Published ahead of print on December 7, 2006, doi:10.1164/rccm.200607-931OC
Am. J. Respir. Crit. Care Med., Volume 175, Number 6, March 2007, 577-586
A more recent version of this article appeared on March 15, 2007
Submitted on July 11, 2006
Accepted on December 5, 2006
Expression of Genes Involved in Oxidative Stress Responses in Airway Epithelial Cells of COPD Smokers
Stefan Pierrou1, Per Broberg1*, Rory O'Donnell2, Krzysztof Pawlowski1, Robert Virtala1, Eva Lindqvist1, Audrey Richter2, Susan Wilson2, Gilbert Angco2, Sebastian Moller1, Hakan Bergstrand1, Witte Koopmann1, Elisabeth Wieslander1, Per-Erik Stromstedt1, Stephen Holgate2, Donna Davies2, Johan Lund1, and Ratko Djukanovic2
1 Department of Biological Sciences, AstraZeneca R and D, Lund, Sweden,
2 Allergy and Inflammation Research, Division of Infection, Inflammation and Repair, University of Southampton, Southampton University General Hospital, Southampton, United Kingdom
* To whom correspondence should be addressed. E-mail: Per.Broberg{at}astrazeneca.com.
Rationale The molecular mechanisms involved in airway oxidative stress responses reported in healthy smokers and with 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 COPD subjects, 14 healthy non-smokers (NS) and 18 healthy smokers (HS).
Results Gene expression analysis using Affymetrix arrays revealed mRNAs representing 341 out of 642 oxidative stress genes from two pre-defined gene sets to be differentially expressed in NS when compared to HS, and 200 differentially expressed oxidative genes in COPD subjects when compared to HS. Gene Set Enrichment Analysis showed that pathways involved in oxidant/antioxidant responses were amongst the most differentially expressed gene pathways in smoking individuals, with further differences seen in COPD. Distinct, non-linear, 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 (MesH C08.381.495.389 )
Oligonucleotide Array Sequence Analysis (MesH E05.196.630.570.660 )
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