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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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