Systemic galectin-3 in smokers with chronic obstructive pulmonary disease and chronic bronchitis: The impact of exacerbations

Purpose: The carbohydrate-binding protein Galectin-3 is increased in several inflammatory diseases and has recently been forwarded as a systemic biomarker in chronic obstructive pulmonary disease (COPD). In this longitudinal study, we characterized the level of systemic Galectin-3 using blood from smokers with a history of COPD and chronic bronchitis (COPD-CB), during stable clinical conditions and exacerbations. Patients and Methods: The study population comprised 56 long-term smokers with COPD-CB, 10 long-term smokers without lung disease (LTS) and 10 clinically healthy never-smokers (HNS). Blood samples were analyzed for levels of Galectin-3, leukocyte populations and C-reactive protein (CRP). In addition, sputum samples from the COPD-CB group were analyzed for bacterial growth. Results: When comparing stable clinical conditions and exacerbations in the COPD-CB group, we found that the level of Galectin-3, just like that of CRP, leukocytes and neutrophils, respectively, was increased during exacerbations. However, this exacerbation-associated increase of Galectin-3 was modest. During stable clinical conditions of COPD-CB, the level of Galectin-3 was not elevated in comparison with HNS or LTS. Nor did this level of Galectin-3 distinguish patients that remained in a clinically stable condition throughout the study to those that developed an exacerbation. In addition, neither during stable clinical conditions nor during exacerbations, did the presence of bacterial growth in sputum alter Galectin-3 levels. In contrast to Galectin-3, the level of CRP, leukocytes and neutrophils, respectively, were increased during clinical stable conditions in the COPD-CB group compared with the other groups and were further enhanced during exacerbations. Conclusion: Systemic Galectin-3 is increased in a reproducible but modest manner during exacerbations in smokers with COPD-CB. During stable clinical conditions, the level of systemic Galectin-3 does not distinguish patients that remain clinically stable from those that develop exacerbations. This makes it less likely that systemic Galectin-3 may become a clinically useful biomarker in the current setting

Single breath N2-test and exhaled nitric oxide in men

SummaryThe N2 slope is an index of inhomogeneous distribution of ventilation and has been suggested to be suited for early testing of chronic obstructive pulmonary disease (COPD) in smokers. The aim of the present study was to examine the association between the fraction of exhaled nitric oxide (FENO) and the N2 slope in a random population of smoking and non-smoking men. Altogether 57 subjects were included in the study, 24 never-smokers, seven ex-smokers and 26 current smokers. Subjects were examined twice, in 1995 when they regarded themselves as healthy, and in a follow-up in 2001. Spirometry, N2 slope and high-resolution computed tomography (HRCT) were performed in 1995 while the follow-up examination included also measurement of FENO.The FENO value was significantly lower and the N2 slope higher in current smokers. In smokers but not in never- or ex-smokers FENO was correlated to the difference in N2 slope between 1995 and 2001 (rs=0.49, P=0.01). We analysed the data by multiple linear regression adjusted for smoking, mild respiratory symptoms and inhaled steroids. There were significant associations between FENO and the N2 slope both in 1995 and in 2001. The strongest association was found to exist with the change in N2 slope during these years.Sixteen of the subjects could be classified as having COPD, six with mild and ten with moderate COPD. There was a trend for an increase in N2 slope with increased severity of COPD; among subjects with no COPD the N2 slope in 2001 was 2.3% N2/L, and those with mild and moderate COPD had 2.5% N2/L and 3.9% N2/L, respectively (P=0.0004). No such trend was seen for FENO (17.8, 15.5 and 20.3 parts per billion (ppb), respectively, P=0.8).The results show that FENO is associated with the N2 slope, indicating that FENO reflects inflammatory changes in the peripheral airways of both non-smoking and smoking subjects

Studies of Neutrophilic Inflammation in Tobacco Smokers

Studies of neutrophilic inflammation in tobacco smokers Kristina Andelid Department of Internal medicine and clinical nutrition, Institute of Medicine Sahlgrenska Academy at University of Gothenburg Göteborg, Sweden ABSTRACT The general aim of this thesis was to characterise markers of neutrophilic inflammation in smokers with and without obstructive pulmonary disease with chronic bronchitis (OPD-CB) in a clinically stable state and during exacerbations compared to heathy controls. Methodology: I) Blood samples were obtained from male smokers without airway symptoms and never-smokers at year 0 and 6. II) Non-atopic and atopic, occasional-smokers plus never-smokers underwent two bronchoscopies, including bronchoalveolar lavage (BAL). III & IV) Smokers with OPD-CB (n=60,) and control groups (n=10 each), underwent blood and sputum sampling every 15: th week and during exacerbations for 15 months. Results: I) Blood MPO was higher in smokers than in never- smokers at year 6. MPO was negatively correlated with time after cessation of smoking. II) Gelatinases in BAL fluid were unchanged after acute exposure to tobacco smoke. III) The concentrations of IL-17A and GRO-α protein were lower in blood from smokers with severe OPD-CB and in smokers with OPD-CB colonised with opportunistic pathogens. IV) In smokers with OPD-CB, blood MPO and NE proteins were increased during exacerbations; the corresponding mRNA was undetectable. Conclusions: Acute exposure to tobacco smoke does not exert a pronounced, lasting impact on gelatinases in the airways of occasional-smokers. During stable clinical conditions, neutrophil and MPO concentrations are increased in smokers without OPD-CB and even more so during exacerbations in smokers with OPD-CB. In smokers with severe OPD-CB, and in those colonised with opportunistic pathogens, specific neutrophil-associated cytokine signaling is down-regulated at the systemic level. The lack of detectable mRNA for MPO and NE in the blood of smokers with OPD-CB makes the location of production uncertain for these markers of neutrophil activity. Keywords: smoking, neutrophils, inflammation ISBN: 978-91-628-9216-6 http://hdl.handle.net/2077/3691

Clinical impact of routine sleep assessment by peripheral arterial tonometry in patients with COPD

Background Coexisting obstructive sleep apnoea (OSA) in patients with COPD, defined as overlap syndrome (OVS), is prevalent and underdiagnosed. Routine assessment of OSA is not common practice in COPD care. Our study assessed the clinical impact of sleep assessment by peripheral arterial tonometry (PAT) in COPD patients. Methods 105 COPD patients (mean age 68.1±9 years, body mass index (BMI) 28.3±6.0 kg·m−2, 44% males, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I to IV in 2%, 40%, 42% and 16%, respectively) underwent assessment at an outpatient COPD clinic including anthropometrics, arterial blood gas (ABG) and spirometry in this clinical cohort study. PAT-based sleep studies were performed. Predictors of OVS and ABG were determined. Rapid eye movement (REM) sleep-related OSA (REM-OSA) was analysed in OVS. Results 49 COPD patients (47%) suffered from moderate to severe OSA (OVS group, mean apnoea–hypopnoea index 30.8±18 events·h−1, REM-oxygen desaturation index (REM-ODI) 26.9±17 events·h−1). OVS was more prevalent in males compared to females (59% and 37%, p=0.029, respectively). Age (70.1±8 versus 66.3±10 years), BMI (30.0±6 versus 26.4±7 kg·m−2) and hypertension prevalence (71% versus 45%) were elevated (all p<0.03, respectively), while deep sleep (12.7±7% and 15.4±6%, p=0.029) and mean overnight oxygenation (90.6±3% and 92.3±2%, p=0.003) were lower in OVS compared to COPD alone. REM-ODI was independently associated with daytime arterial carbon dioxide tension (PaCO2) (β=0.022, p<0.001). REM-OSA was associated with an elevated prevalence of atrial fibrillation compared to no REM-OSA (25% and 3%, p=0.022). Conclusions OVS was highly prevalent, specifically in obese males. REM-related OSA showed strong association with elevated daytime PaCO2 and prevalent cardiovascular disease. PAT was feasible for sleep assessment in COPD

Lung macrophages drive mucus production and steroid-resistant inflammation in chronic bronchitis

Abstract Background Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from chronic bronchitis (CB) and display steroid-resistant inflammation with increased sputum neutrophils and macrophages. Recently, a causal link between mucus hyper-concentration and disease progression of CB has been suggested. Methods In this study, we have evaluated the steroid sensitivity of purified, patient-derived sputum and alveolar macrophages and used a novel mechanistic cross-talk assay to examine how macrophages and bronchial epithelial cells cross-talk to regulate MUC5B production. Results We demonstrate that sputum plug macrophages isolated from COPD patients with chronic bronchitis (COPD/CB) are chronically activated and only partially respond to ex vivo corticosteroid treatment compared to alveolar macrophages isolated from lung resections. Further, we show that pseudo-stratified bronchial epithelial cells grown in air–liquid-interface are inert to direct bacterial lipopolysaccharide stimulation and that macrophages are able to relay this signal and activate the CREB/AP-1 transcription factor complex and subsequent MUC5B expression in epithelial cells through a soluble mediator. Using recombinant protein and neutralizing antibodies, we identified a key role for TNFα in this cross-talk. Conclusions For the first time, we describe ex vivo pharmacology in purified human sputum macrophages isolated from chronic bronchitis COPD patients and identify a possible basis for the steroid resistance frequently seen in this population. Our data pinpoint a critical role for chronically activated sputum macrophages in perpetuating TNFα-dependent signals driving mucus hyper-production. Targeting the chronically activated mucus plug macrophage phenotype and interfering with aberrant macrophage-epithelial cross-talk may provide a novel strategy to resolve chronic inflammatory lung disease