Reduced Frizzled Receptor 4 Expression Prevents WNT/β-Catenin–driven Alveolar Lung Repair in Chronic Obstructive Pulmonary Disease

• DOI: 10.1164/rccm.201605-0904oc
• Publication Date: 2017-03-01T00:13:32Z
• Authors: Wioletta Skronska...; Kathrin Mutze; Hoeke A. Baarsma; Ken R. Bracke; Hani N. Alsafadi; Mareike Lehmann; Rita Costa; Mariano Stornaiuolo; Ettore Novellino; Guy G. Brusselle; Darcy E. Wagner; Ali Ö. Yildirim; Melanie Königshoff
• Keywords: WNT3A; LRP5

Chronic obstructive pulmonary disease (COPD), in particular emphysema, is characterized by loss of parenchymal alveolar tissue and impaired repair. Wingless INT-1 (WNT)/β-catenin signaling reduced COPD; however, the mechanisms thereof, specifically role frizzled (FZD) family WNT receptors, remain unexplored.To identify functionally characterize specific FZD receptors that control downstream lung repair COPD.FZD expression was analyzed homogenates epithelial type II (ATII) cells never-smokers, smokers, patients with COPD, two experimental COPD models quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, immunofluorescence. The functional effects cigarette smoke on FZD4, WNT/β-catenin signaling, elastogenic components were investigated primary ATII vitro three-dimensional cultures ex vivo. Gain- loss-of-function approaches applied to determine FZD4 cell wound healing repair, as well components.FZD4 human tissues from COPD. Cigarette exposure down-regulated vivo, along activity. Inhibition decreased WNT/β-catenin-driven proliferation closure, it interfered ATII-to-ATI transdifferentiation organoid formation, which augmented overexpression. Moreover, restoration overexpression or pharmacological induction led vivo.Reduced contributes capacity.