals; Capillary Permeability; Cell Adhesion; Chemotactic Factors; Endothelium; Endotoxins; Humans; Inflammation; Interleukin-8; Lipopolysaccharides; Lung; Neutrophils; Oligopeptides; Rabbits; Respiratory Distress Syndrome