Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration
- 11 October 2011
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 26 (2), 533-545
- https://doi.org/10.1096/fj.11-192377
Abstract
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.Keywords
Funding Information
- Cystic Fibrosis Foundation
- National Institutes of Health
- National Institutes of Health (5R01DK051870, 5R01DK051619)
- National Institutes of Health (HL084934, HL34332)
- National Institutes of Health (HL084934)
This publication has 49 references indexed in Scilit:
- Peripheral Protein Quality Control Removes Unfolded CFTR from the Plasma MembraneScience, 2010
- Modulation of endocytic trafficking and apical stability of CFTR in primary human airway epithelial culturesAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2010
- Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770Proceedings of the National Academy of Sciences of the United States of America, 2009
- Translating the COPD Transcriptome: Insights into Pathogenesis and Tools for Clinical ManagementProceedings of the American Thoracic Society, 2008
- 17β-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epitheliaJCI Insight, 2008
- A2B Adenosine Receptors Regulate the Mucus Clearance Component of the Lung's Innate Defense SystemAmerican Journal of Respiratory Cell and Molecular Biology, 2008
- Interactions Between Secondhand Smoke and Genes That Affect Cystic Fibrosis Lung DiseaseJama-Journal Of The American Medical Association, 2008
- Endocytic trafficking of CFTR in health and diseaseJournal of Cystic Fibrosis, 2007
- Long-term clearance from small airways decreases with ageEuropean Respiratory Journal, 2005
- Increased Bioelectric Potential Difference across Respiratory Epithelia in Cystic FibrosisThe New England Journal of Medicine, 1981