title: Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis.
abstract: 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.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA.
authors.forename: Jens F
authors.initials: JF
authors.lastname: Poschet
authors.forename: Graham S
authors.initials: GS
authors.lastname: Timmins
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Taylor-Cousar
authors.forename: Wojciech
authors.initials: W
authors.lastname: Ornatowski
authors.forename: Joseph
authors.initials: J
authors.lastname: Fazio
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Perkett
authors.forename: Kari R
authors.initials: KR
authors.lastname: Wilson
authors.forename: Hongwei D
authors.initials: HD
authors.lastname: Yu
authors.forename: Hugo R
authors.initials: HR
authors.lastname: de Jonge
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D003550:Cystic Fibrosis / Q000188:drug therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D012137:Respiratory System / Q000187:drug effects / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D012964:Sodium / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*; D021601:trans-Golgi Network / Q000187:drug effects / Q000378:metabolism
chemical_list: D053503:Epithelial Sodium Channels; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D009569:Nitric Oxide; D012964:Sodium; D000068677:Sildenafil Citrate; D052247:Nitric Oxide Synthase Type II; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517382:Pde5a protein, mouse; D006162:Guanylate Cyclase; D006152:Cyclic GMP