Volume Reduction Surgery Modification in COPD: Lessons From Lung Change in the BODE Index Reflects Disease

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Comorbidities of patients in tiotropium clinical trials : comparison with observational studies of patients with chronic obstructive pulmonary disease

Acknowledgments The authors are fully responsible for all content and editorial decisions made, were involved at all stages of manuscript development, and have approved the final version for publication. Editorial assistance, supported financially by Boehringer Ingelheim and Pfizer, was provided by Godfrey Lisk of PAREXEL International during the preparation of this manuscript. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution - Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited.Peer reviewedPublisher PD

COPD as an endothelial disorder: endothelial injury linking lesions in the lungs and other organs? (2017 Grover Conference Series)

Chronic obstructive pulmonary disease (COPD) is characterized by chronic expiratory airflow obstruction that is not fully reversible. COPD patients develop varying degrees of emphysema, small and large airway disease, and various co-morbidities. It has not been clear whether these co-morbidities share common underlying pathogenic processes with the pulmonary lesions. Early research into the pathogenesis of COPD focused on the contributions of injury to the extracellular matrix and pulmonary epithelial cells. More recently, cigarette smoke-induced endothelial dysfunction/injury have been linked to the pulmonary lesions in COPD (especially emphysema) and systemic co-morbidities including atherosclerosis, pulmonary hypertension, and chronic renal injury. Herein, we review the evidence linking endothelial injury to COPD, and the pathways underlying endothelial injury and the “vascular COPD phenotype” including: (1) direct toxic effects of cigarette smoke on endothelial cells; (2) generation of auto-antibodies directed against endothelial cells; (3) vascular inflammation; (4) increased oxidative stress levels in vessels inducing increases in lipid peroxidation and increased activation of the receptor for advanced glycation end-products (RAGE); (5) reduced activation of the anti-oxidant pathways in endothelial cells; (6) increased endothelial cell release of mediators with vasoconstrictor, pro-inflammatory, and remodeling activities (endothelin-1) and reduced endothelial cell expression of mediators that promote vasodilation and homeostasis of endothelial cells (nitric oxide synthase and prostacyclin); and (7) increased endoplasmic reticular stress and the unfolded protein response in endothelial cells. We also review the literature on studies of drugs that inhibit RAGE signaling in other diseases (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), or vasodilators developed for idiopathic pulmonary arterial hypertension that have been tested on cell culture systems, animal models of COPD, and/or smokers and COPD patients

Altered Gene Expression in Blood and Sputum in COPD Frequent Exacerbators in the ECLIPSE Cohort

Patients with chronic obstructive pulmonary disease (COPD) who are defined as frequent exacerbators suffer with 2 or more exacerbations every year. The molecular mechanisms responsible for this phenotype are poorly understood. We investigated gene expression profile patterns associated with frequent exacerbations in sputum and blood cells in a well-characterised cohort. Samples from subjects from the ECLIPSE COPD cohort were used; sputum and blood samples from 138 subjects were used for microarray gene expression analysis, while blood samples from 438 subjects were used for polymerase chain reaction (PCR) testing. Using microarray, 150 genes were differentially expressed in blood (>±1.5 fold change, p≤0.01) between frequent compared to non-exacerbators. In sputum cells, only 6 genes were differentially expressed. The differentially regulated genes in blood included downregulation of those involved in lymphocyte signalling and upregulation of pro-apoptotic signalling genes. Multivariate analysis of the microarray data followed by confirmatory PCR analysis identified 3 genes that predicted frequent exacerbations; B3GNT, LAF4 and ARHGEF10. The sensitivity and specificity of these 3 genes to predict the frequent exacerbator phenotype was 88% and 33% respectively. There are alterations in systemic immune function associated with frequent exacerbations; down-regulation of lymphocyte function and a shift towards pro-apoptosis mechanisms are apparent in patients with frequent exacerbations

Comparison of arterial and venous blood biomarker levels in chronic obstructive pulmonary disease

Purpose: The development of novel biomarkers is an unmet need in chronic obstructive pulmonary disease (COPD). Arterial blood comes directly from the lung and venous blood drains capillary beds of the organ or tissue supplied. We hypothesized that there would be a difference in levels of the biomarkers metalloproteinase 9 (MMP-9), vascular endothelial growth factor A (VEGF-A) and interleukin 6 (IL-6) in arterial compared with venous blood. Methods: Radial artery and brachial vein blood samples were taken simultaneously in each of 12 patients with COPD and seven controls with normal lung function. Circulating immunoreactive MMP-9, VEGF-A and IL-6 levels in serum were measured using quantitative enzyme-linked immunosorbent assays. Results were compared using a Student’s paired t test. The study was powered to determine whether significant differences in cytokine levels were present between paired arterial and venous blood samples. Results: In the 12 patients with COPD, four were female, and age ranged 53-85 years, mean age 69 years. Three patients in the control group were female, with age range 46-84 years, mean age 64.7 years. In the COPD group, three patients had mild, five moderate and four severe COPD. No significant difference was found between arterial and venous levels of MMP-9, VEGF-A or IL-6. Conclusions: In this pilot study, levels of the measured biomarkers in arterial compared with venous blood in both COPD patients and healthy controls did not differ. This suggests that as we continue to chase the elusive biomarker in COPD as a potential tool to measure disease activity, we should focus on venous blood for this purpose

Comparison of arterial and venous blood biomarker levels in chronic obstructive pulmonary disease

Purpose: The development of novel biomarkers is an unmet need in chronic obstructive pulmonary disease (COPD). Arterial blood comes directly from the lung and venous blood drains capillary beds of the organ or tissue supplied. We hypothesized that there would be a difference in levels of the biomarkers metalloproteinase 9 (MMP-9), vascular endothelial growth factor A (VEGF-A) and interleukin 6 (IL-6) in arterial compared with venous blood. Methods: Radial artery and brachial vein blood samples were taken simultaneously in each of 12 patients with COPD and seven controls with normal lung function. Circulating immunoreactive MMP-9, VEGF-A and IL-6 levels in serum were measured using quantitative enzyme-linked immunosorbent assays. Results were compared using a Student’s paired t test. The study was powered to determine whether significant differences in cytokine levels were present between paired arterial and venous blood samples. Results: In the 12 patients with COPD, four were female, and age ranged 53-85 years, mean age 69 years. Three patients in the control group were female, with age range 46-84 years, mean age 64.7 years. In the COPD group, three patients had mild, five moderate and four severe COPD. No significant difference was found between arterial and venous levels of MMP-9, VEGF-A or IL-6. Conclusions: In this pilot study, levels of the measured biomarkers in arterial compared with venous blood in both COPD patients and healthy controls did not differ. This suggests that as we continue to chase the elusive biomarker in COPD as a potential tool to measure disease activity, we should focus on venous blood for this purpose

Tiotropium reduces risk of exacerbations irrespective of previous use of inhaled anticholinergics in placebo-controlled clinical trials

Data have highlighted the potential bias introduced by withdrawal of inhaled corticosteroids at randomization in chronic obstructive pulmonary disease trials examining inhaled corticosteroids. Analyses were conducted to determine whether this was true of inhaled anticholinergic withdrawal in tiotropium trials.status: publishe

Sexually-dimorphic targeting of functionally-related genes in COPD

Background: There is growing evidence that many diseases develop, progress, and respond to therapy differently in men and women. This variability may manifest as a result of sex-specific structures in gene regulatory networks that influence how those networks operate. However, there are few methods to identify and characterize differences in network structure, slowing progress in understanding mechanisms driving sexual dimorphism. Results: Here we apply an integrative network inference method, PANDA (Passing Attributes between Networks for Data Assimilation), to model sex-specific networks in blood and sputum samples from subjects with Chronic Obstructive Pulmonary Disease (COPD). We used a jack-knifing approach to build an ensemble of likely networks for each sex. By adapting statistical methods to compare these network ensembles, we were able to identify strong differential-targeting patterns associated with functionally-related sets of genes, including those involved in mitochondrial function and energy metabolism. Network analysis also identified several potential sex- and disease-specific transcriptional regulators of these pathways. Conclusions: Network analysis yielded insight into potential mechanisms driving sexual dimorphism in COPD that were not evident from gene expression analysis alone. We believe our ensemble approach to network analysis provides a principled way to capture sex-specific regulatory relationships and could be applied to identify differences in gene regulatory patterns in a wide variety of diseases and contexts. Electronic supplementary material The online version of this article (doi:10.1186/s12918-014-0118-y) contains supplementary material, which is available to authorized users

A post hoc pooled analysis of exacerbations among US participants in randomized controlled trials of tiotropium

SummaryBackgroundExacerbations are a defining outcome of chronic obstructive pulmonary disease (COPD). We evaluated the effect of tiotropium on COPD exacerbations and related hospitalizations among patients from the USA enrolled in clinical trials.MethodsData were pooled from six randomized, double-blind, placebo-controlled trials (6 to ≥12 months' duration) of tiotropium in patients with COPD. Exacerbations were defined retrospectively as an increase in or new onset of >1 respiratory symptom lasting for ≥3 days and requiring treatment with systemic corticosteroids and/or antibiotics. Time to first exacerbation or hospitalization and exacerbation rates were analyzed at 6 months, and at 1 year for studies ≥1 year.ResultsIn total, 4355 patients (tiotropium, 2268, placebo, 2087; mean age 66.5 years; forced expiratory volume in 1 s [FEV1] 1.03 L [35.5% predicted]) were analyzed at 6 months and 2455 at 1 year (tiotropium 1317, placebo 1138; mean age 65.5 years; FEV1 1.03 L [37.0% predicted]). Tiotropium delayed time to first exacerbation or first hospitalized exacerbation at 6 months (hazard ratios [HRs], 0.80, 0.65, respectively; p < 0.001 vs placebo) and 1 year (HRs, 0.73 and 0.55; p < 0.001 vs placebo) and reduced exacerbation rates and hospitalization rates (6 months: HRs, 0.79, 0.64; 1 year: HRs, 0.78, 0.56, respectively; all p < 0.01 vs placebo). Tiotropium significantly reduced exacerbations, irrespective of inhaled corticosteroid use at baseline. Tiotropium was not associated with an increased risk of cardiac-related events.ConclusionsTiotropium significantly reduced the risk and rates of exacerbations and hospitalizations among US patients with COPD