ORKAMBI-Mediated Rescue of Mucociliary Clearance in Cystic Fibrosis Primary Respiratory Cultures Is Enhanced by Arginine Uptake, Arginase Inhibition, and Promotion of Nitric Oxide Signaling to the Cystic Fibrosis Transmembrane Conductance Regulator Channel

• Published in: Molecular pharmacology Vol. 96; no. 4; pp. 515 - 525
• Main Authors: Wu, Yu-Sheng, Jiang, Janet, Ahmadi, Saumel, Lew, Alexandria, Laselva, Onofrio, Xia, Sunny, Bartlett, Claire, Ip, Wan, Wellhauser, Leigh, Ouyang, Hong, Gonska, Tanja, Moraes, Theo J., Bear, Christine E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2019
• Subjects: Aminophenols - pharmacology; Aminopyridines - pharmacology; Animals; Arginase - antagonists & inhibitors; Arginine - metabolism; Benzodioxoles - pharmacology; Bronchi - cytology; Bronchi - drug effects; Bronchi - metabolism; Cells, Cultured; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cytosol - metabolism; Drug Combinations; Humans; Intestinal Mucosa - metabolism; Mice; Mutation; Nitric Oxide - metabolism; Nose - cytology; Nose - drug effects; Quinolones - pharmacology; ACC; NO; CF; CBF; ABH; MCCV; DAF-FM; iNOS; FLIPR; HBSS; WT; ALI; CFTR; FSK

ORKAMBI, a combination of the corrector, lumacaftor, and the potentiator, ivacaftor, partially rescues the defective processing and anion channel activity conferred by the major cystic fibrosis–causing mutation, F508del, in in vitro studies. Clinically, the improvement in lung function after ORKAMBI...