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Endosomal hyperacidification in cystic fibrosis is due to defective nitric oxide–cylic GMP signalling cascade
Author(s) -
Poschet Jens F,
Fazio Joseph A,
Timmins Graham S,
Ornatowski Wojciech,
Perkett Elizabeth,
Delgado Monica,
Deretic Vojo
Publication year - 2006
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7400674
Subject(s) - endosome , nitric oxide , cystic fibrosis transmembrane conductance regulator , microbiology and biotechnology , chemistry , cystic fibrosis , stimulation , proinflammatory cytokine , nitric oxide synthase , phosphodiesterase , cgmp specific phosphodiesterase type 5 , soluble guanylyl cyclase , sildenafil , intracellular , medicine , biochemistry , endocrinology , inflammation , biology , guanylate cyclase , organic chemistry , enzyme
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.