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Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD

Baarsma, Hoeke A.; Skronska-Wasek, Wioletta; Mutze, Kathrin; Ciolek, Florian; Wagner, Darcy E. LU ; John-Schuster, Gerrit; Heinzelmann, Katharina; Günther, Andreas; Bracke, Ken R. and Dagouassat, Maylis, et al. (2017) In Journal of Experimental Medicine 214(1). p.143-163
Abstract

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... (More)

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.

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published
in
Journal of Experimental Medicine
volume
214
issue
1
pages
21 pages
publisher
Rockefeller University Press
external identifiers
  • scopus:85008468138
ISSN
0022-1007
DOI
10.1084/jem.20160675
language
English
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no
id
dee1a81e-ff6b-41ae-bea5-e153cc7ddc68
date added to LUP
2017-08-15 14:33:07
date last changed
2017-08-24 15:18:24
@article{dee1a81e-ff6b-41ae-bea5-e153cc7ddc68,
  abstract     = {<p>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.</p>},
  author       = {Baarsma, Hoeke A. and Skronska-Wasek, Wioletta and Mutze, Kathrin and Ciolek, Florian and Wagner, Darcy E. and John-Schuster, Gerrit and Heinzelmann, Katharina and Günther, Andreas and Bracke, Ken R. and Dagouassat, Maylis and Boczkowski, Jorge and Brusselle, Guy and Smits, Ron and Eickelberg, Oliver and Yildirim, Ali Oe. and Königshoff, Melanie},
  issn         = {0022-1007},
  language     = {eng},
  number       = {1},
  pages        = {143--163},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Experimental Medicine},
  title        = {Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD},
  url          = {http://dx.doi.org/10.1084/jem.20160675},
  volume       = {214},
  year         = {2017},
}