interleukin-8 and Bronchial-Hyperreactivity

There is increasing evidence that inflammatory mechanisms other than eosinophilic inflammation may be involved in producing the final common pathway of enhanced bronchial reactivity and reversible airflow obstruction that characterises asthma. A review of the literature has shown that, at most, only 50% of asthma cases are attributable to eosinophilic airway inflammation. It is hypothesised that a major proportion of asthma is based on neutrophilic airway inflammation, possibly triggered by environmental exposure to bacterial endotoxin, particulate air pollution, and ozone, as well as viral infections. If there are indeed two (or more) subtypes of asthma, and if non-eosinophilic (neutrophil mediated) asthma is relatively common, this would have major consequences for the treatment and prevention of asthma since most treatment and prevention strategies are now almost entirely focused on allergic/eosinophilic asthma and allergen avoidance measures, respectively. It is therefore important to study the aetiology of asthma further, including the underlying inflammatory profiles.

Topics: Asthma; Bronchial Hyperreactivity; Environmental Exposure; Eosinophils; Humans; Inflammation; Interleukin-5; Interleukin-8; Occupational Diseases

Cigarette smoking has been implicated in many pulmonary disorders, including chronic bronchitis and chronic obstructive lung disease. Cigarette smoking is associated with increased airway responsiveness. Acute exposure to cigarette smoke increases airway responsiveness in a dose-dependent manner. A superoxide is involved in airway hyper-responsiveness induced by cigarette smoke, perhaps by direct toxic action. Cigarette smokers have increased numbers of neutrophils present in their lower respiratory tract. Acute exposure to cigarette smoke initiates a superoxide-dependent mechanism that, through NF-kappa B activation and IL-8 expression, induces infiltration of neutrophils into the airways in vivo. The alveolar macrophage is one potential source of NF-kappa B activation and IL-8 production after acute exposure to cigarette smoke. Manipulation of NF-kappa B by antioxidants in vivo may be useful in limiting biologic processes such as pro-inflammatory cytokine production, which may lead to neutrophil accumulation in the lung.

Topics: Animals; Antioxidants; Bronchial Hyperreactivity; Bronchitis; Humans; Interleukin-8; Lung Diseases, Obstructive; Macrophages, Alveolar; Neutrophil Infiltration; NF-kappa B; Respiratory System; Smoking; Superoxides

Airway inflammation is a prominent feature of chronic obstructive diseases of the airways, including asthma, bronchiectasis, chronic bronchitis, and diffuse panbronchiolitis. Neutrophils are implicated in the pathogenesis of these diseases. The present review discusses the role of interleukin-8 (IL-8), a neutrophil chemo-attractant, in neutrophil accumulation in the airways, and the mechanisms of inducing IL-8 expression. IL-8 presents in the sputum of patients with inflammatory airway diseases, and accounts in large part for the chemo-attractant activity present. Focusing on Pseudomonas aeruginosa as the stimulus, it was discovered that when a supernatant of bacterial culture is introduced into the airways in vivo, bacterial products induce IL-8 expression in surface airway epithelial cells and the recruitment of neutrophils into the airways. The neutrophil chemotactic activity of the airway fluid was inhibited by an IL-8 antibody. The luminal IL-8 concentration increased in response to instillation of bacteria, and an inhibitor of neutrophil recruitment markedly reduced the IL-8 levels. From these results, it was speculated that bacteria-induced neutrophil accumulation in the airways involves a cascade of events, and that early neutrophil recruitment in response to bacteria is due to epithelium-derived IL-8, while the amplification of the response is due, at least in part, to IL-8 induction in the neutrophils themselves.

Topics: Bronchial Hyperreactivity; Bronchitis; Chemotaxis, Leukocyte; Humans; Interleukin-8; Neutrophils; Tracheitis

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

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

Obstructive sleep apnea syndrome (OSA) is associated with systemic and upper airway inflammation. Pharyngeal inflammation has a potential role in upper airway collapse, whereas systemic inflammation relates to cardiovascular morbidity. However, the presence of an inflammatory involvement of lower airway has been poorly investigated.. The aim of the study was to demonstrate an inflammatory process at the bronchial level in patients with OSA and to analyze effects of continuous positive airway pressure (CPAP) application and humidification on bronchial mucosa.. The study was conducted by using sequential induced sputum for cell analysis and IL-8 production, nitric oxide exhalation measurement, and methacholine challenge before and after CPAP.. Bronchial neutrophilia and a high IL-8 concentration were observed in untreated OSA compared with controls (75% +/- 20% vs 43% +/- 12%, P < .05; and 25.02 +/- 9.43 ng/mL vs 8.6 +/- 3.7 ng/mL, P < .001, respectively). IL-8 in sputum supernatant was correlated to apnea hypopnea index (P < .01; r = 0.81). After 1 month of CPAP, this inflammatory pattern remained unchanged, and an increase in airway hyperresponsiveness (AHR) was observed (P < .001).. Obstructive sleep apnea syndrome is associated with bronchial inflammation. Our data demonstrate CPAP effect on the development of AHR, possibly facilitated by the pre-existing inflammation. Both issues should be evaluated during long-term CPAP use.. Results showing a spontaneous bronchial inflammation in OSA and the development of a CPAP-related AHR require a long-term follow-up to evaluate consequences on chronic bronchial obstruction.

Topics: Adult; Bronchi; Bronchial Hyperreactivity; Bronchitis; Bronchoconstrictor Agents; Continuous Positive Airway Pressure; Exhalation; Female; Humans; Interleukin-8; Male; Methacholine Chloride; Middle Aged; Neutrophils; Nitric Oxide; Respiratory Mucosa; Sleep Apnea, Obstructive; Sputum

Few studies have compared treatment strategies in patients with asthma poorly controlled on low dose inhaled corticosteroids, and little is known about the effects of different treatments on airway inflammation. In this double-blind, placebo-controlled, parallel group study, we compared the effects of salmeterol plus fluticasone propionate (FP) (Seretide; SFC) and FP plus montelukast (FP/M) on sputum inflammatory markers, airway responsiveness, lung function, and symptoms in adult asthmatics.. Sixty-six subjects were randomised to SFC or FP/M for 12 weeks. The primary outcome was changes in neutrophil, eosinophil, macrophage, lymphocyte, and epithelial cell levels in induced sputum. Additional outcomes included the change in other sputum markers of airway inflammation, airway responsiveness, symptom control, and lung function.. Both treatments had no significant effect on induced sputum inflammatory cells, although there was a trend for a reduction in sputum eosinophils. Both treatments significantly improved airway responsiveness, whereas SFC generally led to greater improvements in symptom control and lung function than FP/M. FP/M led to significantly greater reductions in sputum cysteinyl leukotrienes than SFC (treatment ratio 1.80; 95% CI 1.09, 2.94).. Both treatments led to similar control of eosinophilic airway inflammation, although PEF and symptom control were better with SFC. STUDY NUMBER: SAM40030 (SOLTA).

Topics: Acetates; Adrenergic beta-Agonists; Adult; Albuterol; Androstadienes; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Cyclopropanes; Cysteine; Double-Blind Method; Drug Combinations; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Histamine; Humans; Interleukin-8; Leukotriene Antagonists; Leukotrienes; Lung; Male; Quinolines; Spirometry; Sputum; Sulfides; Time Factors; Treatment Outcome; United Kingdom

A study was conducted to evaluate the acute health effects of wearing an N-95 disposable respirator in a swine confinement facility.. A crossover trial design was used in the study.. The study was carried out at the research facilities of the Centre for Agricultural Medicine, the Royal University Hospital, and the Prairie Swine Centre Inc, Saskatoon, Saskatchewan, Canada.. Twenty-one nonsmoking healthy male subjects with no previous swine barn exposure participated in the study.. The subjects participated in a laboratory session (baseline day), a 4-h exposure in a traditional swine room wearing the respirator (intervention day), and a 4-hour exposure in a traditional swine room without a respirator (nonintervention day).. Lung function, methacholine challenge tests, blood counts, nasal lavage, and cytokines in serum and nasal lavage fluid.. Mean (+/- SE) shift change in FEV(1), from preexposure to postexposure, was highest on nonintervention day (-8.1+/-1.01%) and was significantly different from intervention day (0.32+/-0.62%; p<0.0001) and baseline day (1.57+/-0.51%; p<0.0001). Similar patterns were observed in the mean values of the provocative concentration of a substance (methacholine) causing a 20% fall in FEV(1) (nonintervention day, 130.4+/-36.9 mg/mL; intervention day, 242.0+/-38.0 mg/mL; and baseline day, 328.0 mg/mL +/-34.1 mg/mL). Significant increases in serum neutrophil levels and nasal cell counts were observed on the nonintervention day in comparison to the baseline and intervention days. Significant increases also were found in the levels of cytokines interleukin (IL)-6 and IL-8 in nasal lavage fluid and in the levels of IL-6 in serum for the nonintervention day in comparison to the other 2 days.. The results demonstrate that an N-95 disposable respirator can help to significantly reduce acute negative health effects in subjects not previously exposed to a swine barn environment.

Topics: Adolescent; Adult; Air Pollutants, Occupational; Animals; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cross-Over Studies; Disposable Equipment; Humans; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Methacholine Chloride; Nasal Lavage Fluid; Occupational Diseases; Quality Control; Respiratory Function Tests; Respiratory Protective Devices; Surveys and Questionnaires

The role of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD) is unclear. We investigated the effects of budesonide on airway hyperresponsiveness (AHR) to methacholine (MCh) and adenosine 5'-monophosphate (AMP), to which we hypothesized the existence of greater sensitivity. Additionally, we studied the effects of budesonide on terfenadine and ipratropium bromide and on serum levels of interleukin-8 (IL-8) and histamine. Forty-four hyperresponsive smokers with moderate to severe COPD participated in the study. MCh and AMP challenges were given on three study days, after pretreatment with single doses of ipratropium bromide, terfenadine, or placebo. Thereafter, subjects were randomized to 6 wk treatment with either 1,600 microg budesonide or placebo, and the same three study days were repeated. Budesonide, as compared with placebo, did not significantly change PC20AMP, PC20MCh, or FEV1 after placebo pretreatment. Budesonide increased PC20MCh after ipratropium bromide pretreatment, from 5.05 to 10.20 mg/ml (p = 0.036). Budesonide decreased serum IL-8 from 9.2 +/- 3.7 to 6.2 +/- 2.1 pg/ml (p < 0.001). We conclude that AMP did not elicit greater sensitivity than MCh in assessing short-term effects of budesonide on AHR in smokers with COPD. We suggest that long-term treatment with inhaled corticosteroids might be beneficial, by reducing neutrophil load in the airways and improving the action of anticholinergic drugs.

Topics: Adenosine Monophosphate; Administration, Inhalation; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Female; Forced Expiratory Volume; Glucocorticoids; Histamine; Histamine H1 Antagonists; Humans; Interleukin-8; Ipratropium; Leukocyte Count; Longitudinal Studies; Lung Diseases, Obstructive; Male; Methacholine Chloride; Middle Aged; Neutrophils; Placebos; Smoking; Terfenadine; Time Factors

Asthma exacerbations are closely associated with respiratory virus infections. However, the pathophysiological consequences of such infections in asthma are largely unclear.. To examine the effect of rhinovirus 16 (RV16) infection on airway hypersensitivity to histamine, and on interleukin-8 (IL-8) in nasal lavage.. Twenty-seven non-smoking atopic, mildly asthmatic subjects participated in a placebo-controlled, parallel study. A dose of 0.5-2.9 x 10(4) TCID50 RV16 or placebo was nasally administered. Cold symptoms were recorded by questionnaire throughout the study. Histamine challenges were performed at entry, and on days 4 and 11 after inoculation. Nasal lavages were obtained at entry, and on days 2 and 9. The response to histamine was measured by PC20 (changes expressed as doubling doses: DD) IL-8 levels were obtained by ELISA, and were expressed in ng/ml.. RV infection was confirmed by culture of nasal lavage and/or by antibody titre rise in each of the RV16-treated subjects. Among the 19 RV 16-treated subjects, eight developed severe cold symptoms. Baseline FEV1, did not change significantly during the study in either treatment group (P = 0.99). However, in the RV16-treated subjects there was a decrease in PC20 at day 4, which was most pronounced in those with a severe cold (mean change +/- SEM: -1.14 +/- 0.28 DD, P = 0.01). In addition, IL-8 levels increased in the RV16 group at days 2 and 9 (P < 0.001). The increase in nasal IL-8 at day 2 correlated significantly with the change in PC20 at day 4 (r = -0.48, P = 0.04).. We conclude that the severity of cold, as induced by experimental RV16 infection, is a determinant of the increase in airway hypersensitivity to histamine in patients with asthma. Our results suggest that this may be mediated by an inflammatory mechanism, involving the release of chemokines such as IL-8.

Topics: Adolescent; Adult; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Common Cold; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Forced Expiratory Volume; Histamine; Humans; Interleukin-8; Leukocyte Count; Lung; Male; Nasal Lavage Fluid; Rhinovirus

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

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

Exposure to endotoxin and to its purified derivative lipopolysaccharide (LPS) is related to several occupational pulmonary diseases and to severe domestic asthma. An inhalation of a given dose of pure LPS produces both a systemic and a bronchial inflammatory response. Information on the dose-response relationship to inhaled LPS in normal subjects is a prerequisite to define the safety threshold of exposure. In the present study, the clinical and inflammatory responses to rising doses of inhaled LPS was evaluated. Nine normal volunteers were challenged weekly by inhalation with saline, 0.5, 5, and 50 microg LPS (Escherichia coli). The response determinators are the clinical symptoms, fever, FEV1, blood polymorphonuclear neutrophils (PMNs) with their level of activation (measured by luminol enhanced-chemiluminescence), and both the blood and the urine concentrations of the C-reactive protein (CRP). To assess the bronchial inflammatory response, an induced sputum was obtained 6 h after each dose of LPS, and the total and differential cell counts as well as the MPO, ECP, and TNF-alpha concentrations were measured. Compared with the saline, an inhalation of 0.5 microg LPS induces a significant decrease in the PMN luminol-enhanced chemiluminescence (p < 0.01), which could reflect a process of margination and/or extravascular sequestration of activated PMN. Inhalation of 5 microg LPS is associated with a significant rise in blood CRP (p < 0.01) and PMNs (p < 0.001) and in sputum PMNs (p < 0.05), monocytes (p < 0.05), and MPO (p < 0.05). Inhalation of 50 microg LPS was characterized by a significant increase in temperature (p < 0.01), blood PMNs (p < 0.001), blood and urine CRP (p < 0.01 and < 0.01), and sputum PMNs (p < 0.001), monocytes (p < 0.05), lymphocytes (p < 0.05), MPO (p < 0.01), TNF-alpha (p < 0.01), and ECP (p < 0.01) while five subjects develop symptoms. In normal subjects, the response to inhaled LPS is dose-related, the most sensitive markers of LPS-induced inflammation being the blood PMNs count with their level of activation, the blood CRP concentration, and the sputum PMNs count. The no-response threshold to an acute inhalation of LPS is less than 0.5 microg.

Topics: Administration, Inhalation; Adult; Biomarkers; Bronchi; Bronchial Hyperreactivity; C-Reactive Protein; Dose-Response Relationship, Drug; Escherichia coli; Female; Humans; Interleukin-8; Leukocyte Count; Lipopolysaccharides; Macrophages, Alveolar; Male; Middle Aged; Neutrophils; Peroxidase; Reference Values; Respiratory Function Tests; Single-Blind Method; Sputum; Tumor Necrosis Factor-alpha

Exposure to ozone at levels near the National Ambient Air Quality Standard causes respiratory symptoms, changes in lung function, and airway inflammation. Although ozone-induced changes in lung function have been well characterized in healthy individuals, the relationship between airway inflammation and changes in pulmonary function have not been prospectively examined. The purpose of this study was to determine whether individuals who differ in, lung function responsiveness to ozone also differ in susceptibility to airway inflammation and injury. A secondary goal was to determine whether ozone exposure induces airway inflammation in smokers, a population known to have airway inflammation and an increased burden of toxic oxygen species. Healthy nonsmokers (n = 56) and smokers (n = 34) were exposed to 0.22 parts per million (ppm)* ozone for 4 hours, with intermittent exercise, for the purpose of selecting ozone "responders" (decrement in forced expiratory volume in 1 second [FEV1] > 15%) and "nonresponders" (decrement in FEV1 < 5%). Selected subjects then were exposed twice to ozone (0.22 ppm for 4 hours with exercise) and once to air (with the same exposure protocol), each pair of exposures separated by at least 3 weeks, in a randomized, double-blind fashion. Nasal lavage (NL) and bronchoalveolar lavage (BAL) were performed immediately after one ozone exposure and 18 hours after the other, and either immediately or 18 hours after the air exposure. Indicators of airway effects in lavage fluid included changes in inflammatory cells, proinflammatory cytokines, protein markers of epithelial injury and repair, and generation of toxic oxygen species. In the classification exposure, fewer smokers than nonsmokers were responsive to ozone (11.8% vs. 28.6%, respectively); an insufficient number of smoker-responders were identified to study as a separate group. In the BAL study, all groups developed a similar degree of airway inflammation, consisting of increases in interleukins 6 and 8 (maximal immediately after exposure), and increases in polymorphonuclear leukocytes (PMNs), lymphocytes, and mast cells (maximal 18 hours after exposure). The increase in PMNs was inversely correlated with age (p = 0.013), but gender, nonspecific airway responsiveness, and allergy history were not predictive of inflammation. Alveolar macrophage production of toxic oxygen species decreased after ozone exposure in nonsmokers; however, not in smokers. Findings from nasal lavage did not

Topics: Adolescent; Adult; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Data Interpretation, Statistical; Double-Blind Method; Female; Flow Cytometry; Forced Expiratory Volume; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Macrophages, Alveolar; Male; Mast Cells; Methacholine Chloride; Ozone; Physical Exertion; Reactive Oxygen Species; Respiratory Mechanics; Smoking; Spirometry; Therapeutic Irrigation; Time Factors; Vital Capacity

Neutrophilic inflammation in asthma is associated with interleukin (IL)-17A, corticosteroid-insensitivity and bronchodilator-induced forced expiratory volume in 1 s (FEV

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Albuterol; Asthma; Bronchi; Bronchial Hyperreactivity; Bronchoalveolar Lavage; Cell Line, Tumor; Cytoplasm; Epithelial Cells; Epithelium; Female; Forced Expiratory Volume; Humans; Inflammation; Interleukin-17; Interleukin-8; Lung; Male; Methacholine Chloride; Middle Aged; Neutrophils; Randomized Controlled Trials as Topic; Respiratory Function Tests; Smoking; Tumor Necrosis Factor-alpha; Young Adult

Asthma is frequently reported in endurance athletes. The aim of the present study was to assess the long-term airway inflammatory response to endurance exercise in high-level athletes with and without asthma.. In a cross-sectional design, 20 asthmatic athletes (10 swimmers and 10 cross-country skiers), 19 athletes without asthma (10 swimmers and 9 cross-country skiers), and 24 healthy nonathletes completed methacholine bronchial challenge, lung function tests, and sputum induction on two separate days. All athletes competed on a national or international level and exercised ≥10 h·wk. The nonathletes exercised ≤5 h·wk and reported no previous lung disease. Bronchial hyperresponsiveness (BHR) was defined as a methacholine provocation dose causing 20% decrease in the forced expiratory volume in 1 s of ≤8 μmol.. BHR was present in 13 asthmatic athletes (62%), 11 healthy athletes (58%), and 8 healthy nonathletes (32%), and the prevalence differed among groups (P = 0.005). Sputum inflammatory and epithelial cell counts did not differ between groups and were within the normal range. Median (25th to 75th percentiles) sputum interleukin-8 was elevated in both asthmatic (378.4 [167.0-1123.4]) and healthy (340.2 [175.5-892.4]) athletes as compared with healthy nonathletes (216.6 [129.5-314.0], P = 0.02). No correlations were found between provocation dose causing 20% decrease and sputum cell counts.. Independent of asthma diagnosis, a high occurrence of BHR and an increased sputum interleukin-8 were found in athletes as compared with nonathletes. Airway inflammation or epithelial damage was not related to BHR.

Topics: Adolescent; Adult; Asthma, Exercise-Induced; Athletes; Bronchial Hyperreactivity; Bronchial Provocation Tests; Case-Control Studies; Cross-Sectional Studies; Female; Forced Expiratory Volume; Humans; Inflammation; Interleukin-8; Male; Methacholine Chloride; Skiing; Sputum; Swimming; Young Adult

Little data exist on short- and long-term effects of occupational exposure on airway and systemic inflammation in professional firefighters. We aimed to characterize airway and systemic inflammation in training firefighters with a maximum occupational exposure of 1 year compared to the long-term exposure of professional firefighters.. A questionnaire for symptoms and exposure, pulmonary function, atopy, bronchial hyper-responsiveness, and markers of inflammation in induced sputum, serum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies were assessed in a total of 92 firefighters (63 full-time professionals and 29 trainees).. Professional firefighters showed allergic bronchial sensitization documented by the presence of atopy, and eosinophilia in induced sputum, BAL and bronchial biopsies. IL-8, ECP, VEGF, and TNF-α levels were statistically significantly higher in the sputum supernatants of professional firefighters compared to the trainees (p = 0.04, p = 0.02, p = 0.04, and p = 0.02, respectively). Serum IL-8 and TNF-α levels were also statistically significantly higher in the group of professional firefighters (p = 0.04, p = 0.03, respectively). Finally, there was a linear correlation between the duration of the occupation in Service and the degree of airway and systemic inflammation.. These results indicate a "dose-response" effect of chronic exposure to a polluted environment on bronchial and systemic inflammation in professional firefighters.

Topics: Adult; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Eosinophil Cationic Protein; Eosinophils; Firefighters; Humans; Hypersensitivity; Inflammation; Interleukin-8; Male; Occupational Exposure; Respiratory Function Tests; Respiratory System; Sputum; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Elite athletes frequently experience asthma and airway hyperresponsiveness (AHR). We aimed to investigate predictors of airway pathophysiology in a group of unselected elite summer-sport athletes, training for the summer 2008 Olympic Games, including markers of airway inflammation, systemic inflammation, and training intensity.. Fifty-seven Danish elite summer-sport athletes with and without asthma symptoms all gave a blood sample for measurements of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α), completed a respiratory questionnaire, and underwent spirometry. Bronchial challenges with mannitol were performed in all 57 athletes, and 47 agreed to perform an additional methacholine provocation.. Based on a physician's diagnosis, 18 (32%) athletes were concluded to be asthmatic. Asthmatic subjects trained more hours per week than the 39 nonasthmatics (median (min-max): 25 h·wk (14-30) versus 20 h·wk (11-30), P = 0.001). AHR to both methacholine and mannitol (dose response slope) increased with the number of weekly training h (r = 0.43, P = 0.003, and r = 0.28, P = 0.034, respectively). Serum levels of IL-6, IL-8, TNF-α, and hs-CRP were similar between asthmatics and nonasthmatics. However, there was a positive association between the degree of AHR to methacholine and serum levels of TNF-α (r = 0.36, P = 0.04). Fifteen out of 18 asthmatic athletes were challenged with both agents. In these subjects, no association was found between the levels of AHR to mannitol and methacholine (r = 0.032, P = 0.91).. AHR in elite athletes is related to the amount of weekly training and the level of serum TNF-α. No association was found between the level of AHR to mannitol and methacholine in the asthmatic athletes.

Topics: Adult; Asthma; Biomarkers; Bronchial Hyperreactivity; Bronchial Provocation Tests; C-Reactive Protein; Cross-Sectional Studies; Female; Humans; Interleukin-6; Interleukin-8; Male; Mannitol; Methacholine Chloride; Physical Education and Training; Spirometry; Sports; Tumor Necrosis Factor-alpha; Young Adult

Previous studies investigating the role of toll-like receptors (TLRs) in asthma have been inconclusive. It has remained elusive whether the toll-like receptors (TLR2)/mycloid differentiation factor 88 (MyD88)/nuclear factor (NF)-κB signaling pathway is involved in lipoxin A4 (LXA4)-induced protection against asthma. Therefore, the present study investigated whether ovalbumin (OVA)-induced airway inflammation is mediated by upregulation of the TLR2/MyD88/NF-κB signaling pathway, and whether it proceeds via the inhibition of the activation of the LXA4 receptor and anti-interleukin (IL)-1β antibodies. Mice with airway inflammation induced by OVA administration were treated with or without a LXA4 receptor agonist, BML-111 and anti-IL-1β antibody. Serum levels of IL-1β, IL-4, IL-8 and interferon-γ (IFN-γ) were assessed, and levels of IL-1β, IL-4, IL-8 and OVA-immunoglobulin (Ig)E, as well as leukocyte counts in the bronchoalveolar lavage fluid (BALF) were measured. Pathological features and expression of TLR2, MyD88 and NF-κB in the lungs were analyzed. Expression of TLR2 and MyD88, and activation of NF-κB in leukocytes as well as levels of IL-4, IL-6 and IL-8 released from leukocytes exposed to IL-1β were assessed. OVA treatment increased the levels of IL-1β, IL-4 and IL-8 in the serum and BLAF, the number of leukocytes and the levels of OVA-IgE in the BALF, the expression of TLR2 and MyD88, and the activation of NF-κB in the lung. These increments induced by OVA were inhibited by treatment with BML-111 and anti-IL-1β antibodies. Treatment of the leukocytes with BML-111 or TLR2 antibody, or MyD88 or NF-κB inhibitor, all blocked the IL-1β-triggered production of IL-4, IL-6 and IL-8 and activation of NF-κB. Treatment of the leukocytes with BML-111 or TLR2 antibody suppressed IL-1β-induced TLR2 and MyD88 expression. The present study therefore suggested that OVA-induced airway inflammation is mediated by the TLR2/MyD88/NF-κB pathway. IL-1β has a pivotal role in the airway inflammation and upregulation of the TLR2/MyD88/NF-κB pathway induced by OVA. BML-111 and anti-IL-1β antibody restrains the OVA-induced airway inflammation via downregulation of the TLR2/MyD88/NF-κB pathway.

Topics: Animals; Anti-Asthmatic Agents; Antibodies, Monoclonal; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Gene Expression Regulation; Heptanoic Acids; Interleukin-1beta; Interleukin-4; Interleukin-6; Interleukin-8; Lipoxins; Male; Mice; Mice, Inbred BALB C; Myeloid Differentiation Factor 88; NF-kappa B; Ovalbumin; Receptors, Formyl Peptide; Signal Transduction; Toll-Like Receptor 2

Smoking may modify the inflammatory pattern of the asthmatic airways. Osteopontin (OPN) has been associated with inflammation and fibrosis. In asthma, sputum levels of OPN are elevated and have been related to the underlying severity and to mediators expressing remodeling and inflammation. To evaluate the levels of OPN in sputum supernatants of asthmatic patients and to investigate the possible role of smoking as well as associations with mediators and cells involved in the inflammatory and remodeling process. We studied 103 asthma patients (49 smokers) and 40 healthy subjects (20 smokers) who underwent lung function tests, bronchial hyperresponsiveness to methacholine, and sputum induction for cell count identification and measurement of OPN, TGF-β1, IL-8, IL-13 and ECP in sputum supernatants. The concentrations of all mediators were measured using enzyme immunoassays. OPN levels (pg/ml) were significantly higher in smoking asthmatics compared to non-smoking asthmatics, and both non-smoking and smoking controls [median (interquartile ranges) 1120 (651,1817) vs. 197 (118,341) vs. 50 (42,70) vs. 102 (77,110) pg/ml, respectively; p<0.001]. Regression analysis provided significant associations between OPN and sputum neutrophils, IL-8 and TGF-β1, the most significant being the one with TGF-β1. These associations were present only in smoking asthmatics. Smoking habit significantly affects sputum OPN levels in asthma. The associations of OPN with sputum neutrophils, TGF-β1 and IL-8 in smoking asthmatics suggest a possible role for OPN in the neutrophilic inflammation and remodeling process in this phenotype of asthma.

Topics: Asthma; Bronchial Hyperreactivity; Female; Humans; Inflammation Mediators; Interleukin-13; Interleukin-8; Male; Methacholine Chloride; Middle Aged; Neutrophils; Osteopontin; Respiratory Function Tests; Smoking; Sputum; Transforming Growth Factor beta1

Airway cellular dysfunction is a differentiating feature of severe asthma in children that may be related to an imbalance of the antioxidant, glutathione (GSH). We hypothesized that oxidation of GSH to glutathione disulfide (GSSG) in the epithelial lining fluid (ELF) of children with severe asthma would contribute to altered airway macrophage (AM) GSH homeostasis and AM cellular dysfunction. Bronchoalveolar lavage (BAL) was performed in 64 asthmatic children (severe asthma, n = 43). GSH, GSSG, markers of lipid peroxidation and DNA oxidation, and IL-8 were quantified in the BAL supernatant. GSH, GSSG, activities of histone deacetylase (HDAC) and histone acetyltransferase, apoptosis, and phagocytosis were assessed in isolated AMs. Children with severe asthma had increased GSSG, lipid peroxidation, byproducts of DNA oxidation, and inflammation in the ELF. This imbalance of GSH homeostasis was also noted intracellularly within the AMs and was associated with decreased HDAC activities, increased apoptosis, and impaired phagocytosis. In vitro GSH supplementation inhibited apoptosis and rescued phagocytosis in children with severe asthma. Severe asthma in children is characterized by altered airway and intracellular AM GSH homeostasis that translates to impaired AM function. Interventions to restore airway GSH homeostasis may be warranted in children with severe asthma.

Topics: Adolescent; Apoptosis; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoscopy; Child; DNA Damage; Female; Glutathione; Glutathione Disulfide; Histone Acetyltransferases; Histone Deacetylases; Humans; Interleukin-8; Lipid Peroxidation; Macrophages, Alveolar; Male; Oxidation-Reduction; Oxidative Stress; Phagocytosis; Severity of Illness Index; Spirometry

High neutrophil counts in induced sputum have been found in nonasthmatic amateur runners at rest and after a marathon, but the pathogenesis of airway neutrophilia in athletes is still poorly understood. Bronchial epithelial damage may occur during intense exercise, as suggested by investigations conducted in endurance-trained mice and competitive human athletes studied under resting conditions. To gain further information on airway changes acutely induced by exercise, airway cell composition, apoptosis, IL-8 concentration in induced sputum, and serum CC-16 level were measured in 15 male amateur runners at rest (baseline) and shortly after a half-marathon. Different from results obtained after a marathon, neutrophil absolute counts were unchanged, whereas bronchial epithelial cell absolute counts and their apoptosis increased significantly (P < 0.01). IL-8 in induced sputum supernatants almost doubled postrace compared with baseline (P < 0.01) and correlated positively with bronchial epithelial cell absolute counts (R(2) = 0.373, P < 0.01). Serum CC-16 significantly increased after all races (P < 0.01). These data show mild bronchial epithelial cell injury acutely induced by intense endurance exercise in humans, extending to large airways the data obtained in peripheral airways of endurance-trained mice. Therefore, neutrophil influx into the airways of athletes may be secondary to bronchial epithelial damage associated with intense exercise.

Topics: Air Pollutants; Bronchi; Bronchial Hyperreactivity; Epithelium; Humans; Interleukin-8; Leukocyte Count; Male; Neutrophils; Physical Endurance; Running; Sputum; Uteroglobin

Urban air pollution, especially in developing countries, is a crucial environmental problem. Urban aerosols may contain various kinds of substances and induce harmful effects such as allergic diseases. Therefore, it is critical to clarify the biological effects of urban aerosols on human health. In this study, we evaluated the induction of airway inflammation in vitro and in vivo due to exposure of urban aerosols. We investigated cytokine production and nuclear factor-kappaB (NF-kappaB) activation after stimulation of macrophage cells by exposure of urban aerosols. Urban aerosols were found to induce the production of interleukin (IL)-8, tumor necrosis factor-alpha and IL-1beta on macrophage cells. In addition, we showed that NF-kappaB pathway regulated the urban aerosols-induced inflammatory cytokine response. Moreover, the intranasal administration of urban aerosols resulted in increases in the total cell number in bronchoalveolar lavage and infiltration of eosinophils in lung tissue. These results indicate that urban aerosols induce respiratory inflammation and onset of inflammatory disease due to an activation of the immune system.

Topics: Adjuvants, Immunologic; Administration, Inhalation; Aerosols; Air Pollutants; Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Line; Cytokines; Developing Countries; Environmental Exposure; Eosinophils; Female; Inflammation; Interleukin-1beta; Interleukin-8; Lung; Macrophages; Mice; Mice, Inbred BALB C; NF-kappa B; Signal Transduction; Tumor Necrosis Factor-alpha; Urban Population

Airway responsiveness to methacholine (Mch) in the absence of deep inspirations (DIs) is lower in athletes compared with sedentary individuals. In this prospective study, we tested the hypothesis that a training exercise program reduces the bronchoconstrictive effect of Mch. Ten healthy sedentary subjects (M/F: 3/7; mean + or - SD age: 22 + or - 3 yr) entered a 10-wk indoor rowing exercise program on rowing ergometer and underwent Mch bronchoprovocation in the absence of DIs at baseline, at weeks 5 and 10, as well as 4-6 wk after the training program was completed. Exercise-induced changes on airway cells and markers of airway inflammation were also assessed by sputum induction and venous blood samples. Mean power output during the 1,000 m test was 169 + or - 49 W/stroke at baseline, 174 + or - 49 W/stroke at 5 wk, and 200 + or - 60 W/stroke at 10 wk of training (P < 0.05). The median Mch dose used at baseline was 50 mg/ml (range 25-75 mg/ml) and remained constant per study design. At the pretraining evaluation, the percent reduction in the primary outcome, the inspiratory vital capacity (IVC) after inhalation of Mch in the absence of DIs was 31 +/- 13%; at week 5, the Mch-induced reduction in IVC was 22 + or - 19%, P = 0.01, and it further decreased to 15 + or - 11% at week 10 (P = 0.0008). The percent fall in IVC 4-6 wk after the end of training was 15 + or - 11% (P = 0.87 vs. end of training). Changes in airway cells were not associated with changes in airway responsiveness. Our data show that a course of exercise training can attenuate airway responsiveness against Mch inhaled in the absence of DIs in healthy subjects and suggest that a sedentary lifestyle may favor development of airways hyperresponsiveness.

Topics: Adult; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Exercise; Forced Expiratory Volume; Functional Residual Capacity; Humans; Inflammation Mediators; Inhalation; Interleukin-8; Lung; Male; Methacholine Chloride; Muscle Strength; Prospective Studies; Residual Volume; Sedentary Behavior; Spirometry; Sputum; Time Factors; Total Lung Capacity; Uteroglobin; Vital Capacity; Young Adult

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

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

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

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

Inhibitory M(2) muscarinic receptors on airway parasympathetic nerves normally limit acetylcholine release. Viral infections decrease M(2) receptor function, increasing vagally mediated bronchoconstriction. Since retinoic acid deficiency causes M(2) receptor dysfunction, we tested whether retinoic acid would prevent virus-induced airway hyperreactivity and prevent M(2) receptor dysfunction. Guinea pigs infected with parainfluenza virus were hyperreactive to electrical stimulation of the vagus nerves, but not to intravenous acetylcholine, indicating that hyperreactivity was due to increased release of acetylcholine from parasympathetic nerves. The muscarinic agonist pilocarpine, which inhibits vagally mediated bronchoconstriction in control animals, no longer inhibited vagally induced bronchoconstriction, demonstrating M(2) receptor dysfunction. Treatment with all-trans retinoic acid (1 mg/kg) prevented virus-induced hyperreactivity and M(2) receptor dysfunction. However, retinoic acid also significantly reduced viral titers in the lungs and attenuated virus-induced lung inflammation. In vitro, retinoic acid decreased M(2) receptor mRNA expression in both human neuroblastoma cells and primary cultures of airway parasympathetic neurons. Thus, the protective effects of retinoic acid on airway function during viral infection appear to be due to anti-inflammatory and antiviral mechanisms, rather than to direct effects on M(2) receptor gene expression.

Topics: Acetylcholine; Animals; Antineoplastic Agents; Bronchial Hyperreactivity; Bronchoconstriction; Cell Line, Tumor; Cholinergic Agents; DEAD Box Protein 58; DEAD-box RNA Helicases; Female; Gene Expression; Guinea Pigs; Humans; Interleukin-8; Muscarinic Agonists; Neuroblastoma; Neurons; Paramyxoviridae Infections; Pilocarpine; Receptor, Muscarinic M2; Receptors, Immunologic; Respiratory Mucosa; Trachea; Tretinoin; Virus Replication

Interleukin 9 (IL-9) is a cytokine produced by activated T lymphocytes and that activates in vitro mast cells as well as T and B lymphocytes. In vivo, transgenic mice overexpressing the gene encoding IL-9 show several of the hallmarks of human allergic asthma: increased IgE concentration, bronchial mastocytosis, eosinophilia, increased mucus production, as well as bronchial hyperresponsiveness. Whereas some of these features reflect direct IL-9 activities on target cells such as mast cells and B lymphocytes, increased mucus production and eosinophilia rather result from IL-13 and IL-5 production induced by IL-9 in T lymphocytes and mast cells. Preclinical studies in mice have shown that anti-IL-9 blocking antibodies interfere with the development of asthma-like reactions. In the human species, asthmatic patients produce large amounts of this cytokine and IL-9 production correlates nicely with species biological parameters of the disease. Phase 2 clinical trials are in progress to test the efficacy of anti-IL-9 antibodies in humans.

Topics: Animals; Asthma; Bronchial Diseases; Bronchial Hyperreactivity; Cells, Cultured; Clinical Trials, Phase II as Topic; Disease Models, Animal; Eosinophilia; Humans; Immunoglobulin E; Interleukin-8; Mast Cells; Mastocytosis; Mice; Mice, Transgenic; T-Lymphocytes

Healthy volunteers exposed for 3 hr during weighing of pigs develop an airway inflammation characterized by a massive influx of neutrophilic granulocytes in the upper and lower airways and increased bronchial responsiveness to methacholine. The purpose of the present study was to investigate health effects from exposure during cleaning of the swine confinement building and to evaluate the effect of a respiratory protection device.. Sixteen subjects were exposed for 3 hr during cleaning of a swine confinement room with a high-pressure cleaner. Seven out of sixteen subjects were equipped with a mask during exposure.. The bronchial responsiveness increased in all subjects following exposure, significantly more in the group exposed without a mask (P < 0.05). The cell concentration (mainly neutrophilic granulocytes) in nasal lavage fluid as well as the concentration of interleukin-8, increased significantly only in those subjects exposed without a respiratory protection device. In peripheral blood, an increase of neutrophilic granulocytes was observed in both groups, although it was significantly higher in the group without mask (P < 0.05). The inhalable dust level was 0.94 (0.74 - 1.55) mg/m(3) and respirable dust 0.56 (0.51-0.63) mg/m(3).. Exposure to dust aerosols during the cleaning of the interior of a swine confinement building induces increased bronchial responsiveness and an acute inflammatory reaction in the upper airways. The use of a mask attenuated but did not abolish the inflammatory response. This suggests that gases and/or ultrafine particles in this environment could be important factors in the development of increased bronchial responsiveness.

Topics: Animal Husbandry; Animals; Bronchial Hyperreactivity; Bronchitis; Dust; Humans; Inflammation; Interleukin-8; Leukocyte Count; Methacholine Chloride; Neutrophils; Occupational Diseases; Occupational Exposure; Respiratory Protective Devices; Respiratory Tract Diseases; Swine

Patients with food allergy (FA) have been recently shown to develop bronchial hyperresponsiveness (BHR), despite the absence of any concomitant asthmatic manifestation. In order to explain this observation, we sought to examine the presence of a bronchial inflammation in induced sputum of nonasthmatic patients with FA.. Twelve nonasthmatic patients with FA (urticaria, digestive symptoms, anaphylaxis) were included in the study. Results were compared to these obtained from eight asthmatic patients without food allergy and eight healthy controls. Diagnosis of FA was based on double-blind placebo-controlled challenge. Sputum cells and fluid-phase eosinophil cationic protein (ECP), myeloperoxidase (MPO) and interleukin-8 (IL-8) were measured in induced sputum. BHR was evaluated using methacholine inhalation.. Sputum from asthmatics, in comparison with the sputum of healthy subjects and patients with FA contained a higher proportion of eosinophils and higher levels of ECP (< 0.001). In marked contrast, patients with FA exhibited an increased proportion of neutrophils and IL-8 in comparison with asthmatics and controls (P < 0.05 for neutrophils and P < 0.001 for IL-8). There was a significant correlation between sputum neutrophils and IL-8 (r = 0.68, P < 0.001). MPO levels were not different between the groups. There was a trend toward higher levels of IL-8 and ECP in food allergic patients with BHR in comparison with patients with FA without BHR.. Our results demonstrate that a subclinical neutrophil airway inflammation is present in patients with food allergy free of clinical respiratory symptoms and that IL-8 may be an important mediator of this neutrophilia.

Topics: Adult; Asthma; Blood Proteins; Bronchial Hyperreactivity; Double-Blind Method; Eosinophil Granule Proteins; Eosinophils; Food Hypersensitivity; Humans; Immunoglobulin E; Interleukin-8; Leukocyte Count; Neutrophils; Peroxidase; Respiratory Function Tests; Ribonucleases; Skin Tests; Sputum; Statistics as Topic

The present study aimed to compare the cellular pattern and structural changes in the airways of patients with primary Sjögren's syndrome (pSS) with healthy controls. Bronchial biopsy specimens were obtained from seven subjects with pSS and seven healthy controls. All the patients with pSS had increased bronchial responsiveness to methacholine. In the biopsies inflammatory cells, cytokine-producing cells, tenascin and laminin were visual zed by immunostaining. Patients with pSS had a higher number of neutrophils and mast cells than healthy controls, while the number of eosinophils was similar in the two groups. The number of IL-8-positive cells was higher in pSS butthe numbers of IL-4-and IL-5-positive cells were not significantly different between pSS and healthy controls. The numbers of T cells in patients with pSS were higher than in healthy controls, while the numbers of CD25-positive cells were similar to the healthy controls. The degree of epithelial integrity in patients with pSS was significantly lower than in the control group and the tenascin and laminin layers were significantly thicker in the pSS group. There was a correlation between the number of mast cells and the thickness of the tenascin and laminin layers in pSS. In conclusion, we found that the cellular pattern in the bronchial mucosa of patients with pSS displayed large numbers of neutrophils, mast cells and T-lymphocytes. These changes in inflammatory cell numbers seemed to relate to the observed increased epithelial damage and structural changes of the subepithelium. The structural findings, but not the pattern of inflammatory cells, are shared with atopic asthma and may relate to the increased bronchial hyper-responsiveness seen in both diseases.

Topics: Adult; Biopsy; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Case-Control Studies; Eosinophils; Female; Humans; Interleukin-4; Interleukin-5; Interleukin-8; Laminin; Male; Mast Cells; Methacholine Chloride; Middle Aged; Neutrophils; Sjogren's Syndrome; Statistics, Nonparametric; T-Lymphocytes; Tenascin

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

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

Nitric oxide (NO) is increased in exhaled air of asthmatics. We hypothesized that endogenous NO contributes to airway inflammation and hyperresponsiveness, and that interleukin-8 (IL-8) might be involved in this mechanism. In human transformed bronchial epithelial cells in vitro, NO donors increased IL-8 production dose-dependently. In addition, tumor necrosis factor-alpha (TNF-alpha) plus IL-1beta plus interferon-gamma (IFN-gamma) increased IL-8 in culture supernatant of epithelial cells; the combination of NO synthase (NOS) inhibitors, aminoguanidine (AG) plus N(G)-nitro-L-arginine methyl ester (L-NAME) attenuated the cytokine-induced IL-8 production in epithelial cells. In guinea pigs in vivo, ozone exposure induced airway hyperresponsiveness to acetylcholine and increased neutrophils in bronchoalveolar lavage fluid (BALF), and these changes persisted for at least 5 h. Pretreatment with NOS inhibitors had no effect on airway hyperresponsiveness or neutrophil accumulation immediately after ozone, but significantly inhibited the changes 5 h after ozone. NOS inhibitors also attenuated the increases of nitrite/nitrate levels in BALF and the IL-8 mRNA expression in epithelial cells and in neutrophils in guinea pig airways 5 h after ozone. These results suggest that endogenous NO may play an important role in the persistent airway inflammation and hyperresponsiveness after ozone exposure, presumably partly through the upregulation of IL-8.

Topics: Acetylcholine; Animals; Blotting, Northern; Bronchi; Bronchial Hyperreactivity; Bronchitis; Bronchoalveolar Lavage Fluid; Cells, Cultured; DNA Primers; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Guanidines; Guinea Pigs; Humans; In Situ Hybridization; Interleukin-8; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; omega-N-Methylarginine; Ozone; RNA, Messenger

Using disulphide cysteine-based inhibitors as lead structures, this communication describes our strategy for identifying more stable, potent antagonists of the alpha4beta1 integrin. These studies ultimately discovered potent, low molecular weight inhibitors based on D-thioproline-L-tyrosine.

Topics: Animals; Bronchial Hyperreactivity; Half-Life; Integrin alpha4beta1; Integrins; Interleukin-8; Methacholine Chloride; Parasympathomimetics; Protein Binding; Rats; Receptors, Lymphocyte Homing; Sheep; Structure-Activity Relationship; Tyrosine; Vascular Cell Adhesion Molecule-1

The changes in airway osmolarity have been described to contribute to the production of exercise- induced bronchoconstriction (EIB) and the development of the late-phase response (LPR). The mechanism has been investigated; however, the responsiveness of bronchial epithelial cells (BEC) to hyperosmolarity and the intracellular signals leading to cell activation have not been determined. In this study, we examined the effect of hyperosmolar medium on interleukin-8 (IL-8) expression and the role of p38 mitogen-activated protein (MAP) kinase and c-Jun NH2 terminal kinase ( JNK) in human BEC in this response in order to clarify the intracellular signals regulating IL-8 expression in hyperosmolarity-stimulated BEC. The results showed that hyperosmolarity induced IL-8 expression in a concentration dependent manner, p38 MAP kinase phosphorylation and activation, and JNK activation whether NaCl or mannitol was used as the solute. SB 203580 as the specific p38 MAP kinase inhibitor inhibited hyperosmolarity-induced p38 MAP kinase activation and partially inhibited hyperosmolarity-induced IL-8 expression. These results indicate that p38 MAP kinase, at least in part, regulates hyperosmolarity-induced IL-8 expression in BEC. However, other signals such as JNK are possibly also involved. These results provide new evidence on the mechanism responsible for the development of the LPR induced by EIB, and a strategy for treatment with the specific p38 MAP kinase inhibitor.

Topics: Blotting, Northern; Blotting, Western; Bronchi; Bronchial Hyperreactivity; Calcium-Calmodulin-Dependent Protein Kinases; Cell Line; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Gene Expression; Humans; Imidazoles; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Mannitol; Mitogen-Activated Protein Kinases; Osmolar Concentration; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pyridines; RNA, Messenger; Saline Solution, Hypertonic; Signal Transduction; Tyrosine

The aim was to determine the time courses for the changes in airway function, airway reactivity, influx of inflammatory cells and levels of the pro-inflammatory cytokines, interleukin (IL)-5 and IL-8 in bronchoalveolar lavage fluid (BALF), and the plasma levels of cortisol and ACTH after antigen challenge to determine whether a temporal link could be established between these events.. Airway function was measured as specific airway conductance (sGsw) in conscious ovalbumin (OvA)-sensitized guinea pigs using whole body plethysmography at intervals after an inhalation challenge with ovalbumin (0.5% for 10 min). Airway responses to the inhaled spasmogen, U46619 (30 ng/ml, 60 s), were measured at 3, 6 and 24 h after challenge. In separate animals, bronchoalveolar lavage fluid (BALF) was obtained after anaesthetic overdose either before challenge or at 1, 3, 6, 12, or 24 h after OvA challenge. Total and differential cell counts of eosinophils and neutrophils were performed on BALF and levels of IL-5 and IL-8 determined by scintillation proximity assays and ELISA, respectively. Plasma cortisol and ACTH levels were determined by RIA kits in blood removed by cardiac puncture at intervals after challenge.. An early phase bronchoconstriction occurred which resolved by 3 h and was followed by a late phase between 17 and 24 h. Airway hyperresponsiveness to inhaled U46619, was evident at 3, 6 and 24 h after antigen challenge. Increased IL-5[BALF] was observed by 60 min post challenge implicating a performed storage site. In contrast, IL-8[BALF] was not raised until 3 h post challenge. There was a significant infiltration of neutrophils and eosinophils by 3 and 6 h, respectively. IL-5[BALF] further increased up to 24 h, during the appearance of the late phase of bronchoconstriction and whilst eosinophilia was maximal. Plasma cortisol levels were increased 1 and 3 hours after antigen challenge, thereafter returning to baseline levels.. The hyperresponsiveness appears to be dissociated from the appearance of eosinophils in lavage fluid. The early appearance of IL-5, however, could be a trigger for the migration of eosinophils and development of hyper-responsiveness. The increased plasma cortisol levels occurring after antigen challenge were presumably due to the stress involved and these would be expected to exert an endogenous anti-inflammatory effect.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenocorticotropic Hormone; Airway Resistance; Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Cytokines; Guinea Pigs; Hydrocortisone; In Vitro Techniques; Interleukin-5; Interleukin-8; Leukocytes; Lung; Male; Ovalbumin; Plethysmography, Whole Body; Time Factors

To explore the relationship between interleukin-8 (IL-8) and airway hyper-responsiveness (AHR) of asthma in guinea pigs.. IL-8 at a dose of 0.5 microgram/kg or 5.0 micrograms/kg was administered intranasally to guinea pigs twice a week for 3 weeks. 24 hours after the last administration, airway responsiveness was measured as an overall index of airway response to the increasing concentrations of histamine inhaled (25, 50, 100 and 200 micrograms/ml), and the numbers of different inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted.. The IL-8 treatment significantly enhanced airway responsiveness to histamine in a dose-dependent manner (P < 0.05 or P < 0.01) and induced a significant influx of neutrophils in BALF (P < 0.01), and a great number of neutrophils were seen within the airway wall, but not within the control animals treated with phosphate buffered saline (PBS).. The IL-8 could produce neutrophil inflammation of the airways and induce AHR, which suggested that IL-8 may play an important role in asthma, especially in the development of AHR.

Topics: Animals; Asthma; Bronchi; Bronchial Hyperreactivity; Guinea Pigs; Histamine; Interleukin-8; Lung; Male; Neutrophils; Random Allocation

Repeated intranasal administration of interleukin 8 (IL-8) induces bronchial hyperresponsiveness (BHR) accompanied by lower airway neutrophil accumulation (ANA) in guinea-pigs. Leukotriene B4 (LTB4) is a chemotactic factor for neutrophils. To elucidate whether LTB4 and neutrophil elastase are involved in the IL-8-induced BHR and ANA, the effects of a LTB4 antagonist (ONO-4057) and a neutrophil elastase inhibitor (ONO-5046) on the responses were examined. IL-8 (5 microg x kg[-1]) was administered intranasally to guinea-pigs twice weekly for 3 weeks. One day after the last administration, animals were anaesthetized and artificially ventilated through tracheal cannulae, and lateral pressure at the tracheal cannula (Pao) was measured as an overall index of airway responses to inhaled histamine. ONO-4057 (2 or 20 mg x kg[-1]) or ONO-5046 (30 or 300 mg x kg[-1]) was administered intraperitoneally 24 and 1 h before anaesthesia. ONO-4057, but not ONO-5046, significantly inhibited the IL8-induced BHR and ANA, assessed by bronchoalveolar lavage, in a dose-dependent manner. These findings suggest that interleukin 8 causes bronchial hyperresponsiveness and airway neutrophil accumulation in guinea-pigs in vivo. In part this appears to be due to release of leukotriene B4, whereas it may not be mediated by neutrophil elastase.

Topics: Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Movement; Glycine; Guinea Pigs; Immunosuppressive Agents; Interleukin-8; Leukocyte Elastase; Leukotriene B4; Male; Neutrophils; Phenylpropionates; Sulfonamides

The inflammatory response during allergic airway inflammation involves the recruitment of multiple leukocyte populations, including neutrophils, monocytes, lymphocytes, and eosinophils. All of these populations likely contribute to the pathology observed during repeated episodes of allergic airway inflammation. We have examined the role of a human neutrophil-specific chemokine (C-x-C), ENA-78, in a model of allergic airway responses and identified murine mast cells as a cellular source of an ENA-78-like molecule. Within this allergic airway model, neutrophil infiltration into the airway occurs within 4-8 h post-allergen challenge, persists within the airway until 24 h, and resolves by 48 h post-challenge. Neutrophil influx precedes the eosinophil infiltration, which peaks in the airway at 48 h post-allergen challenge. In this study the production of ENA-78 from challenged lungs demonstrated a significant increase in the allergen-, but not vehicle-, challenged lungs. In vivo neutralization of ENA-78 by passive immunization demonstrated a significant decrease in peak neutrophil infiltration at 8 h, with no effect on the eosinophil infiltration at 48 h post-challenge. Because ENA-78 has been shown to be chemotactic for neutrophils and given the involvement of mast cell degranulation in allergic responses, we examined mast cells for the presence of ENA-78. Cultured mast cells spontaneously released ENA-78, but on activation with IgE + antigen, NG-L-arginine methyl ester or compound 48/80 produced significantly increased levels of ENA-78. Supernatants from sonicated MC-9 mast cells induced an overwhelming influx of neutrophils into the BAL by 4 h post-intratracheal injection into mice, suggesting that the mast cell is a significant source of neutrophil chemotactic factors. Mast cell supernatant-mediated neutrophil infiltration was substantially decreased by preincubation of the supernatant with antibodies specific for ENA-78. These data indicate a major neutrophil chemotactic protein produced by mast cells during allergic responses may be mast cell-derived ENA-78.

Topics: Allergens; Animals; Bronchial Hyperreactivity; Chemokine CXCL5; Chemokines; Chemokines, CXC; Chemotactic Factors; Female; Humans; Inflammation; Interleukin-8; Mast Cells; Mice; Mice, Inbred CBA; Neutralization Tests; Neutrophils

Exposure to ozone causes symptoms, changes in lung function, and airway inflammation. We studied whether individuals who differ in lung-function responsiveness to ozone, or in smoking status, also differ in susceptibility to airway inflammation. Healthy subjects were selected on the basis of responsiveness to a classifying exposure to 0.22 ppm ozone for 4 h with exercise (responders, with a decrease in FEV1 > 15%; and non-responders, with a decrease in FEV1 < 5%). Three groups were studied: nonsmoker-nonresponders (n = 12), nonsmoker-responders (n = 13), and smokers (n = 13, 11 nonresponders and two responders). Each subject underwent two exposures to ozone and one to air, separated by at least 3 wk; bronchoalveolar and nasal lavages were performed on three occasions: immediately (early) and 18 h (late) after ozone exposure, and either early or late after air exposure. Recovery of polymorphonuclear leukocytes (PMN) increased progressively in all groups, and by up to 6-fold late after ozone exposure. Interleukin-6 (IL-6) and IL-8 increased early (by up to 10-fold and up to 2-fold, respectively), and correlated with the late increase in PMN. Lymphocytes, mast cells, and eosinophils also increased late after exposure. We conclude that ozone-induced airway inflammation is independent of smoking status or airway responsiveness to ozone.

Topics: Adolescent; Adult; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Disease Susceptibility; Female; Forced Expiratory Volume; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Neutrophils; Oxidants, Photochemical; Ozone; Smoking

We report here the results of a multiphase project to assess the significance of airway responsiveness and airway injury in ozone (O3)* sensitivity. In Phase I, we measured the preexposure methacholine responsiveness of 66 normal subjects and then exposed these subjects to 0.2 ppm O3 for 4 hours with moderate exercise. Preexposure methacholine responsiveness was weakly correlated with O3-induced increases in specific airway resistance (sRaw) but not O3-induced declines in forced expiratory volume in one second (FEV1) or forced vital capacity (FVC). In addition, O3-induced lower respiratory symptoms were not well correlated with O3-induced changes in lung function. In Phase II, we exposed 23 normal subjects to O3, following an identical protocol to that of Phase I, and then performed bronchoscopy with proximal airway lavage (PAL), bronchoalveolar lavage (BAL), and bronchial biopsy at 18 hours after exposure. Ozone-induced increases in percentage of neutrophils and total protein concentration were observed in both bronchial fraction and BAL fluids; increased percentage of neutrophils also was observed in PAL fluid. These increases were correlated with O3-induced increases in sRaw, but not with O3-induced declines in FEV1 or FVC. Ozone also appeared to increase expression of intercellular adhesion molecule-1, an important mediator of neutrophil recruitment, in bronchial mucosa. In Phase III, we exposed a group of 19 asthmatic subjects to O3, following a protocol identical to that of Phase II. We then compared the lower respiratory symptom and lung function responses of the asthmatic subjects to those of the 81 normal subjects who participated in Phase I, Phase II, or both. The changes in the PAL and BAL fluids of the asthmatic subjects were compared with those of the normal subjects who participated in Phase II. Although both the asthmatic and nonasthmatic subjects showed significant O3-induced changes in lower respiratory symptoms, FEV1, FVC, and sRaw, no significant differences were found between the groups. For sRaw, however, a nonsignificant trend toward a greater O3-induced increase was noted for the asthmatic subjects. In contrast, the O3-induced increases in percentage of neutrophils and total protein concentration in BAL fluid were significantly greater for the asthmatic subjects than for the nonasthmatic subjects. These data suggest that although the lower respiratory symptom and lung function responses to O3 are not markedly greater in asthmatic su

Topics: Adolescent; Adult; Airway Resistance; Asthma; Biopsy; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoscopy; Data Interpretation, Statistical; Female; Forced Expiratory Volume; Humans; Immunohistochemistry; Inflammation; Interleukin-8; Lung; Male; Methacholine Chloride; Middle Aged; Ozone; Physical Exertion; Therapeutic Irrigation; Time Factors; Vital Capacity

To provide bases of comparison between the studies described in Parts I and II of this Research Report, concentrations of interleukin 6 (IL-6)*, interleukin 8 (IL-8), and alpha 2-macroglobulin (a2M) were measured in airway lavage fluids obtained in the Balmes study (Part I) and compared with the same measurements in the Frampton study (Part II). For healthy subjects in the Balmes study, IL-6 and a2M, but not IL-8, increased in association with ozone exposure. Statistical analyses suggested that effects of ozone on IL-8 levels observed in the first exposure and bronchoscopy may have carried over to the second exposure and bronchoscopy, which may have obscured an effect of ozone on IL-8 after the second exposure. For asthmatic subjects in the Balmes study, IL-6 and IL-8 increased in both bronchial and alveolar lavage fluid, but not in proximal airway lavage fluid. The mean interval between exposures was longer for asthmatic subjects than for healthy subjects, and no carryover effects were seen. When the Balmes and Frampton data were analyzed together, subject groups in the two studies (nonsmokers, smokers, and subjects without and with asthma) did not differ significantly in the response of cytokines to ozone exposure. The finding of possible carryover effects in one group suggests that subtle effects of ozone exposure, or bronchoscopy including proximal airway lavage and biopsy, or both, may persist for three weeks in some subjects.

Topics: Adolescent; Adult; alpha-Macroglobulins; Asthma; Biopsy; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoscopy; Data Interpretation, Statistical; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Lung; Male; Ozone; Smoking; Time Factors

1. Although repeated intranasal administration of interleukin-8 (IL-8) causes bronchial hyperresponsiveness (BHR) mediated via thromboxane A2 (TXA2) and airway neutrophil accumulation in guinea-pigs, the acute effect of inhaled IL-8 is unclear. We performed this study to clarify the acute effect of IL-8 on bronchial responsiveness and the role of TXA2. 2. The effects of inhaled IL-8 on bronchial responsiveness and of the TXA2 antagonists, S-1452 (0.01 and 0.1 mg kg-1) and ONO-NT-126 (1.0 or 10 micrograms kg-1), on IL-8-induced BHR were examined by use of a modified Konzett-Rössler method in guinea-pigs. 3. Inhaled IL-8 at 100 ng ml-1, which failed to induce significant changes in Pao (pressure at the airway opening), enhanced an increase in Pao induced by subsequent inhalations of ascending doses (50-200 micrograms ml-1) of methacholine and histamine, suggesting the potentiating effect of IL-8 on bronchial responsiveness. No significant leukocyte infiltration was observed histologically sixteen minutes after the IL-8 inhalation. Both S-1452 and ONO-NT-126 reduced the IL-8-induced BHR. 4. In conclusion, IL-8 rapidly causes BHR via TXA2 release in guinea-pigs.

Topics: Administration, Inhalation; Animals; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Fatty Acids, Monounsaturated; Guinea Pigs; Interleukin-8; Male; Prostaglandin Antagonists; Terfenadine; Thromboxane A2

To explore the relationship between interleukin-8 (IL-8) and airway hyperresponsiveness (AHR) of asthma.. IL-8 at a dose of 0.5 microgram/kg or 5 micrograms/kg was administered intranasally to guinea-pigs twice a week for 3 weeks. 24 hours after the last administration, airway responsiveness was measured as an overall index of airway response to increasing concentrations of inhaled histamine (25, 50, 100 and 200 micrograms/ml) and the numbers of different inflammatory cells in bronchoalveolar lavage fluid (BALF) was counted.. The IL-8 treatment significantly enhanced airway responsiveness to histamine in a dose-dependent manner (P < 0.05 or 0.01) and induced a significant influx of neutrophils in BALF (P < 0.01), and there are many neutrophils within airway wall but not control animals treated with phosphate buffered saline (PBS).. The IL-8 given into the airways can produce neutrophil inflammation of the airways and induce AHR, it may play an important role in asthma, especially in the development of AHR.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Guinea Pigs; Interleukin-8; Leukocyte Count; Male; Neutrophils

Interleukin-8 (IL-8) has been shown to be a chemotactic factor for neutrophils, T-lymphocytes and eosinophils. Repeated intranasal administration of IL-8 enhances bronchial responsiveness to inhaled histamine in guinea-pigs. Neuropeptides which are released from C-fibre nerve-endings have been postulated to induce bronchial hyperresponsiveness through neurogenic inflammation.. This study was conducted to examine whether sensory neuropeptides are involved in the IL-8-induced bronchial hyperresponsiveness.. IL-8 at a dose of 5 micrograms/kg was administered intranasally to guinea-pigs twice a week for 3 weeks. One day after the last administration, animals were anesthetized and artificially ventilated through tracheal cannula, and lateral pressure at the tracheal cannula (Pao) was measured as an overall index of airway responses to increasing concentrations of inhaled histamine (25, 50, 100, and 200 micrograms/mL). A NK1 and NK2 dual antagonist FK224 (10 mg/kg), a selective NK1 antagonist FK888 (10 mg/kg) or vehicle was intravenously administered 10 min before measurement of bronchial responsiveness.. The IL-8 treatment significantly enhanced bronchial responsiveness to histamine (ANOVA P < 0.01). FK224 or FK888 did not alter the IL-8-induced bronchial hyperresponsiveness.. We conclude that repeated intranasal administration of IL-8 causes bronchial hyperresponsiveness (BHR) and that neuropeptides such as neurokinin A and substance P do not directly contribute to the development of BHR induced by IL-8.

Topics: Animals; Bronchial Hyperreactivity; Bronchial Provocation Tests; Dipeptides; Guinea Pigs; Histamine; Indoles; Interleukin-8; Male; Neurokinin A; Peptides, Cyclic; Substance P

Interleukin-8 (IL-8) has been shown to be a chemotactic factor for neutrophils, T-lymphocytes and eosinophils, but it is unknown whether the IL-8-induced inflammatory cell accumulation into the airways can cause the bronchial hyperresponsiveness (BHR) characteristic of asthma. IL-8 at a dose of 0.5 or 5 micrograms/kg was administered intranasally to guinea-pigs twice a week for 3 weeks. One day after the last administration, animals were anesthetized and artificially ventilated through tracheal cannula and lateral pressure at the cannula (Pao) was measured as an overall index of airway responses to increasing concentrations of inhaled histamine (25, 50, 100, and 200 micrograms/ml). The IL-8 treatment significantly enhanced bronchial responsiveness to histamine in a dose-dependent manner (ANOVA P < 0.01). The provocative concentration of histamine causing a 100% increase in Pao (PC100) at a dose of 0.5 and 5 micrograms/kg of IL-8 was 68.1 (GSEM 1.12) and 35.6 (GSEM 1.25) micrograms/ml, respectively. The latter was significantly (P < 0.01) lower than that in control animals treated with PBS (93.3 [GSEM, 1.14] micrograms/ml). The IL-8 treatment also induced a significant influx of neutrophils, but not eosinophils, in bronchoalveolar lavage (BAL) fluid (18.3 +/- 8.8 and 30.6 +/- 8.3% in animals treated with 0.5 and 5 micrograms/kg, respectively, of IL-8 vs 3.6 +/- 0.7% in phosphate buffered saline-(PBS)-treated animals). Furthermore, we examined the effect of the thromboxane receptor antagonist S-1452 (0.01 or 0.1 mg/kg, i.p. 24 and 1 h before anesthesia) on this IL-8 induced BHR. S-1452 significantly inhibited the BHR dose-dependently (ANOVA P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Intranasal; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Fatty Acids, Monounsaturated; Guinea Pigs; Interleukin-8; Male; Neutrophils; Receptors, Prostaglandin; Thromboxane A2