Department of Occupational Medicine and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
The Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Jiangsu 214003, China.
Ecotoxicol Environ Saf. 2021 Sep 1;220:112372. doi: 10.1016/j.ecoenv.2021.112372. Epub 2021 May 31.
Silicosis is a devastating interstitial lung disease arising from long-term exposure to inhalable silica. Regrettably, no therapy currently can effectively reverse the silica-induced fibrotic lesion. Emerging evidence has indicated that the dysregulation of microRNAs is involved in silica-induced pulmonary fibrosis. The aim of this study is to explore the expression pattern and underlying mechanisms of miR-770-5p in silica-induced pulmonary fibrosis. Consistent with our previous miRNA microarray analysis, the results of qRT-PCR showed that miR-770-5p expression was downregulated in silica-induced pulmonary fibrosis in humans and animal models. Administration of miR-770-5p agomir significantly reduced the fibrotic lesions in the lungs of mice exposed to silica dust. MiR-770-5p also exhibited a dramatic reduction in TGF-β1-activated human pulmonary fibroblasts (MRC-5). Transfection of miR-770-5p mimics significantly decreased the viability, migration ability, and S/G0 phase distribution, as well as the expression of fibronectin, collagen I, and α-SMA in TGF-β1-treated MRC-5 cells. Transforming growth factor-β receptor 1 (TGFBR1) was confirmed as a direct target of regulation by miR-770-5p. The expression of TGFBR1 was significantly increased in pulmonary fibrosis. Knockdown of TGFBR1 blocked the transduction of the TGF-β1 signaling pathway and attenuated the activation of MRC-5 cells, while overexpression of TGFBR1 effectively restored the activation of MRC-5 cells inhibited by miR-770-5p. Together, our results demonstrated that miR-770-5p exerted an anti-fibrotic effect in silica-induced pulmonary fibrosis by targeting TGFBR1. Targeting miR-770-5p might provide a new therapeutic strategy to prevent the abnormal activation of pulmonary fibroblasts in silicosis.
硅肺是一种由长期吸入可吸入二氧化硅引起的破坏性间质性肺疾病。遗憾的是，目前尚无有效的治疗方法可以逆转二氧化硅引起的纤维化病变。新出现的证据表明，microRNAs 的失调参与了二氧化硅诱导的肺纤维化。本研究旨在探讨 miR-770-5p 在二氧化硅诱导的肺纤维化中的表达模式及其潜在机制。与我们之前的 miRNA 微阵列分析一致，qRT-PCR 的结果表明，miR-770-5p 在人类和动物模型的二氧化硅诱导的肺纤维化中表达下调。给予 miR-770-5p 激动剂可显著减少暴露于二氧化硅粉尘的小鼠肺部的纤维化病变。miR-770-5p 也显著降低了 TGF-β1 激活的人肺成纤维细胞（MRC-5）的活性。转染 miR-770-5p 模拟物可显著降低 TGF-β1 处理的 MRC-5 细胞的活力、迁移能力和 S/G0 期分布，以及纤连蛋白、胶原 I 和 α-SMA 的表达。转化生长因子-β受体 1（TGFBR1）被确认为 miR-770-5p 调节的直接靶标。TGFBR1 在肺纤维化中表达显著增加。敲低 TGFBR1 阻断了 TGF-β1 信号通路的转导，减弱了 MRC-5 细胞的激活，而过表达 TGFBR1 则有效恢复了 miR-770-5p 抑制的 MRC-5 细胞的激活。总之，我们的结果表明，miR-770-5p 通过靶向 TGFBR1 发挥抗纤维化作用在二氧化硅诱导的肺纤维化中。靶向 miR-770-5p 可能为预防硅肺中肺成纤维细胞的异常激活提供一种新的治疗策略。
