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Translation of genomic alterations to protein changes in chronic obstructive pulmonary disease (COPD) is largely unexplored. Using integrated proteomic and RNA sequencing analysis of COPD and control lung tissues, we identified a protein signature in COPD characterised by extracellular matrix changes and a potential regulatory role for SUMO2. Furthermore, we identified 61 differentially expressed novel, non-reference, peptides in COPD compared with control lungs. This included two peptides encoding for a new splice variant of SORBS1, of which the transcript usage was higher in COPD compared with control lungs. These explorative findings and integrative proteogenomic approach open new avenues to further unravel the pathology of COPD. [ABSTRACT FROM AUTHOR]

Introduction: Asthma‐chronic obstructive pulmonary disease (COPD) overlap (ACO) is a heterogenous condition with clinical features shared by both asthma and COPD. Objectives: This online global survey of respiratory/allergy specialists and primary care practitioners (PCPs) was performed to understand current clinical approaches to the differential diagnosis and management of asthma, COPD and ACO. Methods: Respondents were recruited through: (a) a global online physician respondent community (49,980 PCPs and 7205 specialists); (b) market research agents; (c) experts; (d) professional societies; (e) colleague invitation. Respondents were presented with a survey including hypothetical clinical scenarios of diagnostic uncertainty to identify management approaches. Results: 891 responses (447 PCPs and 444 specialists) were collected across 13 countries. Reported features used for diagnosis of asthma and COPD were consistent with practice guidelines, but there was variability in those selected for ACO diagnosis. Features typically selected by specialists focused on spirometry/history, while PCPs focused on previous treatment/symptoms. Most respondents could correctly diagnose patients with features of ACO; however, features selected for theoretical diagnosis were often different to those selected in the case scenarios. Additionally, treatment selection was often inconsistent with guidelines, with over half of respondents not recommending inhaled corticosteroids in a patient with ACO and dominant features of asthma. Conclusion: While most PCPs and respiratory/allergy specialists can reach a working diagnosis of ACO, there remains uncertainty around which diagnostic features are most important and what constitutes optimal management. It is imperative that clinical studies including patients with ACO are initiated, allowing the generation of evidence‐based management strategies. [ABSTRACT FROM AUTHOR]

Small airways dysfunction (SAD) is well recognised in asthma, yet its role in the severity and control of asthma is unclear. This study aimed to assess which combination of biomarkers, physiological tests, and imaging markers best measure the presence and extent of SAD in patients with asthma. In this baseline assessment of a multinational prospective cohort study (the Assessment of Small Airways Involvement in Asthma [ATLANTIS] study), we recruited participants with and without asthma (defined as Global Initiative for Asthma severity stages 1–5) from general practices, the databases of chest physicians, and advertisements at 29 centres across nine countries (Brazil, China, Germany, Italy, Spain, the Netherlands, the UK, the USA, and Canada). All participants were aged 18–65 years, and participants with asthma had received a clinical diagnosis of asthma more than 6 months ago that had been confirmed by a chest physician. This diagnosis required support by objective evidence at baseline or during the past 5 years, which could be: positive airway hyperresponsiveness to methacholine, positive reversibility (a change in FEV 1 ≥12% and ≥200 mL within 30 min) after treatment with 400 μg of salbutamol in a metered-dose inhaler with or without a spacer, variability in peak expiratory flow of more than 20% (measured over 7 days), or documented reversibility after a cycle (eg, 4 weeks) of maintenance anti-asthma treatment. The inclusion criteria also required that patients had stable asthma on any previous regular asthma treatment (including so-called rescue β2-agonists alone) at a stable dose for more than 8 weeks before baseline and had smoked for a maximum of 10 pack-years in their lifetime. Control group participants were recruited by advertisements; these participants were aged 18–65 years, had no respiratory symptoms compatible with asthma or chronic obstructive pulmonary disease, normal spirometry, and normal airways responsiveness, and had smoked for a maximum of 10 pack-years. We assessed all participants with spirometry, body plethysmography, impulse oscillometry, multiple breath nitrogen washout, CT (in selected participants), and questionnaires about asthma control, asthma-related quality of life (both in participants with asthma only), and health status. We applied structural equation modelling in participants with asthma to assess the contribution of all physiological and CT variables to SAD, from which we defined clinical SAD and CT SAD scores. We then classified patients with asthma into SAD groups with model-based clustering, and we compared asthma severity, control, and health-care use during the past year by SAD score and by SAD group. This trial is registered with ClinicalTrials.gov , number NCT02123667. Between June 30, 2014, and March 3, 2017, we recruited and evaluated 773 participants with asthma and 99 control participants. All physiological measures contributed to the clinical SAD model with the structural equation modelling analysis. The prevalence of SAD in asthma was dependent on the measure used; we found the lowest prevalence of SAD associated with acinar airway ventilation heterogeneity (S acin), an outcome determined by multiple breath nitrogen washout that reflects ventilation heterogeneity in the most peripheral, pre-acinar or acinar airways. Impulse oscillometry and spirometry results, which were used to assess dysfunction of small-sized to mid-sized airways, contributed most to the clinical SAD score and differed between the two SAD groups. Participants in clinical SAD group 1 (n=452) had milder SAD than group 2 and comparable multiple breath nitrogen washout S acin to control participants. Participants in clinical SAD group 2 (n=312) had abnormal physiological SAD results relative to group 1, particularly their impulse oscillometry and spirometry measurements, and group 2 participants also had more severe asthma (with regard to asthma control, treatments, exacerbations, and quality of life) than group 1. Clinical SAD scores were higher (indicating more severe SAD) in group 2 than group 1, and we found that these scores were related to asthma control, severity, and exacerbations. We found no correlation between clinical SAD and CT SAD scores. SAD is a complex and silent signature of asthma that is likely to be directly or indirectly captured by combinations of physiological tests, such as spirometry, body plethysmography, impulse oscillometry, and multiple breath nitrogen washout. SAD is present across patients with all severities of asthma, but it is particularly prevalent in severe disease. The clinical classification of SAD into two groups (a milder and a more severe group) by use of impulse oscillometry and spirometry, which are easy to use, is meaningful given its association with GINA severity stages, asthma control, quality of life, and exacerbations. Chiesi Farmaceutici SpA. [ABSTRACT FROM AUTHOR]

Background and objective: Inflammation is present to a variable degree and composition in patients with COPD. This study investigates associations between both eosinophils and neutrophils in blood, sputum, airway wall biopsies and bronchoalveolar lavage (BAL) and their potential use as biomarkers for clinical response to inhaled corticosteroids (ICS). Methods: In total, 114 steroid‐naïve COPD patients of the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study using ICS or placebo during 30‐month follow‐up were included. Cell counts in blood, sputum, biopsies and BAL were evaluated at baseline. In addition, at baseline, 6 and 30 months, forced expiratory flow in 1 s (FEV1), residual volume/total lung capacity (hyperinflation) and Clinical COPD Questionnaire were evaluated. Results: Cross‐sectional analyses at baseline showed that higher blood eosinophils were significantly associated with higher eosinophil counts in sputum, biopsies and BAL. However, blood neutrophils did not significantly correlate with neutrophil counts in the other compartments. Baseline eosinophils and neutrophils, in whichever compartment measured, did not predict longitudinal FEV1 changes. Higher baseline biopsy eosinophils were associated with an increase in symptoms during 6‐ and 30‐month ICS treatment. In addition, higher biopsy neutrophils were associated with a more marked reduction in hyperinflation during 6‐month ICS treatment compared with placebo. Conclusion: Our findings indicate that blood eosinophils reflect eosinophils in other compartments, in contrast to neutrophils, in ICS‐naïve COPD patients. Both baseline eosinophils and neutrophils do not predict ICS‐induced lung function changes over a period of 6–30 months. The associations of biopsy eosinophils with worsening respiratory symptoms and biopsy neutrophils with improvement in hyperinflation during ICS treatment deserve further investigation. See Letter Blood eosinophils, in contrast to neutrophils, reflect eosinophils in sputum, biopsies and bronchoalveolar lavage (BAL), in inhaled corticosteroids (ICS)‐naïve COPD patients. However, both baseline eosinophils and neutrophils, whether measured in blood, sputum, biopsies and BAL, insufficiently predict lung function response to ICS in COPD over a period of 6–30 months. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare genetic variants underlying COPD through a genome-wide linkage scan. Affectedonly analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14-15q25 [logarithm of the odds (LOD) score = 5.52], 11p15.4-11q14.1 (LOD = 3.71) and 5q14.3-5q33.2 (LOD = 3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF) <0.02), predicted pathogenic, missense variants. These were shared among the affected family members. The identified variants localize to genes including neuroblast differentiation-associated protein (AHNAK), previously associated with blood biomarkers in COPD, phospholipase C Beta 3 (PLCB3), shown to increase airway hyper-responsiveness, solute carrier family 22-A11 (SLC22A11), involved in amino acid metabolism and ion transport, and metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism. Association of SLC22A11 and MTL5 variants were confirmed in the meta-analysis of 9,888 cases and 27,060 controls. In conclusion, we have identified novel rare variants in plausible genes related to COPD. Further studies utilizing large sample whole-genome sequencing should further confirm the associations at chromosome 11 and investigate the chromosome 15 and 5 linked regions. [ABSTRACT FROM AUTHOR]

Abstract: Inflammation and ageing are intertwined in chronic obstructive pulmonary disease (COPD). The histone deacetylase SIRT1 and the related activation of FoxO3 protect from ageing and regulate inflammation. The role of SIRT1/FoxO3 in COPD is largely unknown. This study evaluated whether cigarette smoke, by modulating the SIRT1/FoxO3 axis, affects airway epithelial pro‐inflammatory responses. Human bronchial epithelial cells (16HBE) and primary bronchial epithelial cells (PBECs) from COPD patients and controls were treated with/without cigarette smoke extract (CSE), Sirtinol or FoxO3 siRNA. SIRT1, FoxO3 and NF‐κB nuclear accumulation, SIRT1 deacetylase activity, IL‐8 and CCL20 expression/release and the release of 12 cytokines, neutrophil and lymphocyte chemotaxis were assessed. In PBECs, the constitutive FoxO3 expression was lower in patients with COPD than in controls. Furthermore, CSE reduced FoxO3 expression only in PBECs from controls. In 16HBE, CSE decreased SIRT1 activity and nuclear expression, enhanced NF‐κB binding to the IL‐8 gene promoter thus increasing IL‐8 expression, decreased CCL20 expression, increased the neutrophil chemotaxis and decreased lymphocyte chemotaxis. Similarly, SIRT1 inhibition reduced FoxO3 expression and increased nuclear NF‐κB. FoxO3 siRNA treatment increased IL‐8 and decreased CCL20 expression in 16HBE. In conclusion, CSE impairs the function of SIRT1/FoxO3 axis in bronchial epithelium, dysregulating NF‐κB activity and inducing pro‐inflammatory responses. [ABSTRACT FROM AUTHOR]

Background: It has been observed that mice lacking the sulfatase modifying factor (Sumf1) developed an emphysema-like phenotype. However, it is unknown if SUMF1 may play a role in Chronic Obstructive Pulmonary Disease (COPD) in humans. The aim was to investigate if the expression and genetic regulation of SUMF1 differs between smokers with and without COPD.Methods: SUMF1 mRNA was investigated in sputum cells and whole blood from controls and COPD patients (all current or former smokers). Expression quantitative trait loci (eQTL) analysis was used to investigate if single nucleotide polymorphisms (SNPs) in SUMF1 were significantly associated with SUMF1 expression. The association of SUMF1 SNPs with COPD was examined in a population based cohort, Lifelines. SUMF1 mRNA from sputum cells, lung tissue, and lung fibroblasts, as well as lung function parameters, were investigated in relation to genotype.Results: Certain splice variants of SUMF1 showed a relatively high expression in lung tissue compared to many other tissues. SUMF1 Splice variant 2 and 3 showed lower levels in sputum cells from COPD patients as compared to controls. Twelve SNPs were found significant by eQTL analysis and overlapped with the array used for genotyping of Lifelines. We found alterations in mRNA expression in sputum cells and lung fibroblasts associated with SNP rs11915920 (top hit in eQTL), which validated the results of the lung tissue eQTL analysis. Of the twelve SNPs, two SNPs, rs793391 and rs308739, were found to be associated with COPD in Lifelines. The SNP rs793391 was also confirmed to be associated with lung function changes.Conclusions: We show that SUMF1 expression is affected in COPD patients compared to controls, and that SNPs in SUMF1 are associated with an increased risk of COPD. Certain COPD-associated SNPs have effects on either SUMF1 gene expression or on lung function. Collectively, this study shows that SUMF1 is associated with an increased risk of developing COPD. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by chronic airway inflammation and emphysema, and is caused by exposure to noxious particles or gases, e.g. cigarette smoke. Smoking and oxidative stress lead to accelerated formation and accumulation of advanced glycation end products (AGEs), causing local tissue damage either directly or by binding the receptor for AGEs (RAGE). This study assessed the association of AGEs or RAGE in plasma, sputum, bronchial biopsies and skin with COPD and lung function, and their variance between these body compartments.Methods: Healthy smoking and never-smoking controls (n = 191) and COPD patients (n = 97, GOLD stage I-IV) were included. Autofluorescence (SAF) was measured in the skin, AGEs (pentosidine, CML and CEL) and sRAGE in blood and sputum by ELISA, and in bronchial biopsies by immunohistochemistry. eQTL analysis was performed in bronchial biopsies.Results: COPD patients showed higher SAF values and lower plasma sRAGE levels compared to controls and these values associated with decreased lung function (p <0.001; adjusting for relevant covariates). Lower plasma sRAGE levels significantly and independently predicted higher SAF values (p < 0.001). One SNP (rs2071278) was identified within a region of 50 kB flanking the AGER gene, which was associated with the gene and protein expression levels of AGER and another SNP (rs2071278) which was associated with the accumulation of AGEs in the skin.Conclusion: In COPD, AGEs accumulate differentially in body compartments, i.e. they accumulate in the skin, but not in plasma, sputum and bronchial biopsies. The association between lower sRAGE and higher SAF levels supports the hypothesis that the protective mechanism of sRAGE as a decoy-receptor is impaired in COPD. [ABSTRACT FROM AUTHOR]

Rationale: We have previously shown increased expression of the Frizzled-8 receptor of the Wingless/integrase-1 (WNT) signalling pathway in COPD. Here, we investigated if the Frizzled-8 receptor has a functional role in airway inflammation associated with chronic bronchitis.Methods: Acute cigarette-smoke-induced airway inflammation was studied in wild-type and Frizzled-8-deficient mice. Genetic association studies and lung expression quantitative trait loci (eQTL) analyses for Frizzled-8 were performed to evaluate polymorphisms in FZD8 and their relationship to tissue expression in chronic bronchitis. Primary human lung fibroblasts and primary human airway epithelial cells were used for in vitro studies.Results: Cigarette-smoke-exposure induced airway inflammation in wild-type mice, which was prevented in Frizzled-8-deficient mice, suggesting a crucial role for Frizzled-8 in airway inflammation. Furthermore, we found a significant genetic association (p=0.009) between single nucleotide polymorphism (SNP) rs663700 in the FZD8 region and chronic mucus hypersecretion, a characteristic of chronic bronchitis, in a large cohort of smoking individuals. We found SNP rs663700 to be a cis-eQTL regulating Frizzled-8 expression in lung tissue. Functional data link mesenchymal Frizzled-8 expression to inflammation as its expression in COPD-derived lung fibroblasts was regulated by pro-inflammatory cytokines in a genotype-dependent manner. Moreover, Frizzled-8 regulates inflammatory cytokine secretion from human lung fibroblasts, which in turn promoted MUC5AC expression by differentiated human airway epithelium.Conclusions: These findings indicate an important pro-inflammatory role for Frizzled-8 and suggest that its expression is related to chronic bronchitis. Furthermore, our findings indicate an unexpected role for fibroblasts in regulating airway inflammation in COPD. [ABSTRACT FROM AUTHOR]

Background: The decline in lung function can be reduced by long-term inhaled corticosteroid (ICS) treatment in subsets of patients with chronic obstructive pulmonary disease (COPD). We aimed to identify which clinical, physiological and non-invasive inflammatory characteristics predict the benefits of ICS on lung function decline in COPD. Methods: Analysis was performed in 50 steroid-naive compliant patients with moderate to severe COPD (postbronchodilator forced expiratory volume in one second (FEV1), 30–80% of predicted, compatible with GOLD stages II-III), age 45–75 years, >10 packyears smoking and without asthma. Patients were treated with fluticasone propionate (500 μg bid) or placebo for 2.5 years. Postbronchodilator FEV1, dyspnea and health status were measured every 3 months; lung volumes, airway hyperresponsiveness (PC20), and induced sputum at 0, 6 and 30 months. A linear mixed effect model was used for analysis of this hypothesis generating study. Results: Significant predictors of attenuated FEV1-decline by fluticasone treatment compared to placebo were: fewer packyears smoking, preserved diffusion capacity, limited hyperinflation and lower inflammatory cell counts in induced sputum (p<0.04). Conclusions: Long-term benefits of ICS on lung function decline in patients with moderate-to-severe COPD are most pronounced in patients with fewer packyears, and less severe emphysema and inflammation. These data generate novel hypotheses on phenotype-driven therapy in COPD. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Summary Background Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. Methods We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV 1 ) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV 1 . We also looked for novel variants associated with extremes of FEV 1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 × 10 −8 . Findings UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50 008 unique samples: 10 002 individuals with low FEV 1 , 10 000 with average FEV 1 , and 5002 with high FEV 1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV 1 between heavy smokers and never smokers (p=2·29 × 10 −16 ) and between individuals with and without doctor-diagnosed asthma (p=6·06 × 10 −11 ). We discovered six novel genome-wide significant signals of association with extremes of FEV 1 , including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5′ end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV 1 . We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2 ) that has a trans effect on expression of NCAM1 in brain tissue. Interpretation By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. Funding Medical Research Council. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined whether withdrawal of inhaled corticosteroid (ICS) treatment induces a relapse of forced expiratory volume in one second (FEV1) in chronic obstructive pulmonary disease (COPD) patients. Topics discussed include the findings which suggest that ICS cessation after 30 months in COPD can worsen lung function decline, airway hyperresponsiveness (AHR) and quality of life (QOL).

Background: Debate exists regarding which endpoints most sensitively reflect day-to-day variation in chronic obstructive pulmonary disease (COPD) symptoms and are most useful in clinical practice to predict COPD exacerbations. We hypothesized that short-acting β2-agonist (SABA) reliever use would predict short- and long-term exacerbation risk in COPD patients. Methods: We performed a retrospective analysis of data from a study (ClinicalTrials.gov registration: NCT00419744) comparing budesonide/formoterol 320/9 μg with formoterol 9 μg (both twice daily) in patients with moderate-to-verysevere COPD; reliever salbutamol 90 μg was provided. First occurrence of reliever use >4 (low), >10 (medium), and >20 (high) inhalations/day was assessed as a predictor of short-term (3-week) exacerbation risk. Mean daily reliever use in the week preceding the 2-month visit was investigated as a predictor of the long-term (10-month) exacerbation risk, using intervals of 2-5, 6-9, and ≥10 inhalations/day. Results: Overall, 810 patients were included (61 % male; mean age 63.2 years; post-bronchodilator forced expiratory volume in 1 s 37.7 % of predicted). First occurrence of low, medium, or high reliever use was predictive of an exacerbation within the following 3 weeks; exacerbation risk increased significantly with increasing reliever use. Mean reliever use over 1 week was predictive of long-term exacerbation risk. Patients with mean use of 2-5, 6-9, and ≥10 inhalations/day exhibited 21 %, 67 %, and 135 % higher exacerbation rates, respectively, in the following 10 months, compared with <2 inhalations/day. Budesonide/formoterol was associated with lower short- and long-term exacerbation risk than formoterol in all reliever-use groups. Conclusions: SABA reliever use is a predictor of short- and long-term exacerbation risk in moderate-to-very-severe COPD patients with a history of exacerbations receiving budesonide/formoterol or formoterol.- [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease is mainly a smoking-related disorder and affects millions of people worldwide, with a large effect on individual patients and society as a whole. Although the disease becomes clinically apparent around the age of 40-50 years, its origins can begin very early in life. Different risk factors in very early life—ie, in utero and during early childhood—drive the development of clinically apparent chronic obstructive pulmonary disease in later life. In discussions of which risk factors drive chronic obstructive pulmonary disease, it is important to realise that the disease is very heterogeneous and at present is largely diagnosed by lung function only. In this Review, we will discuss the evidence for risk factors for the various phenotypes of chronic obstructive pulmonary disease during different stages of life. [ABSTRACT FROM AUTHOR]

Background Chronic obstructive pulmonary disease (COPD) is a progressive, incurable lung disease characterised by abnormal tissue repair causing emphysema and small airways fibrosis. Since current therapy cannot modify this abnormal repair, it is crucial to unravel its underlying molecular mechanisms. Unbiased analysis of genome-wide gene expression profiles in lung tissue provides a powerful tool to investigate this. Methods We performed genome-wide gene expression profiling in 581 lung tissue samples from current and ex-smokers with (n=311) and without COPD (n=270). Subsequently, quantitative PCR, western blot and immunohistochemical analyses were performed to validate our main findings Results 112 genes were found to be upregulated in patients with COPD compared with controls, whereas 61 genes were downregulated. Among the most upregulated genes were fibulin-5 (FBLN5), elastin (ELN), latent transforming growth factor β binding protein 2 (LTBP2) and microfibrillar associated protein 4 (MFAP4), all implicated in elastogenesis. Our gene expression findings were validated at mRNA and protein level. We demonstrated higher ELN gene expression in COPD lung tissue and similar trends for FBLN5 and MFAP4, and negative correlations with lung function. FBLN5 protein levels were increased in COPD lung tissue and cleaved, possibly non-functional FBLN5 protein was present. Strong coexpression of FBLN5, ELN, LTBP2 and MFAP4 in lung tissue and in silico analysis indicated cofunctionality of these genes. Finally, colocalisation of FBLN5, MFAP4 and LTBP2 with elastic fibres was demonstrated in lung tissue. Conclusions We identified a clear gene signature for elastogenesis in COPD and propose FBLN5 as a novel player in tissue repair in COPD. [ABSTRACT FROM AUTHOR]

Background: Cigarette smoking is the most important risk factor for Chronic Obstructive Pulmonary Disease (COPD). Only a subgroup of smokers develops COPD and it is unclear why these individuals are more susceptible to the detrimental effects of cigarette smoking. The risk to develop COPD is known to be higher in individuals with familial aggregation of COPD. This study aimed to investigate if acute systemic and local immune responses to cigarette smoke differentiate between individuals susceptible or non-susceptible to develop COPD, both at young (18-40 years) and old (40-75 years) age. Methods: All participants smoked three cigarettes in one hour. Changes in inflammatory markers in peripheral blood (at 0 and 3 hours) and in bronchial biopsies (at 0 and 24 hours) were investigated. Acute effects of smoking were analyzed within and between susceptible and non-susceptible individuals, and by multiple regression analysis. Results: Young susceptible individuals showed significantly higher increases in the expression of FcγRII (CD32) in its active forms (A17 and A27) on neutrophils after smoking (p = 0.016 and 0.028 respectively), independently of age, smoking status and expression of the respective markers at baseline. Smoking had no significant effect on mediators in blood or inflammatory cell counts in bronchial biopsies. In the old group, acute effects of smoking were comparable between healthy controls and COPD patients. Conclusions: We show for the first time that COPD susceptibility at young age associates with an increased systemic innate immune response to cigarette smoking. This suggests a role of systemic inflammation in the early induction phase of COPD. [ABSTRACT FROM AUTHOR]

Background Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) inducing oxidative stress and local tissue injury, resulting in pulmonary inflammation. Advanced glycation end products (AGEs) are produced by glycation and oxidation processes and their formation is accelerated in inflammatory conditions. In this study we assessed whether AGE accumulation in the skin is elevated in COPD and associates with disease severity. Methods 202 mild-to-very-severe COPD patients and 83 old (40-75 years) and 110 young (18-40 years) healthy smokers and never-smokers were included. AGEs were measured by skin autofluorescence (SAF). Demographic variables, smoking habits, co-morbidities and lung function values were obtained. Results COPD patients (FEV1 = 55% predicted) had significantly higher SAF values than old and young healthy controls: 2.5 vs. 1.8 and 1.2 (arbitrary units, p < 0.05). No differences in SAF values were found between GOLD stages I-IV (2.4, 2.3, 2.5, 2.5 respectively). Lower function (FEV1/FVC, MEF50/FVC, RV/TLC) and higher number of packyears were significantly associated with SAF (p < 0.05). Conclusions SAF is increased in mild-to-very severe COPD patients compared with healthy controls. Interestingly, SAF was not associated with disease severity as values were comparable between different GOLD stages (stage I-IV) of COPD. This may suggest that AGEs play a role in the induction phase of COPD in susceptible smokers. Future studies should further investigate the mechanisms underlying AGEs formation and accumulation in COPD. [ABSTRACT FROM AUTHOR]

Cigarette smoking is the main risk factor for COPD (Chronic Obstructive Pulmonary Disease), yet only a subset of smokers develops COPD. Family members of patients with severe early-onset COPD have an increased risk to develop COPD and are therefore defined as “susceptible individuals”. Here we perform unbiased analyses of proteomic profiles to assess how “susceptible individuals” differ from age-matched “non-susceptible individuals” in response to cigarette smoking. Epithelial lining fluid (ELF) was collected at baseline and 24 hours after smoking 3 cigarettes in young individuals susceptible or non-susceptible to develop COPD and older subjects with established COPD. Controls at baseline were older healthy smoking and non-smoking individuals. Five samples per group were pooled and analysed by stable isotope labelling (iTRAQ) in duplicate. Six proteins were selected and validated by ELISA or immunohistochemistry. After smoking, 23 proteins increased or decreased in young susceptible individuals, 7 in young non-susceptible individuals, and 13 in COPD in the first experiment; 23 proteins increased or decreased in young susceptible individuals, 32 in young non-susceptible individuals, and 11 in COPD in the second experiment. SerpinB3 and Uteroglobin decreased after acute smoke exposure in young non-susceptible individuals exclusively, whereas Peroxiredoxin I, S100A9, S100A8, ALDH3A1 (Aldehyde dehydrogenase 3A1) decreased both in young susceptible and non-susceptible individuals, changes being significantly different between groups for Uteroglobin with iTRAQ and for Serpin B3 with iTRAQ and ELISA measures. Peroxiredoxin I, SerpinB3 and ALDH3A1 increased in COPD patients after smoking. We conclude that smoking induces a differential protein response in ELF of susceptible and non-susceptible young individuals, which differs from patients with established COPD. This is the first study applying unbiased proteomic profiling to unravel the underlying mechanisms that induce COPD. Our data suggest that SerpinB3 and Uteroglobin could be interesting proteins in understanding the processes leading to COPD. [ABSTRACT FROM AUTHOR]

Background Co-morbidities are common in chronic obstructive pulmonary disease (COPD). We assessed the contribution of common co-morbidities on health related quality of life (HRQoL) among COPD patients. Methods Using both generic (15D) and respiratory-specific (AQ20) instruments, HRQoL was assessed in a hospital based COPD population (N = 739, 64% males, mean age 64 years, SD 7 years) in this observational study with inferential analysis. The prevalence of their co-morbidities was compared with those of 5000 population controls. The patients represented all severity stages of COPD and the patterns of common concomitant disorders differed between patients. Results Co-morbidities such as psychiatric conditions, alcohol abuse, cardiovascular diseases, and diabetes were more common among COPD patients than in age and gender matched controls. Psychiatric conditions and alcohol abuse were the strongest determinants of HRQoL in COPD and could be detected by both 15D (Odds Ratio 4.7 and 2.3 respectively) and AQ20 (OR 2.0 and 3.0) instruments. Compared to respiratory specific AQ20, generic 15D was more sensitive to the effects of comorbidities while AQ20 was slightly more sensitive for the low FEV1. FEV1 was a strong determinant of HRQoL only at more severe stages of disease (FEV1 < 40% of predicted). Poor HRQoL also predicted death during the next five years. Conclusions The results suggest that co-morbidities may impair HRQoL at an early stage of the disease, while bronchial obstruction becomes a significant determinant of HRQoL only in severe COPD. [ABSTRACT FROM AUTHOR]

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 μg/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<0.05. Lower FEV1 levels and higher RV/TLC ratios were significantly associated with lower skin blanching responses (p = 0.001 and p = 0.004 respectively). GOLD stage I, II, III and IV patients had similar age and packyears. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The soluble cleaved urokinase plasminogen activator receptor (scuPAR) is a circulating protein detected in multiple diseases, including various cancers, cardiovascular disease, and kidney disease, where elevated levels of scuPAR have been associated with worsening prognosis and increased disease aggressiveness. We aimed to identify novel genetic and bio-molecular mechanisms regulating scuPAR levels. Elevated serum scuPAR levels were identified in asthma (n=514) and chronic obstructive pulmonary disease (COPD; n=219) cohorts when compared to controls (n=96). In these cohorts, a genome-wide association study of serum scuPAR levels identified a human plasma kallikrein gene (KLKB1) promoter polymorphism (rs4253238) associated with serum scuPAR levels in a control/asthma population (P = 1.17x 10-7), which was also observed in a COPD population (combined P = 5.04 x 10-12). Using a fluorescent assay, we demonstrated that serum KLKB1 enzymatic activity was driven by rs4253238 and is inverse to scuPAR levels. Biochemical analysis identified that KLKB1 cleaves scuPAR and negates scuPAR's effects on primary human bronchial epithelial cells (HBECs) in vitro. Chymotrypsin was used as a proproteolytic control, while basal HBECs were used as a control to define scuPAR-driven effects. In summary, we reveal a novel post-translational regulatory mechanism for scuPAR using a hypothesis-free approach with implications for multiple human diseases. [ABSTRACT FROM AUTHOR]

Background: WNT signalling is activated during lung tissue damage and inflammation. We investigated whether lung epithelial expression of WNT ligands, receptors (frizzled; FZD) or target genes is dysregulated on cigarette smoking and/or in chronic obstructive pulmonary disease (COPD). Methods: We studied this in human lung epithelial cell lines and primary bronchial epithelial cells (PBEC) from COPD patients and control (non-)smokers, at baseline and on cigarette smoke extract (CSE) exposure. Results: CSE significantly decreased WNT-4, WNT-10B and FZD2 and increased WNT-5B mRNA expression in 16HBE, but did not affect WNT-4 protein. The mRNA expression of WNT-4, but not other WNT ligands, was lower in PBEC from smokers than non-smokers and downregulated by CSE in PBEC from all groups, yet higher in PBEC from COPD patients than control smokers. Moreover, PBEC from COPD patients displayed higher WNT-4 protein expression than both smokers and non-smokers. Exogenously added WNT-4 significantly increased CXCL8/IL-8, IL-6, CCL5/RANTES, CCL2/MCP-1 and vascular endothelial growth factor (VEGF) secretion in 16HBE, but did not affect the canonical WNT target genes MMP-2, MMP-9, fibronectin, β-catenin, Dickkopf and axin-2, and induced activation of the non-canonical signalling molecule p38. Moreover, WNT-4 potentiated the CSE-induced upregulation of IL-8 and VEGF. Conclusions: WNT-4 mRNA and protein levels are higher in PBEC from COPD patients than control (non-) smokers, while cigarette smoke downregulates airway epithelial WNT-4 mRNA, but not protein expression. As WNT-4 further increases CSE-induced pro-inflammatory cytokine release in bronchial epithelium, we propose that higher epithelial WNT-4 levels in combination with cigarette smoking may have important implications for the development of airway inflammation in COPD. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide. Recent genome-wide association studies (GWAS) have identified robust susceptibility loci associated with COPD. However, the mechanisms mediating the risk conferred by these loci remain to be found. The goal of this study was to identify causal genes/variants within susceptibility loci associated with COPD. In the discovery cohort, genome-wide gene expression profiles of 500 non-tumor lung specimens were obtained from patients undergoing lung surgery. Blood-DNA from the same patients were genotyped for 1,2 million SNPs. Following genotyping and gene expression quality control filters, 409 samples were analyzed. Lung expression quantitative trait loci (eQTLs) were identified and overlaid onto three COPD susceptibility loci derived from GWAS; 4q31 (HHIP), 4q22 (FAM13A), and 19q13 (RAB4B, EGLN2, MIA, CYP2A6). Significant eQTLs were replicated in two independent datasets (n = 363 and 339). SNPs previously associated with COPD and lung function on 4q31 (rs1828591, rs13118928) were associated with the mRNA expression of HHIP. An association between mRNA expression level of FAM13A and SNP rs2045517 was detected at 4q22, but did not reach statistical significance. At 19q13, significant eQTLs were detected with EGLN2. In summary, this study supports HHIP, FAM13A, and EGLN2 as the most likely causal COPD genes on 4q31, 4q22, and 19q13, respectively. Strong lung eQTL SNPs identified in this study will need to be tested for association with COPD in case-control studies. Further functional studies will also be needed to understand the role of genes regulated by disease-related variants in COPD. [ABSTRACT FROM AUTHOR]

The ADAM33 gene is associated with the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD) and atherosclerosis. In this study we investigated all-cause, COPD and cardiovascular mortality, in relation to single nucleotide polymorphisms (SNPs) in ADAM33 (Q_1, S_1, S_2, T_1 and T_2) that were genotyped in 1,390 subjects from the Vlagtwedde/Vlaardingen cohort. Participants were examined at entry in 1989/1990 and followed up till evaluation of the vital status on December 31st, 2008. Using Cox proportional hazards regression we estimated the risk of the SNPs in relation to mortality, adjusting for gender, age, FEV1, height, place of residence and packyears of smoking. Additionally, we performed stratified analyses according to gender and smoking habits. After 18 years, 284 (20.4%) subjects had died (107 due to cardiovascular disease and 20 due to COPD). Individuals homozygous for the minor allele of SNP T_2 had an increased risk of all-cause and cardiovascular mortality compared to wild types: hazard ratio 3.6 (95% confidence interval 2.0 to 6.7) and 3.4 (1.2 to 9.5) respectively. Individuals homozygous for the minor allele of S_1, S_2, T_2 or Q_1 had a significantly increased risk of COPD mortality. In stratified analyses the risk of all-cause mortality associated with SNP T_2 did not change: females 3.5 (1.5 to 8.3), males 3.1 (1.2 to 7.6), never smokers 3.8 (0.9 to 16.3), ever smokers 3.6 (1.8 to 7.2). This study shows for the first time that ADAM33 is a pleiotropic gene that is associated with all-cause, COPD and cardiovascular mortality, independent of potential confounders. [ABSTRACT FROM AUTHOR]

Background: Little is known about the factors associated with CT-quantified emphysema progression in heavy smokers. The objective of this study was to investigate the effect of length of smoking cessation and clinical / demographical factors on the rate of emphysema progression and FEV1-decline in male heavy smokers. Methods: 3,670 male smokers with mean (SD) 40.8 (17.9) packyears underwent chest CT scans and pulmonary function tests at baseline and after 1 and 3 years follow-up. Smoking status (quitted ⩾5, ⩾1-<5, <1 years or current smoker) was noted. Rate of progression of emphysema and FEV1-decline after follow-up were assessed by analysis of variance adjusting for age, height, baseline pulmonary function and emphysema severity, packyears, years in study and respiratory symptoms. The quitted ⩾5 group was used as reference. Results: Median (Q1-Q3) emphysema severity,<-950 HU, was 8.8 (5.1 - 14.1) and mean (SD) FEV1 was 3.4 (0.73) L or 98.5 (18.5) % of predicted. The group quitted '>5 years' showed significantly lower rates of progression of emphysema compared to current smokers, 1.07% and 1.12% per year, respectively (p<0.001). Current smokers had a yearly FEV1-decline of 69 ml, while subjects quit smoking >5 years had a yearly decline of 57.5 ml (p<0.001). Conclusion: Quit smoking >5 years significantly slows the rate of emphysema progression and lung function decline. [ABSTRACT FROM AUTHOR]

Genetic variation in nicotinic acetylcholine receptor subunit genes (nAChRs) is associated with lung function level and chronic obstructive pulmonary disease (COPD). It is unknown whether these variants also predispose to an accelerated lung function decline. We investigated the association of nAChR susceptibility variants with lung function decline and COPD severity. The rs1051730 and rs8034191 variants were genotyped in a population-based cohort of 1,226 heavy smokers (COPACETIC) and in an independent cohort of 883 heavy smokers, of which 653 with COPD of varying severity (LEUVEN). Participants underwent pulmonary function tests at baseline. Lung function decline was assessed over a median follow-up of 3 years in COPACETIC. Current smokers homozygous for the rs1051730 A-allele or rs8034191 G-allele had significantly greater FEV1/FVC decline than homozygous carriers of wild-type alleles (3.3% and 4.3%, p = 0.026 and p = 0.009, respectively). In the LEUVEN cohort, rs1051730 AA-carriers and rs8034191 GG-carriers had a two-fold increased risk to suffer from COPD GOLD IV (OR 2.29, 95% confidence interval [CI] = 1.11-4.75; p = 0.025 and OR = 2.42, 95% [CI] = 1.18-4.95; p = 0.016, respectively). The same risk alleles conferred, respectively, a five- and four-fold increased risk to be referred for lung transplantation because of end-stage COPD (OR = 5.0, 95% [CI] = 1.68-14.89; p = 0.004 and OR = 4.06, 95% [CI] = 1.39-11.88; p = 0.010). In Europeans, variants in nAChRs associate with an accelerated lung function decline in current smokers and with clinically relevant COPD. [ABSTRACT FROM AUTHOR]

Abstract: 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 β2-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. [Copyright &y& Elsevier]

Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how genome-wide microRNA expression is altered with regional emphysema severity and how these microRNAs regulate disease-associated gene expression networks. Methods We profiled microRNAs in different regions of the lung with varying degrees of emphysema from 6 smokers with COPD and 2 controls (8 regions × 8 lungs = 64 samples). Regional emphysema severity was quantified by mean linear intercept. Whole genome microRNA and gene expression data was integrated in the same samples to build co-expression networks. Candidate microRNA were perturbed in human lung fibroblasts in order to validate these networks. Results The expression levels of 63 microRNAs (p < 0.05) were altered with regional emphysema. A subset, including miR-638, miR-30c, and miR-181d, had expression levels that were associated with those of their predicted mRNA targets. Genes correlated with these microRNAs were enriched in pathways associated with emphysema pathophysiology (e.g. oxidative stress and accelerated aging). Inhibition of miR-638 expression in lung fibroblasts led to modulation of these same emphysema-related pathways. Gene targets of miR-638 in these pathways were amongst those negatively correlated with miR-638 expression in emphysema. Conclusions Our findings demonstrate that microRNAs are altered with regional emphysema severity and modulate disease-associated gene expression networks. Furthermore, miR-638 may regulate gene expression pathways related to the oxidative stress response and aging in emphysematous lung tissue and lung fibroblasts. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. Methods: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions × 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. Results: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGFβ) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGFβ pathway activation. Treatment of human fibroblasts with GHK recapitulated TGFβ-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin β1. Furthermore, addition of GHK or TGFβ restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. Conclusions: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual's lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGFβ and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression. [ABSTRACT FROM AUTHOR]

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 FEV1 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 rs1 1938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV1 level. Eleven out of 17 SNPs were associated with FEV1 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. [ABSTRACT FROM AUTHOR]

Background: Frequent exacerbations induce a high burden to Chronic Obstructive Pulmonary Disease (COPD). We investigated the course of exacerbations in the published COSMIC study that investigated the effects of 1-year withdrawal of fluticasone after a 3-month run-in treatment period with salmeterol/fluticasone in patients with COPD. Methods: In 373 patients, we evaluated diary cards for symptoms, Peak Expiratory Flow (PEF), and salbutamol use and assessed their course during exacerbations. Results: There were 492 exacerbations in 224 patients. The level of symptoms of cough, sputum, dyspnea and nocturnal awakening steadily increased from 2 weeks prior to exacerbation, with a sharp rise during the last week. Symptoms of cough, sputum, and dyspnea reverted to baseline values at different rates (after 4, 4, and 7 weeks respectively), whereas symptoms of nocturnal awakening were still increased after eight weeks. The course of symptoms was similar around a first and second exacerbation. Increases in symptoms and salbutamol use and decreases in PEF were associated with a higher risk to develop an exacerbation, but with moderate predictive values, the areas under the receiver operating curves ranging from 0.63 to 0.70. Conclusions: Exacerbations of COPD are associated with increased symptoms that persist for weeks and the course is very similar between a first and second exacerbation. COPD exacerbations are preceded by increased symptoms and salbutamol use and lower PEF, yet predictive values are too low to warrant daily use in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Cigarette smoke, the major risk factor for COPD, is known to activate matrix metalloproteinases in airway epithelium. We investigated whether metalloproteinases, particularly A Disintegrin and Metalloproteinase (ADAM)17, contribute to increased pro-inflammatory epithelial responses with respect to the release of IL-8 and TGF-α, cytokines implicated in COPD pathogenesis.Methods: We studied the effects of cigarette smoke extract (CSE) and metalloproteinase inhibitors on TGF-α and IL-8 release in primary bronchial epithelial cells (PBECs) from COPD patients, healthy smokers and non-smokers.Results: We observed that TGF-α was mainly shed by ADAM17 in PBECs from all groups. Interestingly, IL-8 production occurred independently from ADAM17 and TGF-α shedding, but was significantly inhibited by broad-spectrum metalloproteinase inhibitor TAPI-2. CSE did not induce ADAM17-dependent TGF-α shedding, while it slightly augmented the production of IL-8. This was accompanied by reduced endogenous inhibitor of metalloproteinase (TIMP)-3 levels, suggesting that CSE does not directly but rather indirectly alter activity of ADAM17 through the regulation of its endogenous inhibitor. Furthermore, whereas baseline TGF-α shedding was lower in COPD PBECs, the early release of IL-8 (likely due to its shedding) was higher in PBECs from COPD than healthy smokers. Importantly, this was accompanied by lower TIMP-2 levels in COPD PBECs, while baseline TIMP-3 levels were similar between groups.Conclusions: Our data indicate that IL-8 secretion is regulated independently from ADAM17 activity and TGF-α shedding and that particularly its early release is differentially regulated in PBECs from COPD and healthy smokers. Since TIMP-2-sensitive metalloproteinases could potentially contribute to IL-8 release, these may be interesting targets to further investigate novel therapeutic strategies in COPD. [ABSTRACT FROM AUTHOR]

The article discusses small airway disease in patients with asthma and chronic obstructive pulmonary disease (COPD). COPD and asthma are diseases that may be both characterized by an inflammatory process or airway obstruction. The inflammatory process has the tendency to have an impact on a patient's entire respiratory tract.

Objective. Many studies evaluated asthma medication use in children in a cross-sectional manner, yet little is known about longitudinal use patterns. This study describes the formation of a longitudinal data set on asthma medication use and shows first results regarding the prevalence and incidence of medication use. Methods. The PIAMA (Prevention and Incidence of Asthma and Mite Allergy) study is a prospective birth cohort study among 3963 Dutch children. Recruitment took place in 1996–1997. The data of the PIAMA birth cohort study were complemented with pharmacy data. Prescription information of family members was used to determine whether medication histories were complete from birth until age 8. The prevalence and incidence of asthma medication use was studied in children for whom complete medication histories were available. Results. A first prescription for asthma medication was filled before age 8 by 280 (36%) children, with 88% starting therapy before age 5. Of all children who started therapy, 91.1% received short-acting β2-agonists and 61.1% inhaled corticosteroids. Conclusion. The applied method of data collection rendered a data set including 777 children with complete medication histories for their first 8 years of life. This data set provides the opportunity to study longitudinal medication use patterns. First analyses show that asthma medication is initiated in a rather high percentage of children in this cohort and mainly at an age at which an asthma diagnosis cannot yet be firmly established. [ABSTRACT FROM AUTHOR]

Background: Multidrug resistance-associated protein-1 (MRP1) protects against oxidative stress and toxic compounds generated by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (COPD). We have previously shown that single nucleotide polymorphisms (SNPs) in MRP1 significantly associate with level of FEV1 in two independent population based cohorts. The aim of our study was to assess the associations of MRP1 SNPs with FEV1 level, MRP1 protein levels and inflammatory markers in bronchial biopsies and sputum of COPD patients. Methods: Five SNPs (rs212093, rs4148382, rs504348, rs4781699, rs35621) in MRP1 were genotyped in 110 COPD patients. The effects of MRP1 SNPs were analyzed using linear regression models. Results: One SNP, rs212093 was significantly associated with a higher FEV1 level and less airway wall inflammation. Another SNP, rs4148382 was significantly associated with a lower FEV1 level, higher number of inflammatory cells in induced sputum and with a higher MRP1 protein level in bronchial biopsies. Conclusions: This is the first study linking MRP1 SNPs with lung function and inflammatory markers in COPD patients, suggesting a role of MRP1 SNPs in the severity of COPD in addition to their association with MRP1 protein level in bronchial biopsies. [ABSTRACT FROM AUTHOR]

Background: Inhaled corticosteroids (ICSs) and long-acting β2- agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) Setting: 2 university medical centers in The Netherlands. Patients: 114 steroid-naive current or former smokers with moderate to severe COPD. Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 μg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 μg twice daily, and salmeterol, 50 μg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3μ cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4μ cells (-78% [CI, -88% to 60%]; P = 0.001), CD8μ cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV1 decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3+ cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV1 level. Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. Primary Funding Source: Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of The Netherlands, University Medical Center Groningen, and Leiden University Medical Center. [ABSTRACT FROM AUTHOR]

In this article the authors comment on the large variation of definitions of chronic obstructive pulmonary disease (COPD) exacerbations. They say that the definition of a COPD exacerbation has an impact on the effect size of interventions. They emphasize the need for concerted attempts to reach an agreement on its definition. They stress that the exact definition to be used in the study should be specified in the protocol.

Systemic corticosteroids and additional short-acting ββ2-agonists are commonly used in exacerbations of chronic obstructive pulmonary disease (COPD). In this double-blind study, the combination of a high-dose inhaled corticosteroid with a rapid-onset long-acting ββ2-agonist was evaluated in the treatment of out-patient COPD exacerbations. The primary aim was to compare 14-day treatment effects of budesonide/formoterol to placebo on sputum eosinophils and, secondarily, on other indices of inflammation, forced expiratory flow in one second (FEV1), symptoms, health status, and adverse events. Forty-five patients not using steroids (37 male, 21/24 current/ex smoker, median packyears 38, age 65 years, FEV1 61% predicted), experiencing a COPD exacerbation, were treated at home with budesonide/formoterol (320/9 μg 4 times daily), prednisolone (30 mg daily), or placebo for 14 days. Sputum eosinophils were significantly reduced by budesonide/formoterol (-57%) compared to placebo (+24%) (p = 0.01). Budesonide/formoterol reduced total symptom scores significantly (p = 0.01) compared to placebo. The increase in FEV1 by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p = 0.07). Budesonide/ formoterol treatment did not suppress morning serum cortisol compared to placebo (-16 %; p = 0.50). In conclusion, budesonide/formoterol reduces sputum eosinophils and improves symptoms in the treatment of out-patient COPD exacerbations. [ABSTRACT FROM AUTHOR]

The article presents a study on the risk factor for chronic obstructive pulmonary disease (COPD) exacerbations. COPD is characterized by episodic increases in respiratory symptoms called exacerbations. It is associated with an increase in local and systemic inflammation. The study demonstrates that besides lung function impairment, systemic inflammation manifested by elevated fibrinogen levels is an independent risk factor for exacerbations of COPD.

Cigarette smoke is the most important cause for the development of chronic obstructive pulmonary disease (COPD). Since only a minority of smokers and some nonsmokers develop COPD, other factors must be involved as well. NO2 is an important air pollutant associated with respiratory symptoms in humans and emphysema development in animal models. We hypothesized that combined exposure to NO2 and cigarette smoke will enhance pulmonary inflammation and emphysema development. Mice were exposed to 20 ppm NO2 for 17 h/day, to 24 puffs of cigarette smoke 2 times per day, to their combination, or to control air for 5 days/wk during 4 wk. Following the last NO2 exposure and within 24 h after the last smoke exposure the mice were sacrificed. Lungs were removed and analyzed for several inflammatory parameters and emphysema. Cigarette smoke exposure increased eosinophil numbers and levels of tumor necrosis factor (TNF)-α, KC, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6. NO2 exposure increased goblet cells, eosinophils, and the levels of IL-6, while it decreased the levels of IL-10. Four weeks of NO2, cigarette smoke, or their combination was not sufficient to induce significant emphysema, nor did it lead to increased numbers of lymphocytes, neutrophils, or macrophages in lung tissue. Instead, NO2 exposure attenuated the smoke-induced increases in levels of TNF-α, KC, and MCP-1. These dampening effects of NO2 may be due to modulating effects of NO2 on cytokine production by macrophages and epithelial cells, which have been reported earlier. The next step is to translate these findings of combined, controlled exposure in animals to the human situation. [ABSTRACT FROM AUTHOR]

Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by defective extracellular matrix (ECM) turnover as a result of prolonged cigarette smoking. Fibroblasts have a central role in ECM turnover. The TGFβ induced Smad pathway provides intracellular signals to regulate ECM production. We address the following hypothesis: fibroblasts have abnormal expression of genes in the Smad pathway in COPD, resulting in abnormal proteoglycan modulation, the ground substance of ECM. Methods: We compared gene expression of the Smad pathway at different time points after stimulation with TGFβ, TNF or cigarette smoke extract (CSE) in pulmonary fibroblasts of GOLD stage II and IV COPD patients, and controls. Results: Without stimulation, all genes were similarly expressed in control and COPD fibroblasts. TGFβ stimulation: downregulation of Smad3 and upregulation of Smad7 occurred in COPD and control fibroblasts, indicating a negative feedback loop upon TGFβ stimulation. CSE hardly influenced gene expression of the TGFβ-Smad pathway in control fibroblasts, whereas it reduced Smad3 and enhanced Smad7 gene expression in COPD fibroblasts. Furthermore, decorin gene expression decreased by all stimulations in COPD but not in control fibroblasts. Conclusion: Fibroblasts of COPD patients and controls differ in their regulation of the Smad pathway, the contrast being most pronounced under CSE exposure. This aberrant responsiveness of COPD fibroblasts to CSE might result in an impaired tissue repair capability and is likely important with regard to the question why only a subset of smokers demonstrates an excess ECM destruction under influence of cigarette smoking. [ABSTRACT FROM AUTHOR]

Background: In asthma, higher chymase positive mast cell (MC-C) numbers are associated with less airway obstruction. In COPD, the distribution of MC-C and tryptase positive mast cells (MC-T) in central and peripheral airways, and their relation with lung function, is unknown. We compared MC-T and MC-C distributions in COPD and controls without airflow limitation, and determined their relation with lung function. Methods: Lung tissue sections from 19 COPD patients (median [interquartile range] FEV1% predicted 56 [23-75]) and 10 controls were stained for tryptase and chymase. Numbers of MC-T and MC-C were determined in different regions of central and peripheral airways and percentage of degranulation was determined. Results: COPD patients had lower MC-T numbers in the subepithelial area of central airways than controls. In COPD, MC-T numbers in the airway wall and more specifically in the epithelium and subepithelial area of peripheral airways correlated positively with FEV1/VC (Spearman's rho (rs) 0.47, p = 0.05 and rs 0.48, p = 0.05, respectively); MC-C numbers in airway smooth muscle of peripheral airways correlated positively with FEV1% predicted (rs 0.57, p = 0.02). Both in COPD patients and controls the percentage of degranulated MC-T and MC-C mast cells was higher in peripheral than in central airways (all p < 0.05), but this was not different between the groups. Conclusion: More MC-T and MC-C in peripheral airways correlate with better lung function in COPD patients. It is yet to determine whether this reflects a protective association of mast cells with COPD pathogenesis, or that other explanations are to be considered. [ABSTRACT FROM AUTHOR]

The article presents a study which demonstrates that therapy with oral prednisolone is not inferior with intravenous (IV) prednisolone in treating chronic obstructive pulmonary disease exacerbations with the use of a double-blind, double-dummy design. A total of 435 patients were referred for an exacerbation warranting hospitalization, wherein 107 patients received IV therapy and 103 received oral therapy. It concludes that therapy with oral prednisolone is not inferior to IV treatment.

Background: There is controversy about whether therapy with inhaled corticosteroids (ICSs) modifies the natural history of COPD, characterized by an accelerated decline in FEV(1).Methods: The Inhaled Steroids Effect Evaluation in COPD (ISEEC) study is a pooled study of patient-level data from seven long-term randomized controlled trials of ICS vs placebo lasting >/= 12 months in patients with moderate-to-severe COPD. We have previously reported a survival benefit for ICS therapy in COPD patients using ISEEC data. We aimed to determine whether the regular use of ICSs vs placebo improves FEV(1) decline in COPD patients, and whether this relationship is modified by gender and smoking.Results: There were 3,911 randomized participants (29.2% female) in this analysis. In the first 6 months after randomization, ICS use was associated with a significant mean (+/- SE) relative increase in FEV(1) of 2.42 +/- 0.19% compared with placebo (p < 0.01), which is quantifiable in absolute terms as 42 mL in men and 29 mL in women over 6 months. From 6 to 36 months, there was no significant difference between placebo and ICS therapy in terms of FEV(1) decline (-0.01 +/- 0.09%; p = 0.86). The initial treatment effect was dependent on smoking status and gender. Smokers who continued to smoke had a smaller increase in FEV(1) during the first 6 months than did ex-smokers. Female ex-smokers had a larger increase in FEV(1) with ICS therapy than did male ex-smokers.Conclusions: We conclude that in COPD in the first 6 months of treatment, ICS therapy is more effective in ex-smokers than in current smokers with COPD in improving lung function, and women may have a bigger response to ICSs than men. However, it seems that after 6 months, ICS therapy does not modify the decline in FEV(1) among those who completed these randomized clinical trials. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with increasing prevalence and mortality. It is associated with airway obstruction, increased airway hyper-responsiveness (AHR), and ongoing airway and lung inflammation dominated by CD8 lymphocytes and neutrophils. Single- nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene have been associated with AHR and COPD. Objective: To assess whether SNPs in ADAM33 are associated with the severity of AHR and airway inflammation in COPD. Methods: Eight SNPs in ADAM33 (F+1, Q-1, S̱1, S̱2, ST+5, Ṯ1, Ṯ2, V̱4) were genotyped in 11 patients with COPD (96 males, 69 current smokers, mean (standard deviation (SD)), aged 62 (8) years, median pack-years 42 (IQR 31-55), mean postbronchodilator forced expiratory volume in i s (FEV1)% predicted 63 (9). Provocative concentration of methacholine causing a decrease in FEV1 of 20% (PC20 methacholine), sputum and bronchial biopsies were collected. Results: Patients with the ST+5 AA genotype had more severe AHR, higher numbers of sputum inflammatory cells and CD8 cells in bronchial biopsies than patients with the GG genotype (p=0.03, 0.05 and 0.01, respectively). CD8 cell numbers were lower in patients carrying the minor allele of SNP Ṯ1 and Ṯ2, and homozygotic minor variants of SNP S̱2 compared with the wild type (p = 0.02, 0.01 and 0.02, respectively). Conclusions: This is the first study revealing that SNPs in a gene that confers susceptibility to COPD in the general population—that is, ADAM33—are associated with AHR and airway inflammation in COPD. These findings constitute an important step forward in linking gene polymorphisms with COPD pathophysiology, thereby possibly contributing to better treatments for this progressive and disabling disease in the future. [ABSTRACT FROM AUTHOR]

The article assess the safety of sputum induction (SI) during the chronic obstructive pulmonary disease (COPD) exacerbations. The research concluded that SI can be safety carried out in patients with mild-to-moderate COPD who experience an exacerbation. The only independent association was with the larger decrease in FEV1 in the stable phase in a multivariate analysis.

Adenosine is a naturally occurring purine nucleoside with a ubiquitous presence in human tissue, where it plays a key role in many biological processes such as energy generation and protein metabolism. It has been shown that adenosine induces bronchoconstriction in asthmatic and chronic obstructive pulmonary disease (COPD) patients, but not in normal airways. Four different G-protein-coupled adenosine receptors have been described, namely adenosine A1, A2A, A2B and A3 receptors. The main mechanism of adenosine-induced bronchoconstriction appears to involve the release of inflammatory mediators from mast cells via activation of the A2B receptor. However, adenosine can also act on A1, A2A and A3 receptors. In recent years there has been an increasing interest in the role of adenosine receptors in asthma and COPD, since it is now clear that they play an important role in the pathophysiology of asthma and COPD. Adenosine receptors are involved in the production and release of a variety of mediators from inflammatory and structural cells. A therapeutic potential for adenosine receptor modulation has even been anticipated. This review focuses on the role of adenosine and adenosine receptors in the treatment of asthma and COPD. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, bronchoalveolar lavage (BAL) and induced sputum in chronic obstructive pulmonary disease patients. The results of the single-breath N2 test are associated with neutrophilic inflammation in bronchial biopsies and BAL.

Background: Chronic Obstructive Pulmonary Disease (COPD) is associated with bronchial epithelial changes, including squamous cell metaplasia and goblet cell hyperplasia. These features are partially attributed to activation of the epidermal growth factor receptor (EGFR). Whereas smoking cessation reduces respiratory symptoms and lung function decline in COPD, inflammation persists. We determined epithelial proliferation and composition in bronchial biopsies from current and ex-smokers with COPD, and its relation to duration of smoking cessation. Methods: 114 COPD patients were studied cross-sectionally: 99 males/15 females, age 62 ± 8 years, median 42 pack-years, no corticosteroids, current (n = 72) or ex-smokers (n = 42, median cessation duration 3.5 years), postbronchodilator FEV1 63 ± 9% predicted. Squamous cell metaplasia (%), goblet cell (PAS/Alcian Blue+) area (%), proliferating (Ki-67+) cell numbers (/mm basement membrane), and EGFR expression (%) were measured in intact epithelium of bronchial biopsies. Results: Ex-smokers with COPD had significantly less epithelial squamous cell metaplasia, proliferating cell numbers, and a trend towards reduced goblet cell area than current smokers with COPD (p = 0.025, p = 0.001, p = 0.081, respectively), but no significant difference in EGFR expression. Epithelial features were not different between short-term quitters (<3.5 years) and current smokers. Long-term quitters (≥3.5 years) had less goblet cell area than both current smokers and short-term quitters (medians: 7.9% vs. 14.4%, p = 0.005; 7.9% vs. 13.5%, p = 0.008; respectively), and less proliferating cell numbers than current smokers (2.8% vs. 18.6%, p < 0.001). Conclusion: Ex-smokers with COPD had less bronchial epithelial remodelling than current smokers, which was only observed after long-term smoking cessation (>3.5 years). Trial registration: NCT00158847 [ABSTRACT FROM AUTHOR]