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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., Hongwei Yu, Jens Poschet, Graham Timmons, Jennifer Taylor-Cousar, Wojciech Ornatowski, Joseph Fazio, Elizabeth Perkett, Kari Wilson, Hugo De Jonge, Vojo Deretic

Hongwei Yu

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 …