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ATP12A promotes mucus dysfunction during Type 2 airway inflammation

Allergic airway disease is known to cause significant morbidity due to impaired mucociliary clearance, however the mechanism that leads to the mucus dysfunction is not entirely understood. Interleukin 13 (IL-13), a key mediator of Type 2 (T2) inflammation, profoundly alters the ion transport propert...

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Autores principales: Lennox, Alison T., Coburn, Stefanie L., Leech, John A., Heidrich, Elisa M., Kleyman, Thomas R., Wenzel, Sally E., Pilewski, Joseph M., Corcoran, Timothy E., Myerburg, Mike M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794982/
https://www.ncbi.nlm.nih.gov/pubmed/29391451
http://dx.doi.org/10.1038/s41598-018-20444-8
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author Lennox, Alison T.
Coburn, Stefanie L.
Leech, John A.
Heidrich, Elisa M.
Kleyman, Thomas R.
Wenzel, Sally E.
Pilewski, Joseph M.
Corcoran, Timothy E.
Myerburg, Mike M.
author_facet Lennox, Alison T.
Coburn, Stefanie L.
Leech, John A.
Heidrich, Elisa M.
Kleyman, Thomas R.
Wenzel, Sally E.
Pilewski, Joseph M.
Corcoran, Timothy E.
Myerburg, Mike M.
author_sort Lennox, Alison T.
collection PubMed
description Allergic airway disease is known to cause significant morbidity due to impaired mucociliary clearance, however the mechanism that leads to the mucus dysfunction is not entirely understood. Interleukin 13 (IL-13), a key mediator of Type 2 (T2) inflammation, profoundly alters the ion transport properties of airway epithelium. However, these electrophysiological changes cannot explain the thick, tenacious airway mucus that characterizes the clinical phenotype. Here we report that IL-13 dramatically increases the airway surface liquid (ASL) viscosity in cultured primary human bronchial epithelial cells and thereby inhibits mucus clearance. These detrimental rheological changes require ATP12A, a non-gastric H(+)/K(+)-ATPase that secretes protons into the ASL. ATP12A knockdown or inhibition prevented the IL-13 dependent increase in ASL viscosity but did not alter the ASL pH. We propose that ATP12A promotes airway mucus dysfunction in individuals with T2 inflammatory airway diseases and that ATP12A may be a novel therapeutic target to improve mucus clearance.
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spelling pubmed-57949822018-02-12 ATP12A promotes mucus dysfunction during Type 2 airway inflammation Lennox, Alison T. Coburn, Stefanie L. Leech, John A. Heidrich, Elisa M. Kleyman, Thomas R. Wenzel, Sally E. Pilewski, Joseph M. Corcoran, Timothy E. Myerburg, Mike M. Sci Rep Article Allergic airway disease is known to cause significant morbidity due to impaired mucociliary clearance, however the mechanism that leads to the mucus dysfunction is not entirely understood. Interleukin 13 (IL-13), a key mediator of Type 2 (T2) inflammation, profoundly alters the ion transport properties of airway epithelium. However, these electrophysiological changes cannot explain the thick, tenacious airway mucus that characterizes the clinical phenotype. Here we report that IL-13 dramatically increases the airway surface liquid (ASL) viscosity in cultured primary human bronchial epithelial cells and thereby inhibits mucus clearance. These detrimental rheological changes require ATP12A, a non-gastric H(+)/K(+)-ATPase that secretes protons into the ASL. ATP12A knockdown or inhibition prevented the IL-13 dependent increase in ASL viscosity but did not alter the ASL pH. We propose that ATP12A promotes airway mucus dysfunction in individuals with T2 inflammatory airway diseases and that ATP12A may be a novel therapeutic target to improve mucus clearance. Nature Publishing Group UK 2018-02-01 /pmc/articles/PMC5794982/ /pubmed/29391451 http://dx.doi.org/10.1038/s41598-018-20444-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lennox, Alison T.
Coburn, Stefanie L.
Leech, John A.
Heidrich, Elisa M.
Kleyman, Thomas R.
Wenzel, Sally E.
Pilewski, Joseph M.
Corcoran, Timothy E.
Myerburg, Mike M.
ATP12A promotes mucus dysfunction during Type 2 airway inflammation
title ATP12A promotes mucus dysfunction during Type 2 airway inflammation
title_full ATP12A promotes mucus dysfunction during Type 2 airway inflammation
title_fullStr ATP12A promotes mucus dysfunction during Type 2 airway inflammation
title_full_unstemmed ATP12A promotes mucus dysfunction during Type 2 airway inflammation
title_short ATP12A promotes mucus dysfunction during Type 2 airway inflammation
title_sort atp12a promotes mucus dysfunction during type 2 airway inflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794982/
https://www.ncbi.nlm.nih.gov/pubmed/29391451
http://dx.doi.org/10.1038/s41598-018-20444-8
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