interleukin-8 and Lung-Diseases--Obstructive

Neutrophil accumulation in the lung is a prominent feature of chronic obstructive pulmonary disease (COPD) and the activation of these cells, producing proteases and oxygen-derived free radicals, is thought to be important in the pathogenesis of the disease. An important step in recruitment is the local generation of a neutrophil chemoattractant signal which mediates the trapping and firm adhesion of rolling neutrophils on the microvascular endothelium, followed by migration via intercellular junctions. Two neutrophil chemoattractants are particularly important in this respect, C5a generated by cleavage of complement C5 in interstitial fluid, and interleukin (IL)-8 synthesized by cells in the lung, e.g. macrophages, epithelial cells, endothelial cells, smooth muscle cells and neutrophils themselves. Lipid mediators, such as leukotriene B4 (LTB4), are also potentially important. Several studies have been carried out to investigate the role of IL-8 in COPD. IL-8 has been detected in bronchoalveolar lavage fluid and sputum from such subjects and in the systemic circulation. The levels of IL-8 have been found to correlate with neutrophil numbers and markers of neutrophil activation, such as myeloperoxidase activity. Some studies have also found a correlation between IL-8 levels, neutrophil numbers and the degree of lung dysfunction. These parameters are insensitive to steroids. Thus, the mechanisms involved in neutrophil recruitment, i.e. chemoattractant secretion or action, adhesion and endothelial transmigration, are important potential targets for the development of novel therapy. The IL-8 receptors on neutrophils, CXCR1 and CXCR2, are of particular interest.

Topics: Animals; Complement C5a; Humans; Interleukin-8; Lung Diseases, Obstructive; Neutrophils

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

Cigarette smoking is a most important factor of COPD. IL-8 is elevated by cigarette smoking and increases the number of neutrophils in the lung. Surfactant is a complex mixture of phospholipids (PL) and proteins (SP). Both PL and SPs (SP-A and SP-D) decrease in bronchoalveolar lavage fluid in smokers. Decrease of PL enhances injury by elastase secreted from neutrophils and induces collapse of bronchioles, and decrease of SP-A and SP-D attenuate the defense against microbial agents in peripheral airways. Surfactant is thereby associated with COPD. However, little is known about the interaction, which induces COPD, between cytokines and surfactant. Further investigations are needed to clarify the mechanism on onset of COPD.

Topics: Disease Progression; Humans; Interleukin-8; Lung; Lung Diseases, Obstructive; Neutrophil Activation; Pulmonary Surfactants; Smoking

Viable bacteria are often isolated from airway secretions in clinically stable patients with chronic bronchitis. We hypothesized that the number of organisms and bacterial species might be important modulators of airway inflammation.. We performed quantitative sputum cultures in 160 stable patients [55 with chronic obstructive pulmonary disease (COPD) and normal serum alpha(1)-antitrypsin levels, 62 with COPD and severe alpha(1)-antitrypsin deficiency (PiZ), and 43 with idiopathic bronchiectasis]. The results were related to several indicators of the mechanisms and severity of airway inflammation.. Airway bacterial load correlated with sputum myeloperoxidase level, an indirect measure of neutrophil activation and number (r = 0.50, P<0. 001); sputum neutrophil chemoattractants [interleukin-8 level (r = 0. 68, P<0.001) and leukotriene B4 level (r = 0.53, P<0.001)]; sputum leukocyte elastase activity (r = 0.55, P<0.001); and albumin leakage from serum to sputum (r = 0.26, P<0.01). Markers of inflammation increased at bacterial loads of 10(6) to 10(7) colony-forming units per milliliter, and increased progressively with increasing bacterial load. For example, the median (interquartile range) sputum myeloperoxidase level was 0.3 U/mL (0.1 to 0.5 U/mL) for patients who were not colonized or who had mixed normal oropharyngeal flora alone; 0.5 U/mL (0.2 to 0.7 U/mL) for patients with 10(5) to 10(6) colony-forming units per milliliter (P = 0.07); 0.5 U/mL (0.3 to 1.2 U/mL) for patients with 10(6) to 10(7) colony-forming units per milliliter (P<0.01); 0.7 U/mL (0.3 to 1.2 U/mL) for patients with 10(7) to 10(8) colony-forming units per milliliter (P <0.005); and 2.4 U/mL (0.7 to 4.8 U/mL) for patients with 10(8) or greater colony-forming units per milliliter (P<0.0001). The bacterial species influenced airway inflammation; for example, sputum myeloperoxidase activity was greater (P<0.005) in patients colonized with Pseudomonas aeruginosa [median 32 U/mL (interquartile range, 20 to 65 U/mL)] than those colonized with nontypeable Hemophilus influenzae [4 U/mL (2 to 31 U/mL)], which in turn was greater (P = 0.01) than among those colonized with Moraxella catarrhalis [1.1 U/mL (0.6 to 1.8 U/mL)]. We did not find a relation between bacterial load and lung function.. The bacterial load and species contribute to airway inflammation in patients with stable chronic bronchitis. Further studies are required to determine the consequences of bacterial colonization on patient morbidity and decline in lung function.

Topics: Aged; Bacteria; Biomarkers; Bronchitis; Bronchoalveolar Lavage Fluid; Chi-Square Distribution; Chronic Disease; Colony Count, Microbial; Female; Humans; Inflammation Mediators; Interleukin-8; Leukotriene B4; Lung Diseases, Obstructive; Male; Middle Aged; Peroxidase; Prognosis; Reference Values; Severity of Illness Index; Sputum; Statistics, Nonparametric; Stem Cells

Chemokines and cellular adhesion molecules are crucial determinants of the migration of immune effector cells to the tissues asthma and chronic obstructive pulmonary disease (COPD) are a complex of conditions, which have airflow limitation in common. The aim of this study was to determine the numbers and percentages of lymphocytes expressing adhesion molecules: LFA-1, ICAM-1 together with assessment of chemokines concentrations: IL-8 and MCP-1 in bronchoalveolar lavage fluid (BAL) of patients with asthma or chronic obstructive pulmonary disease (COPD). 12 patients with asthma, 14 patients with COPD, and 6 subjects of control group took part in this study. The expression of LFA-1 and ICAM-1 was assessed on lymphocytes by using immunohistochemistry (streptavidyn-biotin, DAKO, Denmark). ELISA test was used to measure IL-8 and MCP-1 concentrations in BAL (kits from R&D, USA). The percentage of lymphocytes expressing LFA-1 and ICAM-1 were: 33.9 +/- 23.8% and 25.8 +/- 12.2% in COPD patients, 23.9 +/- 12.1% and 15.3 +/- 4.42% in asthma patients, and 14.2 +/- 10% and 5.2 +/- 1.6% in the control group respectively. There was observed significant difference between the percentage of lymphocytes expressing LFA-1 and ICAM-1 of COPD and the control group. The concentrations of IL-8 were: 2306 +/- 1501 pg/ml in COPD, 233 +/- 27.3 pg/ml in asthma and 64 +/- 28.7 in the control group (p < 0.05). The concentrations of MCP-1 were: 768.9 +/- 668.1 pg/ml in COPD, 126.8 +/- 30.8 pg/ml in asthma, and 83.0 +/- 16.4 pg/ml in the control group (p < 0.05). There was observed correlation between lymphocytes expressing LFA-1 and IL-8 concentration (r = +0.5, p < 0.05) and between lymphocytes expressing LFA-1 and MCP-1 concentration (r = +0.5, p < 0.05), and between lymphocytes expressing ICAM-1 and MCP-1 concentration (r = +0.4, p < 0.05) only in COPD patients. Our data suggest that LFA-1 and ICAM-1 are important molecules in the recruitment of leukocytes and together with IL-8 and MCP-1 may have a role in pathomechanism of inflammation in asthma and especially in COPD.

Topics: Adult; Asthma; Bronchoalveolar Lavage Fluid; Cell Adhesion Molecules; Chemokine CCL2; Chemokines; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Lung Diseases, Obstructive; Lymphocyte Function-Associated Antigen-1; Lymphocytes; Male

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

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

Inhaled corticosteroids are widely prescribed for the treatment of stable chronic obstructive pulmonary disease (COPD), despite lack of proven efficacy. Because COPD involves airway inflammation and probable protease-antiprotease imbalance, we examined the effect of high dose fluticasone propionate on markers of activity of both pathogenetic mechanisms. Thirteen patients with COPD were treated with fluticasone propionate (500 microg twice a day) for 4 wk, delivered via MDI and spacer, in a double-blind crossover study. There was no clinical benefit in terms of lung function or symptom scores, and induced sputum inflammatory cells, percentage neutrophils, and IL-8 levels were unchanged. Sputum supernatant elastase activity, matrix metalloproteinase (MMP)-1, MMP-9, and the antiproteases secretory leukoprotease inhibitor (SLPI) and tissue inhibitor of metalloproteinase (TIMP)-1 were similarly unaffected by treatment. These results add to previous evidence that inhaled steroids have no anti-inflammatory action in stable COPD. Furthermore, inhaled steroids do not appear to redress the protease-antiprotease imbalance that is thought to be important in the pathogenesis of airway obstruction.

Topics: Administration, Inhalation; Administration, Topical; Adult; Aerosols; Aged; Androstadienes; Anti-Inflammatory Agents; Cross-Over Studies; Cytokines; Double-Blind Method; Endopeptidases; Female; Fluticasone; Glucocorticoids; Humans; Inflammation; Interleukin-8; Lung Diseases, Obstructive; Male; Matrix Metalloproteinases; Middle Aged; Pancreatic Elastase; Proteinase Inhibitory Proteins, Secretory; Proteins; Secretory Leukocyte Peptidase Inhibitor; Serine Proteinase Inhibitors; Sputum; Tissue Inhibitor of Metalloproteinase-1

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

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

When exacerbation of chronic obstructive pulmonary disease (AECOPD) occurs frequently, patients have high levels of airway and systemic inflammation and a poor quality of life. This study compared the nature and course of systemic and airway inflammation during AECOPD between patients who experienced frequent exacerbations and those with non-frequent exacerbations.. Consecutive hospitalized patients with AECOPD were recruited and divided into 2 groups according to the frequency of AECOPD they had experienced in the previous year. Frequent exacerbators (defined as 2 or more AECOPD in the previous year) and non-frequent exacerbators (defined as zero or 1 AECOPD in the previous year). Inflammatory (interleukin 6, interleukin 8, myeloperoxidase, and C-reactive protein) and clinical (dyspnea, COPD assessment test (CAT), and peak expiratory flow) indices were assessed on the day of admission before starting therapy, day 7 of treatment, the day of planned discharge (day 10-14), and 8 weeks after discharge.. We analyzed data from 135 patients; 78 (57.8%) were non-frequent exacerbators and 57 (42.2%) were frequent exacerbators. In both groups, the inflammatory and clinical indices at day 7, the day of planned discharge (day 10-14), and 8 weeks were significantly improved compared to those at admission. Frequent exacerbators had a smaller reduction in their inflammatory indices and CAT scores between exacerbation onset and all the other time points compared with infrequent exacerbators.. Frequent exacerbators have a reduced response to treatment of AECOPD in terms of inflammatory indices and quality of life.

Topics: Aged; Bronchitis; C-Reactive Protein; China; Dyspnea; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung Diseases, Obstructive; Male; Middle Aged; Peak Expiratory Flow Rate; Peroxidase; Prospective Studies; Quality of Life; Recurrence; Statistics, Nonparametric; Time Factors

Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological processes responsible for the development and the persistence of airway inflammation are still largely unknown. Hypoxia-inducible factor (Hif) is mainly known as a major regulator of energy homeostasis and cellular adaptation to hypoxia. More recently however, Hif also emerged as an essential regulator of innate immune responses. Here, we aimed at investigating the potential involvement of Hif1-α in myeloid cells in horse with recurrent airway obstruction.. In vitro, we observed that Hif is expressed in equine myeloid cells after hay dust stimulation and regulates genes such as tumor necrosis factor alpha (TNF-α), interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A). We further showed in vivo that airway challenge with hay dust upregulated Hif1-α mRNA expression in myeloid cells from the bronchoalveolar lavage fluid (BALF) of healthy and RAO-affected horses, with a more pronounced effect in cells from RAO-affected horses. Finally, Hif1-α mRNA expression in BALF cells from challenged horses correlated positively with lung dysfunction.. Taken together, our results suggest an important role for Hif1-α in myeloid cells during hay dust-induced inflammation in horses with RAO. We therefore propose that future research aiming at functional inactivation of Hif1 in lung myeloid cells could open new therapeutic perspectives for RAO.

Topics: Animals; Antitussive Agents; Cells, Cultured; Dust; Gene Expression Regulation; Horse Diseases; Horses; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-8; Lung; Lung Diseases, Obstructive; Monocytes; Noscapine; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Platelet activation occurs in human obstructive airway diseases and in laboratory animal models. However, there is limited evidence that platelets may be involved in equine recurrent airway obstruction (RAO) and other inflammatory diseases. This study investigated whether platelet activation also occurred in RAO.. Platelet function is altered in ponies with active RAO. This alteration can be detected ex vivo by measuring platelet adhesion.. An in vitro platelet adhesion assay measuring acid phosphatase (AcP) activity colorimetrically was adapted for use with equine platelets and responses to selected agonists were established. Platelet adhesion and aggregation was evaluated in vitro on platelets isolated from 6 ponies with RAO before, during and after a 7 h natural antigen challenge. Three ponies with no history of airway disease were also studied.. Adhesion of equine platelets to serum coated plastic was detected at concentrations of 10-100 radicaló 10(9)/l. Adhesion increased in response to stimulation with platelet activating factor and thrombin, but not equine interleukin 8. Prior to the antigen challenge, adhesion of nonstimulated platelets was low and increased significantly (P<0.05) 24 h after initiation of the challenge in RAOs, but not in the normal animals. No changes in platelet aggregation were noted in either group.. The described assay offers an alternative method to evaluate platelet function in healthy and diseased horses and can detect changes not observed using a classic aggregation assay. Circulating platelets are activated 24 h after antigen challenge of ponies with RAO and may play a role in pulmonary inflammation and/or the pathophysiology of RAO.. Investigating platelet function in RAO and airway inflammation may reveal new aspects of the pathogenesis of inflammatory lung disease in the horse.

Topics: Acid Phosphatase; Animals; Antigens; Blood Platelets; Dose-Response Relationship, Drug; Horse Diseases; Horses; Hypersensitivity; Interleukin-8; Lung Diseases, Obstructive; Platelet Activating Factor; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Thrombin

The criteria used to diagnose recurrent airway obstruction (RAO) in affected horses include demonstration of reversible lower airway obstruction and greater than 25% neutrophils in bronchoalveolar lavage fluid (BALF). Additional objective laboratory tests are needed to improve diagnostic accuracy and to monitor response to treatment. The goal of this study was to determine if neutrophil chemoattractant activity of BALF could be measured by using a previously described, rapid, multiwell colorimetric assay for chemotaxis. In this assay, neutrophils that have migrated through a membrane filter are collected into the bottom well of a disposable chemotaxis-cell migration chamber. The number of viable cells collected in the bottom well is quantified by measurement of the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenol tetrazolium bromide (MTT), which is reduced by dehydrogenase in mitochondria of live cells. The number of migrating cells corresponds to the amount of MTT reduced, which is measured with an enzyme-linked immunosorbent assay plate reader. Fourteen adult horses were enrolled in this study, 7 of which had owner histories consistent with RAO. Each horse was sedated, a bronchoalveolar lavage tube was passed, and saline was infused and immediately aspirated. An aliquot of BALF was used for differential cell count, and BALF supernatant was harvested to assess neutrophil chemoattractant activity. Normal control horses and RAO-affected horses were distinguished according to clinical signs and percent neutrophils in BALF. Neutrophil chemoattractant activity of BALF was significantly greater in RAO-affected horses (P = 0.001) compared with control horses. This assay may be useful in future studies for monitoring response to therapy in RAOaffected horses.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cell Count; Chemotaxis, Leukocyte; Colorimetry; Female; Formazans; Horse Diseases; Horses; Interleukin-8; Lung Diseases, Obstructive; Male; Neutrophils; Tetrazolium Salts

The study aims to investigate the changes of interleukin (IL)-17 in induced sputum, and to observe the correlation between concentrations of IL-17 and the number of inflammatory cells in induced sputum in chronic obstructive pulmonary disease (COPD) and in asthma.. Induced sputum was obtained in patients with COPD both during acute exacerbation and stable stage and in asthma during acute attack. Healthy nonsmoking volunteers were included as controls. The concentrations of IL-17 in induced sputum were measured by enzyme-linked immunosorbent assay.. The concentrations of IL-17 both in patients with COPD during acute exacerbation and with asthma were significantly higher than that in the control subjects (P < 0.001). The levels of IL-17 in patients with COPD during acute exacerbation positively correlated with that of IL-8 (r = 0.381, P = 0.038) and with the percentage of neutrophils (r = 0.446, P = 0.010) respectively. There was also a positive correlation between the concentrations of IL-17 and the numbers of eosinophils in patients with asthma.. The concentrations of IL-17 in patients with acute exacerbation of COPD and in patients with asthma were significantly increased. IL-17 may play a role in the airway inflammation in both COPD and asthma.

Topics: Adult; Aged; Asthma; Female; Humans; Interleukin-17; Interleukin-6; Interleukin-8; Leukocyte Count; Lung Diseases, Obstructive; Male; Middle Aged; Sputum

A reactive ability of immunocompetent cells was assessed by the level of cytokines TNF alpha and IL-8 estimated by enzyme immunoassay ("Genzyme diagnostics" kit) in 18 patients with chronic obstructive bronchitis (mean age 58 +/- 4.2 years, mean duration of the disease 11.2 +/- 5.2 years) and 15 control patients matched for age, with normal external respiration function, free of chronic bronchopulmonary pathology and allergic diseases. The greatest differences in cytokine levels were registered between the control group and patients with moderate generalized irreversible obstruction. These patients had similar basal and E. coli LPS induced synthesis of the above cytokines showing the lack of cell reserves, adequate immune response to exogenic antigen.

Topics: Bronchitis, Chronic; Cytokines; Humans; Interleukin-8; Lung Diseases, Obstructive; Tumor Necrosis Factor-alpha

There is increasing evidence that chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation in the airways and lung parenchyma; however, little is known about the inflammatory response during acute COPD exacerbation. The objectives of this study were (1) to determine if inflammatory markers associated with neutrophilic inflammation and activation increase at times of acute COPD exacerbation relative to the clinically stable state, and (2) to determine whether the presence of acute bacterial or viral infection at the time of COPD exacerbation could be correlated with increases in sputum markers of inflammation. Induced sputum was collected from patients with COPD when they were clinically stable, during the time of an acute exacerbation, and 1 mo later. Sputum was analyzed at each time point for soluble markers associated with neutrophilic inflammation; myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-8 (IL-8). Serologic assays on acute and convalescent sera were performed for respiratory viruses, and induced sputum was also subject to quantitative bacterial cultures, viral cultures, and polymerase chain reaction (PCR) for detection of respiratory viruses. Fourteen of the 50 patients enrolled in the study met predetermined criteria for an acute COPD exacerbation over the 15-mo study period. TNF-alpha and IL-8 were significantly elevated in the sputum of patients during acute COPD exacerbation compared with when they were clinically stable (p = 0.01 and p = 0.05, respectively). Concentrations of these cytokines declined significantly 1 mo after the exacerbation. Three of 14 patients (21%) had confirmed bacterial or viral respiratory tract infections. Patients with documented infection did not demonstrate greater increases in sputum levels of inflammatory cytokines during exacerbations compared with patients without demonstrable infection. We conclude that markers of airway neutrophilic inflammation increase at the time of acute COPD exacerbation and then decline 1 mo later, and that this acute inflammatory response appears to occur independently of a demonstrable viral or bacterial airway infection.

Topics: Adult; Aged; Aged, 80 and over; Bacterial Infections; Female; Granulocytes; Humans; Inflammation Mediators; Interleukin-8; Lung Diseases, Obstructive; Male; Middle Aged; Neutrophils; Peroxidase; Respiratory Tract Infections; Sputum; Tumor Necrosis Factor-alpha; Virus Diseases

Neutrophilic airway inflammation may underlie the pathogenesis of COPD. We examined repeated measurements of the fractional concentration of exhaled nitric oxide (FENO) and the correlation with cells and mediators in induced sputum (IS) from patients with COPD.. Eleven COPD subjects (9 men and 2 women, aged 46 to 69 years) with predicted FEV(1) of 45 to 70%.. A hospital research laboratory.. Single-cohort, prospective study with four visits at two weekly intervals.. FENO and spirometry were assessed at all visits, and IS for differential cell count, leukotriene-B(4) (LTB(4)) and interleukin (IL)-8, nitrite, and nitrate at visit 1, visit 3, and visit 4.. During the study, there were significant declines in mean percent predicted FEV(1), from 55.2 to 51.6% (p = 0.029), and mean FEV(1)/FVC ratio, from 50.4 to 45.4% (p = 0.001), accompanied by a significant increase in FENO geometric mean (95% confidence limits), from 15.2 (10.9 to 21.2) to 23.6 (17.1 to 32.4) parts per billion (p = 0.037), and sputum LTB(4), from 1.79 (1.03 to 3.11) to 3.57 (1.95 to 6.53) ng/mL (p = 0.033), but no significant change in other sputum parameters. From visits 1 to 4, the change in percent neutrophils correlated with the changes in FENO and IL-8 (r = 0.648, p = 0.028; r = 0.60, p = 0.05, respectively). Hypertonic saline solution induction of sputum caused a fall in FEV(1), from 1.83 +/- 0.44 to 1.46 +/- 0.44 L (p = 0.049).. The worsening spirometry results were accompanied by significant increases in FENO and sputum LTB(4). FENO may be related to neutrophilic inflammation driven by the chemoattractant IL-8. FENO and IS may be useful markers of airway inflammation in COPD patients. Sputum induction with hypertonic saline solution causes a significant fall in FEV(1) requiring appropriate caution.

Topics: Aged; Breath Tests; Cell Count; Female; Forced Expiratory Volume; Humans; Interleukin-8; Leukotriene B4; Lung Diseases, Obstructive; Male; Middle Aged; Neutrophils; Nitric Oxide; Prospective Studies; Saline Solution, Hypertonic; Spirometry; Sputum; Vital Capacity

Although it is presumed that exacerbations of chronic obstructive pulmonary disease (COPD) are associated with increased airway inflammation, there is little information available on inflammatory markers during an exacerbation and the relationship with severity or time course of recovery. A study was undertaken to investigate the sputum cell and cytokine characteristics of COPD when stable and during an exacerbation.. Induced sputum samples from 57 patients with moderate to severe COPD were analysed (44 samples were taken during a stable period and 37 during an exacerbation). The patients recorded daily symptoms on diary cards. Cell counts and sputum levels of interleukin (IL)-6 and IL-8 were measured.. Patients with >/=3 exacerbations/year had higher median stable sputum levels of IL-6 (110 (95% CI 11 to 215) pg/ml) and IL-8 (6694 (95% CI 3120 to 11995) pg/ml) than those with

Topics: Aged; Cohort Studies; Cytokinins; Female; Forced Expiratory Volume; Humans; Interleukin-6; Interleukin-8; Lung Diseases, Obstructive; Male; Middle Aged; Peak Expiratory Flow Rate; Sputum; Vital Capacity

Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death, with cigarette smoking among the main risk factors. Hallmarks of COPD include chronic airflow obstruction and chronic inflammation in the airway walls or alveolar septa. An earlier study reported elevated numbers of macrophages and mast cells within the bronchiolar epithelium in smokers with COPD, compared with smokers without. Since specific chemokines may be involved in this influx, the in situ protein and mRNA expression of monocyte chemoattractant protein 1 (MCP-1) and of interleukin 8 (IL-8) were studied in tumour-free peripheral lung tissue resected for lung cancer of current or ex-smokers with COPD (FEV(1)<75%; n=14) and without COPD (FEV(1)>84; n=14). MCP-1 was expressed by macrophages, T cells, and endothelial and epithelial cells. Its receptor, CCR2, is expressed by macrophages, mast cells, and epithelial cells. IL-8 was found in neutrophils, epithelial cells, and macrophages. In subjects with COPD, semi-quantitative analysis revealed 1.5-fold higher levels of MCP-1 mRNA and IL-8 mRNA and protein in bronchiolar epithelium (p<0.01) and 1.4-fold higher levels of CCR2 in macrophages (p=0.014) than in subjects without COPD. The bronchiolar epithelial MCP-1 mRNA expression correlated with both CCR2 expression on macrophages and mast cells (p<0.05) and the numbers of intra-epithelial macrophages and mast cells (p<0.04). The epithelial IL-8 expression did not correlate with the numbers of neutrophils, macrophages, CD45RO+, CD8+, or mast cells. These data suggest that MCP-1 and CCR2 are involved in the recruitment of macrophages and mast cells into the airway epithelium in COPD.

Topics: Adult; Aged; Bronchi; CD8-Positive T-Lymphocytes; Chemokine CCL2; Epithelium; Female; Humans; Immunoenzyme Techniques; In Situ Hybridization; Interleukin-8; Lung Diseases, Obstructive; Lymphocyte Count; Male; Middle Aged; Pulmonary Alveoli; Retrospective Studies; RNA, Messenger

The effects of a second generation p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 239063 [trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridim idi n-4-yl)imidazole; IC(50) = 44 nM vs. p38 alpha], were assessed in models that represent different pathological aspects of chronic obstructive pulmonary disease (COPD) [airway neutrophilia, enhanced cytokine formation and increased matrix metalloproteinase (MMP)-9 activity] and in a model of lung fibrosis. Airway neutrophil infiltration and interleukin (IL)-6 levels, assessed by bronchoalveolar lavage 48 h after lipopolysaccharide (LPS) inhalation, were inhibited dose dependently by 3-30 mg/kg of SB 239063 given orally twice a day. In addition, SB 239063 (30 mg/kg orally) attenuated IL-6 bronchoalveolar lavage fluid concentrations (>90% inhibition) and MMP-9 activity (64% inhibition) assessed 6 h after LPS exposure. In guinea pig cultured alveolar macrophages, SB 239063 inhibited LPS-induced IL-6 production (IC(50) of 362 nM). In a bleomycin-induced pulmonary fibrosis model in rats, treatment with SB 239063 (2.4 or 4.8 mg/day via osmotic pump) significantly inhibited bleomycin-induced right ventricular hypertrophy (indicative of secondary pulmonary hypertension) and increases in lung hydroxyproline synthesis (indicative of collagen synthesis and fibrosis). Therefore, SB 239063 demonstrates activity against a range of sequelae commonly associated with COPD and fibrosis, supporting the therapeutic potential of p38 MAPK inhibitors such as SB 239063 in chronic airway disease.

Topics: Animals; Bleomycin; Cells, Cultured; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Guinea Pigs; Humans; Hypertension, Pulmonary; Imidazoles; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Lung Diseases, Obstructive; Male; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinases; Neutrophils; p38 Mitogen-Activated Protein Kinases; Pulmonary Alveoli; Pulmonary Fibrosis; Pyrimidines; Rats; Rats, Inbred Lew; Sialoglycoproteins; Tumor Necrosis Factor-alpha

Common colds are associated with exacerbations of chronic obstructive pulmonary disease (COPD). However, the role of the common cold virus (human rhinovirus) in the production of symptoms and lower airway inflammation at COPD exacerbation is unknown. Thirty three patients with moderate-to-severe COPD were seen at baseline, when the number of chest infections in the previous year was noted, and acutely at COPD exacerbation. Within 48 h after the onset of the exacerbation and at baseline, nasal aspirates and induced sputum were taken for rhinovirus reverse transcriptase polymerase chain reaction (RT-PCR) analysis and determination of cytokine levels. Symptoms, recorded on diary cards, were noted and forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) measured. At exacerbation, mean FEV1 and FVC fell significantly from baseline (p<0.001). Ten of 43 exacerbations were associated with rhinovirus infection, detected in induced sputum. In four of these, nasopharyngeal samples contained no detectable rhinovirus. All baseline samples were negative for rhinovirus. The simultaneous presence of increased nasal discharge/nasal congestion (in 26 of the 43 exacerbations) and increased sputum (29 exacerbations) was strongly associated with the presence of rhinovirus (odds ratio 6.15; p=0.036). Total symptom scores were greater for rhinovirus as compared to nonrhinovirus exacerbations (p=0.039). Median baseline sputum interleukin-6 levels rose from 90.2 to 140.3 pg x mL(-1) at exacerbation (p=0.005); the change was greater in the presence of rhinovirus infection (p=0.008). Rhinovirus infection can be detected at chronic obstructive pulmonary disease exacerbation. This is associated with elevation of lower airway interleukin-6 levels, which may mediate lower airway symptom expression during chronic obstructive pulmonary disease exacerbations.

Topics: Aged; Analysis of Variance; Chi-Square Distribution; Common Cold; Female; Forced Expiratory Volume; Humans; Interleukin-6; Interleukin-8; Lung Diseases, Obstructive; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Rhinovirus; Sputum; Statistics, Nonparametric; Vital Capacity

To analyze effects of hay dust exposure on interleukin-8 (IL-8) concentration, percentage of neutrophils, and neutrophil chemotactic activity in bronchoalveolar lavage fluid (BALF) of horses with chronic obstructive pulmonary disease (COPD).. 16 healthy horses and 29 horses with COPD.. IL-8 concentration, percentage of neutrophils, and neutrophil chemotactic activity in BALF were measured. Values were analyzed with respect to hay dust exposure. These variables were also measured in 5 asymptomatic horses with COPD after the induction of clinical signs by changing feed from silage to hay.. L-8 concentrations and chemotactic activity in BALF were greater in horses with COPD, compared with healthy horses, and greater in horses with COPD exposed to hay dust, compared with nonexposed affected horses. An increase in IL-8 concentration accompanied by an increase in percentage of neutrophils in BALF and development of clinical signs of COPD were induced in asymptomatic horses with COPD by changing feed from silage to hay.. Exposure of horses with COPD to hay dust components resulted in an increase in IL-8 secretion at the bronchoalveolar surface. This chemokine may play a role in the pathogenesis of COPD, because it causes neutrophil accumulation in the bronchoalveolar space. Our results underscore the importance of eliminating dust sources for the treatment and prevention of COPD in horses.

Topics: Animal Feed; Animals; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Dust; Horse Diseases; Horses; Housing, Animal; Interleukin-8; Leukocyte Count; Lung Diseases, Obstructive; Neutrophils; Poaceae

To evaluate the role of cytokines in the pathogenesis of COPD.. Induced sputum samples were obtained from 20 patients with stable COPD, 10 healthy smokers (HS) and 10 healthy nonsmokers (HNS). Total and differential cell counts were examined, and sputum interleukin (IL)-8, tumor necrosis factor (TNF)-alpha, IL-6 level were measured by radioimmunoassay technique.. Sputum IL-8, TNF-alpha level and neutrophil percentages (PMN) in the COPD group were significantly higher than those in the HS group and the HNS group (P < 0.01). Compared with the HNS group, there was a significant increase in the PMN and the level of IL-8 in the HS group (P < 0.05). The sputum level of IL-6 did not differ significantly among three groups (P > 0.05). In the COPD group, the sputum level of IL-8 was correlated positively with the level of TNF-alpha and the PMN (r's = 0.5999, 0.6737). In the HS group the sputum level of IL-8 was also correlated positively with the PMN (rs = 0.8424). The sputum IL-8, TNF-alpha levels and the PMN were all correlated negatively with FEV1% and FEV1/FVC in the COPD group (r's = -0.6453, -0.7341, -0.7341, -0.7624, -0.5262, -0.7353).. IL-8, TNF-alpha and neutrophil are involved in airway inflammation which results in airflow obstruction, thus playing an important role in the pathogenetic process of COPD.

Topics: Aged; Chronic Disease; Female; Humans; Interleukin-6; Interleukin-8; Lung Diseases, Obstructive; Male; Middle Aged; Sputum; Tumor Necrosis Factor-alpha

It has been demonstrated that consecutive samples of induced sputum may differ with respect to cellular composition. The aim of this study was to compare two sequential sputum samples in patients with chronic obstructive pulmonary disease (COPD) and asthma with different severity. Two sputum inductions were performed 30 min apart and processed separately in healthy subjects (n=11), patients with moderate to severe COPD (n=10), asthmatics treated with beta2-agonists alone (group 1, n=11), inhaled steroids (group 2, n=12) or systemic steroids (group 3, n=7). In healthy subjects and asthma group 2, percentages of neutrophils decreased significantly between the two sputum inductions but did not change in COPD and asthma group 3. Percentages of eosinophils did not change significantly in any group of patients. Concentrations of interleukin (IL)-8 decreased significantly in the control group and asthma groups 1 and 2 but not in asthma group 3 and the COPD group. These data demonstrate differences in sputum composition between two consecutive samples which were most pronounced in healthy subjects. Therefore, pooling of sputum samples may affect the results, particularly in healthy subjects, in contrast to subjects with more severe asthma or chronic obstructive pulmonary disease. These findings may be suggestive of differences in the distribution of inflammation along the airways between distinct airway diseases.

Topics: Administration, Inhalation; Administration, Oral; Adrenergic beta-Agonists; Adult; Aged; Albuterol; Asthma; Blood Proteins; Eosinophil Granule Proteins; Eosinophils; Female; Glucocorticoids; Humans; Interleukin-8; Lung Diseases, Obstructive; Male; Middle Aged; Prednisolone; Respiratory Function Tests; Ribonucleases; Sputum

Patients with homozygous (PiZ) alpha(1)-antitrypsin (AAT) deficiency have not only low baseline serum AAT levels (approximately 10 to 15% normal) but also an attenuated acute phase response. They are susceptible to the development of premature emphysema but may also be particularly susceptible to lung damage during bacterial exacerbations when there will be a significant neutrophil influx. The purposes of the present study were to assess the inflammatory nature of acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) in subjects with AAT deficiency, to compare this with COPD patients without deficiency, and to monitor the inflammatory process and its resolution following appropriate antibacterial therapy. At the start of the exacerbation, patients with AAT deficiency had lower sputum AAT (p < 0.001) and secretory leukoprotease inhibitor (SLPI; p = 0.02) with higher elastase activity (p = 0.02) compared with COPD patients without deficiency. Both groups had a comparable acute phase response as assessed by C-reactive protein (CRP) but the AAT-deficient patients had a minimal rise in serum AAT (to < 6 microM). After treatment with antibiotics, in patients with AAT deficiency, there were significant changes in many sputum proteins including a rise in SLPI levels, and a reduction in myeloperoxidase (MPO) and elastase activity (p < 0. 005 for all measures); the sputum chemoattractants interleukin-8 (IL-8) and leukotriene B(4) (LTB(4)) fell (p < 0.01), and protein leak (sputum/serum albumin ratio) became lower (p < 0.01). The changes were rapid and within 3 d of the commencement of antibiotic therapy the biochemical markers had decreased significantly, but took a variable time thereafter to return to baseline values. In conclusion, patients with AAT deficiency had evidence of increased elastase activity at the start of the exacerbation when compared with nondeficient COPD patients which probably reflects a deficient antiproteinase screen (lower sputum AAT and SLPI). The increased bronchial inflammation at presentation resolved rapidly with 14 d of antibiotic therapy.

Topics: Acute Disease; Acute-Phase Reaction; Aged; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Bacterial Infections; Bronchi; C-Reactive Protein; Female; Humans; Inflammation Mediators; Interleukin-8; Leukotriene B4; Lung Diseases, Obstructive; Male; Middle Aged; Pancreatic Elastase; Peroxidase; Phenotype; Proteinase Inhibitory Proteins, Secretory; Proteins; Respiratory Tract Infections; Secretory Leukocyte Peptidase Inhibitor; Serine Proteinase Inhibitors; Serum Albumin; Sputum

Cigarette smoking is the most important cause of chronic obstructive pulmonary disease (COPD). Although the precise sequence of events that leads a smoker to experience airway obstruction is not completely clear, airway inflammation is a relevant factor. To investigate airway inflammation, 12 nonatopic smoking COPD patients with a forced expiratory volume in one second (FEV1) < or = 75% predicted and 10 normal nonsmoking subjects (NS) were studied with bronchoscopy and bronchial lavage (BL). Serum immunoglobulin (Ig)E levels of COPD patients correlated with the smoking history (r=0.7, p=0.008). In BL of COPD patients there was an increase of neutrophils (median, range) (COPD 62.6x10(3), 1.2-323, NS 1.35, 0-19.2, p=0.001), eosinophils (COPD 1.6, 0-6.9, NS 0.15, 0-3.7, p=0.035), the levels of interleukin (IL)-8 (COPD 1079 pg x mL(-1), 121-2,500, NS 20.4, 7.2-59, p=0.001), myeloperoxidase (MPO) (COPD 752 microg x L(-1), 11-5,500, NS 22.1, 8-70, p=0.001) and eosinophil cationic protein (ECP) (COPD 21.5 microg x L(-1), 1.8-161, NS 2, 1.8-4.9, p=0.001). Significant correlations were found in BL of COPD patients between IL-8 and neutrophils (p=0.02), MPO and neutrophils (p=0.02), IL-8 and MPO (p=0.0001) and ECP and eosinophils (p=0.02). In addition, the ratios between the BL levels of MPO and the number of neutrophils and between ECP levels and eosinophils were higher in COPD patients than in NS (p=0.03 and 0.01, respectively). These data suggest that cigarette smoke is associated with increased amounts of airway interleukin-8, a chemotactic factor for neutrophils and eosinophils. Recruited neutrophils and eosinophils are activated and they release increased amounts of inflammatory mediators capable of damaging the bronchial tissue.

Topics: Bronchoalveolar Lavage Fluid; Eosinophils; Female; Humans; Inflammation Mediators; Interleukin-8; Lung Diseases, Obstructive; Male; Middle Aged; Neutrophils; Smoking

Nitric oxide (NO) plays an important role as an inflammatory mediator in the airways. Though direct measurement of endogenous NO has been difficult in humans, we have recently found that measurement of NO derivatives in induced sputum may be useful for assessing airway inflammation in asthmatic patients.. This study was designed to determine the direct in vivo evidence of increased production of endogenous NO in patients with bronchial asthma and chronic obstructive pulmonary disease (COPD).. We have investigated simultaneous assessment of NO using two non-invasive methods, such as NO level in exhaled air and induced sputum, in these patients. We determined the concentration of stable end-products of NO (nitrite plus nitrate) in induced sputum and exhaled NO concentration using a chemiluminescence analyser in 10 normal controls, 10 asthmatic patients and 11 patients with COPD, and evaluated whether endogenous NO levels correlate with percentage of neutrophils and interleukin-8 (IL-8) level in induced sputum in patients with COPD.. We found significantly higher concentrations of exhaled NO in patients with bronchial asthma (25.1 [5.1] p.p.b.) than in patients with COPD (12.1 [1.9] p.p.b.) and normal controls (5.2 [1.4] p.p.b.). However, higher concentrations of NO derivatives in induced sputum were found in patients with bronchial asthma (1190 [106] micromol/L) and COPD (950 [105] micromol/L) than in normal controls (514 [30] micromol/L). In patients with asthma, but not in those with COPD, concentrations of NO derivatives in induced sputum were significantly correlated with concentrations of exhaled NO (r = 0.64, P < 0.05). Moreover, in patients with COPD, concentrations of NO derivatives in induced sputum were significantly correlated with percentage of neutrophils (r = 0.71, P < 0.05) and IL-8 level (r = 0.80, P < 0.01).. We conclude the increased production of endogenous NO in patients with asthma and COPD, and that NO derivatives in induced sputum are more valuable than exhaled NO in assessing airway inflammation in patients with COPD.

Topics: Adult; Aged; Asthma; Biomarkers; Eosinophils; Forced Expiratory Volume; Humans; Interleukin-8; Leukocyte Count; Lung Diseases, Obstructive; Male; Middle Aged; Neutrophils; Nitric Oxide; Sputum

Chronic obstructive pulmonary disease (COPD) is defined as a chronic obstructive inflammatory disease affecting the small airways associated with hay dust exposure (Lowell, F.C., 1964. Observation on heaves. An asthma like syndrome in the horse, J. Allergy 35, 322-330). The disease corresponds histopathologically to a chronic bronchiolitis (Gerber, H., 1973. Chronic pulmonary disease in the horse, Equine Vet. J. 5, 26-33; Winder, N.C., Grünig, G., Hermann, M., Howald, B., von Fellenberg, R., 1989. Comparison of respiratory secretion cytology and pulmonary histology in horses, J. Vet. Med., A36, 32-38) and is mainly characterized by the presence of neutrophil granulocytes in the small bronchioles. Around 12-50% of all horses in Europe and the northern United States suffer from this disease (Mc Pherson, E.A., Lawson, G.H.K., Murphy, J.R., Nicholson, J.M., Fraser, J.A., Breeze, R.G., Pirie, H.M., 1978. Chronic obstructive pulmonary disease (COPD): Identification of affected horses, Eq. Vet. J. 10, 47-53; Larson, V.L., Busch, R.H., 1985. Equine tracheobronchial lavage: Comparison of lavage cytologic features in horses with chronic obstructive pulmonary disease, Am. J. Vet. Res., 46, 144-146; Bracher, V., von Fellenberg, R., Winder, N.C., Grünig, G., 1991. An investigation of the incidence of chronic obstructive pulmonary disease (COPD) in random populations of swiss horses, Equine Vet. J. 23, 136-141). The number of neutrophils in the bronchoalveolar lavage (BAL) and in tracheobronchial secretions (TBS) correlates with the severity of the disease. The present study is focused on the mechanisms which lead to the infiltration of neutrophil granulocytes in the lung of horses. We found that: (1). A strong chemotactic activity in the BAL fluid is associated with high levels of dust exposition. (2). In vitro stimulated alveolar macrophages have impaired phagocytosis efficiency and secrete two chemo-attractants specific for neutrophil granulocytes: Interleukin-8 (IL-8) (Wuyts, A., Proost, P., Put, W., Lenaerts, J.-P., Paemen, L., van Damme, J., 1994. Leucocyte recruitment by monocyte chemotactic proteins (MCPs) secreted by human phagocytes, J. Immunol. Meth. 174, 237-247) and macrophage inflammatory protein-2 (MIP-2) (Wolpe, S.D., Sherry, B., Juers, D., Davatelis, G. Yurt, R.W., Cerami, A., Identification and characterisation of macrophage inflammatory protein-2, Proc. Natl. Acad. Sci. USA 86, 612-616; Tekamp-Olson, P., Gallegos, C., Bauer, D., 1990. Cloning and cha

Topics: Animals; Bronchoalveolar Lavage Fluid; Chemokine CXCL2; Chemotaxis, Leukocyte; Cytokines; Dust; Horse Diseases; Horses; Humans; Interleukin-8; Lung Diseases, Obstructive; Macrophages, Alveolar; Monokines; Neutrophils; Poaceae; RNA, Messenger

Although sputum induction is used as a technique to investigate lower airway inflammation in asthmatic subjects, advantages over spontaneous sputum in patients with chronic obstructive pulmonary disease (COPD) have not been investigated.. Samples of spontaneous sputum and sputum induced with 3% hypertonic saline for 14 minutes were collected from 27 patients with chronic obstructive pulmonary disease (COPD) who usually produced spontaneous sputum. Spirometric indices and oxygen saturation (Sao2) were measured at seven minute intervals. The spontaneous, seven and 14 minute sputum samples were analysed for total and differential cell counts, cell viability, and interleukin 8 levels.. Analysis of the sputum revealed that median cell viability was higher in the seven minute (62.8%; p = 0.004) and 14 minute (65%; p = 0.001) induced sputum samples than in spontaneous sputum (41.2%). There was no significant difference in total and differential cell counts or in interleukin 8 levels between spontaneous and induced sputum. During the sputum induction procedure the mean (SD) fall in forced expiratory volume in one second (FEV1) was 0.098 (0.111) 1 (p < 0.001) and in forced vital capacity (FVC) was 0.247 (0.233) 1 (p < 0.001). There was a small but significant fall in Sao2 during sputum induction (p = 0.03).. Induced sputum contains a higher proportion of viable cells than spontaneous sputum. There are no significant differences between the sputum samples obtained at seven minutes and at 14 minutes of hypertonic saline nebulisation. Sputum induction is safe and well tolerated in patients with COPD.

Topics: Aged; Cell Count; Cell Survival; Forced Expiratory Volume; Humans; Interleukin-8; Lung Diseases, Obstructive; Middle Aged; Nebulizers and Vaporizers; Sputum; Vital Capacity

To assess the characteristics of airway inflammation in patients with COPD.. We measured the sputum concentration of interleukin-8 (IL-8), a chemokine involved in the migration and activation of neutrophils and eosinophils. We also measured myeloperoxidase (MPO) as a parameter of neutrophil activity and eosinophil cationic protein (ECP) as a parameter of eosinophil activity. Spontaneous sputum samples were obtained from 33 patients with stable COPD and 30 patients with asthma. Induced sputum samples were obtained from 12 normal control subjects.. The sputum concentration of IL-8 was significantly higher in the patients with COPD than in the patients with asthma or in the control subjects (p<0.0001). Concentrations of MPO and ECP were significantly higher in the patients with COPD than in the control subjects but did not differ significantly between the patients with COPD and those with asthma. In the patients with COPD, the sputum concentration of IL-8 was significantly correlated with the concentration of MPO (r=0.55, p<0.001) and of ECP (r=0.53, p<0.01). The sputum concentration of IL-8 was negatively correlated with FEV1/FVC (r=-0.78, p<0.0001) in the COPD group.. Results suggest the activation of both neutrophils and eosinophils in the airways of patients with COPD. It appears that IL-8 plays a primary role in this activation. The sputum concentration of IL-8 appeared to be closely associated with the degree of airflow obstruction in patients with COPD and may serve as a marker in evaluating the severity of airway inflammation, which is a risk factor for COPD.

Topics: Adult; Aged; Asthma; Blood Proteins; Case-Control Studies; Eosinophil Granule Proteins; Eosinophils; Female; Humans; Inflammation Mediators; Interleukin-8; Lung Diseases, Obstructive; Lymphocyte Activation; Male; Middle Aged; Neutrophil Activation; Peroxidase; Respiratory Function Tests; Ribonucleases; Smoking; Sputum

We have investigated whether IL-8 is present in airway secretions from patients with asthma and chronic obstructive pulmonary disease (COPD) to obtain information on its possible role in airway inflammation in obstructive airways disease. In the bronchoalveolar lavage fluid (BALF) from 11 clinically stable patients with asthma the levels of IL-8 were increased compared to 10 healthy subjects (median: controls 21.5 pg/ml, asthma 244 pg/ml: p < 0.005). In the patients with asthma the levels of IL-8 correlated with the percentage neutrophils in the BALF (r = 0.81; p < 0.001) and with a parameter of the permeability of the respiratory membrane, the quotient (alpha 2-macroglobulin in BALF)/(alpha 2-macroglobulin in serum) (r = 0.66; p < 0.025). In the sputum sol phase of 9 patients with symptomatic asthma the levels of IL-8 were lower than in 9 patients with COPD (asthma: 6.4 ng/ml; COPD: 16.3 ng/ml; p < 0.02) and significantly correlated with those of neutrophilic myeloperoxidase (MPO; r = 0.85; p < 0.005). The increased levels of IL-8 in the airway secretions from both patients with asthma and COPD may be markers of an ongoing inflammatory process, which is more pronounced in patients with COPD. In patients with asthma the strong correlation between the levels of IL-8 and the percentage neutrophils and/or the levels of MPO points to a role of IL-8 in the recruitment and activation of neutrophils in the airway lumen.

Topics: Adolescent; Adult; Aged; Asthma; Blood Proteins; Bronchoalveolar Lavage Fluid; Eosinophil Granule Proteins; Humans; Immunoglobulin A, Secretory; Inflammation Mediators; Interleukin-8; Lactoferrin; Lung Diseases, Obstructive; Middle Aged; Neutrophil Activation; Neutrophils; Permeability; Peroxidase; Ribonucleases; Sputum

Asthma and chronic obstructive pulmonary disease are characterized by chronic airway inflammation. Studies using bronchoalveolar lavage (BAL) have shown an increased proportion of eosinophils in the BAL fluid from asthmatics compared with that from normal subjects, whereas studies of chronic obstructive pulmonary disease (COPD) have shown increased numbers of neutrophils. Induced sputum allows sampling of respiratory tract secretions from patients and control subjects, providing a noninvasive method of studying airway secretions and allowing characterization of cells and measurement of soluble markers. We investigated whether induced sputum was a useful method of studying airway fluid from patients with moderate to severe COPD and whether it could be used to compare inflammation in this condition with that in asthma. An initial reproducibility study was undertaken. Sputum was induced twice in 13 patients with severe COPD at a 14-d interval. Total and differential cell counts were carried out and were found to be reproducible over this period. Sputum was then induced in 14 patients with COPD, 23 patients with asthma, 12 healthy cigarette smokers, and 16 normal nonsmoking control subjects. We found a significant increase in neutrophils and increased concentrations of tumor necrosis factor-alpha (TNF alpha) and interleukin-8 (IL-8) in the patients with COPD compared with the smoking and nonsmoking control subjects. Interleukin-8, but not TNF alpha, was significantly higher in the COPD group than in the asthmatic group. We conclude that the cytokines TNF alpha and IL-8 may be involved in the inflammation in COPD.

Topics: Adult; Aged; Asthma; Bronchoalveolar Lavage Fluid; Eosinophils; Female; Humans; Inflammation; Interleukin-8; Leukocyte Count; Lung Diseases, Obstructive; Male; Middle Aged; Neutrophils; Reproducibility of Results; Smoking; Sputum; Tumor Necrosis Factor-alpha

In order to elucidate the role of interleukin 8 (IL-8) in the development of chronic lung disease (CLD) of neonates with intra-uterine infection, serial and simultaneous measurements of the concentration of IL-8 and granulocyte elastase alpha 1 proteinase inhibitor complex (E-alpha 1 PI) in the tracheobronchial aspirate of low birth weight infants were conducted. Infants with a high serum IgM level at birth, and who subsequently developed CLD, showed significantly high concentrations of IL-8 and E-alpha 1 PI in the first 48 h. It seemed that IL-8 stimulated neutrophils to release neutrophil enzymes which, in turn, caused the lung tissue injury, resulting in the development of CLD following intra-uterine infection.

Topics: alpha 1-Antitrypsin; Bronchi; Fetal Diseases; Granulocytes; Humans; Infant, Low Birth Weight; Infant, Newborn; Infections; Interleukin-8; Leukocyte Elastase; Lung Diseases, Obstructive; Pancreatic Elastase; Suction; Trachea

An increase in resting energy expenditure (REE) commonly occurs in patients with chronic obstructive pulmonary disease (COPD), the cause of which is as yet unknown. The objective of this study was to assess the relationship between REE, acute phase proteins, and inflammatory mediators in patients with COPD.. Thirty patients were studied and 26 healthy age-matched subjects served as controls. REE was measured by indirect calorimetry and adjusted for fat-free mass (FFM) by bioelectrical impedance analysis. Tumour necrosis factor alpha (TNF-alpha), soluble tumour necrosis receptor (sTNF-R)55 and sTNF-R75, interleukin (IL)-6, IL-8, and lipopolysaccharide binding protein (LBP) were measured by ELISA.. Fourteen patients had a normal REE and in 16 it was raised. The mean body mass index and fat mass were significantly lower in the latter but pulmonary function data were similar in the two groups. In the 30 patients with COPD the mean (SD) sTNF-R75 was 1.7 (1.0) ng/ml compared with 1.1 (0.4) ng/ml in the controls; C-reactive protein (CRP) was detectable (> 5 micrograms/ml) in eight patients compared with none of the control subjects, and LBP was 13.2 (7.7) micrograms/ml compared with 8.6 (3.1) micrograms/ml in the controls. The patients with a raised REE had increased mean levels of CRP compared with the patients with a normal REE (median 5.5 micrograms/ml (range 5-193) and < 5 micrograms/ml, respectively); the same was true for LBP (median 12.4 micrograms/ml (range 8.1-39.1) and 9.5 micrograms/ml (range 5.0-16.6), respectively), but sTNF-R55 and R75 and IL-8 were similar in the two groups. Of the 16 patients with a raised REE, the CRP level was increased in eight and normal in eight. In those with an increased level of CRP the FFM was decreased and LBP, IL-8, and sTNF-R55 and R75 were increased compared with those with normal CRP levels.. A subset of patients with COPD with an increased REE and decreased FFM have increased levels of acute phase reactant proteins and inflammatory cytokines in their serum; these phenomena may be causally related.

Topics: Acute-Phase Proteins; Antigens, CD; Body Composition; Body Mass Index; C-Reactive Protein; Carrier Proteins; Cytokines; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-6; Interleukin-8; Lung; Lung Diseases, Obstructive; Membrane Glycoproteins; Middle Aged; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Tumor Necrosis Factor-alpha

Bronchial inflammation in chronic bronchitis has not been characterised as well as in asthma. The present study was undertaken to assess whether a characteristic pattern of bronchial inflammatory markers could be found in patients with chronic bronchitis.. Bronchoscopy with bronchial lavage was performed in 42 patients with chronic bronchitis and in 13 healthy controls. Twenty three of the patients had non-obstructive chronic bronchitis and 19 had chronic bronchitis and chronic obstructive pulmonary disease (COPD). Eighteen of the patients with bronchitis had recurrent infective exacerbations and 24 did not. Intrabronchial bacterial cultures were taken with a protected specimen brush.. Increased activity of neutrophils, fibroblasts, and eosinophils was found in the patients with chronic bronchitis as assessed by the levels of myeloperoxidase (MPO) and interleukin-8 (IL-8), hyaluronan, and eosinophil cationic protein (ECP), respectively. The levels of tryptase did not differ from the controls. High correlations were found between the levels of MPO and IL-8, as well as ECP and IL-8. No differences were found between the patients with COPD and those with non-obstructive chronic bronchitis.. Recruitment and activation of both neutrophils and eosinophils seem to be a characteristic of chronic bronchitis. This activation is associated with IL-8. The patients with intrabronchial cultures of Streptococcus pneumoniae had the highest individual levels of MPO, ECP, and IL-8 of all subjects in the study, indicating that colonisation with S pneumoniae could promote bronchial inflammation.

Topics: Adult; Aged; Biomarkers; Blood Proteins; Bronchitis; Bronchoalveolar Lavage Fluid; Chronic Disease; Eosinophil Granule Proteins; Eosinophils; Fibroblasts; Humans; Hyaluronic Acid; Interleukin-8; Lung Diseases, Obstructive; Middle Aged; Neutrophils; Peroxidase; Ribonucleases; Streptococcus pneumoniae

To clarify the localization and mechanism of neutrophil infiltration in the lower respiratory tract, we measured neutrophil number, neutrophil chemotactic factor (NCF) activity and content of C5 in bronchial lavage (BL) fluid and bronchoalveolar lavage (BAL) fluid. Numbers of neutrophils, NCF activity and C5 content were higher in the BL fluid from normal volunteers (NV) and control patients (CP) than those in the BAL fluid from the same subjects. The NCF activity in the BL fluid was inhibited approximately 40% by anti-C5 antiserum, and correlated with C5 content in the BL fluid. In the BAL fluids of patients with chronic airway diseases (CAD) and patients with idiopathic interstitial pneumonia (IIP), neutrophil number, NCF activity and C5 content were increased compared to those in BAL fluid from NV or CP. These results indicated that neutrophils are predominant in the bronchial region compared to the alveolar region, and that C5-derived NCF play important roles in the accumulation of neutrophils in the bronchial region. Also C5-derived NCF are thought to be related to, at least, a part of the neutrophil infiltration in the respiratory tract of patients with CAD and IIP.

Topics: Adult; Aged; Bronchi; Bronchoalveolar Lavage Fluid; Complement C5; Humans; Interleukin-8; Lung Diseases, Obstructive; Male; Middle Aged; Neutrophils; Pulmonary Alveoli; Pulmonary Fibrosis

Direct contact of the cells normally present in the bronchial lumen, such as alveolar macrophages, with air pollutants (e.g. cigarette smoke) can lead to the activation of these cells. This activation is beneficial for the cleaning task these cells have in the bronchial tree, but also leads to the release of chemotactic substances, toxic oxygen radicals, enzymes and mediators responsible for bronchial obstruction. As a first step in these processes, an enhanced chemotactic activity can attract neutrophils to the bronchial lumen, where they help by cleaning the lungs from possible dangerous intruders, but can also cause damage to the normal lung architecture. In the present study concerned with the pathogenesis of chronic obstructive lung disease (COLD), broncho-alveolar lavage (BAL) was performed in 35 individuals, who could be divided on he basis of their history and lung function into normal/nonsmokers, normal/smokers, COLD-patients/nonsmokers and COLD-patients/smokers. Neutrophilic chemotactic activity was assayed using Boyden chambers where the patients' own neutrophils were tested. More neutrophils and more neutrophilic chemotactic activity were found in the BAL-fluid of the smokers and COLD-patients. A correlation was demonstrated between the amount of chemotactic activity released during the incubation of cells obtained by BAL and the airway resistance or the airway conductance. These data suggest an enhanced chemotactic activity as one of the initiating factors in the pathogenesis of chronic obstructive lung disease.

Topics: Bronchoalveolar Lavage Fluid; Chemotactic Factors; Female; Humans; Interleukin-8; Lung; Lung Diseases, Obstructive; Male; Middle Aged; Phagocytes; Smoking