Cigarette smoke (CS) exposure induces mucus obstruction and the development of chronic bronchitis (CB). While many of these responses are determined genetically, little is known about the effects CS can exert on pulmonary epithelia at the protein level. We, therefore, tested the hypothesis that CS exerts direct effects on the CFTR protein, which could impair airway hydration, leading to the mucus stasis characteristic of both cystic fibrosis and CB. In vivo and in vitro studies demonstrated that CS rapidly decreased CFTR activity, leading to airway surface liquid (ASL) volume depletion ( i.e. , dehydration). Further studies revealed that CS induced internalization of CFTR. Surprisingly, CS-internalized CFTR did not colocalize with lysosomal proteins. Instead, the bulk of CFTR shifted to a detergent-resistant fraction within the cell and colocalized with the intermediate filament vimentin, suggesting that CS induced CFTR movement into an aggresome-like, perinuclear compartment. To test whether airway dehydration could be reversed, we used hypertonic saline (HS) as an osmolyte to rehydrate ASL. HS restored ASL height in CS-exposed, dehydrated airway cultures. Similarly, inhaled HS restored mucus transport and increased clearance in patients with CB. Thus, we propose that CS exposure rapidly impairs CFTR function by internalizing CFTR, leading to ASL dehydration, which promotes mucus stasis and a failure of mucus clearance, leaving smokers at risk for developing CB. Furthermore, our data suggest that strategies to rehydrate airway surfaces may provide a novel form of therapy for patients with CB.—Clunes, L. A., Davies, C. M., Coakley, R. D., Aleksandrov, A. A., Henderson, A. G., Zeman, K. L., Worthington, E. N., Gentzsch, M., Kreda, S. M., Cholon, D., Bennett, W. D., Riordan, J. R., Boucher, R. C., Tarran, R. Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. aggresome chronic bronchitis ion channel lung disease Received July 19, 2011. Accepted September 30, 2011. © FASEB Facebook Google+ LinkedIn Mendeley Reddit StumbleUpon Technorati Twitter What's this? « Previous | Next Article » Table of Contents This Article Published online before print October 11, 2011 , doi: 10.1096/fj.11-192377 February 2012 The FASEB Journal vol. 26 no. 2 533-545 » Abstract Full Text Full Text (PDF) All Versions of this Article: fj.11-192377v1 26/2/533 most recent Classifications Research Communications Services Email this article to a colleague Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Google Scholar Articles by Clunes, L. A. Articles by Tarran, R. PubMed PubMed citation Articles by Clunes, L. A. Articles by Tarran, R. Related Content Load related web page information Sharing Email this article to a colleague Facebook Google+ LinkedIn Mendeley Reddit StumbleUpon Technorati Twitter What's this? Current Issue February 2012, 26 (2) Alert me to new issues of The FASEB Journal Submit Manuscripts Online Press Room Information for Authors Information for Reviewers Editorial Board Editorial Policies Subscriptions Librarian's Resource Activate Online View Collected Papers Breakthroughs in Bioscience Advertising Copyright Permissions Feedback Subscribe to RSS FASEB Publication Services Go to FASEB Online Copyright © 2012 by the Federation of American Societies for Experimental Biology Print ISSN: 0892-6638 Online ISSN: 1530-6860 var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); var pageTracker = _gat._getTracker("UA-23107677-1"); pageTracker._trackPageview();

/lp/fed-of-american-socs-for-experimental-biology/cigarette-smoke-exposure-induces-cftr-internalization-and-insolubility-gSbkSSoqNE