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WNT5A Is a Regulator of Fibroblast Proliferation and Resistance to Apoptosis

¹ Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy, and Critical Care Medicine, and ² Pittsburgh Development Center, Magee-Women's Research Institute and Foundation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Naftali Kaminski, M.D., University of Pittsburgh, School of Medicine, 3459 Fifth Ave., 628NW Montifore, Pittsburgh, PA 15213. E-mail: kaminskin{at}upmc.edu

Usual interstitial pneumonia (UIP) is a specific histopathologic pattern of interstitial lung fibrosis that may be idiopathic or secondary to autoimmune diseases and environmental exposures. In this study, we compared gene expression patterns in primary fibroblasts isolated from lung tissues with UIP histology and fibroblasts isolated from lung tissues with normal histology using expression microarrays. We found that WNT5A was significantly increased in fibroblasts obtained from UIP lung tissues compared with normal lung fibroblasts, an observation verified by quantitative real-time RT-PCR and Western blot. Because the role of WNT5A in UIP is unknown, we treated normal lung fibroblasts or UIP lung fibroblasts with WNT5A, and found that WNT5A increased proliferation as well as relative resistance to H₂O₂-induced apoptosis. This effect was not mediated through the canonical WNT/β-catenin pathway, as WNT5A induced a decrease in β-catenin levels in the same cells. In addition, WNT5A induced increases in fibronectin and ₅-integrin in normal lung fibroblasts. Collectively, our data suggest that WNT5A may play a role in fibroblast expansion and survival characteristics of idiopathic pulmonary fibrosis and other fibrotic interstitial lung diseases that exhibit UIP histological patterns.

Key Words: gene expression • idiopathic pulmonary fibrosis • cell growth • apoptosis • extracellular matrix

CLINICAL RELEVANCE Our results suggest a mechanism by which enhanced WNT5A secretion may promote fibroblast proliferation and survival in usual interstitial pneumonia (UIP) lungs, despite the presence of multiple proapoptotic signals, and thus suggest a novel explanation for the "apoptosis paradox." They also highlight a potential role for the noncanonical WNT pathway in determining the lung phenotype in UIP.

 

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