Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Chengdu Medical College, No. 278, Baoguang Avenue, Xindu District, Chengdu, Sichuan 610500, China; Chengdu Medical College, No. 783, Xindu Avenue, Xindu District, Chengdu, Sichuan 610500, China.
Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Chengdu Medical College, No. 278, Baoguang Avenue, Xindu District, Chengdu, Sichuan 610500, China.
Peptides. 2022 Sep;155:170842. doi: 10.1016/j.peptides.2022.170842. Epub 2022 Jul 22.
Pulmonary fibrosis, a severe condition that can progress to respiratory failure and death, is characterized by aberrant activation/proliferation of fibroblasts and excessive extracellular matrix (ECM) deposition and has limited therapeutic options. Identifying novel mediators of pulmonary fibrosis is currently needed to facilitate the development of more effective therapeutic strategies targeting pulmonary fibrosis. The present study was designed to investigate whether transforming growth factor-β (TGF-β) induced protein (TGFBI), an extracellular matrix protein, regulates pulmonary fibrosis in vitro and in vivo and the possible mechanism of actions. It was found that protein expressions of TGFBI were significantly upregulated and G-protein signaling modulator 2 (GPSM2) expression downregulated in fibrotic lung tissues from bleomycin (BLM)-induced rats and TGF-β1-stimulated human lung IMR-90 fibroblasts. Either silencing TGFBI with specific siRNA or treatment with the TGF-β signaling inhibitor SB431542 significantly inhibited TGF-β1-induced fibrotic effects and dysregulation of GPSM2 and Snail expressions in IMR-90 fibroblasts. Moreover, GPSM2 overexpression also inhibited TGF-β1-induced fibrotic effects and Snail upregulation in IMR-90 fibroblasts. Silencing Snail with specific siRNA attenuated TGF-β1-induced fibrotic effects. Therefore, our findings suggest that the extracellular matrix protein TGFBI mediates pulmonary fibrosis through regulation of the GPSM2/Snail axis, which identifies TGFBI as a novel mediator of pulmonary fibrosis and may be a potential therapeutic target for the treatment of pulmonary fibrosis.
肺纤维化是一种严重的疾病，可进展为呼吸衰竭和死亡，其特征是成纤维细胞的异常激活/增殖以及细胞外基质（ECM）的过度沉积，并且治疗选择有限。目前需要确定肺纤维化的新介质，以促进针对肺纤维化的更有效的治疗策略的发展。本研究旨在研究转化生长因子-β（TGF-β）诱导蛋白（TGFBI），一种细胞外基质蛋白，是否在体外和体内调节肺纤维化以及可能的作用机制。研究发现，博莱霉素（BLM）诱导的大鼠肺纤维化组织和 TGF-β1 刺激的人肺 IMR-90 成纤维细胞中 TGFBI 的蛋白表达明显上调，G 蛋白信号调节剂 2（GPSM2）表达下调。用特异性 siRNA 沉默 TGFBI 或用 TGF-β 信号抑制剂 SB431542 处理可显著抑制 TGF-β1 诱导的 IMR-90 成纤维细胞的纤维化效应以及 GPSM2 和 Snail 表达的失调。此外，GPSM2 的过表达也抑制了 IMR-90 成纤维细胞中 TGF-β1 诱导的纤维化效应和 Snail 的上调。用特异性 siRNA 沉默 Snail 可减弱 TGF-β1 诱导的纤维化效应。因此，我们的研究结果表明，细胞外基质蛋白 TGFBI 通过调节 GPSM2/Snail 轴介导肺纤维化，这表明 TGFBI 是肺纤维化的一种新介质，可能是肺纤维化治疗的潜在治疗靶点。
