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Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD
Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT–β-catenin signaling is linked to impa...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206496/ https://www.ncbi.nlm.nih.gov/pubmed/27979969 http://dx.doi.org/10.1084/jem.20160675 |
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author | Baarsma, Hoeke A. Skronska-Wasek, Wioletta Mutze, Kathrin Ciolek, Florian Wagner, Darcy E. John-Schuster, Gerrit Heinzelmann, Katharina Günther, Andreas Bracke, Ken R. Dagouassat, Maylis Boczkowski, Jorge Brusselle, Guy G. Smits, Ron Eickelberg, Oliver Yildirim, Ali Ö. Königshoff, Melanie |
author_facet | Baarsma, Hoeke A. Skronska-Wasek, Wioletta Mutze, Kathrin Ciolek, Florian Wagner, Darcy E. John-Schuster, Gerrit Heinzelmann, Katharina Günther, Andreas Bracke, Ken R. Dagouassat, Maylis Boczkowski, Jorge Brusselle, Guy G. Smits, Ron Eickelberg, Oliver Yildirim, Ali Ö. Königshoff, Melanie |
author_sort | Baarsma, Hoeke A. |
collection | PubMed |
description | Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT–β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin–driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal–epithelial cross talk in COPD pathogenesis, which is amenable to therapy. |
format | Online Article Text |
id | pubmed-5206496 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-52064962017-07-01 Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD Baarsma, Hoeke A. Skronska-Wasek, Wioletta Mutze, Kathrin Ciolek, Florian Wagner, Darcy E. John-Schuster, Gerrit Heinzelmann, Katharina Günther, Andreas Bracke, Ken R. Dagouassat, Maylis Boczkowski, Jorge Brusselle, Guy G. Smits, Ron Eickelberg, Oliver Yildirim, Ali Ö. Königshoff, Melanie J Exp Med Research Articles Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT–β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin–driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal–epithelial cross talk in COPD pathogenesis, which is amenable to therapy. The Rockefeller University Press 2017-01 /pmc/articles/PMC5206496/ /pubmed/27979969 http://dx.doi.org/10.1084/jem.20160675 Text en © 2017 Baarsma et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License(Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Baarsma, Hoeke A. Skronska-Wasek, Wioletta Mutze, Kathrin Ciolek, Florian Wagner, Darcy E. John-Schuster, Gerrit Heinzelmann, Katharina Günther, Andreas Bracke, Ken R. Dagouassat, Maylis Boczkowski, Jorge Brusselle, Guy G. Smits, Ron Eickelberg, Oliver Yildirim, Ali Ö. Königshoff, Melanie Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD |
title | Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD |
title_full | Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD |
title_fullStr | Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD |
title_full_unstemmed | Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD |
title_short | Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD |
title_sort | noncanonical wnt-5a signaling impairs endogenous lung repair in copd |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206496/ https://www.ncbi.nlm.nih.gov/pubmed/27979969 http://dx.doi.org/10.1084/jem.20160675 |
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