COPD: recognizing the susceptible smoker

Smoking is the main cause of COPD, a chronic non-curable lung disease. Not all smokers develop COPD and it is still unclear why COPD is only manifested in a small subset of smokers (15-20%). Probably their genetic background makes the difference.We investigated whether young individuals (18-40 years) being susceptible to the development of COPD (having smoking family members with COPD) show different responses to cigarette smoke than young individuals who are not susceptible (having smoking family members without COPD). We show that activation markers of inflammatory cells in blood are increased in susceptible smokers after smoking of 3 cigarettes but not in non-susceptible young smokers. This suggests a role of systemic inflammation in the induction of COPD. Additionally, the amount of AGEs (glycated proteins that are formed during inflammatory processes and accumulate in tissues where they can cause local damage) is increased in the skin of COPD patients. The receptor for AGEs is decreased in blood of COPD patients, indicating an impaired protective mechanism in COPD patients. We investigated effects of corticosteroids (commonly used medication in obstructive lung diseases). Using the corticosteroid skin test we showed that patients with severe COPD are less responsive to corticosteroids than patients with a milder COPD. Smoking can impair the effects corticosteroids. We showed that inhaled corticosteroids in smokers and ex-smokers reduce the number of some inflammatory cells in the airways after both short-term (6 months) and after long-term (3 years) treatment

The Decrease in Serum sRAGE Levels Upon Smoking is Associated with Activated Neutrophils

The serum level of the soluble Receptor for Advanced Glycation End-products (sRAGE) is a promising blood biomarker for the development, severity, and progression of chronic obstructive pulmonary disease (COPD). However, cigarette smoking causes a nearly instant drop in circulating sRAGE levels, strongly impacting on the variability in sRAGE levels. In the current study, we investigated the possible mechanism behind the sudden drop in sRAGE upon smoking. We showed that the number of activated neutrophils in blood significantly increases within two hours upon smoking three cigarettes within one hour. Furthermore, an increased expression of the leukocyte activation marker CD11b, which is a known ligand for RAGE, was observed upon smoking. Additionally, the in vitro activation of neutrophils increased their capacity to bind sRAGE. Together, these data indicate that smoking activates neutrophils in the circulation with concomitant upregulation of the RAGE ligand CD11b, leading to reduced levels of sRAGE in serum

Steroid resistance in COPD?: Overlap and differential anti-inflammatory effects in smokers and ex-smokers

Background: Inhaled corticosteroids (ICS) reduce exacerbation rates and improve health status but can increase the risk of pneumonia in COPD. The GLUCOLD study, investigating patients with mild-to-moderate COPD, has shown that long-term (2.5-year) ICS therapy induces anti-inflammatory effects. The literature suggests that cigarette smoking causes ICS insensitivity. The aim of this study is to compare anti-inflammatory effects of ICS in persistent smokers and persistent ex-smokers in a post-hoc analysis of the GLUCOLD study. Methods: Persistent smokers (n = 41) and persistent ex-smokers (n = 31) from the GLUCOLD cohort were investigated. Effects of ICS treatment compared with placebo were estimated by analysing changes in lung function, hyperresponsiveness, and inflammatory cells in sputum and bronchial biopsies during short-term (0-6 months) and long-term (6-30 months) treatment using multiple regression analyses. Results: Bronchial mast cells were reduced by short-term and long-term ICS treatment in both smokers and ex-smokers. In contrast, CD3(+), CD4(+), and CD8(+) cells were reduced by short-term ICS treatment in smokers only. In addition, sputum neutrophils and lymphocytes, and bronchial CD8(+) cells were reduced after long-term treatment in ex-smokers only. No significant interactions existed between smoking and ICS treatment. Conclusion: Even in the presence of smoking, long-term ICS treatment may lead to anti-inflammatory effects in the lung. Some anti-inflammatory ICS effects are comparable in smokers and ex-smokers with COPD, other effects are cell-specific. The clinical relevance of these findings, however, are uncertain

Lower Corticosteroid Skin Blanching Response Is Associated with Severe COPD

Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation caused by ongoing inflammatory and remodeling processes of the airways and lung tissue. Inflammation can be targeted by corticosteroids. However, airway inflammation is generally less responsive to steroids in COPD than in asthma. The underlying mechanisms are yet unclear. This study aimed to assess whether skin corticosteroid insensitivity is associated with COPD and COPD severity using the corticosteroid skin blanching test. Methods: COPD patients GOLD stage I-IV (n = 27, 24, 22, and 16 respectively) and healthy never-smokers and smokers (n = 28 and 56 respectively) were included. Corticosteroid sensitivity was assessed by the corticosteroid skin blanching test. Budesonide was applied in 8 logarithmically increasing concentrations (0-100 mu g/ml) on subject's forearm. Assessment of blanching was performed after 7 hours using a 7-point scale (normal skin to intense blanching). All subjects performed spirometry and body plethysmography. Results: Both GOLD III and GOLD IV COPD patients showed significantly lower skin blanching responses than healthy never-smokers and smokers, GOLD I, and GOLD II patients. Their area under the dose-response curve values of the skin blanching response were 586 and 243 vs. 1560, 1154, 1380, and 1309 respectively, p Conclusions: In this study, severe and very severe COPD patients had lower skin corticosteroid sensitivity than mild and moderate COPD patients and non-COPD controls with comparable age and packyears. Our findings together suggest that the reduced skin blanching response fits with a subgroup of COPD patients that has an early-onset COPD phenotype

Multiple regression analyses: effects of ICS treatment in smokers and ex-smokers, and the interaction between ICS treatment and smoking (smoking×ICS) on changes in lung function, hyperresponsiveness and inflammatory cells in biopsies and sputum.^*

*<p>Patients were selected from the GLUCOLD cohort <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087443#pone.0087443-Lapperre2" target="_blank">[8]</a>; only persistent smokers and ex-smokers were included. All analyses are adjusted for age and sex. Data are expressed as B, p (regression coefficient, p-value); significant data (p<0.05) are presented in bold; FEV₁, post, L = FEV₁ after salbutamol expressed in liters; PC₂₀ = provocative concentration of metacholine causing a fall in FEV₁ of >20%;</p>‡<p>Cell counts/10⁻⁷ per m² of subepithelium;</p>§<p>Cell counts×10⁴ per mL. The absolute changes in bronchial cell counts and sputum cell counts were normalized by Ln-transformation.</p

Untargeted Lipidomic Analysis in Chronic Obstructive Pulmonary Disease Uncovering Sphingolipids

Rationale: Cigarette smoke is the major risk factor in the development of chronic obstructive pulmonary disease (COPD). Lipidomics is a novel and emerging research field that may provide new insights in the origins of chronic inflammatory diseases, such as COPD. Objectives: To investigate whether expression of the sputum lipidome is affected by COPD or cigarette smoking. Methods: Lipid expression was investigated with liquid chromatography and high-resolution quadrupole time-of-flight mass spectrometry in induced sputum comparing smokers with and without COPD, and never-smokers. Changes in lipid expression after 2-month smoking cessation were investigated in smokers with and without COPD. Measurements and Main Results: More than 1,500 lipid compounds were identified in sputum. The class of sphingolipids was significantly higher expressed in smokers with COPD than in smokers without COPD. At single compound level, 168 sphingolipids, 36 phosphatidylethanolamine lipids, and 5 tobacco-related compounds were significantly higher expressed in smokers with COPD compared with smokers without COPD. The 13 lipids with a high fold change between smokers with and without COPD showed high correlations with lower lung function and inflammation in sputum. Twenty (glyco)sphingolipids and six tobacco-related compounds were higher expressed in smokers without COPD compared with never-smokers. Two-month smoking-cessation reduced expression of 26 sphingolipids in smokers with and without COPD. Conclusions: Expression of lipids from the sphingolipid pathway is higher in smokers with COPD compared with smokers without COPD. Considering their potential biologic properties, they may play a role in the pathogenesis of COPD