Expression of genes involved in oxidative stress responses in airway epithelial cells of smokers with chronic obstructive pulmonary disease

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.