Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity

+Author Affiliations

¹Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
²GRIAC (Groningen Research Institute for Asthma and COPD), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
³Division of Computational Biomedicine, Department of medicine, Boston University School of Medicine, Boston, Massachusetts, USA
⁴Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
⁵Department of Pulmonary Diseases, Leiden University Medical Center, Leiden, The Netherlands
⁶Department of Respiratory Medicine, F5-259, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
⁷Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, USA

Correspondence toDr M van den Berge, Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen 9700 RB, The Netherlands;m.van.den.berge@umcg.nl

Received 16 October 2012
Revised 4 June 2013
Accepted 30 June 2013
Published Online First 7 August 2013

Abstract

Background A core feature of chronic obstructive pulmonary disease (COPD) is the accelerated decline in forced expiratory volume in one second (FEV₁). The recent Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD) study suggested that particular phenotypes of COPD benefit from fluticasone±salmeterol by reducing the rate of FEV₁ decline, yet the underlying mechanisms are unknown.

Methods Whole-genome gene expression profiling using the Affymetrix Gene ST array (V.1.0) was performed on 221 bronchial biopsies available from 89 COPD patients at baseline and after 6 and 30 months of fluticasone±salmeterol and placebo treatment in GLUCOLD.

Results Linear mixed effects modelling revealed that the expression of 138 genes decreased, whereas the expression of 140 genes significantly upregulated after both 6 and 30 months of treatment with fluticasone±salmeterol versus placebo. A more pronounced treatment-induced change in the expression of 50 and 55 of these 278 genes was associated with a lower rate of decline in FEV₁ and Saint George Respiratory Questionnaire, respectively. Genes decreasing with treatment were involved in pathways related to cell cycle, oxidative phosphorylation, epithelial cell signalling, p53 signalling and T cell signalling. Genes increasing with treatment were involved in pathways related to focal adhesion, gap junction and extracellular matrix deposition. Finally, the fluticasone-induced gene expression changes were enriched among genes that change in the airway epithelium in smokers with versus without COPD in an independent data set.

Conclusions 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 molecular phenotype-driven therapy of COPD.

This Article

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