Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity.
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.
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, , Groningen, The Netherlands.
Maarten
M
van den Berge
Katrina
K
Steiling
Wim
W
Timens
Pieter S
PS
Hiemstra
Peter J
PJ
Sterk
Irene H
IH
Heijink
Gang
G
Liu
Yuriy O
YO
Alekseyev
Marc E
ME
Lenburg
Avrum
A
Spira
Dirkje S
DS
Postma
D000368:Aged; D000420:Albuterol / Q000031:analogs & derivatives / Q000627:therapeutic use; D000730:Androstadienes / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D000068298:Fluticasone; D005541:Forced Expiratory Volume / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D000068299:Salmeterol Xinafoate; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D000420:Albuterol
COPD ÀÜ Mechanisms