RT Journal Article
SR Electronic
T1 Non-canonical WNT-5A signaling attenuates endogenous lung repair in COPD
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA4014
DO 10.1183/13993003.congress-2016.PA4014
VO 48
IS suppl 60
A1 Hoeke Baarsma
A1 Wioletta Skronska-Wasek
A1 Kathrin Mutze
A1 Florian Ciolek
A1 Gerrit John-Schuster
A1 Ron Smits
A1 Ali Önder Yildirim
A1 Melanie Königshoff
YR 2016
UL http://erj.ersjournals.com/content/48/suppl_60/PA4014.abstract
AB Introduction: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world. Currently no causal therapy is available for this devastating disease. In COPD/emphysema the endogenous lung repair capacity is impaired due to decreased canonical WNT/β-catenin signalling in the alveolar epithelium. Canonical and non-canonical (β-catenin independent) WNT signaling pathways are interconnected, meaning that components of one pathway regulates the activity of the other. We investigated if non-canonical WNT signaling could affect β-catenin signaling in alveolar epithelial cells thereby contributing to COPD pathogenesis.Methods: Expression of the non-canonical ligands was analyzed in experimental and human COPD. The potential contribution of WNT-5A to COPD pathogenesis was investigated in vitro using primary human lung fibroblasts (PhF) and alveolar epithelial cells and in vivo in a mouse model of elastase-induced emphysema.Results: Non-canonical WNT-5A is differentially expressed and post-translationally modified COPD. WNT-5A is secreted by PhF, which was enhanced by components of cigarette smoke extract and TGF-β. Treatment of alveolar epithelial cells with WNT-5A impaired canonical WNT/β-catenin signaling. Moreover, mature WNT-5A inhibited WNT/β-catenin driven alveolar epithelial cell proliferation, wound repair and transdifferentiation. Lung-specific overexpression of WNT-5A in vivo aggravated airspace enlargement and loss of functional lung tissue in experimental emphysema.Conclusion: WNT-5A secretion by pulmonary fibroblasts attenuates canonical WNT/β-catenin signaling in the lung epithelium thereby compromising endogenous lung repair in COPD.