Variability of Antioxidant-Related Gene Expression in the Airway Epithelium of Cigarette Smokers

Abstract

Cigarette smoking is the major risk factor for developing chronic bronchitis, yet only 15-20% of smokers develop this disorder. Because oxidants are the major mechanism of smoking-induced airway damage, we hypothesized that smoking is associated with upregulation of various antioxidant-related genes in the airway epithelium, but the magnitude of the response shows high interindividual variability. Microarray analysis was used to assess levels of expression of 44 antioxidant-related genes in four categories (catalase/superoxide dismutase family; glutathione metabolism; redox balance; and pentose phosphate cycle) in bronchoscopyobtained airway epithelium of matched cohorts (13 current smokers, 9 nonsmokers), none of whom had lung disease. There was minimal variation in gene expression levels within the same individual (right versus left lung or over time), but significant upregulation of 16/44 antioxidant-related genes in smoker epithelium compared with nonsmokers. Subgroups of smokers were identified with clusters of expression levels of antioxidantrelated genes. We propose that the antioxidant-related genes demonstrating the most variability in the level of expression in smokers may be useful genetic markers in epidemiologic studies assessing susceptibility to smoking-induced chronic bronchitis.Chronic bronchitis, a common form of chronic obstructive pulmonary disease (COPD) associated with persistent inflammation and pathogen colonization of the airway epithelium, is defined clinically by the presence of a chronic productive cough for at least 3 mo in two consecutive years in an individual in whom other causes of chronic cough have been excluded (1). Cigarette smoking is the major risk factor for the development of chronic bronchitis, and there is a dose-dependent link of the cumulative amount of smoking and the incidence of the disease (2, 3). Compelling evidence supports the concept that the pathogenesis of chronic bronchitis is associated with the chronic stress of oxidants in cigarette smoke overwhelming the antioxidant defenses of the airway epithelium, resulting in persistent injury to the airways (4, 5). Despite the clear link of smoking to the risk for chronic bronchitis, only 15-20% of cigarette smokers develop COPD (3, 6), suggesting that there must be risk factors other than smoking that contribute to the susceptibility to this disease. Clues that genetic variability plays an important role come from studies demonstrating familial clustering of impaired lung function in response to smoking, and studies documenting susceptibility to smoking-related airflow obstruction in twins (3,7,8). In this context, the focus of this study is to identify candidate genes linked to the risk for chronic bronchitis in association with cigarette smoking. Because it is the airway epithelium that takes the brunt of the oxidant burden in cigarette smoke, we hypothesize that the airway epithelium responds to smoking by upregulating the expression of genes related to antioxidant protection, but the response to cigarette smok...

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“…64 We found no difference in serum catalase levels. This results agrees with that of Hackett et al, 65 who reported that humans do not up-regulate catalase genes in the airway epithelium in response to oxidative stress.…”

Upper Airway Gene Expression in Smokers: The Mouth as a “Window to the Soul” of Lung Carcinogenesis?

“…They did wholegenome gene expression profiling of punch biopsies from the buccal mucosa of 40 healthy smokers and 40 healthy nonsmokers, a relatively large study for a global comparison of gene expression. Smoking-related gene expression changes identified in the mouth were very similar to previously published gene expression changes in the bronchial epithelium of active smokers (10). This new study also identified several genes that were more strongly induced or suppressed by smoking in women, an intriguing observation given data that have suggested that women may have an increased lung cancer risk (versus men) in association with a given amount of cumulative tobacco smoke exposure.…”

“…Our group and others previously have shown that genome-wide gene expression profiling of bronchial airway epithelial cells collected in bronchoscopic brushings reflects the physiologic response to cigarette smoke exposure and the irreversibility of a number of these responses/ changes after smoking cessation (10)(11)(12)(13). Prior studies have also shown that gene expression profiles in the cytologically normal bronchial airway epithelium can distinguish, with high sensitivity and specificity, smokers with and without lung cancer and can serve as a clinically relevant diagnostic biomarker (14)(15)(16).…”

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