Recently approved therapies that modulate CFTR function have shown significant clinical benefit, but recent investigations regarding their molecular mechanism when used in combination have not been consistent with clinical results. We employed Micro-Optical Coherence Tomography (µOCT) as a novel means to assess the mechanism of action of CFTR modulators, focusing on the effects on mucociliary clearance. Primary human airway monolayers from patients with a G551D mutation responded to ivacaftor treatment with increased ion transport, airway surface liquid depth, ciliary beat frequency, and mucociliary transport rate, in addition to decreased effective viscosity of the mucus layer, a unique mechanism established by our findings. These endpoints are consistent with the benefit observed in G551D patients treated with ivacaftor, and identify a novel mechanism involving mucus viscosity. In monolayers derived from F508del patients, the situation is more complicated, compounded by disparate effects on CFTR expression and function. However, by combining ion transport measurements with functional imaging, we establish a crucial link between in vitro data and clinical benefit, a finding not explained by ion transport studies alone. We establish that F508del cells exhibit increased mucociliary transport and decreased mucus effective viscosity, but only when ivacaftor is added to the regimen, whereas ion transport studies highlight the deleterious effects of ivacaftor. We further show that improvement in the functional microanatomy in vitro correspond with lung function benefit observed in the clinical trials. Functional imaging reveals insights into clinical efficacy that significantly impact our understanding of novel therapies.
- cystic fibrosis
- airway epithelium
- CFTR modulators
- mucociliary transport
- Copyright © 2015, American Journal of Physiology - Lung Cellular and Molecular Physiology