Journal article

Publication year: 2017

Pages: 143-163

Journal: Journal of Experimental Medicine

Volume number: 214

Issue number: 1

ISSN: 0022-1007

eISSN: 1540-9538

Open access status: Green

DOI Link: https://doi.org/10.1084/jem.20160675

Publisher: Rockefeller University Press

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-beta-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-beta, 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 beta-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.

Harvard Citation style: Baarsma, H., Skronska-Wasek, W., Mutze, K., Ciolek, F., Wagner, D., John-Schuster, G., et al. (2017) Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD, Journal of Experimental Medicine, 214(1), pp. 143-163. https://doi.org/10.1084/jem.20160675

APA Citation style: Baarsma, H., Skronska-Wasek, W., Mutze, K., Ciolek, F., Wagner, D., John-Schuster, G., Heinzelmann, K., Guenther, A., Bracke, K., Dagouassat, M., Boczkowski, J., Brusselle, G., Smits, R., Eickelberg, O., Yildirim, A., & Koenigshoff, M. (2017). Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD. Journal of Experimental Medicine. 214(1), 143-163. https://doi.org/10.1084/jem.20160675