Endosomal hyperacidification in cystic fibrosis is due to defective nitric oxide-cylic GMP signalling cascade.

EMBO Reports
Jens F PoschetVojo Deretic

Abstract

Endosomal hyperacidification in cystic fibrosis (CF) respiratory epithelial cells is secondary to a loss of sodium transport control owing to a defective form of the CF transmembrane conductance regulator CFTR. Here, we show that endosomal hyperacidification can be corrected by activating the signalling cascade controlling sodium channels through cyclic GMP. Nitric oxide (NO) donors corrected the endosomal hyperacidification in CF cells. Stimulation of CF cells with guanylate cyclase agonists corrected the pH in endosomes. Exposure of CF cells to an inhibitor of cGMP-specific phosphodiesterase PDE5, Sildenafil, normalized the endosomal pH. Treatment with Sildenafil reduced secretion by CF cells of the proinflammatory chemokine interleukin 8 following stimulation with Pseudomonas aeruginosa products. Thus, the endosomal hyperacidification and excessive proinflammatory response in CF are in part due to deficiencies in NO- and cGMP-regulated processes and can be pharmacologically reversed using PDE5 inhibitors.

Associated Clinical Trials

May 28, 2010·Jennifer Taylor-CousarJennifer Taylor-Cousar

References

Jan 1, 1994·The American Journal of Physiology·J Biwersi, A S Verkman
Aug 11, 1995·Science·M J StuttsR C Boucher
Dec 1, 1995·American Journal of Respiratory and Critical Care Medicine·T L BonfieldM Berger
Jun 28, 1996·The Journal of Biological Chemistry·O SeksekA S Verkman
Apr 6, 2000·American Journal of Physiology. Lung Cellular and Molecular Physiology·A LazrakS Matalon
Aug 15, 2001·American Journal of Physiology. Cell Physiology·G ChandyT E Machen
Nov 22, 2001·Proceedings of the National Academy of Sciences of the United States of America·J F PoschetV Deretic
Nov 8, 2002·Trends in Molecular Medicine·Jens PoschetVojo Deretic
Nov 5, 2003·American Journal of Respiratory and Critical Care Medicine·Toby J TowardKenneth J Broadley
Jan 13, 2004·Nature Immunology·Eicke LatzDouglas T Golenbock
Mar 24, 2004·Brain Research Bulletin·Joshua S KrumenackerFerid Murad
Apr 13, 2004·Molecular Biology of the Cell·Martina GentzschJohn R Riordan
Dec 14, 2004·Journal of Endotoxin Research·Eicke LatzDouglas T Golenbock
Jan 22, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Catherine M GreeneNoel G McElvaney
Feb 16, 2005·Annual Review of Physiology·John R Riordan
May 13, 2005·The New England Journal of Medicine·Steven M RoweEric J Sorscher
Jun 11, 2005·American Journal of Respiratory and Critical Care Medicine·Faruqa LadhaBernard Thébaud
Aug 30, 2005·Annual Review of Genomics and Human Genetics·Garry R Cutting

❮ Previous
Next ❯

Citations

Oct 8, 2008·Pflügers Archiv : European journal of physiology·François Jouret, Olivier Devuyst
Jan 13, 2009·The Journal of Biological Chemistry·Peter M Haggie, A S Verkman
Mar 31, 2009·American Journal of Physiology. Lung Cellular and Molecular Physiology·Peter M Haggie, A S Verkman
Sep 16, 2008·American Journal of Physiology. Lung Cellular and Molecular Physiology·Mary E MansonThomas J Kelley
Nov 17, 2007·American Journal of Respiratory and Critical Care Medicine·Bob LubambaTeresinha Leal
Oct 20, 2007·The Journal of Clinical Investigation·Wojciech OrnatowskiVojo Deretic
Dec 4, 2014·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·J L Taylor-CousarJ A Nick
Nov 7, 2006·American Journal of Physiology. Lung Cellular and Molecular Physiology·Nicole M WhiteThomas J Kelley
Jun 26, 2007·American Journal of Physiology. Lung Cellular and Molecular Physiology·Jens F PoschetVojo Deretic
Aug 29, 2007·The Journal of Biological Chemistry·Peter M Haggie, A S Verkman
Mar 26, 2011·Expert Opinion on Investigational Drugs·Sabina Antonela Antoniu
Jul 12, 2012·Chemical Society Reviews·Daniela Drescher, Janina Kneipp
Aug 30, 2013·American Journal of Physiology. Cell Physiology·Anne M CollacoNadia A Ameen
Jul 2, 2020·Genes and Immunity·Daniel PeckhamAnil Mehta
Dec 22, 2017·Expert Opinion on Emerging Drugs·Kristin M Hudock, John Paul Clancy
Aug 22, 2018·Expert Review of Respiratory Medicine·Oliver J McElvaneyNoel G McElvaney

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle, that can lead to muscular or electrical dysfunction of the heart. It is often an irreversible disease that is associated with a poor prognosis. There are different causes and classifications of cardiomyopathies. Here are the latest discoveries pertaining to this disease.