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1 Department of Physiology, Dartmouth Medical School, Hanover, NH, USA
2 Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, NH, USA
3 Department of Pathology, Dartmouth-Hitchcock Medical Center, Hanover, NH, USA
* To whom correspondence should be addressed. E-mail: Agnieszka.Swiatecka-Urban{at}Dartmouth.edu.
The most common mutation in the CFTR gene in individuals with cystic fibrosis (CF), 
F508, leads to the absence of CFTR Cl- channels in the apical plasma membrane, which in turn results in impairment of mucociliary clearance - the first line of defense against inhaled bacteria. P. aeruginosa is particularly successful at colonizing and chronically infecting the CF lung and is responsible for the majority of morbidity and mortality in CF. Rescue of F508-CFTR, by reduced temperature or chemical means, reveals that the protein is at least partially functional as a Cl- channel. Thus, current efforts focus on identification of drugs that restore the presence of CFTR in the apical membrane in order to alleviate the CF symptoms. Because little is known about the effects of P. aeruginosa on CFTR in the apical membrane, it is unknown whether P. aeruginosa will affect the efficacy of new drugs designed to restore the plasma membrane expression of CFTR. Accordingly, the objective of the present study was to determine whether P. aeruginosa affects CFTR-mediated Cl- secretion in polarized human airway epithelial cells. We report that a cell-free filtrate of P. aeruginosa reduces CFTR-mediated transepithelial Cl- secretion by inhibiting the endocytic recycling of CFTR and, thus, the number of WT-CFTR and F508-CFTR Cl- channels in the apical membrane in polarized human airway epithelial cells. These data suggest that chronic infection with P. aeruginosa may interfere with the therapeutic strategies aimed at increasing the apical membrane expression of F508-CFTR.
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