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

Am J Physiol Lung Cell Mol Physiol. 2007 Sep;293(3):L712-9. doi: 10.1152/ajplung.00314.2006. Epub 2007 Jun 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
  • Animals
  • Cell Line
  • Cells, Cultured
  • Cyclic GMP / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Epithelial Cells / pathology
  • Epithelial Sodium Channels / metabolism
  • Guanylate Cyclase / metabolism
  • Humans
  • Hydrogen-Ion Concentration / drug effects
  • In Vitro Techniques
  • Ion Transport / drug effects
  • Mice
  • Mice, Transgenic
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Purines / pharmacology
  • Purines / therapeutic use
  • Respiratory System / drug effects
  • Respiratory System / pathology*
  • Signal Transduction / drug effects
  • Sildenafil Citrate
  • Sodium / metabolism
  • Sulfones / pharmacology
  • Sulfones / therapeutic use*
  • trans-Golgi Network / drug effects
  • trans-Golgi Network / metabolism

Substances

  • Epithelial Sodium Channels
  • Piperazines
  • Purines
  • Sulfones
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Nitric Oxide
  • Sodium
  • Sildenafil Citrate
  • Nitric Oxide Synthase Type II
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human
  • Pde5a protein, mouse
  • Guanylate Cyclase
  • Cyclic GMP