Airway pathology in COPD : smoking cessation and pharmacological treatment intervention. Results from the GLUCOLD study

This thesis comprises data from the GLUCOLD study (Groningen Leiden Universities and Corticosteroids in Obstructive Lung Disease), a prospective study in COPD. In chapter 2 is shown that airflow limitation, asthma-like components, exhaled nitric oxide and sputum inflammatory cell counts offer separate and additive information about the pathophysiological condition of COPD. Chapter 3 shows that uneven distribution of ventilation and airway closure in stable COPD are associated with neutrophilic inflammation in bronchial biopsies and bronchoalveolar lavage fluid. Chapter 4 and 5 show that ex-smokers with COPD have higher bronchial CD4+ and plasma cell numbers, and less bronchial epithelial mucin stores, proliferating cells, and squamous cell metaplasia than current smokers, whereas neutrophil, macrophage, and CD8+ cell numbers are not different between both groups. Bronchial inflammation and epithelial changes are associated with duration of smoking cessation. Chapter 6 shows that long-term treatment with inhaled corticosteroids in COPD reduces bronchial T-lymphocyte and mast cell numbers, whilst increasing bronchial epithelial integrity and bronchial eosinophil numbers. This is accompanied by a reduced FEV1 decline and improved airway hyperresponsiveness, dyspnea and quality of life. Discontinuation of inhaled corticosteroids at 6 months leads to a relapse of bronchial inflammation and clinical outcome.Nederlands Wetenschappelijk Onderzoek, Nederlands Astma Fonds, GlaxoSmithKline (NL), LUMC, UMCGUBL - phd migration 201

Airway pathology in COPD : smoking cessation and pharmacological treatment intervention. Results from the GLUCOLD study

This thesis comprises data from the GLUCOLD study (Groningen Leiden Universities and Corticosteroids in Obstructive Lung Disease), a prospective study in COPD. In chapter 2 is shown that airflow limitation, asthma-like components, exhaled nitric oxide and sputum inflammatory cell counts offer separate and additive information about the pathophysiological condition of COPD. Chapter 3 shows that uneven distribution of ventilation and airway closure in stable COPD are associated with neutrophilic inflammation in bronchial biopsies and bronchoalveolar lavage fluid. Chapter 4 and 5 show that ex-smokers with COPD have higher bronchial CD4+ and plasma cell numbers, and less bronchial epithelial mucin stores, proliferating cells, and squamous cell metaplasia than current smokers, whereas neutrophil, macrophage, and CD8+ cell numbers are not different between both groups. Bronchial inflammation and epithelial changes are associated with duration of smoking cessation. Chapter 6 shows that long-term treatment with inhaled corticosteroids in COPD reduces bronchial T-lymphocyte and mast cell numbers, whilst increasing bronchial epithelial integrity and bronchial eosinophil numbers. This is accompanied by a reduced FEV1 decline and improved airway hyperresponsiveness, dyspnea and quality of life. Discontinuation of inhaled corticosteroids at 6 months leads to a relapse of bronchial inflammation and clinical outcome

Fixed airways obstruction among patients with severe asthma: Findings from the Singapore General Hospital-Severe Asthma Phenotype Study

10.1186/1471-2466-14-191BMC Pulmonary Medicine14119

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

10.1371/journal.pone.0087443PLoS ONE92e8744

Carlo von Landberg's letter to Ignaz Goldziher

Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV(1) and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV(1) and accelerated decline of FEV(1) and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV(1) level. Eleven out of 17 SNPs were associated with FEV(1) decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD

Multidrug resistance-associated protein 1 and lung function decline with or without long-term corticosteroids treatment in COPD

Multidrug resistance-associated protein-1 (MRP1) reduces the oxidative stress generated by smoking, a risk factor for Chronic Obstructive Pulmonary Disease (COPD). We previously showed that MRP1 variants are associated with the level and decline of annual forced expiratory volume in one second (FEV1) in the general population. Moreover, we showed that MRP1 variants are also associated with FEV1 level and inflammatory markers in COPD patients. We investigate in the current study the association of MRP1 protein expression in bronchial biopsies with FEV1 decline in COPD patients using placebo, or inhaled corticosteroids (ICS) with or without long-acting beta 2-agonists. Additionally we investigate the association of MRP1 variants with FEV1 decline. MRP1 variants (rs212093, rs4148382, rs504348, rs4781699, rs35621) were genotyped in 110 COPD patients. Associations of MRP1 variants and MRP1 protein expression in bronchial biopsies (obtained at baseline, 6 and 30 months) with FEV1 decline were analyzed using linear mixed-effect models. During 30-month ICS treatment, subjects with a moderate staining for MRP1 had less FEV1 decline than those with a weak staining. In subjects stopping ICS after 6 months followed by 24-month placebo, moderate staining for MRP1 was associated with faster FEV1 decline than in those with a weak staining. None of the variants was associated with FEV1 decline. Our unique study suggests a role of MRP1 protein expression in bronchial biopsies in FEV1 decline occurring selectively in COPD patients with long-term (30-month) ICS therapy. (C) 2012 Elsevier B.V. All rights reserved

Relapse in FEV1 Decline After Steroid Withdrawal in COPD

Pathogenesis and treatment of chronic pulmonary disease

Prediction of long-term benefits of inhaled steroids by phenotypic markers in moderateto-severe COPD: A randomized controlled trial

10.1371/journal.pone.0143793PLoS ONE101214379

Prediction of Long-Term Benefits of Inhaled Steroids by Phenotypic Markers in Moderate-to-Severe COPD: A Randomized Controlled Trial

Pathogenesis and treatment of chronic pulmonary disease

Clinical and inflammatory determinants of bronchial hyperresponsiveness in COPD

Bronchial hyperresponsiveness (BHR) is regarded as a hallmark of asthma, yet it is also present in a considerable number of chronic obstructive pulmonary disease (COPD) patients. Epidemiological studies have shown that BHR provides complementary information to forced expiratory volume in 1 s (FEV1) for development and progression of COPD. We hypothesised that the severity of BHR and its longitudinal changes associate with both clinical and airway inflammation measures in COPD. Our hypothesis was tested in 114 COPD patients (median age 62.9 years, smoking exposure 45.9 pack-yrs) participating in the GLUCOLD (Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease) study, which previously showed an improvement in BHR with fluticasone and fluticasone/salmeterol. At baseline, and 6 and 30 months after treatment, we investigated lung function, including body plethysmography, provocative concentration of methacholine causing a 20% fall in FEV1, sputum induction, and bronchial biopsies. By performing both cross-sectional and longitudinal analyses, we show that BHR in COPD is predominantly associated with residual volume/total lung capacity (a measure of air trapping) and airway inflammation reflected by the number of neutrophils, macrophages and lymphocytes in sputum and bronchial biopsies. Our findings indicate that BHR is an independent trait in COPD and provides important information on phenotype heterogeneity and disease activity