Reduced Frizzled Receptor 4 Expression Prevents WNT/β-Catenin–driven Alveolar Lung Repair in Chronic Obstructive Pulmonary Disease
| Autor: | Mareike Lehmann, Hoeke A. Baarsma, Ken R. Bracke, Rita Costa, Wioletta Skronska-Wasek, Darcy E. Wagner, Melanie Königshoff, Hani N. Alsafadi, Mariano Stornaiuolo, Guy Brusselle, Ettore Novellino, Ali Önder Yildirim, Kathrin Mutze |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Pulmonary and Respiratory Medicine Pathology medicine.medical_specialty Frizzled Beta-catenin Down-Regulation Critical Care and Intensive Care Medicine Pulmonary Disease Chronic Obstructive 03 medical and health sciences Humans Medicine Receptor Lung Wnt Signaling Pathway beta Catenin Aged COPD biology business.industry Wnt signaling pathway LRP5 Middle Aged respiratory system medicine.disease Frizzled Receptors respiratory tract diseases Wnt Proteins 030104 developmental biology medicine.anatomical_structure Alveolar Epithelial Cells Catenin biology.protein Cancer research Female business |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine. 196:172-185 |
| ISSN: | 1535-4970 1073-449X |
| Popis: | Chronic obstructive pulmonary disease (COPD), in particular emphysema, is characterized by loss of parenchymal alveolar tissue and impaired tissue repair. Wingless and INT-1 (WNT)/β-catenin signaling is reduced in COPD; however, the mechanisms thereof, specifically the role of the frizzled (FZD) family of WNT receptors, remain unexplored.To identify and functionally characterize specific FZD receptors that control downstream WNT signaling in impaired lung repair in COPD.FZD expression was analyzed in lung homogenates and alveolar epithelial type II (ATII) cells of never-smokers, smokers, patients with COPD, and two experimental COPD models by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunofluorescence. The functional effects of cigarette smoke on FZD4, WNT/β-catenin signaling, and elastogenic components were investigated in primary ATII cells in vitro and in three-dimensional lung tissue cultures ex vivo. Gain- and loss-of-function approaches were applied to determine the effects of FZD4 signaling on alveolar epithelial cell wound healing and repair, as well as on expression of elastogenic components.FZD4 expression was reduced in human and experimental COPD lung tissues as well as in primary human ATII cells from patients with COPD. Cigarette smoke exposure down-regulated FZD4 expression in vitro and in vivo, along with reduced WNT/β-catenin activity. Inhibition of FZD4 decreased WNT/β-catenin-driven epithelial cell proliferation and wound closure, and it interfered with ATII-to-ATI cell transdifferentiation and organoid formation, which were augmented by FZD4 overexpression. Moreover, FZD4 restoration by overexpression or pharmacological induction led to induction of WNT/β-catenin signaling and expression of elastogenic components in three-dimensional lung tissue cultures ex vivo.Reduced FZD4 expression in COPD contributes to impaired alveolar repair capacity. |
| Databáze: | OpenAIRE |
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