S1PR3 deficiency alleviates radiation‐induced pulmonary fibrosis through the regulation of epithelial–mesenchymal transition by targeting miR‐495‐3p

作者：Linjing Gong, Xu Wu, Xinyi Li, Xiaoying Ni, Wenyu Gu, Xinyuan Wang, Haiying Ji, Lijuan Hu, Lei Zhu · 发表于：Journal of Cellular Physiology · 年份：2019 · DOI：10.1002/jcp.29138 · 被引用次数：34 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Effects of Radiation Exposure、Chronic Obstructive Pulmonary Disease (COPD) Research

Radiation-induced pulmonary fibrosis (RIPF) is a life-threatening complication of thoracic radiotherapy, which contributes to continued deterioration in pulmonary function. Sphingosine-1 phosphate receptor 3 (S1PR3) has been identified as a crucial molecule in fibrosis. Accumulating evidence indicated that the inhibition of the S1PRs ameliorates fibrogenesis. Thus, this study aims to explore whether S1PR3 participates in RIPF and elucidates the molecular mechanisms underlying S1PR3-modulated epithelial-mesenchymal transition (EMT) in transforming growth factor-β1-induced pulmonary epithelia. A recombinant adeno-associated viral-mediated S1PR3 (AAV-S1PR3) gene therapy analyzed the effect of S1PR3 gene deficiency on the altered histology structure and molecular mechanisms in the lung of mice with whole-lung irradiation. Compared with the AAV-negative control mice, AAV-mediated S1PR3 knockdown in the lung of mice attenuated pulmonary fibrosis induced by the radiation, as indicated by the alleviation of collagen accumulation, lessened histopathological alterations, and the suppression of inflammatory cells infiltration. S1PR3 deficiency reversed the RIPF concomitantly with abrogated EMT-related protein (α-smooth muscle actin). Consistently, S1PR3-deficient pulmonary epithelia inhibited the EMT process changes and fibrosis formation. Furthermore, S1PR3 was designated as one of the target genes for microRNA-495-3p (miR-495-3p). The inhibition of miR-495-3p promoted the expression o...