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Cystic Fibrosis Transmembrane Conductance Regulator Function Is Suppressed in Cigarette Smokers

Pulmonary Research Unit, Faculty of Medicine, Université de Sherbrooke, Sherbrooke; Department of Physiology, McGill University, Montreal, Quebec; and Program in Integrative Biology, Research Institute, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to André M. Cantin, M.D., Pulmonary Research Unit, Faculty of Medicine, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Quebec, J1H 5N4 Canada. E-mail: andre.cantin{at}usherbrooke.ca

Rationale: Cigarette smoke extract inhibits chloride secretion in human bronchial epithelial cells. Oxidants decrease gene expression, protein expression, and function of the cystic fibrosis transmembrane conductance regulator (CFTR).

Objectives: Because cigarette smoke is a rich source of oxidants, we verified the hypothesis that CFTR may be suppressed by exposure to cigarette smoke in vitro and in vivo.

Methods: The effects of cigarette smoke exposure on Calu-3 and T84 cell CFTR expression and function were observed. Also studied were the nasal potential differences (PDs) in 26 men (9 smokers, 17 nonsmokers) who had no detectable CFTR gene mutations as determined during investigations for infertility. CFTR expression and function were determined by Northern blotting, Western blotting, and cAMP-dependent ¹²⁵I efflux assays. Extensive CFTR genotyping was performed in each subject. Nasal PD measurements were made at baseline and during amiloride, chloride-free buffer, and isoproterenol perfusions.

Main Results: Cigarette smoke decreased CFTR expression and function in Calu-3 and T84 cell lines. Furthermore, the nasal PDs of cigarette smokers showed a pattern typical of CFTR deficiency with a blunted response to chloride-free buffer and isoproterenol compared with nonsmokers (–9.6 ± 4.0 vs. –22.3 ± 10.1 mV; p < 0.001).

Conclusions: We conclude that cigarette smoke decreases the expression of CFTR gene, protein, and function in vitro and that acquired CFTR deficiency occurs in the nasal respiratory epithelium of cigarette smokers. We suggest that acquired CFTR deficiency may contribute to the physiopathology of cigarette-induced diseases such as chronic bronchitis.

Key Words: antioxidants • chloride channels • cystic fibrosis • epithelial cells • oxidants • reactive oxygen species

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