PT  - JOURNAL ARTICLE
AU  - Yu-Sheng Wu
AU  - Janet Jiang
AU  - Saumel Ahmadi
AU  - Alexandria Lew
AU  - Onofrio Laselva
AU  - Sunny Xia
AU  - Claire Bartlett
AU  - Wan Ip
AU  - Leigh Wellhauser
AU  - Hong Ouyang
AU  - Tanja Gonska
AU  - Theo J. Moraes
AU  - Christine E. Bear
TI  - 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
AID  - 10.1124/mol.119.117143
DP  - 2019 Oct 01
TA  - Molecular Pharmacology
PG  - 515--525
VI  - 96
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/96/4/515.short
4100  - http://molpharm.aspetjournals.org/content/96/4/515.full
SO  - Mol Pharmacol2019 Oct 01; 96
AB  - 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 treatment is modest and variable, prompting the search for complementary interventions. As our previous work identified a positive effect of arginine-dependent nitric oxide signaling on residual F508del-Cftr function in murine intestinal epithelium, we were prompted to determine whether strategies aimed at increasing arginine would enhance F508del–cystic fibrosis transmembrane conductance regulator (CFTR) channel activity in patient-derived airway epithelia. Now, we show that the addition of arginine together with inhibition of intracellular arginase activity increased cytosolic nitric oxide and enhanced the rescue effect of ORKAMBI on F508del-CFTR–mediated chloride conductance at the cell surface of patient-derived bronchial and nasal epithelial cultures. Interestingly, arginine addition plus arginase inhibition also enhanced ORKAMBI-mediated increases in ciliary beat frequency and mucociliary movement, two in vitro CF phenotypes that are downstream of the channel defect. This work suggests that strategies to manipulate the arginine–nitric oxide pathway in combination with CFTR modulators may lead to improved clinical outcomes.SIGNIFICANCE STATEMENT These proof-of-concept studies highlight the potential to boost the response to cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, lumacaftor and ivacaftor, in patient-derived airway tissues expressing the major CF-causing mutant, F508del-CFTR, by enhancing other regulatory pathways. In this case, we observed enhancement of pharmacologically rescued F508del-CFTR by arginine-dependent, nitric oxide signaling through inhibition of endogenous arginase activity.