Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion transporter that regulates mucus hydration, viscosity and acidity of the airway epithelial surface. Genetic defects in CFTR impair regulation of mucus homeostasis, causing severe defects of mucociliary clearance as seen in cystic fibrosis. Recent work has established that CFTR dysfunction can be acquired in chronic obstructive pulmonary disease (COPD) and may also contribute to other diseases that share clinical features of cystic fibrosis, such as asthma, allergic bronchopulmonary aspergillosis and bronchiectasis. Protean causes of CFTR dysfunction have been identified including cigarette smoke exposure, toxic metals and downstream effects of neutrophil activation pathways. Recently, CFTR modulators, small molecule agents that potentiate CFTR or restore diminished protein levels at the cell surface, have been successfully developed for various CFTR gene defects, prompting interest in their use to treat diseases of acquired dysfunction. The spectrum of CFTR dysfunction, strategies for CFTR modulation, and candidate diseases for CFTR modulation beyond cystic fibrosis will be reviewed in this manuscript.
Abstract
CFTR dysfunction may be part of the pathophysiology of many diseases of the airways. Exploration of mechanisms of dysfunction and options for CFTR-directed therapies are examined in this article. http://bit.ly/33o6nDu
Footnotes
Number 4 in the Series “Controversies in bronchiectasis” Edited by James Chalmers and Michal Shteinberg
Previous articles in this series: No. 1: Amati F, Simonetta E, Gramegna A, et al. The biology of pulmonary exacerbations in bronchiectasis. Eur Respir Rev 2019; 28: 190055. No. 2: Shteinberg M, Flume PA, Chalmers JD. Is bronchiectasis really a disease? Eur Respir Rev 2019; 28: 190051. No. 3: Tiddens HAWM, Meerburg JJ, van der Eerden MM. The radiological diagnosis of bronchiectasis: what's in a name? Eur Respir Rev 2019; 28: 190120.
Provenance: Commissioned article, peer reviewed.
Conflict of interest: S.D. Patel has nothing to disclose.
Conflict of interest: T.R. Bono has nothing to disclose.
Conflict of interest: S.M. Rowe reports grants from Bayer, Forest Research Institute, AstraZeneca, N30/Nivalis, Novartis, Galapagos/AbbVie, Proteostasis, Eloxx and PTC Therapeutics, grants and personal fees from Celtaxsys, grants, personal fees and non-financial support from Vertex Pharmaceuticals Incorporated, and personal fees from Bayer and Novartis, outside the submitted work.
Conflict of interest: G.M. Solomon reports grants from NIH and the CF Foundation, during the conduct of the study; grants and personal fees from Vertex Pharamceuticals, Electromed, Inc. and Insmed Inc., and grants from Saavara, Inc. and Parion Sciences, outside the submitted work.
Support statement: Funding support has been received from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (P30-2P30DK072482 to S.M. Rowe and G.M. Solomon), National Institutes of Health (1K08-HL138153 to G.M. Solomon and R35HL135816 to S.M. Rowe) and Cystic Fibrosis Foundation (Solomon18YO) to G.M. Solomon. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received June 13, 2019.
- Accepted March 9, 2020.
- Copyright ©ERS 2020.
This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.