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Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matri...

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Autores principales: Stancil, Ian T., Michalski, Jacob E., Davis-Hall, Duncan, Chu, Hong Wei, Park, Jin-Ah, Magin, Chelsea M., Yang, Ivana V., Smith, Bradford J., Dobrinskikh, Evgenia, Schwartz, David A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316442/
https://www.ncbi.nlm.nih.gov/pubmed/34315881
http://dx.doi.org/10.1038/s41467-021-24853-8
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author Stancil, Ian T.
Michalski, Jacob E.
Davis-Hall, Duncan
Chu, Hong Wei
Park, Jin-Ah
Magin, Chelsea M.
Yang, Ivana V.
Smith, Bradford J.
Dobrinskikh, Evgenia
Schwartz, David A.
author_facet Stancil, Ian T.
Michalski, Jacob E.
Davis-Hall, Duncan
Chu, Hong Wei
Park, Jin-Ah
Magin, Chelsea M.
Yang, Ivana V.
Smith, Bradford J.
Dobrinskikh, Evgenia
Schwartz, David A.
author_sort Stancil, Ian T.
collection PubMed
description The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.
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spelling pubmed-83164422021-08-03 Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional Stancil, Ian T. Michalski, Jacob E. Davis-Hall, Duncan Chu, Hong Wei Park, Jin-Ah Magin, Chelsea M. Yang, Ivana V. Smith, Bradford J. Dobrinskikh, Evgenia Schwartz, David A. Nat Commun Article The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression. Nature Publishing Group UK 2021-07-27 /pmc/articles/PMC8316442/ /pubmed/34315881 http://dx.doi.org/10.1038/s41467-021-24853-8 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Stancil, Ian T.
Michalski, Jacob E.
Davis-Hall, Duncan
Chu, Hong Wei
Park, Jin-Ah
Magin, Chelsea M.
Yang, Ivana V.
Smith, Bradford J.
Dobrinskikh, Evgenia
Schwartz, David A.
Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional
title Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional
title_full Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional
title_fullStr Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional
title_full_unstemmed Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional
title_short Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional
title_sort pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316442/
https://www.ncbi.nlm.nih.gov/pubmed/34315881
http://dx.doi.org/10.1038/s41467-021-24853-8
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