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1 United States; Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, New Mexico, United States
2 School of Pharmacy, University of New Mexico, Albuquerque, New Mexico, United States
3 Department of Medicine, University of New Mexico, Albuquerque, New Mexico, United States
4 Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, New Mexico, United States
5 Molecular Genetics and Micorbiology, University of New Mexico, Albuquerque, New Mexico, United States
6 United States
7 Biochemistry and Microbiology, Joan C. Edwards School of Medicine Marshall University, Huntington, West Virginia, United States
8 Biochemistry, Erasmus University Medical Center, Rotterdam, Netherlands
9 Molecular Genetics and Microbiology & Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
* To whom correspondence should be addressed. E-mail: vderetic{at}salud.unm.edu.
The CFTR gene encodes a chloride channel with pleiotropic effects on cell physiology and metabolism. Here we show that increasing cGMP levels to inhibit ENaC in CF respiratory epithelial cells corrects several aspects of the downstream pathology in CF. Cell culture models, using a range of CF cell lines and primary cells, showed that complementary pharmacological approaches to increasing intracellular cGMP, by elevating guanyl cyclase activity though nitric oxide, addition of cell-permeable cGMP analogs, or inhibition of phosphodiesterase 5', corrected multiple aspects of the CF pathological cascade. These included correction of defective protein glycosylation, bacterial adherence and proinflammatory responses. Furthermore, pharmacological inhibition of phosphodiesterase 5 in tissues ex vivo or in animal models, improved transepithelial currents across nasal mucosae from transgenic F508del Cftrtm1Eur mice, and reduced neutrophil infiltration upon bacterial aerosol challenge in Pseudomonas aeruginosa susceptible DBA/2 mice. Our findings define phosphodiesterase 5 as a specific target for correcting a number of previously disconnected defects in the CF respiratory tract, now linked through this study. Our study suggests that phosphodiesterase 5 inhibition provides an opportunity for simultaneous and concerted correction of seemingly disparate complications in CF.
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