interleukin-8 and Lung-Diseases

Persistent neutrophilia is implicated in the pathology of several chronic lung diseases and consequently targeting the signals that drive the recruitment of these cells offers a plausible therapeutic strategy. The tripeptide Pro-Gly-Pro (PGP) is a neutrophil chemoattractant derived from extracellular matrix collagen and implicated in diseases such as COPD and cystic fibrosis. It was anticipated that PGP exerts its chemoatactic activity by mimicking key sequences found within classical neutrophil chemokines, such as CXCL8, and binding their receptors, CXCR1/2. Recently, however, the role of CXCR1/2 as the receptors for PGP has been questioned. In this issue of European Journal of Pharmacology, three studies address this controversy and demonstrate CXCR1/2 to be a common receptor for CXCL8 and PGP. Accordingly, these studies demonstrate the therapeutic potential of targeting this shared receptor to simultaneously alleviate neutrophilic inflammation driven by multiple neutrophil chemoattractants.

Topics: Acetylation; Chronic Disease; Humans; Interleukin-8; Lung Diseases; Molecular Targeted Therapy; Neutrophils; Oligopeptides; Proline; Receptors, CXCR

Fifteen years have passed since the first description of interleukin (IL)-8/CXCL8 as a potent neutrophil chemotactic factor. Accumulating evidence has demonstrated that various types of cells can produce a large amount of IL-8/CXCL8 in response to a wide variety of stimuli, including proinflammatory cytokines, microbes and their products, and environmental changes such as hypoxia, reperfusion, and hyperoxia. Numerous observations have established IL-8/CXCL8 as a key mediator in neutrophil-mediated acute inflammation due to its potent actions on neutrophils. However, several lines of evidence indicate that IL-8/CXCL8 has a wide range of actions on various types of cells, including lymphocytes, monocytes, endothelial cells, and fibroblasts, besides neutrophils. The discovery of these biological functions suggests that IL-8/CXCL8 has crucial roles in various pathological conditions such as chronic inflammation and cancer. Here, an overview of its protein structure, mechanisms of production, and receptor system will be discussed as well as the pathophysiological roles of IL-8/CXCL8 in various types of lung pathologies.

Topics: Animals; Humans; Interleukin-8; Lung Diseases

Chronic lung disease (CLD) has been associated with chorioamnionitis and upper respiratory tract colonisation with Ureaplasma urealyticum. The aim of this review is to describe the increasing evidence that inflammation plays a critical role in the early stages of CLD of the neonate. Ongoing lung damage in the premature infant may be caused by failure to downregulate and control this inflammatory response. Tumour necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and IL-8 are important pro-inflammatory cytokines of which IL-8 is an important chemotactic factor in the lung. Data suggest that preterm newborns with lung inflammation may be unable to activate the anti-inflammatory cytokine IL-10. Therefore, early post-natal anti-inflammatory therapy could help in preventing development of CLD. Prophylactic dexamethasone therapy cannot yet be recommended. There are a number of potential interactions between surfactant and cytokine effects on the preterm lung which have not been evaluated. Surfactant protein A may be an important modulator of the immune response to lung injury. The role of high-frequency ventilation in the prevention of CLD still remains unclear.. Many aspects of the pathogenesis of the inflammatory response in the development of chronic lung disease remain to be elucidated. Further research to identify preterm infants at highest risk for the development of this multifactorial and complex disease is needed.

Topics: Chorioamnionitis; Chronic Disease; Cytokines; Female; Humans; Infant, Newborn; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Lung Diseases; Pregnancy; Pulmonary Surfactants; Tumor Necrosis Factor-alpha

Inflammatory cells are thought to be instrumental in the pathophysiology of pulmonary diseases, and control of their recruitment and activation in the lung would appear to be an attractive strategy for therapeutic intervention. Interleukin-8 and related CXC chemokines are involved in the function of neutrophils and T cells, and have been implicated in several lung diseases. Small-molecule antagonists of the interleukin-8 receptors have been identified, which may help elucidate the role of interleukin-8 and related chemokines in the pathophysiology of lung diseases.

Topics: Animals; Humans; Interleukin-8; Lung Diseases; Receptors, Interleukin-8A

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

Patients with head injury must overcome central as well as peripheral metabolic insults. In addition to specific tissue damage to the brain, a cellular biochemical cascade occurs that can negatively affect organ function, cause a systemic response to injury, and may cause secondary tissue injury. The metabolites involved in this cascade are numerous and complex. Cytokines are important cell-to-cell communication mediators during injury. It is speculated that cytokines, such as interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF), and interleukin 8 (IL-8), which are found in elevated amounts in both human and basic trials after head injury, play a role in the cellular cascade of injury. Some of the metabolic events produced by small doses of cytokine infusion in animals, as well as humans, include fever, neutrophilia, muscle breakdown, altered amino acid metabolism, depression of serum zinc levels, production of hepatic acute phase reactants, increased endothelial permeability, and expression of endothelial adhesion molecules. These are all known sequelae of severe head injury. Cytokines have also been implicated in organ failure. Infusion of cytokines in basic science trials revealed that organ functions of the gut, liver, and lung are negatively altered by high-dose cytokine infusion. Infusion of certain cytokines has been shown to cause death of brain cells, increase blood-brain barrier permeability, and cause cerebral edema. This suggests that cytokines may also play a role in the sequelae of organ demise. These effects of cytokines have been attenuated in basic trials by blocking the initial signaling system of cytokines or by decreasing serum cytokine activity. We hypothesize that cytokines that are elevated after head injury play a role in the pathology of injury, including altered metabolism and organ demise.

Topics: Animals; Craniocerebral Trauma; Cytokines; Gastrointestinal Diseases; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Liver Diseases; Lung Diseases; Rabbits; Tumor Necrosis Factor-alpha

Neutrophil infiltration into inflammatory sites is one of the hallmarks of acute inflammation. Locally produced chemotactic factors are presumed to mediate the sequence of events leading to the infiltration at inflammatory sites. Interleukin-8 (IL-8), a novel leukocyte chemotactic activating cytokine (chemokine), is produced by various types of cells upon stimulation with inflammatory stimuli and exerts a variety of functions on leukocytes, particularly, neutrophils in vitro. However, no definitive evidence has been presented on its role in recruiting and activating neutrophils in the lesions of various types of inflammatory reactions. We administered a highly specific neutralizing antibody against IL-8 in several types of acute inflammatory reactions, including lipopolysaccharide (LPS)-induced dermatitis, LPS/IL-1-induced arthritis, lung reperfusion injury, and acute immune complex-type glomerulonephritis. Anti-IL-8 treatment prevented neutrophil-dependent tissue damage as well as neutrophil infiltration in these conditions. These results suggest that IL-8 plays a causative role in acute inflammation by recruiting and activating neutrophils.

Topics: Animals; Antibodies; Antigen-Antibody Complex; Arthritis; Cross Reactions; Dermatitis; Glomerulonephritis; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-8; Lipopolysaccharides; Lung Diseases; Neutrophil Activation; Neutrophils; Rabbits; Reperfusion Injury

Topics: Animals; Chemotactic Factors; Humans; Interleukin-8; Lung Diseases; Neutrophils; Receptors, Interleukin; Receptors, Interleukin-8A

Topics: Arteriosclerosis; Arthritis, Rheumatoid; Chemokine CCL2; Chemotactic Factors; Humans; Interleukin-8; Lung Diseases; Neutrophils; Reperfusion Injury

Topics: Animals; Asthma; Blood Platelets; Eosinophils; Humans; Inflammation; Interleukin-8; Lung Diseases

Postoperative pulmonary complications (PPCs) following orthotopic liver transplantation (OLT) are associated with high morbidity and mortality rates. The effect of

Topics: Acetylcysteine; Administration, Inhalation; Breath Tests; Exhalation; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Liver Transplantation; Lung; Lung Diseases; Male; Middle Aged; Oxidative Stress; Postoperative Complications; Tumor Necrosis Factor-alpha; Uteroglobin

The aim of this study was to evaluate in patients with cystic fibrosis (CF) the effect of Lactobacillus reuteri (LR) on the rate of respiratory exacerbations and of the infections of both upper respiratory and gastrointestinal tracts.. Prospective randomized, double-blind, placebo-controlled study enrolling 61 patients with CF with mild-to-moderate lung disease at the Regional Center for CF of the Department of Pediatrics, University of Rome "La Sapienza." All of the patients were not hospital inpatients at the time of the enrollment. Inclusion criteria were forced expiratory volume in the first second (FEV1) >70% predicted; no inhaled or systemic steroids, no anti-inflammatory drugs, antileukotrienes, and mast cell membrane stabilizers; and no serious organ involvement. Exclusion criteria were a history of pulmonary exacerbation or upper respiratory infection in the previous 2 months; changes in medications in the last 2 months; a history of hemoptysis in the last 2 months; and colonization with Burkholderia cepacia or mycobacteria. Patients were randomly assigned to receive LR (30 patients) in 5 drops per day (10(10) colony-forming units) or placebo (31 patients) for 6 months. Main outcomes were number of episodes of pulmonary exacerbations and hospital admissions for pulmonary exacerbations, number of gastrointestinal and upper respiratory tract infections. FEV1, fecal calprotectin, and cytokine profile in induced sputum and plasma were assessed at baseline and at the end of the trial.. Pulmonary exacerbations were significantly reduced in the LR group compared with the placebo group (P<0.01; odds ratio 0.06 [95% confidence interval {CI} 0-0.40]; number needed to treat 3 [95% CI 2-7]). Similarly, the number of upper respiratory tract infections (in our series only otitis) was significantly reduced in the LR group compared with the placebo group (P<0.05; odds ratio 0.14 [95% CI 0-0.96]; number needed to treat 6 [95% CI 3-102]). The 2 groups did not differ statistically in the mean number and duration of hospitalizations for pulmonary exacerbations and gastrointestinal infections. There was no significant statistical difference in the mean delta value of FEV1, fecal calprotectin concentration, and tested cytokines (tumor necrosis factor-α and interleukin-8) between the 2 groups.. LR reduces pulmonary exacerbations and upper respiratory tract infections in patients with CF with mild-to-moderate lung disease. LR administration may have a beneficial effect on the disease course of CF.

Topics: Adolescent; Adult; Child; Cystic Fibrosis; DNA-Binding Proteins; Double-Blind Method; Female; Forced Expiratory Volume; Gastrointestinal Diseases; Hospitalization; Humans; Interleukin-8; Leukocyte L1 Antigen Complex; Limosilactobacillus reuteri; Lung; Lung Diseases; Male; Nuclear Proteins; Numbers Needed To Treat; Probiotics; Prospective Studies; Respiratory Tract Infections; Transcription Factors; Tumor Necrosis Factor-alpha; Young Adult

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

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

To evaluate the effects of leukocyte-depleting filtration on myocardial and pulmonary protection and the inflammatory response in patients undergoing valve surgery.. Fifty-two patients who underwent mitral valve or mitral and aortic valve replacement were randomized into two groups with or without a leukocyte-depleting filter during surgery. The filter was used from 10 minutes before the release of the aortic cross-clamp to the end of cardiopulmonary bypass.. Total leukocyte and neutrophil counts showed a short-term reduction in patients undergoing leukocyte filtration, but there was no significant difference between the two groups during the study. Serum levels of cardiac troponin I were lower than that of the control group (p=0.030). Leukocyte depletion resulted in a significantly higher oxygenation index (p=0.002) and a lower respiratory index (p=0.003) compared with the control group. Serum levels of interleukin-8 were significantly elevated in patients undergoing leukocyte filtration compared with patients without leukocyte filtration (p=0.001). There were no statistically significant differences between the two groups with regards to the concentration of interleukin-6 and TNFα, or the duration of intensive care and hospital stay.. Leukocyte depletion is associated with improved myocardial and lung protection but does not appear to attenuate the inflammatory response in valve surgery.

Topics: Adult; Analysis of Variance; Aortic Valve; Biomarkers; Cardiopulmonary Bypass; China; Female; Heart Diseases; Heart Valve Prosthesis Implantation; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Leukocyte Reduction Procedures; Lung Diseases; Male; Middle Aged; Mitral Valve; Prospective Studies; Time Factors; Treatment Outcome; Troponin I; Tumor Necrosis Factor-alpha

Acute respiratory failure in neonates (e.g. ARDS, meconium aspiration pneumonitis, pneumonia) is characterized by an excessive inflammatory response, governing the migration of polymorpho-nuclear leukocytes (PMNLs) into lung tissue and causing consecutive impairment of gas exchange and lung function. Critical to this inflammatory response is the activation of nuclear factor-kappaB (NF-kappaB) that is required for transcription of the genes for many pro-inflammatory mediators. We asked whether the inhibition of NF-kappaB activity using either a selective inhibitor (IKK-NBD peptide) or dexamethasone would be more effective in decreasing NF-kappaB activity and chemokine expression in pulmonary cells. Changes in lung function were repeatedly assessed for 24h following induction of acute respiratory failure and therapeutic intervention. We conducted a randomized, controlled, prospective animal study with mechanically ventilated newborn piglets which underwent repeated airway lavage (20+/-2 [SEM]) to remove surfactant and to induce lung inflammation. Admixed to 100 mg kg(-1) surfactant, piglets then received either IKK-NBD peptide (S+IKK), a selective inhibitor of NF-kappaB activation, its control peptide without intrinsic activity, dexamethasone (S+Dexa), its solvent aqua, or an air bolus only (all groups n=8). After 24h of mechanical ventilation, the following differences were measured: PaO(2)/FiO(2) (S+IKK 230+/-9 mm Hg vs. S+Dexa 188+/-14, p<0.05); ventilation efficiency index (0.18+/-0.01 [3800/(PIP-PEEP)(*)f(*)PaCO(2)] vs. 0.14+/-0.01, p<0.05); extravascular lung water (24+/-1 ml kg(-1) vs. 29+/-2, p<0.05); PMNL in BAL fluid (112+/-21 cells microl(-1) vs. 208+/-34, p<0.05), IL-8 (351+/-117 pg ml(-1) vs. 491+/-144, p=ns) and leukotriene B(4) (23+/-7 pg ml(-1) vs. 71+/-11, p<0.01) in BAL fluid. NF-kappaB activity in the nucleus of pulmonary cells differed by 32+/-5% vs. 55+/-3, p<0.001. Differences between these two intervention groups were more pronounced in the second half of the observation period (hours 12-24). At 24h of mechanical ventilation, inhibition of NF-kappaB activity by IKK-NBD peptide admixed to surfactant as a carrier caused improved gas exchange, lung function and reduced pulmonary inflammation, as evidenced by reduction in PMNL migration into lung tissue due to reduced nuclear NF-kappaB activity. We conclude that IKK-NBD admixture to surfactant in acute neonatal respiratory failure is superior to dexamethasone administration within the fir

Topics: Acute Disease; Animals; Animals, Newborn; Anti-Inflammatory Agents; Blood Cell Count; Bronchoalveolar Lavage Fluid; Dexamethasone; Inflammation; Interleukin-8; Leukotriene B4; Lung Diseases; Neutrophils; NF-kappa B; Organ Size; Pulmonary Gas Exchange; Pulmonary Surfactants; Respiration, Artificial; Respiratory Tract Diseases; Swine

The purpose of this study is to examine the effects of neutrophil elastase inhibitor on postoperative cytokine levels in patients after esophagectomy.. Fifteen patients were divided into two groups; group 1: 9 patients receiving neutrophil elastase inhibitor (0.2 mg x kg(-1) x hr(-1) from the admission to ICU to extubation), group 2: 6 patients as a control. We measured neutrophil elastase activity, interleukin 1-beta, interleukin 6 and interleukin 8 preoperatively, just after the admission to ICU, and 24, 48 and 72 hours after the surgery.. There were significant differences in neutrophil elastase activity and interleukin 8 in group 1 24 hours after the surgery, compared with those in group 2. The time necessary for mechanical ventilation in group 1 was shorter than that in group 2 (group 1: 44.7 +/- 24.7 hrs, group 2: 112.8 +/- 90.3 hrs, P = 0.048).. The administration of neutrophil elastase inhibitor may be useful for patients after esophagectomy to reduce overexpression of plasma cytokine levels after surgery.

Topics: Cytokines; Esophageal Neoplasms; Esophagectomy; Glycine; Humans; Interleukin-8; Leukocyte Elastase; Lung Diseases; Postoperative Complications; Postoperative Period; Respiration, Artificial; Serpins; Sulfonamides; Time Factors

Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-8 play a key role in the inflammatory cascade after cardiopulmonary bypass (CPB) and may induce cardiac and lung dysfunction. Antiinflammatory cytokines such as IL-10 may also significantly limit these complications. Corticosteroid administration before CPB increases blood IL-10 levels and prevents proinflammatory cytokine release. This study examined the association of increased release of IL-10, stimulated by steroid pretreatment, with reduced myocardial and lung injury after CPB.. Twenty patients undergoing coronary artery bypass grafting (CABG) received either preoperative steroid (n = 10, protocol group) or no steroid (n = 10, control group). Perioperative care was standardized, and all caregivers were blinded to treatment group. Seven intervals of blood samples were obtained and assayed for TNF-alpha, IL-6, IL-8, and IL-10. Various hemodynamic and pulmonary measurements were obtained perioperatively. Levels of MB isoenzyme creatine kinase (CK-MB) were also measured.. In the protocol group, proinflammatory cytokines were significantly reduced while IL-10 levels were much higher after CPB. The protocol group had a lower alveolar-arterial oxygen gradient and higher ratio of arterial oxygen pressure to fraction of inspired oxygen after CPB. Creatine kinase (CK) and CK-MB were reduced in the patients treated with steroid. Correlations were found between plasma cytokines levels and cardiac index, and CK-MB.. This study confirms that corticosteroids abolish proinflammatory cytokines release and increase blood IL-10 levels after CPB. Our findings demonstrate a greater release of IL-10 induced by steroid pretreatment, and better heart and lung protection after CPB.

Topics: Aged; Analysis of Variance; Biomarkers; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Artery Disease; Cytokines; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Lung Diseases; Lung Injury; Male; Middle Aged; Myocardial Reperfusion Injury; Postoperative Period; Predictive Value of Tests; Preoperative Care; Prognosis; Prospective Studies; Reference Values; Risk Assessment; Statistics, Nonparametric; Steroids; Treatment Outcome; Tumor Necrosis Factor-alpha

Pro-inflammatory cytokines such as IL-8 play an important role in the inflammatory response to neonatal airway injury. Difficulty in detecting counter-regulatory cytokines such as IL-10 in lavage fluid from preterm infants led to the suggestion that its deficit may be a factor in the etiology of chronic lung disease of prematurity (CLD). The aim of the study was to determine IL-8 and IL-10 concentrations in lavage fluid from preterm infants ventilated for respiratory distress syndrome. Fifty infants <30 wk gestation were studied who had been randomized to receive a natural or synthetic surfactant. Lavage samples were collected daily for the first week and twice weekly thereafter. Samples were immediately centrifuged and stored at -70 degrees C. Cytokine concentrations were quantified in duplicate using commercially available sandwich ELISA kits. Lavage IL-10 concentration, at a minimum initially, rose significant over the first five postnatal days (p = 0.009). In the same samples, lavage IL-8 concentrations rose significantly over the first postnatal week (p < 0.001), the rise preceding that of IL-10. Infants dying or developing CLD had a significant early rise in both cytokine concentrations. Compared with infants developing CLD, lavage IL-10 concentrations were significantly higher on d 1 among those not developing CLD but significantly lower on d 4 (p < 0.05). To conclude, IL-10 is detectable in lavage fluid from ventilated preterm infants and its concentrations rise significantly over the first five postnatal days. In the same samples, IL-8 concentration also rises and this increase precedes the rise in IL-10.

Topics: Bronchoalveolar Lavage Fluid; Chronic Disease; Humans; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-8; Lung Diseases; Prognosis; Pulmonary Surfactants; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Time Factors

Cardiopulmonary bypass (CPB) induces an inflammatory response believed to contribute to postoperative morbidity. We hypothesized that the magnitude of the inflammatory response following CPB would be associated with adverse clinical outcomes.. Twenty-nine patients had plasma TNF, IL-6, IL-8, elastase, histamine, complement C5a, and complement C3a measured by ELISA before, during, and after cardiac operations employing CPB. Inflammatory mediator levels were analyzed with respect to outcomes.. Mediator levels peaked at 4 h post-CPB and either returned to baseline or substantially decreased by 24 h. Patients with peak mediator levels above the median for the group as a whole were classified as 'hyper-responders'; those with levels below the median were classified as 'normal responders'. While IL-8, C3a, and IL-6 levels were independently associated with adverse outcomes, TNF, histamine, and C5a levels were not. Elastase levels trended towards adverse outcomes. IL-8 'hyper-responders' experienced significantly greater postoperative weight gain and had higher IL-8 levels at 24 h (p<0.05), with trends towards renal impairment and protracted supplemental oxygen requirements. C3a 'hyper-responders' strongly trended towards increased bleeding, delayed extubation, greater postoperative weight gain, and decreased levels of independent functioning at discharge (p < or = 0.10). IL-6 'hyper-responders' experienced significantly more postoperative bleeding, delayed extubation, and higher IL-6 levels at 24 h compared to 'normal responders' (p < 0.05). They strongly trended towards greater postoperative weight gain and decreased levels of independent functioning at discharge (p < or = 0.10).. Patients who have an exaggerated inflammatory response to CPB tend to bleed more, require more respiratory support, demonstrate greater capillary leak via weight gain, and display a decline in independent functioning relative to normal responders. Thus, it appears that the magnitude of the inflammatory response to CPB adversely influences clinical outcomes.

Topics: Aged; Biomarkers; Cardiopulmonary Bypass; Complement C3a; Enzyme-Linked Immunosorbent Assay; Female; Heart Diseases; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Kidney Diseases; Lung Diseases; Male; Middle Aged; Pancreatic Elastase; Postoperative Complications; Treatment Outcome

The purpose of this study was to compare the effects of daily inhaled beclomethasone (3 x 500 microg) started on day 3 of life, with that of systemic dexamethasone (0.5 mg/kg/day) started between days 11-13 on clinical variables, lung inflammation, and pulmonary microvascular permeability in preterm infants at risk for chronic lung disease (CLD). Following administration of surfactant, preterm neonates with RDS and a birth weight of less than 1,200 g were included in this comparative observational pilot study when still mechanically ventilated and with an oxygen requirement on the third day of life. The patients (gestational age 26.1+/-0.9 weeks, birth weight 826+/-140 g, mean+/-SD) were alternately allocated to prophylactic treatment with inhaled beclomethasone (n = 7), or to early systemic dexamethasone therapy after day 10 of life, if clinically indicated (n = 9). Pulmonary inflammation and lung permeability were assessed by analyzing the levels of interleukin-8, elastase alpha1 proteinase inhibitor, free elastase activity, and albumin in tracheal aspirates on days 10 and 14 of life. The secretory component of IgA served as reference protein. We observed no significant differences in the concentrations of interleukin-8, elastase alpha1 proteinase inhibitor, and albumin between the two groups on day 10 of life. On day 14, 3 (median; range, 1-3) days following initiation of dexamethasone treatment, concentrations of the inflammatory mediators and of albumin were significantly lower in the group on systemic steroid therapy than in the group treated with inhaled steroids (P < 0.01). Additionally, there was a significant difference in oxygen requirements between both groups on day 14. In the group treated with inhaled steroids, concentrations of the inflammatory mediators, albumin, and oxygen requirements did not show a difference between day 10 and 14. We conclude that, in contrast to systemic dexamethasone treatment, a 12-day course of inhaled beclomethasone does not affect lung inflammation and pulmonary microvascular permeability in preterm infants at risk for CLD within the first 2 weeks of life.

Topics: Administration, Inhalation; Beclomethasone; Capillary Permeability; Chronic Disease; Dexamethasone; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Inflammation Mediators; Interleukin-8; Lung; Lung Diseases; Pancreatic Elastase; Pilot Projects; Protease Inhibitors; Respiration, Artificial

To determine if erythromycin given from birth reduces the inflammatory response and the incidence and severity of chronic lung disease.. Seventy five infants less than 30 weeks of gestation and ventilated from birth for lung disease were randomly assigned to receive erythromycin intravenously for 7 days or to no treatment. Ureaplasma urealyticum was detected in tracheal secretions by culture and polymerase chain reaction. Differential cell counts were obtained from bronchoalveolar lavage fluid collected daily for 5 days and concentrations of the cytokines interleukins IL-1 beta and IL-8, and tumour necrosis factor alpha (TNF-alpha) were measured. Chronic lung disease (CLD) was defined as oxygen dependency at 36 weeks of gestation.. Nine infants (13%) were positive for U urealyticum. The inflammatory cytokines in the lungs increased over the first 5 days of life in all babies, but no association was found between their concentrations and the development of CLD. Those treated with erythromycin showed no significant differences from the non-treated group in the differential cell counts or concentrations of the cytokines. The two groups had a similar incidence of CLD. Babies infected with U urealyticum did not have a more pronounced cytokine response than those without infection. Chorioamnionitis was associated with significantly higher concentrations of IL-1 beta and IL-8 on admission: these babies had less severe acute lung disease and developed significantly less CLD.. U urealyticum in the trachea was not associated with an increased inflammatory response in preterm infants. Erythromycin did not reduce the incidence or severity of CLD.

Topics: Anti-Bacterial Agents; Chronic Disease; Erythromycin; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Interleukin-1; Interleukin-8; Lung Diseases; Male; Trachea; Ureaplasma Infections; Ureaplasma urealyticum

The object of this study was to examine the hypothesis that meter-dosed, inhaled beclomethasone administered to premature infants beginning at birth in a tapering dosage schedule over the first 12 days of life attenuates bronchoalveolar lining fluid oxyradical inflammation concomitant with modulation of bronchopulmonary dysplasia. The design of this study was an unblinded, uncontrolled phase I, pilot investigation of inhaled beclomethasone primarily examining safety and administration. The setting was a tertiary care neonatal intensive care unit. Intubated, premature infants were studied longitudinally to 36 weeks corrected gestational age. Meter-dosed, inhaled beclomethasone was administered in a tapering dosage schedule over the first 12 days of life. Endotracheal tube aspirates were collected on Days 2, 4, and 6 of life and assayed for various markers of bronchoalveolar lining fluid oxyradical stress. Infants were also assessed with regards to a number of relevant clinical variables and presence or absence of bronchopulmonary dysplasia at 36 weeks corrected gestational age. Although no differences in clinical outcome were apparent in comparing nine control infants with nine beclomethasone-treated infants, bronchoalveolar lining fluid from control infants exhibited evidence of apparent phospholipid peroxidation (enhanced polyunsaturated fatty acid consumption) on Day 2 of life compared to beclomethasone-treated infants. Significant differences were noted for percent arachidonic acid, total polyunsaturated fatty acids and ratio of polyunsaturated fatty acids, to saturated fatty acids. The ratio of monohydroxyl linolenic acid to native linoleic acid (a more specific marker of lipid peroxidation) as well as myeloperoxidase activity (a marker of neutrophil oxyradical stress) tended to be higher in the control group but did not achieve statistical significance for this small subject number study. No adverse reactions related to meter-dosed, inhaled beclomethasone were noted in the treatment group; most specifically no evidence of hypothalamic-pituitary-adrenal axis suppression was noted in either control or beclomethasone-treated infants. Meter-dosed, inhaled beclomethasone in the dosage schedule utilized was safe and appeared to moderate bronchoalveolar lining fluid phospholipid peroxidation. Small numbers of infants entered into the present investigation preclude comments on clinical efficacy because of the likelihood of a statistical type 2 error. However

Topics: Administration, Inhalation; Beclomethasone; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Fatty Acids; Female; Gestational Age; Humans; Hypothalamo-Hypophyseal System; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-8; Lipid Peroxidation; Lung Diseases; Male; Nebulizers and Vaporizers; Peroxidase; Phospholipids; Pilot Projects; Pituitary-Adrenal System; Reactive Oxygen Species; Severity of Illness Index

Crack cocaine has become a major drug of abuse in the United States and its use is associated with a broad spectrum of pulmonary complications. The present study was conducted to determine whether controlled in vivo administration of cocaine (inhaled or IV) alters the function of circulating inflammatory cells in a manner capable of contributing to acute lung injury. Subjects who regularly smoked crack cocaine were asked to abstain from illicit drug use for at least 8 h, and were then administered one of the following treatments on each of 4 study days: inhaled cocaine base (45 mg), inhaled placebo (4.5 mg cocaine base, a subphysiologic dose), IV cocaine HCl (0.35 to 0.50 mg/kg), or IV placebo (saline solution). Samples of blood were obtained from a peripheral venous catheter and blood cells were isolated before and 10 to 45 min after treatment. The administration of either cocaine base or cocaine HCl, but not their corresponding placebos, resulted in the activation of circulating polymorphonuclear neutrophils (PMNs). Exposure to cocaine in vivo enhanced the antibacterial activity of PMNs, as measured by their ability to kill Staphylococcus aureus. Antitumor activity, as measured in an antibody-dependent cell-mediated cytotoxicity assay, also increased following short-term administration of cocaine. Finally, short-term exposure to cocaine enhanced production of interleukin 8, a potent PMN chemoattractant and neutrophil-activating factor associated with both acute and chronic lung injury. These studies demonstrate that short-term in vivo exposure to cocaine activates the effector function and cytokine production of circulating PMNs. Therefore, it is possible that bursts of acute inflammatory activity resulting from crack use could contribute to lung injury.

Topics: Administration, Inhalation; Adult; Antibody-Dependent Cell Cytotoxicity; Crack Cocaine; Female; Humans; Injections, Intravenous; Interleukin-8; Lung Diseases; Male; Middle Aged; Neutrophil Activation; Neutrophils; Phagocytosis; Substance-Related Disorders

Increasing evidences have suggested an important role of microRNAs (miRNAs) in regulating cell death processes including NETosis and apoptosis. Dysregulated expression of miRNAs and increased formation of neutrophil extracellular traps (NETs) and apoptosis participate in autoimmune-mediated diffuse alveolar hemorrhage (DAH), mostly associated with pulmonary capillaritis in systemic lupus erythematosus (SLE) patients. In particular, besides the inhibition of apoptosis, miR-146a can control innate and acquired immune responses, and regulate the toll-like receptor pathway through targeting TRAF6 to reduce the expression of pro-inflammatory cytokines/chemokines like IL-8, a NETosis inducer.. Expression of miR-146a, TRAF6 and NETs were examined in peripheral blood neutrophils (PBNs) and lung tissues from SLE-associated DAH patients, and in neutrophils and pristane-induced DAH lung tissues from C57BL/6 mice. To assess NETs formation, we examined NETosis-related DNAs morphology and crucial mediators including protein arginine deiminase 4 and citrullinated Histone 3. Expression of miR-146a and its endogenous RNA SNHG16 were studied in HL-60 promyelocytic cells and MLE-12 alveolar cells during NETosis and apoptosis processes, respectively. MiR-146a-overexpressed and CRISPR-Cas13d-mediated SNHG16-silenced HL-60 cells were investigated for NETosis. MiR-146a-overexpressed MLE-12 cells were analyzed for apoptosis. Pristane-injected mice received intra-pulmonary miR-146a delivery to evaluate therapeutic efficacy in DAH.. In DAH patients, there were down-regulated miR-146a levels with increased TRAF6 expression and PMA/LPS-induced NETosis in PBNs, and down-regulated miR-146a levels with increased TRAF6, high-mobility group box 1 (HMGB1), IL-8, NETs and apoptosis expression in lung tissues. HMGB1-stimulated mouse neutrophils had down-regulated miR-146a levels with increased TRAF6, IL-8 and NETs expression. PMA-stimulated HL-60 cells had down-regulated miR-146a levels with enhanced NETosis. MiR-146a-overexpressed or SNHG16-silenced HL-60 cells showed reduced NETosis. Apoptotic MLE-12 cells had down-regulated miR-146a expression and increased HMGB1 release, while miR-146a-overexpressed MLE-12 cells showed reduced apoptosis and HMGB1 production. There were down-regulated miR-146a levels with increased TRAF6, HMGB1, IL-8, NETs and apoptosis expression in mouse DAH lung tissues. Intra-pulmonary miR-146a delivery could suppress DAH by reducing TRAF6, IL-8, NETs and apoptosis expression.. Our results demonstrate firstly down-regulated pulmonary miR-146a levels with increased TRAF6 and IL-8 expression and NETs and apoptosis formation in autoimmune-mediated DAH, and implicate a therapeutic potential of intra-pulmonary miR-146a delivery.

Topics: Animals; Apoptosis; Extracellular Traps; Hemorrhage; HMGB1 Protein; Humans; Interleukin-8; Lung Diseases; Lupus Erythematosus, Systemic; Mice; Mice, Inbred C57BL; MicroRNAs; Neutrophils; TNF Receptor-Associated Factor 6

Exposure to benzo[a]pyrene (B[a]P) may be a risk factor for pulmonary diseases. To investigate the correlations among B[a]P exposure level, DNA strand breaks and pulmonary inflammation, we recruited 83 children diagnosed with pulmonary diseases and 63 healthy children from Guangzhou, China. Results showed that the levels of Benzo[a]pyrene diol epoxide (BPDE) DNA adduct in blood and IL-8 in serum in case group were significantly higher than those in control group (

Topics: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; Adolescent; Air Pollutants; Biological Monitoring; Child; Child, Preschool; China; Comet Assay; DNA Adducts; DNA Breaks; Female; Humans; Interleukin-8; Lung Diseases; Lymphocytes; Male; Polycyclic Aromatic Hydrocarbons; Risk Assessment

Brominated flame-retardant (BFRs) exposure promotes multiple adverse health outcomes involved in oxidative stress, inflammation, and tissues damage. We investigated BFR effects, known as polybrominated diphenyl ethers (PBDEs) (47, 99 and 209) in an air-liquid-interface (ALI) airway tissue derived from A549 cell line, and compared with ALI culture of primary human bronchial epithelial cells (pHBEC). The cells, exposed to PBDEs (47, 99 and 209) (0.01-1 μM) for 24 h, were studied for IL-8, Muc5AC and Muc5B (mRNAs and proteins) production, as well as NOX-4 (mRNA) expression. Furthermore, we evaluated tight junction (TJ) integrity by Trans-Epithelial Electrical Resistance (TEER) measurements, and zonula occludens-1 (ZO-1) expression in the cells, and pH variations and rheological properties (elastic G', and viscous G″, moduli) in apical washes of ALI cultures. N-acetylcysteine (NAC) (10 mM) effects were tested in our experimental model of A549 cells. PBDEs (47, 99 and 209) exposure decreased TEER, ZO-1 and pH values, and increased IL-8, Muc5AC, Muc5B (mRNAs and proteins), NOX-4 (mRNA), and rheological parameters (G', G″) in ALI cultures of A549 cell line and pHBEC. NAC inhibited PBDE effects in A549 cells. PBDE inhalation might impairs human health of the lungs inducing oxidative stress, inflammatory response, loss of barrier integrity, unchecked mucus production, as well as altered physicochemical and biological properties of the fluids in airway epithelium. The treatment with anti-oxidants restored the negative effects of PBDEs in epithelial cells.

Topics: A549 Cells; Aged; Bronchi; Electric Impedance; Epithelial Cells; Flame Retardants; Halogenated Diphenyl Ethers; Humans; Interleukin-8; Lung Diseases; Mucin 5AC; Mucin-5B; NADPH Oxidase 4; Oxidative Stress; Tight Junctions

Ginkgo biloba has long been used in ancient China for the treatment of cough, asthma, and other lung diseases. However, the active constituents in G. biloba for pulmonary disease treatment remain unclear. The objective of this study was to evaluate the anti-inflammatory active constituents in G. biloba and clarify their associated molecular mechanisms. The biological effects of different G. biloba extracts were evaluated in an ovalbumin-induced allergic mouse model. Anti-inflammatory compounds were present in the ethyl acetate phase of the extract, which were analysed by HPLC-MS. Biflavones were identified as the main compounds, which were further evaluated by docking calculations. Leukocyte elastase showed a high fit score with ginkgetin, one of the identified biflavones. The lowest binding free energy was -6.69 kcal mol-1. The effects of biflavones were investigated in vivo and in vitro. Ginkgetin markedly suppressed the abnormal expression of the Akt and p38 pathways in human neutrophil elastase (HNE)-stimulated A549 cells. Biflavones also decreased MUC5AC mRNA expression in HNE-stimulated A549 cells and the allergic mouse model. Inflammatory cells (neutrophils) and cytokines (IL-8) also decreased in mice treated with biflavones. The results suggest that G. biloba biflavones could inhibit the activity of leukocyte elastase. This in turn implicates G. biloba as a functional food for the treatment of airway inflammation.

Topics: Animals; Anti-Inflammatory Agents; Biflavonoids; Female; Ginkgo biloba; Humans; Interleukin-8; Lung Diseases; Male; Mice; Mice, Inbred BALB C; Mucin 5AC; Plant Extracts; Plant Leaves

The effects of methylamine on human health have been debated for several years, but the exact adverse outcomes and definite signaling cascades have not been elucidated yet. Herein, a NF-κB signal pathway, a positive regulator of inflammation was identified as the main pathway of methylamine exposure induced adverse effects in bronchial airway cells (16HBE) for the first time. The results indicated that methylamine could stimulate the overproduction of reactive oxygen species (ROS) in cytoplasm and mitochondria of 16HBE cells. Moreover, ROS accelerate the translocation and phosphorylation of NF-κB in nucleic and promote the expression of inflammatory, such as IL-8 and IL-6. As a result, methylamine was found to be increased ROS-mediated NF-κB activation in cells, leading to the production of inflammatory cytokine. Furthermore, the results also showed that methylamine could affect the expression of cytokines related genes, p53, STAT3, Bcl2, c-myc, Cyclin D, Hes1, Mcl-1, TGF-β2. The breakdown of those cell proliferation and apoptosis related genes were leading to a common toxic mechanism of cell death. In summary, our work uncovers a mechanism by which methylamine can induce the formation of inflammation response and demonstrates potential inflammation and carcinogenesis in human airway cell upon the methylamine inhaled.

Topics: Air Pollutants; Apoptosis; Cell Line; Cell Proliferation; Cytokines; Environmental Exposure; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung Diseases; Methylamines; Mitochondria; Phosphorylation; Protein Transport; Reactive Oxygen Species; Signal Transduction; Transcription Factor RelA

Neutrophil elastase (NE) is a key risk factor for severity of cystic fibrosis (CF) lung disease. Recent studies identified increased NE activity on the surface of airway neutrophils from CF-like mice and patients with CF. However, the role of surface-bound NE in CF lung disease remains unknown. We determined the relationship between surface-bound NE activity and severity of lung disease in CF.Surface-bound NE activity was measured on sputum neutrophils from 35 CF patients and eight healthy controls using novel lipidated Förster resonance energy transfer reporters and correlated with free NE activity, neutrophil counts, interleukin-8, myeloperoxidase and antiproteases in sputum supernatant, and with lung function parameters.Surface-bound NE activity was increased in CF compared to healthy controls (p<0.01) and correlated with free NE activity (p<0.05) and other inflammation markers (p<0.001). Surface-bound and free NE activity correlated with forced expiratory volume in 1 s % predicted (p<0.01 and p<0.05), but only surface-bound NE activity correlated with plethysmographic functional residual capacity % pred (p<0.01) in patients with CF.We demonstrate that surface-bound NE activity on airway neutrophils correlates with severity of lung disease in patients with CF. Our results suggest that surface-bound NE activity may play an important role in the pathogenesis and serve as novel biomarker in CF lung disease.

Topics: Adult; Cystic Fibrosis; Female; Humans; Interleukin-8; Leukocyte Elastase; Lung Diseases; Male; Middle Aged; Neutrophils; Peroxidase; Respiratory Function Tests; Risk Factors; Severity of Illness Index; Spirometry; Sputum; Young Adult

Airway inflammation is often associated with bacterial infections and represents a major determinant of lung disease. The in vivo determination of the pro-inflammatory capabilities of various factors is challenging and requires terminal procedures, such as bronchoalveolar lavage and the removal of lungs for in situ analysis, precluding longitudinal visualization in the same mouse. Here, lung inflammation is induced through the intratracheal instillation of Pseudomonas aeruginosa culture supernatant (SN) in transiently transgenized mice expressing the luciferase reporter gene under the control of a heterologous IL-8 bovine promoter. Luciferase expression in the lung is monitored by in vivo bioluminescent image (BLI) analysis over a 2.5- to 48-h timeframe following the instillation. The procedure can be repeated multiple times within 2 - 3 months, thus permitting the evaluation of the inflammatory response in the same mice without the need to terminate the animals. This approach permits the monitoring of pro- and anti-inflammatory factors acting in the lung in real time and appears suitable for functional and pharmacological studies.

Topics: Animals; Disease Models, Animal; Inflammation; Interleukin-8; Luminescent Measurements; Lung Diseases; Male; Mice; Mice, Transgenic; Pseudomonas aeruginosa; Transfection

To what extent the risks of neonatal morbidities are directly related to premature birth or to biological mechanisms of preterm birth remains uncertain. We aimed to examine the effect of exposure to amniotic fluid (AF) infection and elevated cytokine levels on the mortality and pulmonary, intestinal, and neurologic outcomes of preterm infants, and whether these associations persist after adjustment for gestational age at birth. This retrospective cohort study included 152 premature singleton infants who were born at ≤ 32 weeks. AF obtained by amniocentesis was cultured; and interleukin-6 (IL-6) and IL-8 levels in AF were determined. The primary outcome was adverse perinatal outcome defined as the presence of one or more of the followings: stillbirth, neonatal death, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, and periventricular leukomalacia. Logistic regression analysis was adjusted for gestational age at birth and other potential confounders. In bivariate analyses, elevated AF IL-6 and IL-8 levels were significantly associated with adverse perinatal outcome. These results were not changed after adjusting for potential confounders, such as low Apgar scores, mechanical ventilation, and surfactant application. However, the independent effect of elevated cytokine levels in AF disappeared when additionally adjusted for low gestational age at birth; consequently, low gestational age remained strongly associated with the risk of adverse perinatal outcome. In conclusion, elevated levels of pro-inflammatory cytokines in AF are associated with increased risk of adverse perinatal outcomes, but this risk is not independent of low gestational age at birth. Culture-proven AF infection is not associated with this risk.

Topics: Adult; Amniotic Fluid; Area Under Curve; Chorioamnionitis; Enterocolitis, Necrotizing; Enzyme-Linked Immunosorbent Assay; Female; Gestational Age; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Interleukin-6; Interleukin-8; Leukomalacia, Periventricular; Logistic Models; Lung Diseases; Male; Multivariate Analysis; Odds Ratio; Perinatal Mortality; Pregnancy; Premature Birth; Retrospective Studies; Risk Factors; ROC Curve; Young Adult

The severity of cystic fibrosis (CF) is associated with classes of mutations in the CFTR gene (cystic fibrosis transmembrane regulator), physical environment and modifier genes interaction. The IL8 gene (interleukin 8), according to its respective polymorphisms, influences inflammatory responses. This study analyzed IL8 gene polymorphisms (rs4073, rs2227306 and rs2227307), by means of PCR/RFLP, and their association with pulmonary function markers and clinical severity scores in 186 patients with CF, considering the CFTR genotype. There was an association between rs2227307 and precocity of the disease. The severity of lung disease was associated with the following markers: transcutaneous arterial hemoglobin oxygen saturation (SaO2) (regardless of CFTR genotype, for the polymorphisms rs4073, rs2227306 and rs2227307); mucoid Pseudomonas aeruginosa (regardless of CFTR genotype, for the polymorphisms rs2227306 and rs2227307). Pulmonary function markers (SaO2 and spirometric variables) and clinical severity scores were also associated with IL8 gene polymorphisms. This study identified the IL8 gene, represented by rs4073 and rs2227306 polymorphisms, and particularly the rs2227307 polymorphism, as potentiating factors for the degree of variability in the severity of CF, especially in pulmonary clinical manifestation correlated with increased morbidity and mortality.

Topics: Adolescent; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genetic Association Studies; Genotype; Hemoglobins; Humans; Inflammation; Interleukin-8; Lung Diseases; Male; Oxygen; Polymorphism, Single Nucleotide; Pseudomonas aeruginosa; Pseudomonas Infections; Severity of Illness Index

Epidemiological studies have demonstrated the exacerbation of respiratory diseases following sandstorm-derived particulate matter (PM) exposure. The presence of anthropogenic and biological agents on the sandstorm PM and the escalation of PM<2.5μm (PM2.5) pollution in China have led to serious concerns regarding the health effects of PM2.5 during Asian sandstorms. We investigated how changes in PM2.5 composition, as the weather transitioned towards a sandstorm, affected human airway epithelial cells. Six PM2.5 samples covering two sandstorm events and their respective background and transition periods were collected in Baotou, an industrial city near the Gobi Desert in China. PM samples from all three periods had mild cytotoxicity in human bronchial epithelial cell line BEAS-2B, which was positively correlated with the contents of polycyclic aromatic hydrocarbons and several metals. All PM samples potently increased the release of interleukin-6 (IL-6) and interleukin-8 (IL-8). Endotoxin in all samples contributed significantly to the IL-6 response, with only a minor effect on IL-8. Cr was positively correlated with both IL-6 and IL-8 release, while Si was only associated with the increase of IL-6. Our study suggests that local agricultural and industrial surroundings in addition to the sandstorm play important roles in the respiratory effects of sandstorm-derived PM.

Topics: Air Pollutants; China; Environmental Exposure; Epithelial Cells; Humans; Interleukin-6; Interleukin-8; Lung Diseases; Meteorological Concepts; Particulate Matter

β-Glucuronidase is a lysosomal enzyme released into the extracellular fluid during inflammation. Increased β-glucuronidase activity in the cerebrospinal and peritoneal fluid has been shown to be a useful marker of bacterial inflammation. We explored the role of β-glucuronidase in the detection of bacterial infection in bronchoalveolar lavage fluid (BALF) of paediatric patients.. In this case-control study, % polymorphonuclear cell count (PMN%), β-glucuronidase activity, interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α) and elastase were measured in culture-positive (≥10(4) cfu/mL, C+) and -negative (C-) BALF samples obtained from children.. A total of 92 BALF samples were analysed. The median β-glucuronidase activity (measured in nanomoles of 4-methylumbelliferone (4-MU)/mL BALF/h) was 246.4 in C+ (interquartile range: 71.2-751) and 21.9 in C- (4.0-40.8) (P < 0.001). The levels of TNF-α and IL-8 were increased in C+ as compared with C- (5.4 (1.7-12.6) vs 0.7 (0.2-6.2) pg/mL, P < 0.001 and 288 (76-4300) vs 287 (89-1566) pg/mL, P = 0.042, respectively). Elastase level and PMN% did not differ significantly (50 (21-149) vs 26 (15-59) ng/mL, P = 0.051 and 20 (9-40) vs 18 (9-34) %, P = 0.674, respectively). The area under the curve of β-glucuronidase activity (0.856, 95% confidence interval (CI): 0.767-0.920) was higher than that of TNF-α (0.718; 95% CI: 0.614-0.806; P = 0.040), IL-8 (0.623; 95% CI: 0.516-0.722; P = 0.001), elastase (0.645; 95% CI: 0.514-0.761; P = 0.008) and PMN% (0.526; 95 % CI: 0.418-0.632; P < 0.001).. This study demonstrates a significant increase of β-glucuronidase activity in BALF of children with culture-positive bacterial inflammation. In our population β-glucuronidase activity showed superior predictive ability for bacterial lung infection than other markers of inflammation.

Topics: Adolescent; Area Under Curve; Bacterial Infections; Biomarkers; Bronchoalveolar Lavage Fluid; Case-Control Studies; Child; Child, Preschool; Female; Glucuronidase; Humans; Inflammation; Interleukin-8; Leukocyte Count; Lung; Lung Diseases; Male; Neutrophils; Pancreatic Elastase; Respiratory Tract Infections; ROC Curve; Tumor Necrosis Factor-alpha

This study aimed to evaluate the ability of the forced oscillation technique (FOT) to detect underlying lung disease in preschool children with cystic fibrosis (CF) diagnosed following newborn screening.184 children (aged 3-6 years) with CF underwent lung function testing on 422 occasions using the FOT to assess respiratory resistance and reactance at the time of their annual bronchoalveolar lavage collection and chest computed tomography scan. We examined associations between FOT outcomes and the presence and progression of respiratory inflammation, infection and structural lung disease.Children with CF who had pronounced respiratory disease, including free neutrophil elastase activity, infection with pro-inflammatory pathogens and structural lung abnormalities had similar FOT outcomes to those children without detectable lung disease. In addition, the progression of lung disease over 1 year was not associated with worsening FOT outcomes.We conclude that the forced oscillation technique is relatively insensitive to detect underlying lung disease in preschool children with CF. However, FOT may still be of value in improving our understanding of the physiological changes associated with early CF lung disease.

Topics: Airway Resistance; Bronchoalveolar Lavage; Child; Child, Preschool; Cohort Studies; Cross-Sectional Studies; Cystic Fibrosis; Female; Humans; Interleukin-8; Leukocyte Count; Longitudinal Studies; Lung; Lung Diseases; Male; Neutrophils; Respiratory Function Tests; Tomography, X-Ray Computed

The mechanism underlying pulmonary inflammation in thermal inhalation injury remains elusive. Cystic fibrosis, also hallmarked with pulmonary inflammation, is caused by mutations in CFTR, the expression of which is temperature-sensitive. We investigated whether CFTR is involved in heat-induced pulmonary inflammation. We applied heat-treatment in 16HBE14o- cells with CFTR knockdown or overexpression and heat-inhalation in rats in vivo. Heat-treatment caused significant reduction in CFTR and, reciprocally, increase in COX-2 at early stages both in vitro and in vivo. Activation of ERK/JNK, NF-κB and COX-2/PGE2 were detected in heat-treated cells, which were mimicked by knockdown, and reversed by overexpression of CFTR or VX-809, a reported CFTR mutation corrector. JNK/ERK inhibition reversed heat-/CFTR-knockdown-induced NF-κB activation, whereas NF-κB inhibitor showed no effect on JNK/ERK. IL-8 was augmented by heat-treatment or CFTR-knockdown, which was abolished by inhibition of NF-κB, JNK/ERK or COX-2. Moreover, in vitro or in vivo treatment with curcumin, a natural phenolic compound, significantly enhanced CFTR expression and reversed the heat-induced increases in COX-2/PGE2/IL-8, neutrophil infiltration and tissue damage in the airway. These results have revealed a CFTR-regulated MAPK/NF-κB pathway leading to COX-2/PGE2/IL-8 activation in thermal inhalation injury, and demonstrated therapeutic potential of curcumin for alleviating heat-induced pulmonary inflammation.

Topics: Aminopyridines; Animals; Benzodioxoles; Cell Line; Curcumin; Cyclooxygenase 2; Cystic Fibrosis Transmembrane Conductance Regulator; Dinoprostone; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases; Hot Temperature; Inflammation; Inhalation; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lung Diseases; Male; Microscopy, Fluorescence; Mitogen-Activated Protein Kinases; NF-kappa B; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA Interference; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Up-Regulation

Lung disease in cystic fibrosis (CF) is often exacerbated following acute upper respiratory tract infections caused by the human rhinovirus (HRV). Pathophysiology of these exacerbations is presently unclear and may involve deficient innate antiviral or exaggerated inflammatory responses in CF airway epithelial cells. Furthermore, responses of CF cells to HRV may be adversely affected by pre-exposure to virulence factors of Pseudomonas (P.) aeruginosa, the microorganism that frequently colonizes CF airways. Here we examined production of antiviral cytokine interferon-β and inflammatory chemokine interleukin-8, expression of the interferon-responsive antiviral gene 2'-5'-oligoadenylate synthetase 1 (OAS1), and intracellular virus RNA load in primary CF (delF508 CFTR) and healthy airway epithelial cells following inoculation with HRV16. Parallel cells were exposed to virulence factors of P. aeruginosa prior to and during HRV16 inoculation. CF cells exhibited production of interferon-β and interleukin-8, and expression of OAS1 at levels comparable to those in healthy cells, yet significantly higher HRV16 RNA load during early hours post-inoculation with HRV16. In line with this, HRV16 RNA load was higher in the CFBE41o- dF cell line overexpessing delF508 CFTR, compared with the isogenic control CFBE41o- WT (wild-type CFTR). Pre-exposure to virulence factors of P. aeruginosa did not affect OAS1 expression or HRV16 RNA load, but potentiated interleukin-8 production. In conclusion, CF cells demonstrate elevated HRV RNA load despite preserved interferon-β and OAS1 responses. High HRV load in CF airway epithelial cells appears to be due to deficiencies manifesting early during HRV infection, and may not be related to interferon-β.

Topics: 2',5'-Oligoadenylate Synthetase; Adult; Bronchi; Cell Line; Cystic Fibrosis; Epithelial Cells; Female; Genotype; Humans; Interferon-beta; Interleukin-8; Lung Diseases; Male; Primary Cell Culture; Pseudomonas aeruginosa; Recombinant Proteins; Rhinovirus; RNA, Viral; Viral Load; Virulence; Young Adult

Moringa oleifera Lam. (MO) has been reported to harbor anti-oxidation and anti-inflammatory activity and useful in the treatment of inflammatory diseases. However, despite these findings there has been little work done on the effects of MO on immune cellular function. Since macrophages, TNF and related cytokines play an important pathophysiologic role in lung damage induced by cigarette smoke, we examined the effects of MO on cigarette smoke extract (CSE)-induced cytokine production by human macrophages. An ethyl acetate fraction of MO (MOEF) was prepared from fresh leaves extract of Moringa and shown to consist of high levels of phenolic and antioxidant activities. Human monocyte derived macrophages (MDM) pre-treated with varying concentrations of MOEF showed decreased production of TNF, IL-6 and IL-8 in response to both LPS and CSE. The decrease was evident at both cytokine protein and mRNA levels. Furthermore, the extract inhibited the expression of RelA, a gene implicated in the NF-κB p65 signaling in inflammation. The findings highlight the ability of MOEF to inhibit cytokines (IL-8) which promote the infiltration of neutrophils into the lungs and others (TNF, IL-6) which mediate tissue disease and damage.

Topics: Acetates; Gene Expression; Humans; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Lung Diseases; Macrophages; Moringa oleifera; Neutrophils; NF-kappa B; Nicotiana; Plant Exudates; Signal Transduction; Smoke; Tumor Necrosis Factor-alpha

Applicability of cord blood interleukin-6 (IL-6) and interleukin-8 (IL-8) as markers for early prediction of the onset of chronic lung disease (CLD) due to intrauterine infection was investigated in the present study.. Eighty very low-birthweight infants with chorioamnionitis were divided into two groups: the CLD group (42 patients) and the non-CLD group (38 patients), according to the presence or absence of CLD, and the clinical background and cord blood IL-6 and IL-8 levels in each group were compared and investigated.. The CLD group had significantly longer duration of mechanical ventilation and hospitalization (P < 0.05) and significantly higher IL-6 and IL-8 (P < 0.01) than the non-CLD group. Using the receiver operating characteristic curves of CLD onset for both IL-6 and IL-8, the cut-off value of IL-6 for predicting onset of CLD was 48.0 pg/mL, and its sensitivity and specificity were 76% and 96%, respectively. The cut-off value for IL-8 was 66.0 pg/mL, and its sensitivity and specificity were 71% and 82%, respectively.. The cord blood levels of both IL-6 and IL-8 were significantly higher in the CLD group, indicating that both IL-6 and IL-8 are useful predictors of onset of CLD.

Topics: Age of Onset; Chronic Disease; Fetal Blood; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Interleukin-6; Interleukin-8; Lung Diseases; Predictive Value of Tests

Chronic rejection is the major problem hampering long-term survival after lung transplantation. Recently, it became clear that patients may develop an obstructive (bronchiolitis obliterans syndrome [BOS]) or a restrictive lung function defect (restrictive allograft syndrome [RAS]), for which specific risk factors are unknown.. A retrospective analysis of our lung transplantation cohort was performed (n=380). Patients with an irreversible decline in forced expiratory volume in 1 second were identified and classified as BOS or RAS. Patient characteristics, bronchoalveolar lavage (BAL) cellularity, rates of respiratory tract infection, colonization, acute rejection, and lymphocytic bronchiolitis were compared between BOS, RAS, and stable patients.. There were 103 patients suffering from chronic rejection, of which 79 had BOS and 24 were diagnosed with RAS. There were more patients with infection and pseudomonal colonizations in BOS and RAS compared with control (P=0.0090 and P=0.0034, respectively). More patients ever experienced acute and severe acute rejections (A≥2; both P<0.0001) and lymphocytic bronchiolitis (P=0.0006) in BOS and RAS versus control. There were more patients experiencing severe lymphocytic bronchiolitis in RAS compared with BOS (P=0.031). BAL neutrophilia in BOS and RAS were elevated at days 360, 540, and 720 versus control. BOS, but especially RAS patients, experienced more frequent episodes of increased BAL eosinophilia (≥2%; P<0.0001).. Acute rejection, lymphocytic bronchiolitis, colonization with pseudomonas, infection, and BAL eosinophilia and neutrophilia are risk factors for the later development not only of RAS but also of BOS.

Topics: Adult; Azithromycin; Bronchiolitis Obliterans; C-Reactive Protein; Female; Graft Rejection; Humans; Immunosuppressive Agents; Interleukin-8; Lung Diseases; Lung Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Transplantation, Homologous

Exposure to diesel engine exhaust particles (DEPs), representing a complex and variable mixture of components, has been associated with lung disease and induction of pro-inflammatory mediators and CYP1A1 expression. The aim of this study was to further characterise DEP-components accounting for these effects. Human bronchial epithelial cells (BEAS-2B) were exposed to either native DEPs, or corresponding methanol DEP-extract or residual DEPs, and investigated with respect to cytotoxicity and expression and release of multiple inflammation-related mediators. Both native DEPs and DEP-extract, but not residual DEPs, induced marked mRNA expression of COX-2, IL-6 and IL-8, as well as cytotoxicity and release of IL-6. However, CYP1A1 was primarily induced by the native and residual DEPs. Overall, the results of near-edge X-ray absorption fine structure (NEXAFS) spectroscopy and gas chromatography with mass spectrometry (GC/MS) analysis of DEP-extracts indicated that the majority of the analysed PAHs and PAH-derivatives were extracted from the particles, but that certain PAH-derivatives, probably their carboxylic isomers, tended to be retained on the residual DEPs. Moreover, it appeared that certain components of the methanol extract may suppress CYP1A1 expression. These results provide insight into how different components of the complex DEP-mixture may be differently involved in DEP-induced pro-inflammatory responses and underscore the importance of identifying and clarifying the roles of active DEP-components in relation to different biological effects.

Topics: Air Pollutants; Bronchi; Cell Line; Cell Survival; Cyclooxygenase 2; Cytochrome P-450 CYP1A1; Epithelial Cells; Humans; Interleukin-6; Interleukin-8; Lung Diseases; Polycyclic Aromatic Hydrocarbons; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vehicle Emissions; X-Ray Absorption Spectroscopy

MUC1 is a membrane-tethered mucin glycoprotein expressed on the apical surface of mucosal epithelial cells. Previous in vivo and in vitro studies established that MUC1 counterregulates airway inflammation by suppressing TLR signaling. In this article, we elucidate the mechanism by which MUC1 inhibits TLR5 signaling. Overexpression of MUC1 in HEK293 cells dramatically reduced Pseudomonas aeruginosa-stimulated IL-8 expression and decreased the activation of NF-κB and MAPK compared with cells not expressing MUC1. However, overexpression of MUC1 in HEK293 cells did not affect NF-κB or MAPK activation in response to TNF-α. Overexpression of MyD88 abrogated the ability of MUC1 to inhibit NF-κB activation, and MUC1 overexpression inhibited flagellin-induced association of TLR5/MyD88 compared with controls. The MUC1 cytoplasmic tail associated with TLR5 in all cells tested, including HEK293T cells, human lung adenocarcinoma cell line A549 cells, and human and mouse primary airway epithelial cells. Activation of epidermal growth factor receptor tyrosine kinase with TGF-α induced phosphorylation of the MUC1 cytoplasmic tail at the Y46EKV sequence and increased association of MUC1/TLR5. Finally, in vivo experiments demonstrated increased immunofluorescence colocalization of Muc1/TLR5 and Muc1/phosphotyrosine staining patterns in mouse airway epithelium and increased Muc1 tyrosine phosphorylation in mouse lung homogenates following P. aeruginosa infection. In conclusion, epidermal growth factor receptor tyrosine phosphorylates MUC1, leading to an increase in its association with TLR5, thereby competitively and reversibly inhibiting recruitment of MyD88 to TLR5 and downstream signaling events. This unique ability of MUC1 to control TLR5 signaling suggests its potential role in the pathogenesis of chronic inflammatory lung diseases.

Topics: Animals; Cell Line; Epithelial Cells; ErbB Receptors; Flagellin; Gene Expression Regulation; HEK293 Cells; Humans; Interleukin-8; Lung; Lung Diseases; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Mucin-1; Myeloid Differentiation Factor 88; NF-kappa B; Phosphorylation; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Mucosa; Signal Transduction; Toll-Like Receptor 5; Tumor Necrosis Factor-alpha

Interleukin (IL)-6, when complexed with soluble IL-6 receptor (sIL-6R), has emerged as an important modulator of chemokine expression and leukocyte recruitment during inflammation and in this state can be specifically antagonised by soluble gp130 (sgp130). The expression of these modifiers of IL-6 activity during ventilator-induced inflammation remains poorly understood.. To ascertain the expression pattern of IL-6, sIL-6R and sgp130 in response to mechanical ventilation in the preterm neonatal lung and define its relationship to associated markers of inflammation.. Inflammatory cell recruitment and expression of IL-6, sIL-6R, sgp130, IL-8 and monocyte chemotactic protein-1 (MCP-1) were quantified in tracheal aspirate fluid collected over a 14-day period from preterm (125 days) baboons undergoing mechanical ventilation.. Over the period of ventilation, the ratio of agonistic IL-6/sIL-6R increased 4.3-fold between days 3 and 10-11 (p < 0.01) while the ratio of antagonistic sgp130/IL-6 decreased 2.6-fold over the same period (p < 0.05). Over the same period, the relative numbers of neutrophils compared to mononuclear cells shifted from an excess of 1.8 on day 1 to 0.6 on day 14 (p < 0.01). Both IL-8 and MCP-1 were elevated between days 1 and 10-11 of ventilation (p < 0.01).. In the ventilated preterm baboon lung, expression of sIL-6R and dynamic modulation of sgp130 expression appear to modulate the activity and inflammatory potential of IL-6.

Topics: Animals; Animals, Newborn; Biomarkers; Chemokine CCL2; Cytokine Receptor gp130; Disease Models, Animal; Female; Inflammation; Interleukin-6; Interleukin-8; Lung; Lung Diseases; Neutrophils; Papio cynocephalus; Pregnancy; Premature Birth; Receptors, Interleukin-6; Respiration, Artificial

Respiratory insufficiency is the major cause of morbidity and mortality in patients affected by cystic fibrosis (CF). An excessive neutrophilic inflammation, mainly orchestrated by the release of IL-8 from bronchial epithelial cells and amplified by chronic bacterial infection with Pseudomonas aeruginosa, leads to progressive tissue destruction. The anti-inflammatory drugs presently used in CF patients have several limitations, indicating the need for identifying novel molecular targets. To address this issue, we preliminarily studied the association of 721 single nucleotide polymorphisms from 135 genes potentially involved in signal transduction implicated in neutrophil recruitment in a cohort of F508del homozygous CF patients with either severe or mild progression of lung disease. The top ranking association was found for a nonsynonymous polymorphism of the phospholipase C-β3 (PLCB3) gene. Studies in bronchial epithelial cells exposed to P. aeruginosa revealed that PLCB3 is implicated in extracellular nucleotide-dependent intracellular calcium signaling, leading to activation of the protein kinase Cα and Cβ and of the nuclear transcription factor NF-κB p65. The proinflammatory pathway regulated by PLCB3 acts by potentiating the Toll-like Receptors' signaling cascade and represents an interesting molecular target to attenuate the excessive recruitment of neutrophils without completely abolishing the inflammatory response.

Topics: Adenosine Triphosphate; Calcium; Cell Line, Transformed; Cystic Fibrosis; Enzyme Activation; Epithelial Cells; Gene Expression; Gene Frequency; Genotype; Green Fluorescent Proteins; Host-Pathogen Interactions; Humans; Interleukin-8; Isoenzymes; Lung Diseases; Microscopy, Fluorescence; Phospholipase C beta; Polymorphism, Single Nucleotide; Protein Kinase C; Protein Kinase C beta; Pseudomonas aeruginosa; RNA Interference; Toll-Like Receptors; Transcription Factor RelA

Our previous study showed that the interleukin-17 (IL-17) concentration in lung tissue and in bronchoalveolar lavage fluid (BALF) of rats with tobacco-smoke-induced chronic obstructive pulmonary disease (COPD) was higher than that of control group. However, whether IL-17 inhibitor could decrease the effect of tobacco smoking is not known yet.. To investigate the significance of IL-17 antibodies (Ab) in tobacco-smoke-exposed (TSE) mice.. Male C57/BL6 mice were randomly divided into three groups: TSE group, TSE + anti-IL-17 Ab group, and control group. The number of cells in BALF and the concentrations of IL-17, IL-6, IL-8 and MUC5AC in BALF and lung tissue homogenate were measured. Pulmonary function was measured by pressure sensors, and histologic analysis of the lungs was done in each group.. Lung function tests in TSE + anti-IL-17 Ab group were the same compared with TSE group (P > 0.05). The total cell count and the number of neutrophil cells in BALF were significantly higher in TSE group than the normal control group (P < 0.01). Compared with the TSE group, the total cell count in TSE + anti-IL-17 Ab group was decreased, and the percentage of neutrophils in BALF was highly decreased (P < 0.01). Airway inflammation was alleviated in TSE + anti-IL-17 Ab group by histologic analysis. The concentrations of IL-17 in lung tissue were significantly lower in TSE + anti-IL-17 Ab group than in TSE group (P < 0.01). IL-17 was mainly expressed in the epithelial cells in the airways of TSE mice. The concentration of IL-6, IL-8 and MUC5AC in BALF was decreased in TSE + anti-IL-17 Ab group compared with TSE group.. These data support a potential role for IL-17 in airway neutrophilic inflammation in TSE mice. Anti-IL-17 decreased the number of neutrophils as well as the concentration of MUC5AC in the BALF and attenuated neutrophilic airway inflammation.

Topics: Animals; Antibodies; Bronchoalveolar Lavage Fluid; Inflammation; Inhalation Exposure; Interleukin-17; Interleukin-6; Interleukin-8; Lung; Lung Diseases; Male; Mice; Mice, Inbred C57BL; Nicotiana; Smoke

The aim of the present study was to investigate the association of chronic lung disease (CLD), neonatal Ureaplasma colonization, and interleukin-8 (IL-8) level of cord blood in preterm infants.. In 77 infants of <32 weeks gestation, the relationship between IL-8 level of cord blood, neonatal colonization of Ureaplasma, histological chorioamnionitis (CAM), and development of CLD was studied.. Five infants died and 29 infants developed CLD. The CLD group had significantly lower gestation (mean ± SD: 26.6 ± 1.8 weeks) compared with the infants without CLD (28.9 ± 1.9 weeks, P < 0.0001). Logistic analysis showed that the development of CLD was associated with gestational age (odds ratio [OR], 0.5; 95% confidence interval (CI): 0.4-0.8) and Ureaplasma colonization (OR, 4.1; 95%CI: 1.2-14.4). Ureaplasma colonization was also associated with CAM (OR, 6.5; 95%CI: 1.8-23.5), absence of respiratory distress syndrome (OR, 6.2; 95%CI: 1.3-30.5), and development of CLD (OR, 4.0; 95%CI: 1.1-15.3). Elevated cord blood IL-8 ≥100 pg/mL was associated with female sex and the isolation of microorganisms (OR, 49.4; 95%CI: 4.6-525).. The development of CLD defined by oxygen requirement at 36 weeks was associated with neonatal Ureaplasma colonization but not with IL-8 level of cord blood. Elevated cord blood IL-8 was associated with neonatal microorganisms isolation.

Topics: Analysis of Variance; Biomarkers; Chronic Disease; Cohort Studies; Confidence Intervals; Female; Fetal Blood; Gestational Age; Humans; Incidence; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Interleukin-8; Lung Diseases; Male; Multivariate Analysis; Odds Ratio; Pregnancy; Prognosis; Prospective Studies; Respiratory Distress Syndrome, Newborn; Survival Rate; Ureaplasma; Ureaplasma Infections

Upon activation, neutrophils release DNA fibers decorated with antimicrobial proteins, forming neutrophil extracellular traps (NETs). Although NETs are bactericidal and contribute to innate host defense, excessive NET formation has been linked to the pathogenesis of autoinflammatory diseases. However, the mechanisms regulating NET formation, particularly during chronic inflammation, are poorly understood. Here we show that the G protein-coupled receptor (GPCR) CXCR2 mediates NET formation. Downstream analyses showed that CXCR2-mediated NET formation was independent of NADPH oxidase and involved Src family kinases. We show the pathophysiological relevance of this mechanism in cystic fibrosis lung disease, characterized by chronic neutrophilic inflammation. We found abundant NETs in airway fluids of individuals with cystic fibrosis and mouse cystic fibrosis lung disease, and NET amounts correlated with impaired obstructive lung function. Pulmonary blockade of CXCR2 by intra-airway delivery of small-molecule antagonists inhibited NET formation and improved lung function in vivo without affecting neutrophil recruitment, proteolytic activity or antibacterial host defense. These studies establish CXCR2 as a receptor mediating NADPH oxidase-independent NET formation and provide evidence that this GPCR pathway is operative and druggable in cystic fibrosis lung disease.

Topics: Animals; Cell Death; Chemokine CXCL2; Cystic Fibrosis; Enzyme Inhibitors; Extracellular Space; Humans; Inflammation; Interleukin-8; Lung Diseases; Mice; NADPH Oxidases; Neutrophil Activation; Neutrophils; Onium Compounds; Receptors, Interleukin-8B

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular pathogens, typically Staphylococcus aureus, which preferentially affect the skin and lung. Previous studies reported the defective differentiation of T helper 17 (Th17) cells in HIES patients caused by hypomorphic STAT3 mutations. However, the apparent contradiction between the systemic Th17 deficiency and the skin/lung-restricted susceptibility to staphylococcal infections remains puzzling. We present a possible molecular explanation for this enigmatic contradiction. HIES T cells showed impaired production of Th17 cytokines but normal production of classical proinflammatory cytokines including interleukin 1beta. Normal human keratinocytes and bronchial epithelial cells were deeply dependent on the synergistic action of Th17 cytokines and classical proinflammatory cytokines for their production of antistaphylococcal factors, including neutrophil-recruiting chemokines and antimicrobial peptides. In contrast, other cell types were efficiently stimulated with the classical proinflammatory cytokines alone to produce such factors. Accordingly, keratinocytes and bronchial epithelial cells, unlike other cell types, failed to produce antistaphylococcal factors in response to HIES T cell-derived cytokines. These results appear to explain, at least in part, why HIES patients suffer from recurrent staphylococcal infections confined to the skin and lung in contrast to more systemic infections in neutrophil-deficient patients.

Topics: Animals; Antigens, Bacterial; Antigens, Fungal; beta-Defensins; Chemokines; Cytokines; Epithelial Cells; Humans; Interleukin-8; Job Syndrome; Keratinocytes; Lung Diseases; Receptors, Interleukin-1; Respiratory Mucosa; Staphylococcal Infections; Staphylococcal Skin Infections; STAT3 Transcription Factor; T-Lymphocytes, Helper-Inducer

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

Topics: Bacterial Proteins; Blotting, Western; Humans; Immunohistochemistry; Interleukin-8; Internal Fixators; Lung; Lung Diseases; Pharmaceutical Solutions; Porins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Solutions

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 literature on cytokine response in systemic lupus erythematosus (SLE) is confusing. It is possible that different disease phenotypes have different cytokine profiles. Our aim was to examine the levels of selected pro-inflammatory and anti-inflammatory cytokines in SLE patients with and without pulmonary involvement.. Patients with SLE were interviewed and were subjected to the pulmonary function test and high-resolution computed tomography studies. Serum levels of interleukin (IL)-6, IL-8, IL-10, Il-12, interferon (IFN) gamma, and tumor necrosis factor (TNF) alpha were estimated by enzyme-linked immunosorbent assay.. Forty-nine of the 61 SLE patients had pulmonary involvement. Median levels of IL-8, IFNgamma, and TNFalpha were significantly higher in the pulmonary group as compared to the non-pulmonary group (p = 0.027, 0.027 and 0.002, respectively). Ratios of pro-inflammatory cytokines to anti-inflammatory cytokines were higher in the pulmonary group as compared to the non-pulmonary group as well as in the pulmonary restrictive subgroup compared to the obstructive subgroup.. Lupus patients with pulmonary involvement have a stronger pro-inflammatory cytokine bias than those without pulmonary involvement.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Female; Humans; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-6; Interleukin-8; Lung Diseases; Lupus Erythematosus, Systemic; Male; Middle Aged; Phenotype; Plethysmography, Whole Body; Spirometry; Tumor Necrosis Factor-alpha

Angiogenesis is a feature of chronic lung diseases such as asthma and pulmonary fibrosis; however, the pathways controlling pathological angiogenesis during lung disease are not completely understood. Adenosine is a signaling molecule that has been implicated in the exacerbation of chronic lung disease and in the regulation of angiogenesis; however, the relationship between these factors has not been investigated. The current study utilized adenosine deaminase (ADA)-deficient mice to determine whether chronic elevations in adenosine in vivo result in pulmonary angiogenesis. Results demonstrate substantial angiogenesis in the tracheas of ADA-deficient mice in association with adenosine elevations. ADA replacement enzyme therapy resulted in a lowering of adenosine levels and reversal of tracheal angiogenesis, indicating that the increases in vessel number are dependent on adenosine elevations. Levels of the angiogenic chemokine CXCL1 (mouse functional homologue of human IL-8) were found to be elevated in an adenosine-dependent manner in the lungs of ADA-deficient mice. Neutralization of CXCL1 and its receptor, CXCR2, resulted in the inhibition of angiogenic activity, which suggests that CXCL1 signaling through the CXCR2 receptor mediated the observed increases in angiogenesis. Our findings suggest that adenosine plays an important role, via CXCL1, in the induction of pulmonary angiogenesis.

Topics: Adenosine; Adenosine Deaminase; Animals; Chemokine CXCL1; Chemokines, CXC; Humans; Interleukin-8; Lung; Lung Diseases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neovascularization, Pathologic; Polyethylene Glycols; Receptors, Interleukin-8B; Signal Transduction

To investigate the effects of lycopene on T lymphocyte subpopulations and pulmonary alveolar macrophagic (PAM) functions in rats with acute lung injury (ALI).. Rats were randomly divided into the following groups. (1) Control group, (2) ALI model group, (3) Low dose group,(4) Mid dose group and (5) High dose group. Control group and ALI model group were treated with solvent of lycopene, and the other groups were gastrically incubated with lycopene. Thirty-five days later, control group were given physiological saline, ALI model group and lycopene administrated groups were injected with lipopolysaccharide (LPS) (6.0 mg/kg) to induce ALI. One hour, four hours or six hours after LPS or physiological saline challenged, abdominal aorta blood for measuring lymphocyte subpopulations and bronchoalveolar lavage fluid for measuring function of PAM were gathered respectively.. (1) At h 1, the percentages of CD3(+), CD4(+) and CD8(+) of lycopene administrated groups compared with control group were not significantly different. At h 4, the percentage of CD4(+) was similar to that at h 1. As for the percentages of CD3(+), except high dose group [(28.8+/-9.9)%] was significantly lower, low dose, mid dose and ALI model group showed no significant difference compared with control group[(39.5+/- 4.5)%]. The percentages of CD8(+) of ALI model and lycopene administrated rats, separately (10.2+/-3.9)%, (10.3+/-2.8)%, (9.8+/-2.8)%, (10.1+/-3.5)% , had been significantly reduced compared with control group[(15.1+/-2.5)%]; between ALI model and lycopene administrated groups there was no significant difference. The instance at h 6 was the same as that at h 4. The percentage ratios of CD4(+) T-lymphocyte to CD8(+) T-lymphocyte of ALI model rats were not significantly different compared with control group or lycopene administrated groups at h 1 and h 6. At h 4, the ratio of the CD4(+) and CD8(+) in Low dose and Mid dose groups had significant difference and ALI model, high dose hadn't when they were compared with control group. (2) Lycopene increased the phagocytic function of PAMs significantly at h 1(P<0.01), the optical density of PAM of control group, ALI model group, low dose group, mid dose group, high dose group was 0.136+/-0.025, 0.215+/-0.095, 0.239+/-0.052, 0.275+/-0.068 and 0.297+/-0.049; what happened at h 4 was similar to that at h 1; Phagocytic function of PAM of lycopene administrated groups was increased compared with control group. (3) The concentrations of tumor necrosis factor-alpha (TNF-alpha) in control group, ALI model group, low dose group, mid dose group, high dose groups were 1.50+/-0.30, 1.87+/-0.30, 1.76+/-0.40, 1.74+/- 0.38,1.62+/-0.35 microg/L;and those of IL-8 were 0.82+/-0.08, 0.99+/-0.14, 0.82+/-0.16, 0.84+/-0.16, 0.83+/-0.11 microg/L. The concentrations of TNF-alpha and interleukin-8 (IL-8) in BALF were decreased by lycopene, especially the levels of IL-8 were reduced significantly.. Lycopene might attenuate lipopolysaccharide-induced impairment of lungs and improve ALI prognosis by increasing the phagocytic function of PAMs significantly and restraining the secretion of TNF-alpha and IL-8.

Topics: Acute Disease; Adjuvants, Immunologic; Animals; Bronchoalveolar Lavage Fluid; Carotenoids; CD3 Complex; CD4-CD8 Ratio; Dose-Response Relationship, Drug; Interleukin-8; Lipopolysaccharides; Lung Diseases; Lycopene; Macrophages; Male; Phagocytosis; Random Allocation; Rats; Rats, Sprague-Dawley; T-Lymphocyte Subsets; Tumor Necrosis Factor-alpha

Chronic infection in cystic fibrosis (CF) and airway inflammation leads to progressive lung injury. Neutrophils are considered to be responsible for the onset and promotion of the inflammatory response within the CF lung. The relationship between infection and inflammation is complex but circulating inflammatory markers may not truly reflect the local inflammatory response in the lung. The aims of this study were to investigate the change of inflammatory biomarkers and cells within sputum and blood before and after intravenous antibiotics for a pulmonary exacerbation of CF.. Assays included neutrophil elastase (NE) and complex, interleukin-8 (IL-8) and soluble intercellular adhesion molecule-1 (sICAM-1), fas ligand (FAS-L), and TNFr-1. Analysis of sputum cell differential and absolute cell counts and immunocytochemistry (CD11b and CD95) on sputum and isolated blood neutrophils were carried out.. There were no significant differences in absolute or differential sputum cell counts or sputum sol measurements following antibiotics. There was a significant increase in the percentage of blood neutrophils with minimal CD11b staining, 28 (4.1) mean percentage (SEM) versus 41 (2.9) and a decrease in the percentage showing maximal staining 30 (0.5) versus 15 (2.5). There was a significant increase in the percentage of blood neutrophils without CD95 staining, 43 (5.4) mean percentage versus 52 (5.1).. These data suggest a modifiable systemic response to i.v. antibiotics but a local sustained inflammatory response in the lung.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Biomarkers; CD11b Antigen; Cell Survival; Cystic Fibrosis; Fas Ligand Protein; fas Receptor; Histocytochemistry; Humans; Injections, Intravenous; Intercellular Adhesion Molecule-1; Interleukin-8; Leukocyte Count; Lung Diseases; Neutrophils; Receptors, Tumor Necrosis Factor, Type I; Sputum

Protective ventilation strategies have been universally embraced because of reduced mortality. We tested the hypothesis that tidal volume (VT) in an in vivo model of mechanical ventilation would modulate bactericidal function of alveolar macrophages (AMs). Adult New Zealand White rabbits were mechanically ventilated for 4 h with a VT of 6 ml/kg (low) or a VT of 12 ml/kg (traditional), with each group receiving 3 cm H2O positive end-expiratory pressure with and without intratracheal lipopolysaccharide (LPS) instillation (20 mg/kg). AMs were isolated from bronchoalveolar lavage fluid taken from the whole left lung and used for bacterial killing assays. There were no significant differences in steady-state levels of nitrite or AM phagocytosis and killing of Klebsiella pneumoniae, although these values trended to be slightly higher in the traditional VT group. However, bronchoalveolar lavage fluid protein concentrations were significantly increased in traditional VT groups receiving LPS compared with animals ventilated with a low VT (1,407.8 +/- 121.4 versus 934.7 +/- 118.2; P < 0.001). Lung wet:dry weight ratio in the traditional VT group was increased when compared with the low VT group without LPS (7.3 +/- 0.4 versus 6.1 +/- 0.3, respectively; P < 0.05). Additionally, IL-8 expression was significantly greater under conditions of LPS treatment and mechanical ventilation at VT of 12 ml/kg. These results suggest that the traditional ventilator approach (12 ml/kg VT) in a model of in vivo mechanical ventilation results in lung pathology without affecting AM antibacterial function.

Topics: Animals; Bronchoalveolar Lavage Fluid; Extravascular Lung Water; Interleukin-8; Klebsiella pneumoniae; Lipopolysaccharides; Lung; Lung Diseases; Macrophages, Alveolar; Nitrites; Phagocytosis; Positive-Pressure Respiration; Proteins; Rabbits; Respiration, Artificial; Tidal Volume; Tumor Necrosis Factor-alpha

Local anesthetics inhibit mediator and free radical release from polymorphonuclear granulocytes and migration to their site of action. In a recent study, lidocaine significantly improved the alveolar-arterial oxygen difference gradients (A-aDO2) after tracheal instillation of acid in rabbits. The purpose of the current study was to evaluate the effects of lidocaine and pulse-dose steroids on human breast milk (HBM)-induced lung injury in rabbits.. After Animal Care Committee approval, six adult rabbits were assigned to each of three treatments: control, lidocaine, and steroids. After induction of anesthesia and controlled ventilation, acidified HBM at pH 1.8 and volume 1.2 ml.kg(-1) was instilled into the trachea. Rabbits in the lidocaine group received lidocaine 2 mg.kg(-1) i.v. before tracheal instillation and then 2 mg.kg(-1).h(-1) i.v. continuously. Rabbits in the steroid group received 30 mg.kg(-1) methylprednisolone before tracheal instillation. A-aDO2, static compliance and blood for white cell count, and cytokine interleukin-8 (IL-8) concentration were obtained at baseline and at 1 and 4 h postinstillation. After 4 h, the rabbits were killed. The left upper lobe was isolated and excised to determine the wet/dry ratio. The right lung was lavaged with 30 ml normal saline to determine the white cell count and the concentrations of albumin and IL-8. Data were analyzed using one- or two-way anova with repeated measures and an Student-Newman-Keuls (SNK) posthoc test (P < 0.05).. All rabbits completed the protocol. A-aDO2 and CO2 tensions increased significantly at 1 and 4 h compared with baseline, although there were no differences among the treatments (P < 0.05). Compliance in the control group decreased compared with lidocaine and steroids.. We conclude that preemptive lidocaine and steroids attenuate in part HBM-induced lung injury in rabbits.

Topics: Anesthetics, Local; Animals; Anti-Inflammatory Agents; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Data Interpretation, Statistical; Hydrogen-Ion Concentration; Interleukin-8; Leukocyte Count; Lidocaine; Lung Compliance; Lung Diseases; Milk, Human; Rabbits; Steroids

Topics: Epithelial Cells; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Interleukin-8; Lung Diseases; Toll-Like Receptors; Viruses

We recently found that low-molecular-weight hyaluronan was induced by cyclic stretch in lung fibroblasts and accumulated in lungs from animals with ventilator-induced lung injury. The low-molecular-weight hyaluronan produced by stretch increased interleukin-8 production in epithelial cells, and was accompanied by an upregulation of hyaluronan synthase-3 mRNA. We hypothesized that low-molecular-weight hyaluronan induced by high VT was dependent on hyaluronan synthase 3, and was associated with ventilator-induced lung injury. Effects of high VT ventilation in C57BL/6 wild-type and hyaluronan synthase-3 knockout mice were compared. Significantly increased neutrophil infiltration, macrophage inflammatory protein-2 production, and lung microvascular leak were found in wild-type animals ventilated with high VT. These reactions were significantly reduced in hyaluronan synthase-3 knockout mice, except the capillary leak. Wild-type mice ventilated with high VT were found to have increased low-molecular-weight hyaluronan in lung tissues and concomitant increased expression of hyaluronan synthase-3 mRNA, neither of which was found in hyaluronan synthase-3 knockout mice. We conclude that high VT induced low-molecular-weight hyaluronan production is dependent on de novo synthesis through hyaluronan synthase 3, and plays a role in the inflammatory response of ventilator-induced lung injury.

Topics: Algorithms; Animals; Chemokine CXCL2; Disease Models, Animal; Female; Glucuronosyltransferase; Hyaluronan Synthases; Interleukin-8; Lung; Lung Diseases; Lung Injury; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monokines; Respiration, Artificial; Tidal Volume

Persistence of neutrophils in the tracheal fluid of premature infants is associated with chronic lung disease (CLD). Interleukin-8 (IL-8) is a potent neutrophil chemoattractant. This study investigated whether IL-8 is increased in the bronchoalveolar lavage fluid of premature infants with different types of CLD.. Forty two very low birth weight infants who required mechanical ventilation were recruited. Twenty eight of these infants developed CLD and 14 infants recovered without developing CLD. Four additional infants receiving mechanical ventilation for non-respiratory reasons were also enrolled as controls. CLD was defined as requirement for supplemental oxygen at 28 days of age and chest radiograph showing characteristic appearance. CLD was further classified into 3 subtypes: bronchopulmonary dysplasia (BPD), Wilson-Mikity syndrome (WMS) and chronic pulmonary insufficiency of prematurity (CPIP).. IL-8 in bronchoalveolar lavage fluid was significantly increased in the CLD group by 8 days of age compared to those who did not develop CLD (p < 0.05). For infants without CLD, IL-8 increased from 963 pg/mL on day 1 after delivery to 1463 pg/mL on day 4, and decreased to 1,000 pg/mL on day 8. For infants with BPD, IL-8 increased from 925 pg/mL on day 1 after delivery to 2,650 pg/mL on day 8, and then gradually decreased to 1,500 pg/mL on day 28. Infants with WMS had significantly higher IL-8 from the first day after delivery (4,567 pg/mL) than infants with BPD or CPIP and this difference persisted to age 28 days (2475 pg/mL).. Persistent inflammation could be a major contributory factor in the development of CLD. The different patterns of response to inflammation in different types of CLD may have implications for the design of appropriate strategies to prevent and treat CLD.

Topics: Bronchoalveolar Lavage Fluid; Chronic Disease; Humans; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Interleukin-8; Lung Diseases; Respiration, Artificial

Despite that advances in neonatal medicine have significantly reduced the early mortality of premature infants, a considerable number of them are still prone to develop chronic lung disease (CLD) later. To find a method of early prevention, we investigated the efficacy of using certain early proinflammatory responses to predict the development of CLD. In the present study, 34 premature infants who required endotracheal intubation within 4 h of birth were recruited for analysis of IL-8, IL-10, and TNF-alpha levels in their bronchoalveolar lavage (BAL) fluid and blood. It was found that level of IL-8 but not TNF-alpha or IL-10 in initial BAL fluid was significantly correlated to neutrophils in the BAL and inversely correlated to the gestational age of prematurity. Elevation of IL-8 level in BAL on the first day of life was correlated to the development of CLD. Further studies showed that neonatal cord blood released significantly higher IL-8 but lower TNF-alpha levels after stimulation by endotoxin. The augmented IL-8 mRNA expression in cord blood was inhibited by actinomycin D but enhanced by cycloheximide, suggesting that IL-8 production is controlled by de novo transcriptional induction as well as posttranscriptional up-regulation of IL-8 by neonatal leukocytes, relating to the development of CLD. Thus, an appropriate modulation of initial IL-8 production in premature infants might be beneficial for the prevention of the development of CLD.

Topics: Adult; Bronchoalveolar Lavage Fluid; Chronic Disease; Cycloheximide; Cytokines; Dactinomycin; Endotoxins; Female; Fetal Blood; Gene Expression Regulation; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-8; Leukocytes; Lung Diseases; Male; Protein Synthesis Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA Processing, Post-Transcriptional; RNA, Messenger; Time Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha; Up-Regulation

Many epidemiology studies have reported associations between inhaled environmental pollutants, especially particles, and mortality or morbidity. Despite these impressive associations, fundamental uncertainties exist as to the underlying pathophysiological mechanisms responsible for mortality or morbidity following exposure to air pollutants. In vitro toxicology provides a powerful approach to describe these mechanisms at the cellular, biochemical, and molecular level. This manuscript will describe some advantages and limitations of in vitro toxicology studies in comparison with epidemiology studies, and human and animal exposure studies. A recent example will also be presented which demonstrates that the response of cultured cells to air pollution particles is similar to the response seen following in vivo exposure to the same particles. This coherence between an in vivo and in vitro response provides relevance to additional in vitro studies that characterize the mechanisms by which these particles cause adverse health effects.

Topics: Air Pollutants; Animals; Bronchi; Bronchoalveolar Lavage Fluid; Cell Line; Dose-Response Relationship, Drug; Humans; Inhalation Exposure; Interleukin-8; Lung Diseases; Respiratory Mucosa; Toxicity Tests

Pulmonary complications after orthotopic liver transplantation (OLT) include high morbidity and mortality. Experimental data have suggested hepatic ischemia and reperfusion are induced by pro-inflammatory cytokines. The high level of inflammatory cytokines might additionally influence pulmonary capillary fluid filtration. The objectives of this study were to measure the concentrations of tumor necrotic factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8) during OLT and to investigate the relationship between these cytokines and postoperative pulmonary complications.. Twenty-two patients undergoing OLT were divided into two groups according to whether they had postoperative pulmonary complications: group A consisting of 8 patients with postoperative pulmonary complications, and group B consisting of 14 patients without postoperative pulmonary complications. Enzyme-linked immunoassay (ELISA) was used to determine serum TNF-alpha, IL-6 and IL-8. Blood samples were taken at the beginning of operation (T0), clamping and cross-clamping of the inferior cava and portal vein (T1, T2), 90 minutes and 3 hours after reperfusion (T3, T4) and 24 hours after operation (T5).. The level of PaO2/FiO2 in group A was lower than that in group B (P<0.05). The concentrations of TNF-alpha, IL-6 and IL-8 in the two groups increased rapidly at T2, peaked at T3, decreased rapidly after T3 until 24 hours after operation. The concentrations of TNF-alpha, IL-6 and IL-8 in group A were higher than those in group B at T2, T3, and T4 (P<0.05).. After un-clamping of the inferior cava and portal vein, the serum concentrations of TNF-alpha, IL-6 and IL-8 increased may be related to pulmonary injury after hepatic ischemic reperfusion.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Interleukin-6; Interleukin-8; Liver Transplantation; Lung Diseases; Male; Middle Aged; Postoperative Complications; Postoperative Period; Probability; Risk Assessment; Sampling Studies; Statistics, Nonparametric; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha

Bronchoalveolar lavage fluid (BALF) in cystic fibrosis (CF) shows increased inflammation, which could be due to abnormal cytokine regulation. Bronchial epithelial cells and migratory inflammatory cells produce these cytokines, but few quantitative in vivo data are available comparing young CF patients with controls. We hypothesized that IL-8 mRNA abundance was higher in young CF vs. non-CF disease control patients in lung epithelium and inflammatory cells. Bronchial epithelial cells (BEC) were obtained by brush biopsy, and airway inflammatory cells (BALFC) by bronchoalveolar lavage, in 17 CF and 21 non-CF patients <5 years old undergoing clinically indicated bronchoscopy. Cellular mRNA expression was quantified by real-time PCR and normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Abundance of IL-8/GAPDH in BEC was significantly higher in CF (14.8 +/- 3.3) than non-CF (4.2 +/- 0.6) samples, and this difference was also significant when patients were stratified according to infection. In BALFC, the difference in IL-8 expression did not reach statistical significance: CF (17.1 +/- 6.5) vs. non-CF (6.8 +/- 1.9), but BALF cell number/ml was significantly higher in CF. IL-10 mRNA was very low in all samples, without showing a decrease in CF vs. non-CF patients. We conclude that early in the disease, IL-8 mRNA expression in BEC is increased in CF in vivo. Although IL-8 mRNA in migratory cells was not significantly higher in CF, these cells may still contribute to elevated IL-8 in airway secretions, secondary to increased cell density in BALF.

Topics: Bronchoalveolar Lavage Fluid; Child, Preschool; Cystic Fibrosis; Humans; Infant; Interleukin-10; Interleukin-8; Lung Diseases; RNA, Messenger

Burkholderia cenocepacia is an opportunistic pathogen that can cause severe lung infections in cystic fibrosis patients. To understand the contribution of B. cenocepacia flagella to infection, a strain mutated in the major flagellin subunit, fliCII, was constructed in B. cenocepacia K56-2 and tested in a murine agar bead model of lung infection. C57/BL6 mice infected with approximately 10(8) wild-type K56-2 bacteria exhibited 40% mortality after 3 days, whereas no mortality was noted in mice infected with the fliCII mutant. Among the mice surviving the infection with either strain, there was no significant difference in the bacterial loads in the lungs and spleen, bacteremia, weight loss, or infiltration of immune effector cells at 3 days postinfection. Similar results were observed at 24 h, prior to expression of the lethality phenotype. KC, a murine interleukin-8 (IL-8) homolog, was elevated in both the bronchoalveolar lavage fluid and serum of mice infected with the wild type compared to the fliCII mutant at 24 h, suggesting that flagella stimulated host cells. To demonstrate that flagella contributed to these responses, the interaction between B. cenocepacia and Toll-like receptor 5 (TLR5) was investigated. Infection of HEK293 cells with heat-killed wild-type K56-2, but not infection with the fliCII mutant, resulted in both NF-kappaB activation and IL-8 secretion that was dependent upon expression of TLR5. Together, these results demonstrate that B. cenocepacia flagella contribute to virulence in an in vivo infection model, and that induction of host immune responses through interaction with TLR5 may contribute to its overall pathogenic potential.

Topics: Agar; Animals; Burkholderia cepacia; Burkholderia Infections; Cell Line; Disease Models, Animal; Female; Flagella; Flagellin; Humans; Inflammation; Interleukin-8; Lung Diseases; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Microspheres; Mutation; Receptors, Cell Surface; Toll-Like Receptor 5; Toll-Like Receptors; Virulence

It has been suggested that inflammatory mediators such as cytokines released during intestinal ischemia and reperfusion increase permeability in the lungs. Cytokines exist at concentrations several hundred times higher at the site of inflammation than in the blood. When absorbed, the locally produced cytokines may affect multiple remote organs. We thus investigated whether the isolation of the intestine in a bag during ischemia and reperfusion can reduce subsequent lung injury.. Rats were divided into three groups: group 1, simple laparotomy (sham); group 2, intestinal ischemia and reperfusion (I/R); and group 3, intestinal ischemia and reperfusion with an intestinal bag (IB). Lung permeability was assessed using the Evans Blue leakage method. Cytokines (interleukin-1beta, tumor necrosis factor alpha, interleukin-8) in the plasma and ascites were measured by enzyme-linked immunosorbent assay.. The increase in lung permeability of I/R significantly decreased in IB (1.73 +/- 0.48 vs 1.05 +/- 0.22, P < 0.01). The plasma cytokine concentrations were also lower in IB than in I/R. In addition, the cytokine levels in the intestinal bag fluid were extremely high.. The isolation of the intestine during ischemia and reperfusion was found to reduce the degree of subsequent lung injury, possibly due to the reduced absorption of locally produced cytokines via the parietal peritoneum.

Topics: Analysis of Variance; Animals; Biomarkers; Capillary Permeability; Cytokines; Disease Models, Animal; Interleukin-1; Interleukin-8; Intestines; Ischemia; Lung Diseases; Male; Probability; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sensitivity and Specificity; Tumor Necrosis Factor-alpha

In order to predict the late-development of chronic lung disease of prematurity (CLD), cytokines in the cord blood were assessed in this study.. Eighteen premature infants with CLD were enrolled. Cord blood plasma levels of cytokines of these infants and 12 control infants without CLD were measured including interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, soluble TNF receptor-I, and soluble IL-6 receptor using a cytometric bead array and an enzyme-linked immunosorbent assay.. The cord blood IL-6, IL-8, and sTNFR-I levels were significantly elevated in CLD infants compared with those in control (P < .05). IL-1beta, IL-2, IL-4, IL-10, and IFN-gamma were undetectable in both groups. CLD infants with maternal chorioamnionitis had higher IL-6 than those without chorioamnionitis (P < .01). In CLD infants, IL-6 was higher in the infants who required prolonged oxygen therapy (P < .05).. Elevated inflammatory cytokines in the cord blood are associated with the progression to CLD.

Topics: Case-Control Studies; Chronic Disease; Cytokines; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Lung Diseases; Male; Predictive Value of Tests; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome, Newborn

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

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

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

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

Pentoxifylline (PTX) attenuates end-organ injury in models of sepsis and hemorrhage. PTX is thought to act by inhibiting phosphodiesterase, thus increasing cAMP and decreasing tumor necrosis factor-alpha (TNF-alpha) synthesis. The effects of PTX on neutrophil and endothelial cell adhesion molecules and, ultimately, organ injury in a chronic endotoxemia model have not been studied. We hypothesized that continuous infusion of PTX reduces acute lung injury (ALI) caused by chronic lipopolysaccharide (LPS) exposure.. Male Sprague-Dawley rats were given continuous infusion of LPS, PTX + LPS combined, or saline (sham) by implantable pumps. Neutrophil CD11b expression, lung histopathology, lung intercellular adhesion molecule-1 (ICAM-1) expression assessed by immune staining, serum TNF-alpha, serum interleukin-6 (IL-6), and bronchoalveolar lavage (BAL) IL-8 were evaluated at different time points. Lung injury was graded in a blinded fashion from 0 (normal) to 4 (severe) for interstitial inflammation, neutrophil infiltration, congestion, and edema. Total lung injury score (TLIS) was calculated by adding listed categories. White cell count in the peripheral blood and in the BAL was also performed.. Animals treated with PTX + LPS showed a significant reduction in lung injury score, a marked decrease in ICAM-1 expression, and a significant decrease in IL-8 levels in the BAL and serum IL-6 levels when compared with LPS-treated animals.. Continuous infusion of PTX reduces ALI caused by chronic endotoxemia. The effect seems to be a result of decreased expression of endothelial and epithelial ICAM-1 and modulation of proinflammatory cytokine synthesis.

Topics: Animals; Bronchoalveolar Lavage Fluid; CD11b Antigen; Chronic Disease; Edema; Endotoxemia; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Leukocyte Count; Lipopolysaccharides; Lung; Lung Diseases; Male; Neutrophils; Pentoxifylline; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

To understand the pathogenesis of meconium aspiration syndrome, we compared the pulmonary and inflammatory effects of the water and lipid extracts of human meconium instilled into the lungs of newborn piglets. The piglets were artificially ventilated, made hypoxemic, and randomized into three groups. At start of reoxygenation, 3 ml/kg of one of the following mixtures was instilled intratracheally: (1) meconium (n = 12); (2) water extract of meconium (n = 12), and (3) lipid extract of meconium (n = 12). During 8 h of reoxygenation, hemodynamics, pulmonary gas exchange, lung mechanics, and interleukin-8 concentrations in tracheobronchial aspirates were monitored. Oxygenation index (p = 0.04) and mean airway pressure (p = 0.04) increased more in the lipid extract group than in the water extract group. Dynamic compliance and mean arterial blood pressure decreased (p < 0.05) in the meconium and lipid extract groups, but not in the water extract group. At 8 h of reoxygenation, the interleukin-8 concentration in the tracheobronchial aspirates was three times higher in the lipid extract group as compared with the water extract group (110 +/- 102 vs. 37 +/- 27 pg/ml; p = 0.02). In conclusion, pulmonary dysfunction in meconium aspiration syndrome is caused by both the water- and lipid-soluble fractions of meconium, with stronger inflammatory and more detrimental effects promoted by the lipid extract than the water extract.

Topics: Animals; Animals, Newborn; Blood Pressure; Humans; Hypoxia; Infant, Newborn; Inflammation; Interleukin-8; Lipids; Lung; Lung Diseases; Meconium; Meconium Aspiration Syndrome; Oxygen; Pulmonary Gas Exchange; Respiration, Artificial; Solubility; Swine; Tissue Extracts; Vascular Resistance; Water

Pulmonary hemorrhage (PH) is a serious complication causing acute respiratory distress in the premature infant, and it is associated with significant mortality and morbidity. The role of inflammatory mediators in this condition is largely undefined. Serial tracheal aspirates (TA) were obtained at intervals from 65 mechanically ventilated infants with birth weights less than 1,250 g during the first 21 days of life. Clinically significant PH developed in 15 infants. TA concentrations of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) were determined by enzyme-linked immunosorbent assay (ELISA).PH was associated with an increased risk of death, bronchopulmonary dysplasia, intraventricular hemorrhage, and prolonged need for mechanical ventilation and supplemental oxygen. TA aspirate concentrations of IL-8 and MCP-1 (P = 0.001, ANOVA) were significantly increased in infants with PH compared to infants who did not develop this condition. TA cytokine concentrations were also significantly increased in infants who developed bronchopulmonary dysplasia (BPD). Peak TA concentrations of IL-8 and MCP-1 were significantly higher in infants with poor outcome (BPD or death). TA MCP-1 but not IL-8 concentrations were significantly higher in infants who were oxygen-dependent at 36 weeks postconceptional age. These data suggest a pathogenic role for IL-8 and MCP-1 in the development of adverse pulmonary outcome in preterm infants with clinically significant PH.

Topics: Chemokine CCL2; Hemorrhage; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Interleukin-8; Lung Diseases; Outcome Assessment, Health Care; Predictive Value of Tests; Respiration, Artificial; Suction; Trachea

To investigate the mechanism of perioperative lung injury in patients of ventricular septal defect (VSD) with severe pulmonary hypertension.. The thromboxane B(2) (TXB(2)), 6-keto-prostagladin F(1 alpha) (6-keto-PGF(1 alpha)), malonyldiadehyde (MDA), interleukin-6 (IL-6), and IL-8, and blood pressure, pulmonary arterial pressure (PAP) and total pulmonary pressure (TPR) in thirty-one patients of VSD, 16 cases without pulmonary hypertension and 15 cases with severe pulmonary hypertension, were examined after anesthesia (AA), over extracorporeal circulation (OEC), and 1 hour (PEC1), 6 hours (PEC6), 24 hours (PEC24), 48 hours (PEC48), and 72 hours (PEC72) post extracorporeal circulation. The respiratory index (RI) and ratio of 6-keto-PGF(1alpha) and TXB(2) (P/T) were calculated. Before and after extracorporeal circulation, pulmonary tissues were taken to be examined by light microscopy and electron microscopy.. In the cases with severe pulmonary hypertension the P/T was 0.81 +/- 0.26 after anesthesia, then decreased 0.65 +/- 0.28 over extracorporeal circulation, and reached its lowest value (0.51 +/- 0.32) 1 hour post extracorporeal circulation. MDA was 2.4 micromol/L +/- 0.6 micromol/L after anesthesia, then increased, was 7.0 micromol/L +/- 1.7 micromol/L OEC, and reached its peak value (7.3 micromol/L +/- 0.9 micromol/L) PEC1. IL-6 was 0.27 ng/L +/- 0.12 ng/L after anesthesia, then increased, and reached its peak value (0.50 ng/L +/- 0.19 ng/L) PEC1. IL-8 was 7.5 ng/L +/- 1.5 ng/L after anesthesia, then increased, was 152 ng/L +/- 50 ng/L PEC1, and reached its peak (183 ng/L +/- 63 ng/L) PEC6. TXB(2) was 251 ng/L +/- 44 ng/L after anesthesia, then increased, and reached its peak (967 ng/L +/- 145 ng/L) at PEC1. The PAP was 72.1 +/- 18.8 mm Hg after anesthesia, 55 mm Hg +/- 15.3 mm Hg OPC, and 7.4 +/- 2.1 at PEC1, then decreased, and was 53 mm Hg +/- 15 mm Hg at PEC72. The total pulmonary resistance (TPR) was 10.6 +/- 2.9 mm Hg x min(-1) x L(-1) after anesthesia, then increased, and reached its peak (15.0 +/- 3.9 mm Hg x min(-1) x L(-1) at PEC6. Respiratory index (RI) was 0.88 +/- 0.23, then increased, and reached its peak (2.35 +/- 0.72) at PEC6. TXB(2) and RI were positively correlated with pulmonary vascular resistance (gamma = 0.283, P < 0.05; gamma = 0.403, P < 0.05). RI was positively correlated with MDA (gamma = 0.403, P < 0.05). Morphologic studies revealed discontinuities in the endothelial cell lining of pulmonary capillaries, infiltration of inflammatory cells, plugging of pulmonary capillaries with neutrophils, and intraalveolar hemorrhage.. During the perioperative period, the pulmonary damage, which leads to pulmonary hypertensive crisis, is more severe among the cases of VSD with severe pulmonary hypertension than among the case without pulmonary hypertension.

Topics: Adolescent; Blood Pressure; Child; Extracorporeal Circulation; Female; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Interleukin-6; Interleukin-8; Lung Diseases; Lung Injury; Male; Malondialdehyde; Postoperative Complications; Pulmonary Artery; Thromboxane B2; Time Factors

In patients with atrial septal defect in whom pulmonary hypertension could develop as a consequence of left-to-right shunt, the extent of neutrophil-mediated lung injury induced by cardiopulmonary bypass (CPB) is related to the degree of increase in the preoperative pulmonary artery pressure. In the present study, we investigated the relationship between levels of granulocyte elastase (GEL) after CPB and preoperative pulmonary hemodynamics or changes in pulmonary function after the operation in patients with mitral valve disease, in whom pulmonary hypertension could develop as a result of pulmonary venous congestion. The plasma levels of GEL were measured before and after CPB in patients who underwent mitral valve replacement. Respiratory index (RI) was evaluated preoperatively and postoperatively. Preoperative pulmonary hemodynamics were determined within one month of the operation. Granulocyte elastase level rose significantly after CPB from baseline (134.3 +/- 44.6 mg/L versus 2042.1 +/- 1215.0 mg/L; p <0.001). Peak level of GEL was significantly correlated with preoperative systolic pulmonary artery pressure (r = 0.71; p = 0.020), mean pulmonary artery pressure (r = 0.64; p = 0.046), pulmonary capillary wedge pressure (r = 0.68; p = 0.032), and pulmonary-to-systemic arterial pressure ratio (r = 0.64; p = 0.045), but not with the hemodynamic variables for pulmonary blood flow or pulmonary resistance. Moreover, the value of (Postoperative RI - Preoperative RI)/Preoperative RI was positively correlated with the peak level of GEL (r = 0.76; p = 0.011). In conclusion, in patients with mitral valvular disease, as in those with atrial septal defect, the increase in GEL level after CPB is proportional to the increase in preoperative pulmonary artery pressure, which may cause the accordant pulmonary vascular damage.

Topics: Aged; Cardiopulmonary Bypass; Female; Heart Valve Prosthesis Implantation; Hemodynamics; Humans; Interleukin-6; Interleukin-8; Intraoperative Period; Leukocyte Elastase; Lung Diseases; Male; Middle Aged; Mitral Valve Insufficiency; Mitral Valve Stenosis; Predictive Value of Tests; Pulmonary Circulation; Vascular Diseases

A high concentration of interleukin (IL)-8 has been observed in the tracheobronchial aspirate of infants with chronic lung disease (CLD), although the pattern varies depending on the type of CLD. Alveolar fluid from patients with adult respiratory distress syndrome (ARDS) also contains an elevated level of IL-8. Recently, the presence of anti-IL-8 autoantibody was demonstrated in the alveolar fluid from patients with ARDS.. The concentration of anti-IL-8 autoantibody in the tracheobronchial aspirate of infants with CLD was measured in order to discover whether there was any correlation with the concentration of IL-8. Similar to IL-8 concentration, the anti-IL-8 IgM antibody concentration in all infants with CLD following intrauterine infection was already high during the first 48 h. However, the concentration in infants with CLD following respiratory distress syndrome began to increase after 11 days of life, in contrast with the rise in IL-8 between 48 h after birth and day 5.. The presence of anti-IL-8 autoantibody may provide a mechanism that limits the bioavailability of free IL-8 in the lungs. In addition, the time lag between the increase in IL-8 and anti-IL-8 IgM autoantibody demonstrated in the present study could be used to estimate the time when the inflammation begins, even if the IL-8 concentration is already high.

Topics: Autoantibodies; Bronchoalveolar Lavage Fluid; Chronic Disease; Humans; Immunoglobulin M; Infant; Infant, Newborn; Interleukin-8; Lung Diseases; Respiratory Distress Syndrome, Newborn

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

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

We investigated whether or not interleukin-8 (IL-8) and granulocyte elastase (GE) can be associated with pulmonary complication after esophagectomy (the most common cause of postoperative death).. We measured serial changes in the IL-8 concentration and GE activity in the plasma and bronchoalveolar lavage fluid (BALF) of 17 patients who had undergone esophagectomy, and examined the relationship between these mediators and postoperative pulmonary complication.. Pulmonary complication occurred in 6 patients (35%, Pneum+ group). Plasma IL-8 increased at the end of the surgery then decreased, but there was no significant difference between the Pneum+ group and the group without pulmonary complication (11[65%], Pneum- group). IL-8 and GE in BALF were significantly higher in the Pneum+ group than in the Pneum- group on days 1 and 3 after the operation. There was a significant and positive correlation between IL-8 and GE in BALF.. Our results indicate that IL-8 and GE in BALF may be useful for the prediction of postoperative pulmonary complication.

Topics: Aged; Bronchoalveolar Lavage Fluid; Esophageal Neoplasms; Esophagectomy; Female; Humans; Interleukin-8; Leukocyte Elastase; Lung Diseases; Middle Aged; Pneumonia, Bacterial; Postoperative Complications; Predictive Value of Tests

Fetal intrauterine exposure to proinflammatory cytokines present in amniotic fluid has been associated with an increased risk of chronic lung disease. However, the impact of histologically confirmed chorioamnionitis on the fetal lung has not yet been elucidated. We therefore investigated cellular immune response, cell proliferation, and messenger ribonucleic acid cytokine expression in fetal pulmonary tissue in the presence or absence of chorioamnionitis.. Serial tissue sections were obtained from 27 fetuses at the time of autopsy. Three mothers had received antibiotics for treatment of clinical chorioamnionitis before abortion. Immunohistochemical staining of lung tissue comprised lineage-specific markers (CD68(+), CD3(+), neutrophil elastase). Positively stained cells were evaluated with a graticule, and cells per 5 mm(2) were counted. We undertook in situ hybridization to assess the expression of interleukin 8 messenger ribonucleic acid in the fetal lung.. Seven of 27 fetuses had been exposed to chorioamnionitis. Fetal lungs showed a marked increase in the presence of histologically confirmed chorioamnionitis in densities of CD68(+) macrophages (68 vs 9.5 cells/5 mm(2), median group vs control group; P =.02) and lymphocytes (7 vs 2.5 cells/5 mm(2), median chorioamnionitis vs control group; P =.05) and a similar but lesser increase in neutrophil density (16 vs 4 cells/5 mm(2); difference not significant). Interleukin 8 messenger ribonucleic acid was expressed in 4 of 6 tissue specimens investigated in the chorioamnionitis group. Exposure to chorioamnionitis resulted in interleukin 8 messenger ribonucleic acid expression 7-fold higher than in the nonchorioamnionitis group; however, this difference did not achieve statistical significance.. Chorioamnionitis was associated with an intrauterine inflammatory response of the fetal lung characterized by a severe infiltration of macrophages, neutrophils, and lymphocytes and also by an increased expression of interleukin 8 messenger ribonucleic acid.

Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; CD3 Complex; Chorioamnionitis; Female; Fetal Death; Fetal Diseases; Humans; Immunohistochemistry; In Situ Hybridization; Interleukin-8; Leukocyte Elastase; Lung; Lung Diseases; Lymphocytes; Macrophages; Neutrophils; Placenta; Pregnancy; RNA, Messenger

Cigarette smoking is known to contribute to inflammatory diseases of the respiratory tract by promoting recruitment of inflammatory-immune cells such as neutrophils and perhaps by altering neutrophil functional properties. We investigated whether acrolein, a toxic unsaturated aldehyde found in cigarette smoke, could directly affect neutrophil function. Exposure of freshly isolated human neutrophils to acrolein markedly inhibited spontaneous neutrophil apoptosis as indicated by loss of membrane asymmetry and DNA fragmentation and induced increased neutrophil production of the chemokine interleukin-8 (IL-8). Acrolein (1--50 microM) was found to induce marked activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (MAPKs), and inhibition of p38 MAPK activation by SB-203580 prevented acrolein-induced IL-8 release. However, inhibition of either ERK or p38 MAPK did not affect acrolein-dependent inhibition of apoptosis. Acrolein exposure prevented the activation of caspase-3, a crucial step in the execution of neutrophil apoptosis, presumably by direct inhibition of the enzyme. Our results indicate that acrolein may contribute to smoke-induced inflammatory processes in the lung by increasing neutrophil recruitment and reducing neutrophil clearance by apoptosis.

Topics: Acrolein; Apoptosis; Caspase 3; Caspase Inhibitors; Enzyme Activation; Glutathione; Humans; Interleukin-8; Intracellular Membranes; Lung Diseases; Mitogen-Activated Protein Kinases; NADPH Oxidases; Neutrophils; Smoking

Epidemiologic investigation has established an association between exposure to particulate matter (PM) and human health in the Utah Valley. Reduction of particle mass during the temporary closure of a local steel mill was associated with diminished morbidity and mortality. We tested the hypothesis that the biologic effect of PM would reflect findings of epidemiology with a greater injury after exposure to an equal mass of particles from those years in which the mill was in operation. Filters containing PM were collected prior to closure of the steel mill, during the closure, and after its reopening. Aqueous extracts of the filters were prepared. One of three extracts (500 microg) was instilled through the bronchoscope into the lungs of nonsmoking volunteers. Twenty-four hours later, the same subsegment was lavaged. Exposure to aqueous extracts of PM collected before closure and after reopening of the steel mill provoked a greater inflammatory response relative to PM extract acquired during the plant shutdown. This is the first demonstration that pulmonary effects after experimental exposure of humans to PM can correlate with health outcomes observed in epidemiologic studies of the same material under normal exposure conditions. Findings suggest that mass may not be the most appropriate metric to use in assessing health effects after PM exposure but rather specific components must be identified and assessed.

Topics: Adult; Air Pollutants; Analysis of Variance; Bronchoalveolar Lavage Fluid; Bronchoscopy; Environmental Monitoring; Epidemiological Monitoring; Female; Humans; Inflammation; Interleukin-8; Leukocyte Count; Lung Diseases; Male; Metallurgy; Models, Biological; Morbidity; Neutrophils; Oxidative Stress; Proteins; Severity of Illness Index; Utah

Previous publications demonstrated that elevated systemic levels of interleukin (IL)-8 decrease local neutrophil recruitment. We tested whether sustained, high plasma levels of IL-8 would prevent local inflammation after inflammatory insults. Mice carrying the transgene for human IL-8 were separated on the basis of their plasma levels of IL-8 into IL-8-positive (plasma levels >90 ng/ml) and IL-8-negative (IL-8 below detection). Presence of the IL-8 transgene did not improve survival or morbidity nor did it alter peritoneal neutrophil recruitment induced by the cecal ligation and puncture model of sepsis. In an acute lung injury model created by intratracheal injection of acid, IL-8-positive mice showed no reduction in alveolar neutrophil recruitment. There was no difference in the local recruitment of neutrophils when either thioglycollate or glycogen was injected intraperitoneally. We examined the chemotactic response to murine chemokines to test how neutrophil recruitment occurs in the setting of elevated plasma IL-8 and found that neutrophils from both IL-8-positive and -negative mice respond equally well to recombinant KC or macrophage inflammatory protein (MIP)-2. We measured KC and MIP-2 in the peritoneum after thioglycollate injection and demonstrated that IL-8-positive mice have significantly higher levels of the chemokines compared to the IL-8-negative mice. Antibody inhibition of KC and MIP-2 in the IL-8-positive mice significantly decreased peritoneal neutrophil recruitment in response to thioglycollate, clarifying their important role in the local neutrophil recruitment. Our data demonstrate that despite the presence of high plasma levels of IL-8, neutrophils may still be recruited to sites of local inflammation because of chemokine redundancy.

Topics: Acute Disease; Animals; Cecum; Chemokines, CXC; Glycogen; Humans; Hydrochloric Acid; Inflammation; Interleukin-8; Ligation; Lung Diseases; Mice; Mice, Transgenic; Morbidity; Neutrophil Infiltration; Peritoneum; Punctures; Reference Values; Thioglycolates; Transgenes

The success of haematopoietic (bone marrow or peripheral blood) stem cell transplantation (SCT) is compromised by pulmonary complications. We hypothesised that a proinflammatory alveolar microenvironment, reflected in alveolar macrophage (AM) cytokine production, would predispose to such complications.. AM were isolated from adult SCT recipients by bronchoalveolar lavage before SCT (n=32) and during post-transplant pancytopenia (n=23). Concentrations of tumour necrosis factor (TNF)alpha, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-1 beta, IL-6, and IL-8 in 24 hour AM culture medium were measured by enzyme linked immunosorbent assay and compared with both the occurrence of post-SCT lung disease and with subjects' previous respiratory histories.. Eleven subjects developed lung disease within 6 months of SCT. These subjects had higher median pre-transplant AM TNFalpha (8 (IQR 1-8) v 2 (1-5) ng/10(6)AM, p=0.01, median difference (D) = 3, 95% CI 0.1 to 7), GM-CSF (5 (0.7-8) v 0.2 (0.1-0.8), p=0.006, D = 4, 95% CI 0.5 to 7), and IL-6 (0.5 (0.1-1) v 0.1 (0.02-0.3), p=0.049, D = 0.3, 95% CI 0.0002 to 1) production than remaining subjects; IL-1 beta and IL-8 did not differ. During pancytopenia high AM GM-CSF production again predicted later lung disease (1 (0.7-9) v 0.1 (0.06-0.3), p=0.01, D = 1, 95% CI 0.1 to 6). A history of recent chest disease was associated with high AM TNFalpha and GM-CSF production and with post-SCT lung disease. Pre-SCT lung function was unrelated to post-SCT lung disease.. Recent respiratory disease and persistent proinflammatory AM behaviour detectable before transplantation are associated with lung disease following SCT. These associations may prove useful in pre-transplant risk assessment.

Topics: Adolescent; Adult; Bronchoalveolar Lavage Fluid; Cells, Cultured; Confidence Intervals; Enzyme-Linked Immunosorbent Assay; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-1; Interleukin-8; Lung Diseases; Macrophages, Alveolar; Male; Middle Aged; Normal Distribution; Pancytopenia; Prospective Studies; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

In view of cytokine's effects in promoting or inhibiting inflammation, the objective of this study was to explore the characteristics of the proinflammatory cytokine, interleukin-8 (IL-8), and the inhibitory cytokine, interleukin-10 (IL-10), in the bronchoalveolar lavage (BAL) fluid of premature infants suffering from respiratory distress disease. Eighteen premature neonates with respiratory distress disease with gestational age (GA) ranging from 24 to 37 weeks were recruited for study. BAL fluids were collected following endotracheal intubation during an episode of hypoxemia or dyspnea. A series of BAL samples were obtained on day 1, 2, 4 and 7 after intubation for measuring IL-8 and IL-10 levels. The results indicate that premature infants with GA ranging from 24 to 32 weeks had a higher level of IL-8 (p = 0.029), but not level of IL-10 (p = 0.109), in the BAL obtained during the first intubation compared to premature infants with GA ranging from 33 to 37 weeks. The administration of exogenous surfactant did not influence the profiles of IL-8 and IL-10, as compared to those in-patients without treatment. Levels of IL-8 were correlated with IL-10 levels (r = 0.613, p = 0.007) in BAL fluid samples obtained on the day of intubation. The level of IL-8, but not IL-10, was significantly correlated with the duration of intubation. IL-8 and IL-10 levels in BAL fluid samples collected on the day of intubation were correlated with the development of chronic lung disease (CLD). The results suggest that extreme prematurity tends to have increased IL-8 and IL-10 levels in BAL fluid compared to premature infants with older GA, and that these increased levels are associated with the development of CLD.

Topics: Bronchoalveolar Lavage Fluid; Chronic Disease; Humans; Infant; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-8; Lung Diseases; Respiratory Distress Syndrome, Newborn

We have already reported that there are some periods when a high interleukin 8 (IL-8) concentration is observed in the tracheobronchial aspirate of infants with chronic lung disease (CLD), although the changing pattern of the IL-8 concentration varies depending on the type of CLD. Interleukin 8 is known as a neutrophil chemotactic agent. Therefore, we asked whether IL-8 is an important neutrophil chemotactic factor in the tracheobronchial aspirate of infants who later develop CLD.. We measured the neutrophil chemotactic activity of the tracheobronchial aspirate in CLD infants with or without anti-IL-8 antibody. Preincubation with anti-IL-8 immunoglobulinG resulted in a significant reduction of neutrophil chemotactic activity in the tracheobronchial aspirate. In infants with CLD following respiratory distress syndrome, there was a significant relationship between the IL-8 concentration and the neutrophil chemotactic activity of tracheobronchial aspirate without anti-IL-8 antibody, although no significant relationship was seen in infants with CLD following intra-uterine infection or with other CLD.. Interleukin 8 in the tracheobronchial aspirate seems to play a significant role in recruiting neutrophils into the airways of patients with CLD, especially CLD following respiratory distress syndrome. We believe that in this type of CLD, IL-8 in the lung is generated as a result of hyperoxia rather than infection. In this situation, production of other neutrophil chemotactic factors or some factors that inhibit IL-8 activity may be insignificant.

Topics: Chronic Disease; Humans; Infant, Newborn; Infections; Interleukin-8; Lung Diseases; Neutrophil Activation; Respiratory Distress Syndrome, Newborn; Sputum

Two antiinflammatory therapies that have been effective in preventing acid-induced lung injury were evaluated. Specifically, their effects on a subsequent bacterial-airspace challenge were compared. Bacteria were instilled 24 h after acid-induced lung injury. Pseudomonas aeruginosa PAO-1 was used as the bacteria, because its effects in healthy lungs was documented previously.. New Zealand white rabbits were anesthetized and three pretreatments were administered: (1) pentoxifylline pretreatment (a 20-mg/kg bolus dose and then 6 mg x kg(-1) x h(-1) given intravenously), (2) 1 ml anti-tumor necrosis factor alpha antiserum given intravenously, or (3) normal saline given intravenously. The pretreatment doses were shown previously to prevent acid-induced lung injury. Then 1.2 ml/kg hydrochloric acid (HCl), pH 1.25, was instilled into the rabbits' right lungs. All the animals underwent mechanical ventilation for 8 h. Twenty-four hours after the acid instillation, the rabbits were anesthetized again and 2 ml/kg (10(9) colony forming units/ml) PAO-1 was instilled into their left lungs. The rabbits' breathing was aided by mechanical ventilation for another 8 h, and then they were killed and exsanguinated.. Both pretreatments attenuated the acid-induced lung injury of the noninstilled left lungs. Arterial oxygen tension and the lung edema of pretreated, acid-exposed animals were significantly and almost equally improved (compared with no pretreatments) by either of the pretreatments. However, when the bacteria were instilled into the left lungs 24 h after the acid injury, the pentoxifylline pretreatment but not the anti-tumor necrosis factor alpha pretreatment prevented much of the bacteria-induced lung injury. Pentoxifylline pretreatment significantly improved the measurements of left lung edema and epithelial and endothelial permeability. There was also a trend for improved oxygenation in the pentoxifylline-pretreated and infected animals. In contrast, the anti-tumor necrosis factor alpha pretreatment did not prevent the bacteria-induced lung injury and increased some of the measurements of lung injury.. Two antiinflammatory therapies that prevented acid-induced lung injury to the noninstilled left lungs had significantly different effects on a subsequent bacteria-induced lung injury to the left lungs. The therapies differed in their mechanism of tumor necrosis factor alpha blockade, and this may have affected the bacteria-induced injury to the lungs.

Topics: Animals; Anti-Inflammatory Agents; Bacterial Infections; Goats; Immune Sera; Interleukin-8; Lung Diseases; Male; Oxygen; Pentoxifylline; Peroxidase; Rabbits; Tumor Necrosis Factor-alpha

Cell adhesion molecule expression (CAM) and IL-8 release in lung microvascular endothelium facilitate neutrophil accumulation in the lung. This study investigated the effects of lipoteichoic acid (LTA), a cell wall component of Gram-positive bacteria, alone and with LPS or TNF-alpha, on CAM expression and IL-8 release in human lung microvascular endothelial cells (HLMVEC). The concentration-dependent effects of Staphylococcus aureus (S. aureus) LTA (0.3-30 microg/ml) on ICAM-1 and E-selectin expression and IL-8 release were bell shaped. Streptococcus pyogenes (S. pyogenes) LTA had no effect on CAM expression, but caused a concentration-dependent increase in IL-8 release. S. aureus and S. pyogenes LTA (30 microg/ml) abolished LPS-induced CAM expression, and S. aureus LTA reduced LPS-induced IL-8 release. In contrast, the effects of S. aureus LTA with TNF-alpha on CAM expression and IL-8 release were additive. Inhibitory effects of LTA were not due to decreased HLMVEC viability, as assessed by ethidium homodimer-1 uptake. Changes in neutrophil adhesion to HLMVEC paralleled changes in CAM expression. Using RT-PCR to assess mRNA levels, S. aureus LTA (3 microg/ml) caused a protein synthesis-dependent reduction (75%) in LPS-induced IL-8 mRNA and decreased the IL-8 mRNA half-life from >6 h with LPS to approximately 2 h. These results suggest that mechanisms exist to prevent excessive endothelial cell activation in the presence of high concentrations of bacterial products. However, inhibition of HLMVEC CAM expression and IL-8 release ultimately may contribute to decreased neutrophil accumulation, persistence of bacteria in the lung, and increased severity of infection.

Topics: Cell Adhesion Molecules; Drug Interactions; E-Selectin; Endothelium, Vascular; Half-Life; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Lipopolysaccharides; Lung; Lung Diseases; Microcirculation; Neutrophil Infiltration; RNA Stability; RNA, Messenger; Sepsis; Streptococcus; Streptococcus pyogenes; Teichoic Acids; Tumor Necrosis Factor-alpha

Chronic endobronchial inflammation and bacterial infection are the main causes of morbidity and mortality in cystic fibrosis (CF), an autosomal recessive genetic disorder associated with improper function of chloride channels. Inflammation in CF lung is greatly amplified after Pseudomonas aeruginosa infection. In this study the relationship between P. aeruginosa status and inflammatory markers has been investigated. Seventeen CF children in acute lung exacerbation were examined. CF patients without P. aeruginosa infection were characterized by elevated activity of sputum elastase, reduced response of peripheral blood lymphocytes to PHA and significant resistance to the antiproliferative action of glucocorticoids. These parameters were normalized after antibiotic treatment. The patients with prolonged P. aeruginosa infection demonstrated extremely high levels of elastase activity and elevated amounts of sputum IL-8 and TNF-alpha. Although antibiotic treatment resulted in clinical improvement, it failed to suppress excessive immune response in the lung. The data indicate that CF patients with prolonged P. aeruginosa need the modified treatment, which should include immunomodulating drugs and protease inhibitors as well as antibacterial therapy.

Topics: Anti-Bacterial Agents; Cells, Cultured; Child; Cystic Fibrosis; Dexamethasone; Humans; Inflammation; Interleukin-8; Leukocyte Elastase; Lung Diseases; Lymphocyte Activation; Lymphocytes; Phytohemagglutinins; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum; Tumor Necrosis Factor-alpha; Vital Capacity

Animal studies have reported that diesel exhaust particles (DEP), which constitute an important fraction of particulate air pollution, lead to inflammation and/or damage of the airways. To investigate the mechanisms underlying DEP-induced airway disease in humans, we have cultured human bronchial epithelial cells (HBEC) from surgically obtained bronchial explants and investigated the effects of purified DEP on the permeability and ciliary beat frequency (CBF) of HBEC, and on the release of inflammatory mediators from these cells. Exposure to 10-100 microg/ml DEP and a filtered solution of 50 microg/ml DEP significantly increased the electrical resistance of the cultures, reaching a maximum of 200% over baseline after 6 h incubation with 100 microg/ml DEP. In contrast, movement of 14C-labeled bovine serum albumin across cell cultures was not significantly altered by incubation of HBEC with DEP. Exposure to 50 microg/ml DEP, filtered DEP solution, and 100 migrog/ml DEP significantly attenuated the CBF of these cells by 51%, 33%, and 73%, respectively, from baseline after 24 h incubation. Similarly, 50 microg/ml DEP, filtered DEP solution, and 100 microg/ml DEP significantly increased the release of interleukin-8 from 12.9 pg/microg cellular protein to 41.6, 114.9, and 44.3 pg/microg cellular protein, respectively, after 24 h incubation. The release of granulocyte-macrophage colony stimulating factor (GM-CSF) and soluble intercellular adhesion molecule-1 (sICAM-1) was also significantly increased after exposure for 24 h to 50 microg/ml DEP (GM-CSF from 0.033 pg/microg cellular protein to 0.056 pg/mug cellular protein and sICAM-1 from 7.2 pg/microg cellular protein to 12.5 pg/microg cellular protein). These results suggest that exposure of HBEC to DEP may lead to adverse functional changes and release of proinflammatory mediators from these cells, and that these effects may influence the development of airway disease.

Topics: Adult; Air Pollutants; Bronchi; Cell Membrane Permeability; Cells, Cultured; Cilia; Epithelial Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-8; Lung Diseases; Middle Aged; Polycyclic Compounds; Vehicle Emissions

Proinflammatory cytokines (eg, tumor necrosis factor [TNF]-alpha, interleukin [IL]-1 and Il- 8) are believed to play an important role in the pathogenesis of acute necrotizing pancreatitis (ANP) and its systemic complications. Recently, IL-10 has emerged as a major anti-inflammatory cytokine, inhibiting the secretion and activities of inflammatory cytokines. Further, a protective effect of IL-10 has recently been shown in experimental acute pancreatitis. The purpose of this study was to test the potential role of a newly developed IL-10 agonist, IT 9302, in a model of ANP in rabbits.. ANP was induced in 18 rabbits by retrograde injection of 5% chenodeoxycholic acid in the pancreatic duct, followed by duct ligation. The rabbits were allocated to pretreatment with intravenous physiologic saline solution or IT 9302 (200 micrograms/kg) 30 minutes before the induction of ANP.. Injection of IT 9302 resulted in a significant reduction in the blood levels of TNF-alpha and IL-8 from 3 to 6 hours. IT 9302 also reduced the amount of ascitic fluid and significantly inhibited neutrophil infiltration and margination, as well as the number of CD11b- and CD18-positive cells in the lung tissues. By contrast, the local pancreatic necrosis, as well as the biochemical changes such as serum amylase, lipase, and calcium, was sever and similar in both groups. Survival was improved significantly after treatment with IT 9302.. As expected, IT 9302 cannot change the degree of ANP induced by 5% bile acid but does reduce mortality rates and the development of acute lung injury, probably through the inhibition of circulating levels of TNF-alpha, IL-8, and the expression of the adhesion molecule complex CD11b/CD18.

Topics: Amylases; Animals; Ascites; Bile; Blood Glucose; Calcium; CD18 Antigens; Disease Models, Animal; Female; Interleukin-10; Interleukin-8; Leukocyte Count; Leukocytes; Lipase; Lung Diseases; Macrophage-1 Antigen; Male; Oligopeptides; Pancreas; Pancreatitis, Acute Necrotizing; Pulmonary Alveoli; Rabbits; Survival Analysis; Tumor Necrosis Factor-alpha

Very little is known about the pathogenesis of pulmonary non-tuberculous mycobacteriosis in immunocompetent individuals. Local inflammatory response was assessed by examining bronchoalveolar lavage fluid from 13 HIV-negative patients (12 F) without known cell-mediated immunosuppression, aged 48-72 y (median age 60 y), with non-tuberculous lung mycobacteriosis. Macrophages, lymphocytes, polymorphonuclear neutrophils and eosinophils in bronchoalveolar lavage fluid were analysed morphologically, and the subsets of T-lymphocytes (CD3+, CD4+, CD8+), HLA-DR+, B-lymphocytes (CD19+) and CD16+/CD56+ cells (natural killer, NK cells) were analysed by flow cytometry. Interleukin-1 beta (IL-1beta), IL-2, IL-4, IL-6, IL-8, IL-10 and interferon-gamma (IFN-gamma) levels were assessed by ELISA. The total number of cells/ml was significantly higher in BAL fluid from the patients (median value=880 x 10(3)/ml) compared to six healthy controls (200 x 10(3)/ml). The polymorphonuclear neutrophil population was significantly increased in the patients both proportionally and in the count/ml. The proportion of macrophages was significantly reduced in the patients but not the count/ml. The count of lymphocytes/ml was significantly higher in the patients but the proportion of lymphocytes was unchanged. No significant difference was seen in the relative proportion of NK cells, B- or T-lymphocytes and HLA-DR+ compared to the healthy controls. The IL-1beta and IL-8 levels were significantly increased in the patients. No differences were seen between the patients and controls in the leukocyte or lymphocyte subsets in peripheral blood. The local inflammatory response in BAL fluid from the studied patients was characterized by granulocytosis, and increase in the IL-1beta and IL-8 levels. There was no specific T-cell response.

Topics: Aged; Bronchoalveolar Lavage Fluid; Cytokines; Female; HIV Seronegativity; Humans; Immunocompetence; Inflammation; Interferon-gamma; Interleukin-8; Leukocyte Count; Lung Diseases; Male; Middle Aged; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections, Nontuberculous; Neutrophils; T-Lymphocytes

Interleukin 8 (IL-8) has recently been proposed to have an important role in mediating the development of the systemic sequelae associated with severe acute pancreatitis.. To define the role of IL-8 in acute pancreatitis by neutralising its effects with a monoclonal anti-IL-8 antibody (WS-4), in a rabbit model of severe acute pancreatitis.. Acute pancreatitis was induced by retrograde injection of 5% chenodeoxycholic acid into the pancreatic duct and duct ligation. Twenty rabbits were divided equally into two groups: acute pancreatitis controls received physiological saline and the treated group received WS-4, 30 minutes before induction of acute pancreatitis.. Pretreatment of animals with WS-4 resulted in significant down regulation of serum IL-8 and tumour necrosis factor alpha (TNF-alpha) from three to six hours after induction of acute pancreatitis (p = 0.011 and 0.047 for IL-8 and 0.033 and 0.022 for TNF-alpha, respectively). In addition, a significant reduction in the CD11b and CD18 positive cells and the amount of interstitial neutrophil infiltration in the lungs from WS-4 treated animals was seen. In contrast, WS-4 did not alter the amount of pancreatic necrosis and the serum concentrations of amylase, lipase, calcium, and glucose.. WS-4 cannot change the amount of pancreatic necrosis induced by injection of 5% bile acid, but does reduce the acute lung injury, presumably through inhibition of circulating IL-8 and TNF-alpha, and CD11b/CD18 in lung tissue. Therefore, a role of IL-8 in the progression of acute pancreatitis and the development of its systemic complications is suggested.

Topics: Amylases; Animals; Antibodies, Monoclonal; Antigens, CD; Ascitic Fluid; Blood Glucose; Calcium; Female; Immunohistochemistry; Interleukin-8; Lipase; Lung Diseases; Male; Neutrophils; Pancreatitis, Acute Necrotizing; Rabbits; Tumor Necrosis Factor-alpha

To elucidate the mechanism of the development of chronic lung disease (CLD) in infants without respiratory distress syndrome or intra-uterine infection, we serially measured the concentrations of interleukin 8 (IL-8) and granulocyte elastase alpha 1 proteinase inhibitor complex (E-alpha 1 PI) and elastase activity in the tracheobronchial aspirate of very low birth weight infants without respiratory distress syndrome or intra-uterine infection until day 28. IL-8 concentration and elastase activity between day 21 and 28 in infants who developed CLD later were significantly higher compared with those in infants who did not develop CLD. E-alpha 1 PI concentration between day 25 and 28 in infants who developed CLD later was significantly higher compared with those in infants who did not develop CLD. The area under the curve of the IL-8 and E-alpha 1 PI concentrations and elastase activity between day 1 and day 28 in infants with CLD was significantly higher than those in infants without CLD. These data suggest that the lung tissue injury caused by the enzymes from neutrophils accumulated and activated by IL-8 also play an important role in the development of this type of CLD.

Topics: Bronchoalveolar Lavage Fluid; Chronic Disease; Female; Humans; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Interleukin-8; Leukocyte Elastase; Lung Diseases; Male

Reactive oxygen intermediates such as hydrogen peroxide play an important role in the pathophysiology of acute lung injury, not only as terminal effectors, but also as second messengers in signal transduction; we studied their role in adhesion molecule expression and cytokine production. N-acetylcysteine, an antioxidant, decreased the TNF alpha-induced expression of intercellular adhesion molecule-1 on cultured epithelial cells from human bronchi (BEAS-2A), and inhibited IL-8 production by those cells. In vivo, N-acetylcysteine attenuated the sequestration of polymorphonuclear neutrophils in rat lungs caused by intratracheal lipopolysaccharide. These findings suggest that adhesion molecule expression and cytokine production in the lung are mediated by the production of reactive oxygen intermediates. Because adhesion molecules and cytokines play a crucial role in the pathophysiology of neutrophil-mediated acute lung injury, the inhibition of adhesion molecule expression and cytokine production with anti-oxidants such as N-acetylcysteine may be a useful therapeutic strategy.

Topics: Acetylcysteine; Animals; Antioxidants; Bronchi; Cells, Cultured; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Lung Diseases; Rats; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Pulmonary neutrophilia characterises both the relatively transient inflammation associated with infant respiratory distress syndrome (IRDS) and the persistent inflammation of chronic lung disease. The possibility that persistently raised markers of inflammation indicate the development of chronic lung disease in low birth weight (< 1730 g) preterm (< 31 weeks) infants was therefore investigated.. Soluble ICAM-1 (sICAM-1) levels in plasma, and interleukin (IL)-8 and myeloperoxidase (MPO) levels in bronchial lavage fluid (BLF) obtained from 17 infants on days 1, 5, and 14 following birth were measured and correlations with the number of neutrophils in BLF sought. Peripheral neutrophils were isolated on Polymorphoprep and chemotactic responsiveness to IL-8 was assessed using micro Boyden chambers.. Sixteen infants developed IRDS and, of these, 10 infants subsequently developed chronic lung disease. Levels of IL-8 in BLF at 14 days of age correlated with the long term requirement for intermittent positive pressure ventilation (IPPV). Interleukin 8 levels in BLF correlated with neutrophil numbers and MPO concentration, suggesting both recruitment and activation in response to this cytokine. Antibody depletion studies showed that approximately 50% of total neutrophil chemotactic activity in BLF was due to IL-8. No difference in peripheral neutrophil chemotactic responsiveness at any age was observed for infants with IRDS or chronic lung disease. Plasma soluble intercellular adhesion molecule (sICAM-1) was higher at 14 days of age in infants who developed chronic lung disease than in those with resolving IRDS, and correlated with severity of disease, as indicated by duration of IPPV.. The results indicate that high levels of plasma sICAM-1 and IL-8 in BLF at day 14 correlate with the development of chronic lung disease and indicate the severity of disease.

Topics: Biomarkers; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Chronic Disease; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Intercellular Adhesion Molecule-1; Interleukin-8; Lung Diseases; Neutrophils; Respiratory Distress Syndrome, Newborn

The mechanisms underlying the initiation of lung disease and early respiratory morbidity in cystic fibrosis (CF) are poorly understood. By identifying infants with CF through a statewide neonatal screening program, we investigated whether airway inflammation was present in these infants, with the goal of furthering our understanding of the early events in this lung disease. Bronchoalveolar lavage fluid (BALF) from 16 infants with CF (mean age, 6 mo) and 11 disease control infants (mean age, 12 mo) was examined for the following inflammatory parameters: (1) neutrophil count; (2) activity of free neutrophil elastase; (3) elastase/alpha 1-antiprotease inhibitor complexes; and (4) the level of interleukin-8 (IL-8). We also quantified the spontaneous level of expression of IL-8 mRNA transcripts by airway macrophages. Each index of airway inflammation was increased in the BALF of infants with CF as compared with control infants. In addition, both the number of neutrophils and IL-8 levels were increased in infants with CF who had negative cultures (n = 7) for common bacterial CF-related pathogens, as well as for common respiratory viruses and fungi at the time of bronchoalveolar lavage (BAL). These findings suggest that airway inflammation is already present in infants with CF who are as young as 4 wks. Furthermore, although many different cell types (e.g., epithelial cells) may express IL-8, airway macrophages appear to be a source of this chemokine, and may thus play a prominent role in early neutrophil influx into the lung.

Topics: alpha 1-Antitrypsin; Base Sequence; Bronchoalveolar Lavage Fluid; Cystic Fibrosis; Humans; Infant; Infant, Newborn; Inflammation; Interleukin-8; Leukocyte Count; Leukocyte Elastase; Lung Diseases; Macrophages, Alveolar; Molecular Sequence Data; Neutrophils; Pancreatic Elastase; RNA, Messenger

Interleukin-8 (IL-8), soluble intercellular adhesion molecule-1 (sICAM), elastase and neutrophils were assessed in bronchoalveolar lavage fluid from nine infants who developed chronic lung disease (CLD) after respiratory distress syndrome (RDS), seven who had recovered from RDS, and in four control infants. IL-8, sICAM, elastase and neutrophils in bronchoalveolar lavage fluid were increased in the CLD group, the differences being most pronounced at 10 days of age. When babies with and without CLD were compared at 10 days of age, bronchoalveolar lavage fluid from the babies with CLD had significantly increased IL-8 (114.0 vs 12.7 ng/ml), sICAM (19.0 vs 1.1 micrograms/ml), elastase (6.9 vs 0.9 micrograms/ml) and neutrophils (1.9 vs 0.4 x 10(9)/l). In serum the increased concentration of IL-8 observed at birth in the CLD (247 pg/ml) and RDS (192 pg/ml) groups decreased over three weeks to the concentrations observed in the controls (< 70 pg/ml). Persistent inflammation could be a major contributory factor in the development of CLD.

Topics: Bronchoalveolar Lavage Fluid; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intercellular Adhesion Molecule-1; Interleukin-8; Leukocyte Count; Leukocyte Elastase; Lung Diseases; Neutrophils; Pancreatic Elastase; Respiratory Distress Syndrome, Newborn; Time Factors

Topics: Bronchoalveolar Lavage Fluid; Chronic Disease; Humans; Infant, Newborn; Infant, Premature; Interleukin-8; Lung Diseases; Predictive Value of Tests; Prognosis

Topics: Dexamethasone; Exudates and Transudates; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Interleukin-8; Lung Diseases

To investigate the pathogenesis of lung injury in Pneumocystic carinii pneumonia and nonspecific interstitial pneumonitis (NIP), common pulmonary complications of human immunodeficiency virus (HIV) infection. The efficacy of corticosteroid therapy in P carinii pneumonia and the observation that bronchoalveolar lavage (BAL) neutrophilia predicts a poor prognosis support the premise that the lung injury of P carinii pneumonia is due to the host's inflammatory response to the infection.. In vitro measurements on previously collected BAL fluid samples.. The Clinical Center of the National Institutes of Health, a research hospital and tertiary care referral center.. Five normal volunteers, 5 asymptomatic HIV-positive patients, 10 HIV-positive patients with NIP (5 asymptomatic and 5 with respiratory symptoms), and 19 HIV-positive patients with P carinii pneumonia.. BAL leukotriene B4 (LTB4), interleukin 8 (IL-8), and phospholipase A2 (PLA2) were measured. IL-8 and PLA2 were elevated in patients with P carinii pneumonia, and IL-8 correlated with BAL fluid absolute neutrophil count. LTB4, IL-8, and PLA2 levels were elevated in patients with NIP; LTB4 and PLA2 levels correlated with absolute neutrophil count, and IL-8 correlated with alveolar-arterial oxygen pressure difference. IL-8 was elevated in the asymptomatic HIV-positive patients, and there was a trend toward elevation of PLA2 in this group.. IL-8 appears to play a role in the pathogenesis of lung injury in P carinii pneumonia and may be the principal neutrophil chemotaxin in this disease; PLA2 may also be involved in the pathogenesis of P carinii pneumonia. Both LTB4 and IL-8 may be involved in the recruitment of neutrophils and subsequent lung injury of NIP. These data suggest that there are varying mechanisms by which inflammatory cells are recruited to the lung in different HIV-related lung diseases.

Topics: Adult; AIDS-Related Opportunistic Infections; Bronchoalveolar Lavage Fluid; Chromatography, High Pressure Liquid; Female; HIV Infections; HIV Seropositivity; Humans; Interleukin-8; Leukotriene B4; Lung Diseases; Male; Middle Aged; Phospholipases A; Phospholipases A2; Pneumonia, Pneumocystis; Pulmonary Fibrosis

Re-establishing blood flow to ischaemic tissues causes greater injury than that induced during the ischaemic period. This type of tissue injury, reperfusion injury, is involved in frostbite, multiple organ failure after hypovolaemia and in myocardial infarction. Depletion of neutrophils alleviates reperfusion injury, implying a causal role of neutrophil infiltration. Among members of the recently discovered family of chemotactic cytokines (chemokines), interleukin-8 (IL-8) is a major neutrophil chemotactic and activating factor produced by various types of human cells. We investigated its pathophysiological role in a rabbit model of a lung reperfusion injury. Reperfusion of ischaemic lung caused neutrophil infiltration and destruction of pulmonary structure, as well as local production of IL-8. Furthermore, the administration of a neutralizing monoclonal antibody against IL-8 prevented neutrophil infiltration and tissue injury, proving a causal role of locally produced IL-8 in this model.

Topics: Animals; Antibodies, Monoclonal; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Female; Guinea Pigs; Interleukin-8; Ischemia; Lung; Lung Diseases; Neutrophils; Rabbits; Reperfusion Injury

Idiopathic pulmonary fibrosis is an immunologically mediated pulmonary disorder in which activated alveolar macrophages (AM) and neutrophils play cardinal roles in the pathogenesis of the inflammatory lung lesion. The factors responsible for the induction and perpetuation of the neutrophilic alveolitis are not known. Recently, a novel cytokine (Interleukin-8) was described that is released by activated mononuclear phagocytes and a variety of other cell types, and it exhibits potent chemotactic activity for polymorphonuclear leukocytes (PMN). Increased expression of IL-8 has been described in other inflammatory disorders characterized by neutrophilic infiltration, including psoriasis, rheumatoid arthritis, and the sepsis syndrome, but no studies have assessed this cytokine in the context of interstitial pulmonary disorders. We have previously shown that normal human AM release IL-8 upon appropriate stimulation, but data assessing the expression of IL-8 by human AM in specific pulmonary disease states are lacking. In this study, we examined the expression of steady-state mRNA for IL-8 by human alveolar macrophages obtained by bronchoalveolar lavage (BAL) from patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis and from healthy volunteers. Because it is known that adherence to plastic culture plates may up-regulate gene expression for IL-8 in the absence of additional stimulation, we extracted mRNA immediately from the cell pellet obtained by BAL rather than using cultured alveolar macrophage monolayers. Northern blot analysis was performed to determine IL-8 mRNA expression. We found that BAL cells from patients with IPF constitutively expressed mRNA for IL-8, and the amount of IL-8 mRNA (as assessed by laser densitometry) correlated with the percent of neutrophils on BAL.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Bronchoalveolar Lavage Fluid; Female; Gene Expression; Humans; Interleukin-8; Lung Diseases; Macrophages, Alveolar; Male; Middle Aged; Neutrophils; Pulmonary Fibrosis; RNA, Messenger; Sarcoidosis

Topics: Animals; Humans; Interleukin-8; Lung; Lung Diseases; Neutrophils; Rabbits; Recombinant Proteins

A 69-year-old woman had plasma cell granuloma of the left middle lobe of the lung. Her symptoms and roentgenologic findings improved with antibiotic treatment. Before treatment, the number of neutrophils and NCA were markedly increased in BAL fluid obtained from the affected region of the left lung and moderately increased in BAL fluid obtained from the nonaffected region of the right lung. The number of neutrophils, the NCA as well as the contents of C5 and C5a des Arg (neutrophil chemotactic factors) in the BAL fluids from both these regions decreased during treatment. These findings suggest that plasma cell granuloma was due to chronic immune and inflammatory reactions in the lung, that neutrophils are involved in development of the symptoms and signs of this disease, and that neutrophil chemotactic factors, including complement-derived factors, are important in neutrophil recruitment at the lesion and in nonaffected parts of the lung.

Topics: Aged; Albumins; Bronchoalveolar Lavage Fluid; Cell Count; Chemotactic Factors; Complement C5; Female; Granuloma; Granuloma, Plasma Cell; Humans; Immunoglobulins; Interleukin-8; Lung Diseases; Neutrophils; Radiography

Intraalveolar leukocytosis is integral in initiating and perpetuating airspace inflammatory reactions. We used intratracheal instillation of silica suspensions in adult male rats to cause neutrophil flux (32% increase over saline controls) without creating a protein leak, so simulating an early inflammatory response. We examined the in vivo effects of a known phospholipase A2 inhibitor (mepacrine) and the two mast cell active agents (cyproheptadine and reserpine) on lung lavage fluid chemotactic capability, alveolar macrophage (AM) production of chemotactic factor(s), and neutrophil diapedesis. Only mepacrine significantly depressed the leukocytosis (from 32% to 8% of total cells), with a similar diminution in AM chemotaxin production. Separate in vitro experiments using mepacrine-pretreated neutrophils and macrophages gave evidence that mepacrine: (1) diminishes neutrophil response to chemotaxin(s), (2) inhibits spontaneous, random neutrophil movement, and (3) diminishes macrophage-derived chemotactic factor production. These observations suggest that the earliest events in alveolar inflammatory reactions probably involve local production of chemotactic factors by AM, and that mepacrine's anti-inflammatory action results from inhibitory influences on both macrophage and neutrophil populations.

Topics: Acute Disease; Animals; Cell Movement; Chemotactic Factors; Instillation, Drug; Interleukin-8; Lung Diseases; Male; Mast Cells; Neutrophils; Quinacrine; Rats; Rats, Inbred F344; Silicon Dioxide; Trachea

We have previously shown that prior exposure to hyperoxia intensifies the influx of polymorphonuclear leukocytes into bronchoalveolar spaces after endotoxemia (E), but the mechanism is unknown. Because pulmonary alveolar macrophages (PAM) regulate the migration of polymorphonuclear leukocytes into the lung in several types of acute and chronic alveolitis, we studied the effect of pretreatment with hyperoxia in vivo on production of chemotactic factors by PAM after E. In this study, we cultured PAM recovered by lung lavage from oxygen- and air-pretreated rats 4, 15, and 48 h after E to determine whether a direct effect of hyperoxia on the release of chemotactic factors by PAM in response to E in vivo could contribute to the previous observations. We found that the chemotactic activity of the culture media supernatants from PAM recovered from oxygen-pretreated rats given E was 80% higher than that of media from PAM recovered from air-exposed rats given E. Neither PAM from air-exposed rats nor those from oxygen-exposed rats spontaneously released chemotaxins selective for other PAM. In contrast, when PAM were stimulated with zymosan in vitro, those from the oxygen-breathing group produced 50% more chemotactic activity for other PAM than did those from the air-breathing group. These differences in secretion of chemotactic factors were not associated with decreased viability of PAM either in vivo or in tissue culture, or with impaired adherence by PAM in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cell Movement; Chemotactic Factors; Endotoxins; Escherichia coli; Inflammation; Interleukin-8; Lung Diseases; Macrophages; Male; Microscopy, Electron; Neutrophils; Oxygen; Pulmonary Alveoli; Rats; Rats, Inbred Strains; Therapeutic Irrigation