Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy
| Autor: | Marina Mazur, William E. Grizzle, George M. Solomon, Guillermo J. Tearney, Susan E. Birket, Peter A. Sloane, Vivian Y. Lin, Linbo Liu, Grace H. Houser, Justin Hanes, Courtney M. Fernandez, Kengyeh K. Chu, Steven M. Rowe, Suresh Shastry, Eric J. Sorscher |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Pathology medicine.medical_specialty Cystic Fibrosis Physiology Mucociliary clearance Drug Evaluation Preclinical Mutation Missense Cystic Fibrosis Transmembrane Conductance Regulator Quinolones Pharmacology Aminophenols Cystic fibrosis Membrane Potentials Amiloride Ivacaftor Mice 03 medical and health sciences 0302 clinical medicine Physiology (medical) medicine Animals Humans Chloride Channel Agonists Cells Cultured Ion transporter biology Colforsin Cell Biology medicine.disease Mucus Cystic fibrosis transmembrane conductance regulator 030104 developmental biology 030228 respiratory system Mechanism of action NIH 3T3 Cells Call for Papers biology.protein Drug Therapy Combination medicine.symptom medicine.drug |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 310:L928-L939 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | 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 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. We further show that improvement in the functional microanatomy in vitro corresponds with lung function benefit observed in the clinical trials, whereas ion transport in vitro corresponds to changes in sweat chloride. Functional imaging reveals insights into clinical efficacy and CFTR biology that significantly impact our understanding of novel therapies. |
| Databáze: | OpenAIRE |
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