Published ahead of print on February 23, 2006, doi:10.1164/rccm.200508-1330OC
Am. J. Respir. Crit. Care Med., Volume 173, Number 10, May 2006, 1139-1144
A more recent version of this article appeared on May 15, 2006
Submitted on August 27, 2005
Accepted on February 21, 2006
Cystic Fibrosis Transmembrane Conductance Regulator Function is Suppressed in Cigarette Smokers
Andre M Cantin1*, John W Hanrahan2, Ginette Bilodeau1, Lynda Ellis3, Annie Dupuis3, Jie Liao2, Julian Zielenski3, and Peter Durie3
1 Pulmonary Research Unit, University of Sherbrooke, Faculty of Medicine, Sherbrooke, Quebec, Canada,
2 Department of Physiology, McGill University, Montreal, Quebec, Canada,
3 Program in Integrative Biology, The Hospital for Sick Children and the University of Toronto, Research Institute, Toronto, Ontario, Canada
* To whom correspondence should be addressed. 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: Since cigarette smoke is a rich source of oxidants we verified the hypothesis that CFTR may be suppressed by exposure to cigarette smoke both 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 in 26 men (9 smokers, 17 non-smokers) who had no detectable CFTR gene mutations as determined during investigations for infertility. Measurements: 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 potential difference 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 potential differences of cigarette smokers showed a pattern typical of CFTR deficiency with a blunted response to chloride-free buffer and isoproterenol compared to non-smokers (-9.6 ± 4.0 vs -22.3 ± 10.1 millivolts, 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, at least in part, to the physiopathology of cigarette-induced diseases such as chronic bronchitis.
Key words: Oxidants, antioxidants, chloride channels, epithelial cells, cystic fibrosis, reactive oxygen species.
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