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

Mol Pharmacol. 2019 Oct;96(4):515-525. doi: 10.1124/mol.119.117143. Epub 2019 Aug 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • Aminophenols
  • Aminopyridines
  • Benzodioxoles
  • CFTR protein, human
  • Drug Combinations
  • Quinolones
  • lumacaftor, ivacaftor drug combination
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Nitric Oxide
  • Arginine
  • Arginase