Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Bronchial airway gene expression reflects a COPD-associated field of injury that changes with disease severity and is reversible with therapy

ABSTRACT: RNA was isolated from bronchial brushings obtained from current and former smokers with and without COPD. mRNA expression was profiled using Affymetrix Human Gene 1.0 ST Arrays. RNA isolated from bronchial brushings was processed and hybridized to Affymetrix Human Gene 1.0 ST Arrays. A total of 269 arrays from 267 subjects were hybridized. Data from the 269 microarrays were used for RMA normalization. Data from 238 subjects was used in the analysis to determine the association of gene expression with COPD-related phenotypes.

ORGANISM(S): Homo sapiens

SUBMITTER: Katrina Steiling

PROVIDER: E-GEOD-37147 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment.

Steiling Katrina K van den Berge Maarten M Hijazi Kahkeshan K Florido Roberta R Campbell Joshua J Liu Gang G Xiao Ji J Zhang Xiaohui X Duclos Grant G Drizik Eduard E Si Huiqing H Perdomo Catalina C Dumont Charles C Coxson Harvey O HO Alekseyev Yuriy O YO Sin Don D Pare Peter P Hogg James C JC McWilliams Annette A Hiemstra Pieter S PS Sterk Peter J PJ Timens Wim W Chang Jeffrey T JT Sebastiani Paola P O'Connor George T GT Bild Andrea H AH Postma Dirkje S DS Lam Stephen S Spira Avrum A Lenburg Marc E ME

American journal of respiratory and critical care medicine 20130501 9

<h4>Rationale</h4>Molecular phenotyping of chronic obstructive pulmonary disease (COPD) has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function.<h4>Objectives</h4>We sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy.<h4>Methods</h4>Gene expression profiling of bronchial brushings obtained from 238 current and former smokers w ...[more]

PMID: 23471465

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Project description:Introduction: In the recently completed Dutch GLUCOLD study, treatment of COPD patients with fluticasone ± salmeterol reduced the rate of decline in FEV1. These results indicate that ICS can have therapeutic efficacy in COPD. Aim: To explore the molecular mechanisms by which ICS exert their effects, we performed genome-wide gene expression profiling on bronchial biopsies from COPD patients who participated in the GLUCOLD study. Methods: An Affymetrix Human Gene Array ST version 1.0 was performed in a total of 221 bronchial biopsies that were available from 90 COPD patients at baseline and after 6 and 30 months of therapy. Linear mixed effects modeling was used to analyze treatment-specific changes in gene expression. A validation set was included and pathway analysis was performed with Gene Set Enrichment Analysis (GSEA). Results: The expression of 138 genes significantly decreased after both 6 and 30 months of treatment with fluticasone ± salmeterol versus placebo, whereas the expression of 140 genes increased. A more pronounced treatment-induced change in expression of 51 of these 278 genes was associated with a slower rate of decline in FEV1. Genes that decreased with treatment were involved in pathways related to cell cycle, oxidative phosphorylation, epithelial cell signaling, p53 signaling and T cell signaling. Genes that increased with treatment were involved in pathways related to focal adhesion, gap junction and extracellular matrix deposition. Conclusion: The present study suggests that gene expression in biological pathways of COPD is dynamic with treatment and reflects disease activity. This study opens the gate to targeted and phenotype-driven therapy of COPD. First, a total of 162 samples were analysed (RNA derived from bronchial biopsies from COPD patients before and after treatment with fluticasone +/- salmeterol or placebo [GLUCOLD study]), 107 samples before and after 6 and 30 months of treatment with fluticasone +/- salmeterol and 55 samples before and after treatment with placebo. A total of 278 genes were found that changed in expression after both 6 and 30 months of treatment with fluticasone +/- salmeterol versus placebo. Next, an additional number of 59 samples from the fouth GLUCOLD treatment were put on array. In this study arm, COPD patients were treated for 6 months with fluticasone and then fluticasone was discontinued and patients switched to placebo for the remaining 24 months of the study.

Project description: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 x 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 (TGF beta) 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 TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta 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 individualÂ¿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 TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression. Paired samples were obtained from 8 regions at regular intervals between the apex and base of each explanted lung from six patients with severe COPD and two donors. The degree of emphysematous destruction was quantified in one sample from each region by mean linear intercept (Lm), while gene expression was profiled in the adjacent sample from the same region using the Affymetrix Human Exon 1.0 ST GeneChip. Human fibroblast cell lines (HLF-1) were treated with GHK or TGF-Beta1 for 48 hours and profiled using the Affymetrix Human Gene 1.0 ST GeneChip.

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Dataset Information

Bronchial airway gene expression reflects a COPD-associated field of injury that changes with disease severity and is reversible with therapy

Publications

A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment.

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