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

TitleA dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment.
Publication TypeJournal Article
Year of Publication2013
AuthorsSteiling, K, van den Berge, M, Hijazi, K, Florido, R, Campbell, J, Liu, G, Xiao, J, Zhang, X, Duclos, G, Drizik, E, Si, H, Perdomo, C, Dumont, C, Coxson, HO, Alekseyev, YO, Sin, D, Paré, P, Hogg, JC, McWilliams, A, Hiemstra, PS, Sterk, PJ, Timens, W, Chang, JT, Sebastiani, P, O'Connor, GT, Bild, AH, Postma, DS, Lam, S, Spira, A, Lenburg, ME
JournalAm J Respir Crit Care Med
Volume187
Issue9
Pagination933-42
Date Published2013 May 1
ISSN1535-4970
KeywordsActivating Transcription Factor 4, Aged, Analysis of Variance, Androstadienes, Bronchi, Bronchodilator Agents, Bronchoscopy, Epithelial Cells, Female, Humans, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive, Real-Time Polymerase Chain Reaction, Respiratory Function Tests, Smoking, Transcriptome
Abstract

RATIONALE: 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.

OBJECTIVES: We sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy.

METHODS: Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays.

MEASUREMENTS AND MAIN RESULTS: We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified activating transcription factor 4 (ATF4) as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline after therapy with the inhaled corticosteroid fluticasone in independent cohorts.

CONCLUSIONS: Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD.

DOI10.1164/rccm.201208-1449OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID23471465
PubMed Central IDPMC3707363
Grant List1R01 HL095388 / HL / NHLBI NIH HHS / United States
KL2RR025770 / RR / NCRR NIH HHS / United States
N01-CN 35000 / CN / NCI NIH HHS / United States
P01 CA096964-01A1 / CA / NCI NIH HHS / United States
R01 GM085601 / GM / NIGMS NIH HHS / United States
U01CA96109 / CA / NCI NIH HHS / United States