Pharmacological rescue of mutant CFTR protein improves the viscoelastic properties of CF mucus

J Cyst Fibros. 2016 May;15(3):295-301. doi: 10.1016/j.jcf.2015.11.003. Epub 2015 Dec 9.

Abstract

Background: In CF patients, the defective ion transport causes a simultaneous reduction of fluid, Cl(-) and HCO3(-) secretion. We aimed to demonstrate that the resulting altered properties of mucus can be recovered using lumacaftor, a CFTR corrector.

Methods: The micro-rheology of non-CF and CF mucus was analysed using Multiple Particle Tracking.

Results: The diffusion coefficient of nano-beads imbedded in mucus from CF human bronchial epithelium was lower than in non-CF mucus, and the elastic and viscous moduli were higher. We found that 25% correction of F508del-CFTR mutation with lumacaftor was enough to improve significantly CF mucus properties. Surprisingly, also incubation with amiloride, a compound that reduces fluid absorption but might not change the secretion of HCO3(-) towards the airway surface fluid, improved CF mucus properties.

Conclusion: CF mucus properties can be recovered by either improving the hydration of the airways or recovering Cl(-) and HCO3(-) secretion across the mutated protein treated with a corrector compound.

Keywords: CFTR; Ivacaftor; Micro-rheology; Mucus; Multiple particle tracking; lumacaftor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amiloride* / administration & dosage
  • Amiloride* / pharmacokinetics
  • Aminopyridines* / administration & dosage
  • Aminopyridines* / pharmacokinetics
  • Benzodioxoles* / administration & dosage
  • Benzodioxoles* / pharmacokinetics
  • Biological Availability
  • Cell Culture Techniques
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / genetics
  • Epithelial Sodium Channel Blockers / administration & dosage
  • Epithelial Sodium Channel Blockers / pharmacokinetics
  • Humans
  • Microfluidics / methods
  • Models, Theoretical
  • Mucus* / drug effects
  • Mucus* / metabolism
  • Mutant Proteins / genetics
  • Respiratory Mucosa* / drug effects
  • Respiratory Mucosa* / metabolism

Substances

  • Aminopyridines
  • Benzodioxoles
  • Epithelial Sodium Channel Blockers
  • Mutant Proteins
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Amiloride
  • lumacaftor