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Lookup NU author(s): Livia Delpiano, Matthew Burke, Dr Glyn NelsonORCiD, Dr Michael Gray
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copyright © 2023 the Author(s). Published by PNAS. In cystic fibrosis (CF), defects in the CF transmembrane conductance regulator (CFTR) channel lead to an acidic airway surface liquid (ASL), which compromises innate defence mechanisms, predisposing to pulmonary failure. Restoring ASL pH is a potential therapy for people with CF, particularly for those who cannot benefit from current highly effective modulator therapy. However, we lack a comprehensive understanding of the complex mechanisms underlying ASL pH regulation. The calcium-activated chloride channel, TMEM16A, and the anion exchanger, SLC26A4, have been proposed as targets for restoring ASL pH, but current results are contradictory and often utilise nonphysiological conditions. To provide better evidence for a role of these two proteins in ASL pH homeostasis, we developed an efficient CRISPR-Cas9-based approach to knock-out (KO) relevant transporters in primary airway basal cells lacking CFTR and then measured dynamic changes in ASL pH under thin-film conditions in fully differentiated airway cultures, which better simulate the in vivo situation. Unexpectantly, we found that both proteins regulated steady-state as well as agonist-stimulated ASL pH, but only under inflammatory conditions. Furthermore, we identified two Food and Drug Administration (FDA)-approved drugs which raised ASL pH by activating SLC26A4. While we identified a role for SLC26A4 in fluid absorption, KO had no effect on cyclic adenosine monophosphate (cAMP)-stimulated fluid secretion in airway organoids. Overall, we have identified a role of TMEM16A in ASL pH homeostasis and shown that both TMEM16A and SLC26A4 could be important alternative targets for ASL pH therapy in CF, particularly for those people who do not produce any functional CFTR.
Author(s): Delpiano L, Rodenburg LW, Burke M, Nelson G, Amatngalim GD, Beekman JM, Gray MA
Publication type: Article
Publication status: Published
Journal: Proceedings of the National Academy of Sciences of the United States of America
Year: 2023
Volume: 120
Issue: 47
Online publication date: 15/11/2023
Acceptance date: 28/09/2023
Date deposited: 25/01/2024
ISSN (print): 0027-8424
ISSN (electronic): 1091-6490
Publisher: National Academy of Sciences
URL: https://doi.org/10.1073/pnas.2307551120
DOI: 10.1073/pnas.2307551120
Data Access Statement: All data generated during this research are openly available at https://doi.org/10.25405/data.ncl.24085257.v1 (54). All other data are included in the manuscript and/or SI Appendix.
PubMed id: 37967223
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