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Background: Macrophages constitute a heterogeneous cell population with pro- (MΦ1) and anti-inflammatory (MΦ2) cells. The soluble chitinase-like-protein YKL-40 is expressed in macrophages and various other cell types, and has been linked to a variety of inflammatory diseases, including COPD. Dexamethasone strongly reduces YKL-40 expression in peripheral blood mononuclear cells (PBMC) in vitro. We hypothesized that: a) YKL-40 is differentially expressed by MΦ1 and MΦ2, b) is decreased by corticosteroids and c) that long-term treatment with inhaled corticosteroids (ICS) affects YKL-40 levels in serum and sputum of COPD patients., Methods: Monocytes of healthy subjects were cultured in vitro for 7 days with either GM-CSF or M-CSF (for MΦ1 and MΦ2, respectively) and stimulated for 24 h with LPS, TNFα, or oncostatin M (OSM). MΦ1 and MΦ2 differentiation was assessed by measuring secretion of IL-12p40 and IL-10, respectively. YKL-40 expression in macrophages was measured by quantitative RT-PCR (qPCR) and ELISA; serum and sputum YKL-40 levels were analyzed by ELISA., Results: Pro-inflammatory MΦ1 cells secreted significantly more YKL-40 than MΦ2, which was independent of stimulation with LPS, TNFα or OSM (p < 0.001) and confirmed by qPCR. Dexamethasone dose-dependently and significantly inhibited YKL-40 protein and mRNA levels in MΦ1. Serum YKL-40 levels of COPD patients were significantly higher than sputum YKL-40 levels but were not significantly changed by ICS treatment., Conclusions: YKL-40 secretion from MΦ1 cells is higher than from MΦ2 cells and is unaffected by further stimulation with pro-inflammatory agents. Furthermore, YKL-40 release from cultured monocyte-derived macrophages is inhibited by dexamethasone especially in MΦ1, but ICS treatment did not change YKL-40 serum and sputum levels in COPD. These results indicate that YKL-40 expression could be used as a marker for MΦ1 macrophages in vitro, but not for monitoring the effect of ICS in COPD., Trial Registration: ClinicalTrials.gov, registration number: NCT00158847.

Objectives: Occupational exposures are important and possibly modifiable contributors to the global burden of chronic obstructive pulmonary disease (COPD). Exposure to vapours, gases, dusts and fumes (VGDF) has been associated with a two- to threefold higher COPD risk. Less is known about effects of occupational exposure to pesticides and solvents. In the current study, we assessed if VGDF, pesticides and solvents are associated with the level of lung function and the prevalence of airway obstruction in the general population., Methods: We included 11 851 subjects aged 18-89 years from the LifeLines cohort study. Regression models assessing associations between occupational exposures (no/low/high), level of lung function (prebronchodilator FEV(1), FEV(1)/FVC) and mild and moderate/severe airway obstruction were adjusted for sex, age, height, weight, current/ex-smoking and packyears. Additionally, we stratified by smoking status and gender and tested for interaction. A second general population cohort (n=2364) was used to verify our initial findings., Results: Occupational exposure to VGDF and pesticides was associated with a lower level of FEV(1) and FEV(1)/FVC and with a higher prevalence of mild and moderate/severe airway obstruction in the two general populations investigated. There were no associations with exposure to solvents., Conclusions: Occupational exposure to both VGDF and pesticides is associated with airway obstruction in the general population.

Cigarette smoking, the major cause of chronic obstructive pulmonary disease (COPD), induces aberrant airway epithelial structure and function. The underlying mechanisms are unresolved so far. We studied effects of cigarette smoke extract (CSE) on epithelial barrier function and wound regeneration in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBECs) from COPD patients, nonsmokers and healthy smokers. We demonstrate that CSE rapidly and transiently impairs 16HBE barrier function, largely due to disruption of cell-cell contacts. CSE induced a similar, but stronger and more sustained, defect in PBECs. Application of the specific epidermal growth factor receptor (EGFR) inhibitor AG1478 showed that EGFR activation contributes to the CSE-induced defects in both 16HBE cells and PBECs. Furthermore, our data indicate that the endogenous protease calpain mediates these defects through tight junction protein degradation. CSE also delayed the reconstitution of 16HBE intercellular contacts during wound healing and attenuated PBEC barrier function upon wound regeneration. These findings were comparable between PBECs from smokers, healthy smokers and COPD patients. In conclusion, we demonstrate for the first time that CSE reduces epithelial integrity, probably by EGFR and calpain-dependent disruption of intercellular contacts. This may increase susceptibility to environmental insults, e.g. inhaled pathogens. Thus, EGFR may be a promising target for therapeutic strategies to improve mucosal barrier function in cigarette smoking-related disease.

Wine intake is associated with a better lung function in the general population, yet the source of this effect is unknown. Resveratrol, a polyphenol in wine, has anti-inflammatory properties in the lung, its effects being partially mediated via induction of Sirtuin (SIRT)1 activity. We assessed the impact of wine and resveratrol intake, and SIRT1 single-nucleotide polymorphisms (SNPs) on lung function in the general population. Effects of red and white wine and resveratrol intake on forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC were analysed in the population-based Doetinchem cohort (n=3,224). Associations of four tagging SIRT1 SNPs with lung function were analysed in the Doetinchem (n=1,152) and Vlagtwedde-Vlaardingen (n=1,390) cohorts. Resveratrol intake was associated with higher FVC levels, and white wine intake with higher FEV(1) levels and lower risk of airway obstruction. SIRT1 SNPs were not significantly associated with level or course of lung function, either directly or indirectly via wine or resveratrol intake. This study shows a positive association of resveratrol intake with lung function in the general population, confirms the previously reported positive association of white wine intake with higher levels of FEV(1), and additionally shows an association with a higher FEV(1)/FVC ratio. These effects probably do not run via SNPs in SIRT1.

Spirometry is used worldwide to diagnose respiratory disease, and it is a validated measure to assess airway obstruction. Irreversible airway obstruction is the defining feature of chronic obstructive pulmonary disease (COPD). Thus, an FEV(1)/FVC ratio <70% is used to diagnose COPD, and the severity is thereafter based on the level of FEV(1). This definition is widely used in clinical practice and research, yet may lead to confusion with respect to the diagnosis associated with the presence of airway obstruction. The three main reasons are the following: (1) fixed airflow obstruction may be the result of specific diagnoses such as cystic fibrosis; (2) FEV(1)/FVC ratio changes with ageing, and it is therefore inappropriate to use the same ratio at 40 and 90 years, leaving aside gender differences; (3) even when specific diagnoses are excluded, fixed airflow obstruction may be the end-stage of many different underlying processes. The authors believe that they have strong arguments that a COPD diagnosis based solely on spirometric values is nonsense. More sophisticated lung function tests, such as plethysmography, forced oscillation and lung clearance index, may help further to delineate the characteristics of low lung function. However, these are not feasible in most clinical contexts and in epidemiologic studies. Therefore, the authors throw down the gauntlet: spirometry is an essential tool in patient evaluation but dangerous for disease diagnosis, and the term COPD should only be used in the appropriate clinical (diagnostic) context.

Background: An imbalance in matrix metalloproteases (MMPs) and tissue inhibitors of MMPs (TIMPs) contributes to chronic obstructive pulmonary disease (COPD) development. Longitudinal studies investigating Single Nucleotide Polymorphisms (SNPs) in MMPs and TIMPs with respect to COPD development and lung function decline in the general population are lacking., Methods: We genotyped SNPs in MMP1 (G-1607GG), MMP2 (-1306 C/T), MMP9 (3 tagging SNPs), MMP12 (A-82G and Asn357Ser) and TIMP1 (Phe124Phe and Ile158Ile) in 1390 Caucasians with multiple FEV1 measurements from a prospective cohort study in the general population. FEV1 decline was analyzed using linear mixed effect models adjusted for confounders. Analyses of the X-chromosomal TIMP1 gene were stratified according to sex. All significant associations were repeated in an independent general population cohort (n=1152)., Results: MMP2 -1306 TT genotype carriers had excess FEV1 decline (-4.0 ml/yr, p=0.03) compared to wild type carriers. TIMP1 Ile158Ile predicted significant excess FEV1 decline in both males and females. TIMP1 Phe124Phe predicted significant excess FEV1 decline in males only, which was replicated (p=0.10) in the second cohort. The MMP2 and TIMP1 Ile158Ile associations were not replicated. Although power was limited, we did not find associations with COPD development., Conclusions: We for the first time show that TIMP1 Phe124Phe contributes to excess FEV1 decline in two independent prospective cohorts, albeit not quite reaching conventional statistical significance in the replication cohort. SNPs in MMPs evidently do not contribute to FEV1 decline in the general population.

Background: Chronic obstructive pulmonary disease (COPD) is associated with a higher prevalence of antinuclear autoantibodies (ANAs). However, a significant subgroup of patients is ANA negative. It remains to be determined which patient groups carry autoantibodies., Methods: The association of smoking behaviour, disease status, gender, age and body mass index (BMI) with the presence of autoantibodies in the serum was determined in 124 patients with COPD and 108 non-COPD control subjects. In addition, the role of B cells in autoantibody generation in COPD was investigated by sequencing the antibody repertoire of B cells in the lungs of patients with COPD and of ex-smoking and never-smoking control subjects., Results: Patients with COPD had a significantly higher risk of being serum positive for ANAs (OR 3.12, 95% CI 1.68 to 5.76, p<0.001). ANAs were not significantly associated with age, smoking status, gender or pack-years of smoking. Within the COPD population, subjects with BMI <22 kg/m2 had a significantly higher risk of ANAs (OR 4.93, 95% CI 1.50 to 16.50, p=0.009) than those with normal or high BMI. The antibody repertoire of B cells in the lungs of patients with COPD had a high frequency of positively charged CDR3 residues, a feature which is associated with self-reactive antibodies., Conclusion: The results show that COPD is a heterogeneous disease with respect to the prevalence of ANAs. ANAs are primarily associated with the presence of COPD and with low BMI, but not with smoking and forced expiratory volume in 1 s.

Studies using genetic isolates with limited genetic variation may be useful in chronic obstructive pulmonary disease (COPD) genetics, but are thus far lacking. The associations between single nucleotide polymorphisms (SNPs) in candidate genes and lung function in COPD were studied in a genetic isolate. In 91 subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage >or=1 COPD, who were members of an extended pedigree including 6,175 people from the Genetic Research in Isolated Populations study, 32 SNPs were analysed in 13 candidate genes: a disintegrin and metalloprotease domain 33 gene (ADAM33), transforming growth factor-beta1 gene ( TGFB1), matrix metalloprotease-1 gene (MMP1), MMP2, MMP9, MMP12, tissue inhibitor of metalloprotease-1 gene (TIMP1), surfactant protein A1 gene (SFTPA1 ), SFTPA2, SFTPB, SFTPD, glutathione S-transferase P1 gene (GSTP1), and haem oxygenase 1 gene ( HMOX1). Their relation to forced expiratory volume in 1 s (FEV( 1)), inspiratory vital capacity (IVC) and FEV(1)/IVC were studied using restricted maximum likelihood linear mixed modelling, accounting for pedigree structure. Significant associations were replicated in the general Vlagtwedde/Vlaardingen study. Six SNPs in TGFB1, SFTPA1, SFTPA2 and SFTPD were significantly associated with FEV(1)/IVC in subjects with GOLD stage >or=1 COPD. Two SNPs in TGFB1 (C to T substitution at nucleotide -509 and substitution of leucine 10 with proline (Leu10Pro)), Leu50Val in SFTPA1 and Ala160Thr in SFTPD showed evidence suggestive of association with FEV(1)/IVC in subjects with GOLD stage >or=2 COPD. The TGFB1 associations were replicated in GOLD stage >or=2 patients from the Vlagtwedde/Vlaardingen population, with similar effect sizes. It was shown that a genetic isolate can be used to determine the genetics of lung function, which can be replicated in COPD patients from an independent population.

Oxidative stress is an important causative factor in the onset and progression of smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD). Superoxide dismutases (SODs) can prevent an increase in oxidative burden. A total of 1,390 subjects from the prospective Vlagtwedde-Vlaardingen cohort were genotyped for two single nucleotide polymorphisms (SNPs) in SOD2 and four SNPs in SOD3, which were further analysed for associations with the presence of bronchial hyperresponsiveness (BHR; provocative concentration causing a 10% fall in the forced expiratory volume in one second (FEV(1); PC(10)

In vitro and in vivo studies have shown that carbon monoxide (CO) has both anti-inflammatory and anti-oxidant capacities. Since chronic obstructive pulmonary disease (COPD) is characterised by inflammation and oxidative stress, low-dose CO could be of therapeutic use. The aim of the present study was to investigate the feasibility and anti-inflammatory effects of 100-125 ppm CO inhalation in patients with stable COPD. In total, 20 ex-smoking COPD patients with post-bronchodilator forced expiratory volume in one second (FEV(1)) >1.20 L and FEV(1)/forced vital capacity <70% were enrolled in a randomised, placebo-controlled, crossover study. Effects on inflammation were measured in induced sputum and blood. CO inhalation was feasible and patients' vital signs were unaffected; 2 h.day(-1) inhalation of low-dose CO on 4 consecutive days led to a maximal individual carboxyhaemoglobin level of 4.5%. Two exacerbations occurred in the CO period. CO inhalation led to trends in reduced sputum eosinophils (median reduction 0.25% point) and improved responsiveness to methacholine (median provocative concentration causing a 20% fall in FEV(1) 0.85 versus 0.63 mg.mL(-1)). Inhalation of 100-125 ppm carbon monoxide by patients with chronic obstructive pulmonary disease in a stable phase was feasible and led to trends in reduction of sputum eosinophils and improvement of responsiveness to methacholine. Further studies need to confirm the safety and efficacy in inflammatory lung diseases.

Although small airway remodeling (SAR) leading to airflow obstruction is a common consequence of human cigarette smoking, the airways have been largely ignored in animal models of chronic obstructive pulmonary disease (COPD). We examined lung structure in a guinea pig model of chronic cigarette smoke exposure to ascertain whether smoke induced SAR, and to evaluate how these anatomic lesions correlate with physiologic changes. We used tissue from guinea pigs exposed to cigarette smoke or air for 6 mo. Pulmonary function tests were performed, and histologic sections were prepared. Airspace size (Lm) and changes in the structure of the small airways were evaluated by morphometric analysis. Chronic smoke exposure was associated with increased airway wall thickness and increased amounts of thick collagen fibers in the walls of the small airways, as well as with increased Lm. The increase in thick collagen fibers related negatively to peak expiratory volume (PEF) and the ratio of forced expiratory volume in 1 s to forced ventilatory capacity (FEV(0.1)/FVC), and positively to airway resistance. Physiologic lung volumes were predicted by airspace size, but residual volume (RV) and total lung capacity (TLC) also were related to airway wall thickness. Amounts of smooth muscle were not changed and did not predict any physiologic abnormalities. We conclude that cigarette smoke exposure results in SAR in the guinea pig, alterations that are reflected in increased airways resistance with diminished airflow and air trapping, mimicking human disease. This model should prove useful in further investigations into the mechanisms of airway remodeling.

Severe asthma exacerbations are periods of intense airway inflammation that have been hypothesised to contribute to structural changes in the airways. If so, accelerated lung function decline over time should be more prevalent in adult patients with asthma who have frequent exacerbations than those without, but to date this has not been demonstrated. A cohort study was performed in order to investigate the effect of severe exacerbations on the progression of airway obstruction in 93 nonsmoking asthmatics with moderate-to-severe disease prior to treatment with inhaled corticosteroids. Subjects were followed for > or =5 yrs (median follow-up 11 yrs). In total, 56 (60.2%) subjects experienced at least one severe exacerbation (median rate 0.10.yr(-1)). Oral corticosteroid use and more severe airway obstruction at baseline were associated with a higher exacerbation rate. Independent of these variables, asthma patients with frequent exacerbations had a significantly larger annual decline in forced expiratory volume in one second (FEV(1); median difference (95% confidence interval) 16.9 (1.5-32.2) mL.yr(-1)). Exacerbation rate significantly predicted an excess decline in FEV(1), such that one severe exacerbation per year was associated with a 30.2 mL greater annual decline in FEV(1). These data support the hypothesis that exacerbations, indicating intermittent periods of worsening airway inflammation, are associated with excess lung function decline in asthma.

Epidemiological studies have indicated that chronic obstructive pulmonary disease (COPD) may be associated with an increased incidence of ischaemic cardiac events. The current authors performed a post hoc analysis of the European Respiratory Society's study on Chronic Obstructive Pulmonary Disease (EUROSCOP); a 3-yr, placebo-controlled study of an inhaled corticosteroid budesonide 800 microg.day(-1) in smokers (mean age 52 yrs) with mild COPD. The current study evaluates whether long-term budesonide treatment attenuates the incidence of ischaemic cardiac events, including angina pectoris, myocardial infarction, coronary artery disorder and myocardial ischaemia. Among the 1,175 patients evaluated for safety, 49 (4.2%) patients experienced 60 ischaemic cardiac events. Patients treated with budesonide had a significantly lower incidence of ischaemic cardiac events (18 out of 593; 3.0%) than those receiving placebo (31 out of 582; 5.3%). The results of the present study support the hypothesis that treatment with inhaled budesonide reduces ischaemic cardiac events in patients with mild chronic obstructive pulmonary disease.

Introduction: Most patients with asthma and many patients with COPD show bronchial hyperresponsiveness to adenosine (BHR(AMP)). BHR(AMP) may be caused by release of mast cell histamine, which induces smooth muscle contraction., Aim of the Study: To evaluate whether mast cell numbers in airway smooth muscle are increased in patients with asthma and COPD compared to their age-matched controls, and whether mast cell numbers are correlated with BHR(AMP)., Patients: Twenty-two non-smoking subjects with asthma (age 31yr, FEV(1): 89% pred, PC(20)AMP: 2.7mg/ml), 18 ex-smoking subjects with COPD (age 62yr, FEV(1): 58% pred, PC(20)AMP: 52.4mg/ml)., Methods: Snap-frozen bronchial biopsies were immunostained with anti-mast cell tryptase and anti-desmin antibodies. Mast cell number was expressed as the number of tryptase positive cells per area of smooth muscle., Results: There were no significant differences in mast cell number between patients with asthma, COPD, and their respective age-matched healthy controls. Furthermore, there was no significant correlation between mast cell number and FEV(1) or PC(20)AMP in any of the groups. Surprisingly, the mast cell number was negatively correlated with reversibility to salbutamol in COPD patients (rho -0.47, P<0.05)., Conclusion: Mast cell numbers in central airway smooth muscle apparently do not contribute importantly to bronchial hyperresponsiveness to adenosine.

Smoking is the leading cause of preventable death worldwide. Hundreds of millions of individuals still smoke, affecting their health as well as that of their peers, family and offspring. Smoking is a well-established prime risk factor for chronic obstructive pulmonary disease and hampers the response to treatment in asthma and chronic obstructive pulmonary disease. In the present paper, new concepts are discussed with respect to pathology, treatment, smoking cessation and tobacco control. Recommendations for future directions are given.

Pulmonary emphysema, as a feature of chronic obstructive pulmonary disease (COPD), is characterised by destruction of alveolar tissue. The present authors previously demonstrated reduced decorin expression in the peribronchial area of COPD patients, reflecting an altered extracellular matrix (ECM) modulation. Decorin transcription is regulated by the transforming growth factor (TGF)-beta-Smad pathway, the key intracellular signal route for initiation of ECM component gene transcription. Whether this pathway is aberrantly expressed in COPD is not known. An immunohistochemical study was performed to compare protein expression of TGF-beta1 and TGF-beta receptors, Smad 2, 3, 4 and 7, and decorin in lung tissue of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II and IV COPD patients and controls. Epithelial expression of the inhibitory Smad 7 was significantly lower in patients with GOLD stages II and IV than in controls, with other Smad protein expressions being similar in the groups. The expression of TGF-beta1 and TGF-beta receptor type I was significantly lower in stage II patients. Decorin staining of the adventitia and alveolar walls was significantly reduced in COPD stage IV. In conclusion, the transforming growth factor-beta-Smad pathway is aberrantly expressed in chronic obstructive pulmonary disease patients, implying an abnormal tissue repair ultimately resulting in reduced decorin production. The results of the present study contribute to better understanding of the pathogenesis of emphysema and the airway fibrosis observed in chronic obstructive pulmonary disease patients.

Objective: The present study focuses on the prevalence of nutritional depletion in relation to functional performance, airflow limitation, experienced dyspnoea and health status in a large multi-center out-patient population with chronic obstructive pulmonary disease (COPD)., Methods: In 39 out-patient centers in The Netherlands, 389 patients with moderate to severe COPD (217 men) were recruited. The study evaluated on the baseline characteristics of the COSMIC study. Measurements included body composition by bioelectrical impedance analysis, dyspnoea by MRC-score, peripheral muscle function by isometric handgrip strength and disease-specific health status by St. George Respiratory Questionnaire., Results: The prevalence of nutritional depletion (defined as body mass index (BMI)

Although chronic obstructive pulmonary disease (COPD) patients frequently report symptoms, it is not known which factors determine the course of symptoms over time and if these differ according to the sex of the patient. The current study investigated predictors for presence, development and remission of COPD symptoms in 816 males and 312 females completing 3-yr-follow-up in the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP). The following were included in generalised estimating equations logistic regression analyses: explanatory variables of treatment; pack-yrs smoking; age, forced expiratory volume in one second % predicted (FEV1 % pred); annual increase in FEV1 and number of cigarettes smoked; body mass index; and phadiatop. Interaction terms of sex multiplied by explanatory variables were tested. Over 3 yrs, similar proportions of males and females reported symptoms. In males only, higher FEV1 % pred was associated with reduction in new symptoms of wheeze and dyspnoea, and symptom prevalence was reduced with annual FEV1 improvement and phlegm prevalence reduced with budesonide treatment (odds ratio 0.66; 95% confidence interval 0.52-0.83). Additionally an increase in the number of cigarettes smoked between visits increased the risk of developing phlegm (1.40 (1.14-1.70)) and wheeze (1.24 (1.03-1.51)) in males but not females. The current study shows longitudinally that symptom reporting is similar by sex. The clinical course of chronic obstructive pulmonary disease can differ by sex, as males show greater response to cigarette exposure and treatment.

Chronic obstructive pulmonary disease (COPD) is characterised by destruction of extracellular matrix (ECM) in parenchymal areas, whereas the bronchial walls can show fibrosis. In addition, an extensive inflammatory process is observed. CD8+ T-cells, located throughout the lung, and epithelial cells in centrally located airways, produce cytokines involved in the inflammatory process. These cytokines may influence the present fibroblasts, the key effectors in the defective ECM repair and maintenance in COPD. The current authors explored the effects of the cytokine microenvironment on cell-cell interaction gene expression in pulmonary fibroblasts of controls (n = 6), and Global Initiative for Chronic Obstructive Lung Disease stage II (n = 7) and stage IV (n = 7) COPD patients. The current authors simulated the in vivo microenvironment using supernatants of CD3/CD28 stimulated CD8+ T-cells isolated from peripheral blood of COPD patients, supernatant of a bronchial-epithelial cell line, or a combination of both. The present data show that fibroblasts of chronic obstructive pulmonary disease patients display an altered response to the cytokine microenvironment, depending on both the disease stage and the central or peripheral location in the lung. Especially adhesion-related genes are upregulated in fibroblasts of chronic obstructive pulmonary disease patients, which can indicate a more pronounced role of fibroblasts in the inflammatory process in chronic obstructive pulmonary disease, possibly resulting in reduced function as effectors of extracellular matrix repair.

Background: There is increasing appreciation of gender differences in COPD but scant data whether risk factors for low lung function differ in men and women. We analysed data from 3 years follow-up in 178 women and 464 men with COPD, participants in the Euroscop Study who were smokers unexposed to inhaled corticosteroids., Methods: Explanatory variables of gender, age, starting age and pack-years smoking, respiratory symptoms, FEV(1)%FVC and FEV(1)%IVC (clinically important measures of airway obstruction), body mass index (BMI), and change in smoking were included in multiple linear regression models with baseline and change in post-bronchodilator FEV(1) as dependent variables., Results: Reduced baseline FEV(1) was associated with respiratory symptoms in men only. Annual decline in FEV(1) was not associated with respiratory symptoms in either men or women, and was 55 ml less in obese men (BMI 30 kg/m(2)) than men having normal BMI, an effect not seen in women. It was 32 ml faster in women with FEV(1)%FVC

Background: Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation. Although smoking cessation improves symptoms and the decline in lung function in COPD, it is unknown whether bronchial inflammation in patients with established COPD varies with the duration of smoking cessation., Methods: 114 patients (99 men) with COPD of mean (SD) age 62 (8) years, a median (IQR) smoking history of 42 (31-55) pack years, no inhaled or oral corticosteroids, all current or ex-smokers (n = 42, quit >1 month, median cessation duration 3.5 years), post-bronchodilator FEV(1) 63 (9)% predicted, and FEV(1)/IVC 48 (9)% were studied cross sectionally. The numbers of subepithelial T lymphocytes (CD3, CD4, CD8), neutrophils, macrophages, eosinophils, mast cells, and plasma cells were measured in bronchial biopsy specimens (median (IQR)/0.1 mm(2)) using fully automated image analysis., Results: Ex-smokers with COPD had higher CD3+, CD4+, and plasma cell numbers than current smokers with COPD (149 (88-225) v 108 (61-164), p = 0.036; 58 (32-90) v 40 (25-66), p = 0.023; and 9.0 (5.5-20) v 7.5 (3.1-14), p = 0.044, respectively), but no difference in other inflammatory cells. Short term ex-smokers (<3.5 years) had higher CD4+ and CD8+ cell numbers than current smokers (p = 0.017, p = 0.023; respectively). Conversely, long term ex-smokers (quit > or =3.5 years) had lower CD8+ cell numbers than short term ex-smokers (p = 0.009), lower CD8/CD3 ratios than both current smokers and short-term ex-smokers (p = 0.012, p = 0.003; respectively), and higher plasma cell numbers than current smokers (p = 0.003)., Conclusions: With longer duration of smoking cessation, CD8 cell numbers decrease and plasma cell numbers increase. This indicates that bronchial T lymphocyte and plasma cell counts, but not other inflammatory cells, are related to duration of smoking cessation in patients with COPD.

Recently, it has been shown that the accumulated volume of B-cells in small airways is increased in chronic obstructive pulmonary disease (COPD) Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 3 and 4. Little is known about the number of B-cells in central airways in COPD. The present authors hypothesised that the number of B-cells in bronchial biopsies of large airways is higher in patients with COPD than in controls without airflow limitation and higher in more severe COPD. Therefore, bronchial biopsies were collected from 114 COPD patients (postbronchodilator forced expiratory volume in one second (FEV1) 63+/-9 % predicted value, FEV1/inspiratory vital capacity (IVC) 48+/-9%) and 28 controls (postbronchodilator FEV1 108+/-12 % predicted value, FEV1/IVC 78+/-4%). Paraffin sections were stained for B-cells (CD20+) and their number was determined in the subepithelial area (excluding muscle, glands and vessels). B-cell numbers were higher in patients with COPD versus controls (8.5 versus 3.9 cells x mm(-2), respectively) and higher in patients with GOLD severity stage 3 (n = 11) than stage 2 (n = 103; 22.3 versus 7.8 cells x mm(-2)). No relationship was found between the number of B-cells and clinical characteristics within the chronic obstructive pulmonary disease group. The authors suggest that these increased B-cell numbers may have an important contribution to the pathogenesis of chronic obstructive pulmonary disease.

Background: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown., Methods: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality., Results: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93)., Conclusions: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2-3 years.

Smoking cessation is the only treatment in patients with chronic obstructive pulmonary disease (COPD) effective in slowing down disease progression. Its effect on airway inflammation in COPD is unknown, although cross-sectional studies suggest ongoing inflammation in ex-smokers. In order to elucidate the effect of smoking cessation on airway inflammation, 28 smokers with COPD (mean age: 55 yrs; forced expiratory volume in one second: 71% predicted) and 25 asymptomatic smokers with normal lung function (aged 50 yrs) were included in a 1-yr smoking cessation programme. Effects of smoking cessation on airway inflammation were investigated in bronchial biopsies (baseline, 12 months) and sputum samples (baseline, 2, 6 and 12 months). In the 12 candidates with COPD who successfully ceased smoking, airway inflammation persisted in bronchial biopsies, while the number of sputum neutrophils, lymphocytes, interleukin (IL)-8 and eosinophilic-cationic-protein levels significantly increased at 12 months. In the 16 asymptomatic smokers who successfully quitted, inflammation significantly reduced (i.e. number of sputum macrophages, percentage of eosinophils and IL-8 levels) or did not change. The current authors suggest that the observed persistent airway inflammation in patients with chronic obstructive pulmonary disease is related to repair of tissue damage in the airways. It remains to be elucidated whether this reflects a beneficial or detrimental effect.

Smoking induces chronic obstructive pulmonary disease (COPD) and is associated with airway inflammation and airway hyperresponsiveness (AHR). It has not been studied in COPD whether direct (methacholine) and indirect (adenosine-5'-monophosphate (AMP)) stimuli are associated with airway inflammation and neither whether smoking cessation improves these features. The current authors cross-sectionally investigated the relationship of AHR to methacholine and AMP with lung function and inflammatory cells in the sputum of 33 smokers with COPD. In addition, changes in these parameters were prospectively assessed in 14 smokers who successfully quit smoking for 1 yr. The presence of AHR to both methacholine and AMP was associated with lower lung function, but not with sputum inflammation. AHR to methacholine and AMP improved significantly after a 1-yr smoking cessation, yet this was unrelated to changes in sputum cell counts. The numbers of neutrophils and epithelial cells significantly increased with smoking cessation. Both direct and indirect airway hyperresponsiveness are associated with lower lung function, but not with sputum inflammation in chronic obstructive pulmonary disease. Interestingly, 1-yr smoking cessation improved both direct and indirect airway hyperresponsiveness, yet without a significant association with changes in lung function or sputum inflammation. Thus, other factors are likely to induce these improvements, e.g. a reduction in stimulation of irritant receptors, airway wall changes or mucus hypersecretion.

Smoking is the main risk factor in the development of chronic obstructive pulmonary disease (COPD), and smoking cessation is the only effective treatment for avoiding or reducing the progression of this disease. Despite the fact that smoking cessation is a very important health issue, information about the underlying mechanisms of the effects of smoking cessation on the lungs is surprisingly scarce. It is likely that the reversibility of smoke-induced changes differs between smokers without chronic symptoms, smokers with nonobstructive chronic bronchitis and smokers with COPD. This review describes how these three groups differ regarding the effects of smoking cessation on respiratory symptoms, lung function (forced expiratory volume in one second), airway hyperresponsiveness, and pathological and inflammatory changes in the lung. Smoking cessation clearly improves respiratory symptoms and bronchial hyperresponsiveness, and prevents excessive decline in lung function in all three groups. Data from well-designed studies are lacking regarding the effects on inflammation and remodelling, and the few available studies show contradictory results. In chronic obstructive pulmonary disease, a few histopathological studies suggest that airway inflammation persists in exsmokers. Nevertheless, many studies have shown that smoking cessation improves the accelerated decline in forced expiratory volume in one second, which strongly indicates that important inflammatory and/or remodelling processes are positively affected.

Chronic obstructive pulmonary disease (COPD) is the most rapidly rising cause of death in individuals >65 yrs of age, the most rapidly growing segment of the USA population. Advancing the clinical research agenda for COPD entails careful consideration of several issues and problems: defining COPD, reliance on physiological testing, outcome measurements and comorbidities. In addition, issues pertaining to the recent dramatic increase in chronic obstructive pulmonary disease mortality in females, smoking susceptibility and the relationship of respiratory symptoms with hyperresponsiveness, as well as chronic obstructive pulmonary disease heterogeneity, are discussed.

Chronic obstructive pulmonary disease (COPD) is a chronic disorder of the lungs and airways that imposes a huge socioeconomic burden on both the patients and society. COPD is the only major chronic disease for which both the incidence and mortality are still rising worldwide. From the literature evidence-based insights can be obtained about maintenance medication for reducing symptoms and disease progression. Both anticholinergics and beta 2-sympathicomimetics have been proven to be effective bronchodilators for COPD, even though many patients fail to respond. This is confounded by the fact that a symptomatic response is not always reflected by an objective improvement in lung function. These substances do not have a favourable effect on the progressive deterioration of lung function. Theophyllines have limited effectiveness and the benefit-to-risk ratio is unfavourable. It has now been demonstrated that inhaled corticosteroids have no effect on the loss of lung function, and their prescription rates in patients with COPD should therefore be reduced. A reduction in exacerbation frequency seems to exist in some studies, yet this has not yet been conclusively demonstrated. Acetylcysteine has been proven to reduce exacerbation frequency. There is no place for maintenance therapy with antibiotics.

There is a need for studying the effects of long-term inhaled corticosteroid therapy on bone mineral density (BMD) and vertebral fracture rates in patients with mild chronic obstructive pulmonary disease (COPD). Patients (n=912, mean age 52 yrs) with mild COPD (mean forced expiratory volume in one second (FEV1) 77% of predicted; mean FEV1/slow vital capacity ratio 62%) were randomized to receive budesonide 400 microg, or placebo twice daily via Turbuhaler. BMD was measured at the L2-L4 vertebrae and the femoral neck, trochanter and Ward's triangle by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24 and 36 months (n=161). Radiographs of the thoracic and lumbar spine were obtained at the beginning and end of treatment (n=653). Previous fractures were present at baseline in 43 budesonide-treated patients (13.4%) and 38 placebo-treated patients (11.5%). New fractures occurred in five budesonide-treated patients, compared with three in the placebo group (p=0.50). There were no significant changes in BMD at any site in budesonide-treated patients, compared with the placebo group, during the course of the study. Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin. In the present study, involving a large group of patients with chronic obstructive pulmonary disease, long-term treatment with budesonide 800 microg x day(-1) via Turbuhaler had no clinically significant effects on bone mineral density or fracture rates.