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Expression of Genes Involved in Oxidative Stress Responses in Airway Epithelial Cells of Smokers with Chronic Obstructive Pulmonary Disease

Stefan Pierrou¹, Per Broberg¹, Rory A. O'Donnell², Krzysztof Pawowski¹, Robert Virtala¹, Eva Lindqvist¹, Audrey Richter², Susan J. Wilson², Gilbert Angco², Sebastian Möller¹, Håkan Bergstrand¹, Witte Koopmann¹, Elisabet Wieslander¹, Per-Erik Strömstedt¹, Stephen T. Holgate², Donna E. Davies², Johan Lund¹ and Ratko Djukanovic²

¹ AstraZeneca R&D, Department of Biological Sciences, Lund, Sweden; and ² Allergy and Inflammation Research, Division of Infection, Inflammation, and Repair, University of Southampton, Southampton University General Hospital, Southampton, United Kingdom

Correspondence and requests for reprints should be addressed to Per Broberg, Ph.D., Associate Principal Scientist, AstraZeneca R&D Lund, S221 87 Lund, Sweden. E-mail: per.broberg{at}astrazeneca.com

Rationale: The molecular mechanisms involved in airway oxidative stress responses reported in healthy smokers and in those with chronic obstructive pulmonary disease (COPD) are poorly understood.

Objectives: To assess the expression of genes involved in oxidative stress responses in the bronchial epithelium of smokers with or without COPD and in relation to disease severity.

Methods: Global gene expression was assessed in bronchial brushings in 38 subjects with COPD, 14 healthy nonsmokers, and 18 healthy smokers.

Results: Gene expression analysis using Affymetrix arrays revealed mRNAs representing 341 out of 642 oxidative stress genes from two predefined gene sets to be differentially expressed in healthy nonsmokers when compared with healthy smokers, and 200 differentially expressed oxidative genes in subjects with COPD when compared with healthy smokers. Gene set enrichment analysis showed that pathways involved in oxidant/antioxidant responses were among the most differentially expressed gene pathways in smoking individuals, with further differences seen in COPD. Distinct, nonlinear gene expression patterns were identified across the severity spectrum of COPD, which correlated with the presence of certain transcription factor binding sites in their promoters. Significant changes in oxidant response genes observed in vivo were reproduced in vitro using primary bronchial epithelial cells from the same donors cultured at an air–liquid interface and exposed to cigarette smoke extract.

Conclusions: Cigarette smoke induces significant changes in oxidant defense responses; some of these are further amplified, but not in a linear fashion, in individuals who develop COPD.

Key Words: pulmonary disease, chronic obstructive • oligonucleotide array sequence analysis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Knowledge on gene expression profiles of the bronchial epithelium of COPD patients has been limited, particularly with respect to oxidative stress responses. What This Study Adds to the Field This study identifies a set of oxidative stress response genes expressed in the bronchial epithelium in COPD as well as transcription factors involved in their regulation.

 

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