The Journal of experimental medicine, 2017-01, Vol.214 (1), p.143-163
2017
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- Autor(en) / Beteiligte
- Titel
- Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD
- Ist Teil von
- The Journal of experimental medicine, 2017-01, Vol.214 (1), p.143-163
- Ort / Verlag
- United States: Rockefeller University Press
- Erscheinungsjahr
- 2017
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-1007eISSN: 1540-9538DOI: 10.1084/jem.20160675Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5206496
- Format
- –
- Schlagworte
- Airspace, Alveoli, Animals, Attenuation, beta Catenin - physiology, Cells, Cultured, Chronic obstructive pulmonary disease, Cigarette smoke, Crosstalk, Elastase, Emphysema, Emphysema - etiology, Enlargement, Epithelial cells, Female, Fibroblasts, Gene expression, Life Sciences, Lung - physiopathology, Lung diseases, Mesenchyme, Mice, Mice, Inbred C57BL, Obstructive lung disease, Pathogenesis, Pulmonary Disease, Chronic Obstructive - etiology, Pulmonary Disease, Chronic Obstructive - physiopathology, Regeneration, Repair, Respiratory function, Senescence, Signaling, Smoke, Smoking - adverse effects, Wnt protein, Wnt Signaling Pathway - physiology, Wnt-5a Protein - physiology, Wound healing, β-Catenin