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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 293/3/L712    most recent 00314.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Poschet, J. F. Articles by Deretic, V. Search for Related Content PubMed PubMed Citation Articles by Poschet, J. F. Articles by Deretic, V.

Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis

¹Department of Molecular Genetics and Microbiology, ²College of Pharmacy, Departments of ³Internal Medicine, ⁴Pediatrics, and ⁵Cell Biology and Physiology, University of New Mexico Health Science Center, Albuquerque, New Mexico; ⁶Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine Marshall University, Huntington, West Virginia; and ⁷Department of Biochemistry, Erasmus University Medical Center, Rotterdam, The Netherlands

Submitted 16 August 2006 ; accepted in final form 29 May 2007

The CFTR gene encodes a chloride channel with pleiotropic effects on cell physiology and metabolism. Here, we show that increasing cGMP levels to inhibit epithelial Na⁺ channel in cystic fibrosis (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 reduced 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 Cftr^tm1Eur mice and reduced neutrophil infiltration on 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.

epithelial Na⁺ channel; reduced nitric oxide

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