Vuga Louis J, Ben-Yehudah Ahmi, Kovkarova-Naumovski Elizabetha, Oriss Timothy, Gibson Kevin F, Feghali-Bostwick Carol, Kaminski Naftali
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Am J Respir Cell Mol Biol. 2009 Nov;41(5):583-9. doi: 10.1165/rcmb.2008-0201OC. Epub 2009 Feb 27.
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/beta-catenin pathway, as WNT5A induced a decrease in beta-catenin levels in the same cells. In addition, WNT5A induced increases in fibronectin and alpha(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.
寻常型间质性肺炎（UIP）是一种间质性肺纤维化的特定组织病理学模式，可能是特发性的，也可能继发于自身免疫性疾病和环境暴露。在本研究中，我们使用表达微阵列比较了从具有UIP组织学特征的肺组织中分离的原代成纤维细胞与从具有正常组织学特征的肺组织中分离的成纤维细胞的基因表达模式。我们发现，与正常肺成纤维细胞相比，从UIP肺组织获得的成纤维细胞中WNT5A显著增加，这一观察结果通过定量实时RT-PCR和蛋白质印迹得到验证。由于WNT5A在UIP中的作用尚不清楚，我们用WNT5A处理正常肺成纤维细胞或UIP肺成纤维细胞，发现WNT5A增加了细胞增殖以及对H2O2诱导的细胞凋亡的相对抗性。这种作用不是通过经典的WNT/β-连环蛋白途径介导的，因为WNT5A导致同一细胞中β-连环蛋白水平降低。此外，WNT5A诱导正常肺成纤维细胞中纤连蛋白和α(5)整合素增加。总体而言，我们的数据表明，WNT5A可能在特发性肺纤维化和其他表现出UIP组织学模式的纤维化间质性肺疾病的成纤维细胞扩增和存活特征中发挥作用。
