Department of Internal Medicine, Jiangxi Provincial Chest Hospital, Nanchang, Jiangxi, China.
Department of Cardiology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
J Cell Biochem. 2019 Mar;120(3):2983-2993. doi: 10.1002/jcb.27038. Epub 2018 Dec 9.
Pulmonary fibrosis (PF) is a fibroproliferative disease that can eventually lead to fatal lung failure. It is characterized by abnormal proliferation of fibroblasts, dysregulated fibroblast differentiation to myofibroblast, and disorganized collagen and extracellular matrix production, deposition and degradation. There is still a lack of effective treatment strategies for PF. Extracellular high-mobility group box protein 1 (HMGB1) induces PF through NF-κB-mediated TGF-β1 release. Herein, we first validate the suppressive effect of HMGB1 knockdown on TGF-β1-induced α-smooth muscle actin (α-SMA) and collagen I protein expression. In PF, miRNAs exert different effects through targeting various downstream target messenger RNAs. We searched an online database for dysregulated miRNAs in PF tissues; among them, miR-627 was predicted by online tools to target HMGB1 to inhibit its expression. miR-627 overexpression could partially reverse TGF-β1-induced normal human lung fibroblast proliferation, as well as α-SMA and collagen I protein expression. miR-627 inhibition could partially reverse the suppressive effect of HMGB1 knockdown on TGF-β1-induced α-SMA and collagen I protein expression through direct binding to the 3'-untranslated region of HMGB1. Moreover, miR-627/HMGB1 affected TGF-β1 release through RAGE/NF-κB signaling; miR-627/HMGB1 and RAGE/NF-κB signaling formed a regulatory loop to modulate TGF-β1-induced PF in vitro. In conclusion, miR-627 may be a potential agent that targets HMGB1 to inhibit its expression, thereby improving TGF-β1-induced PF in vitro.
肺纤维化 (PF) 是一种纤维增生性疾病，最终可导致致命性肺衰竭。其特征为成纤维细胞异常增殖、成纤维细胞向肌成纤维细胞分化失调以及胶原和细胞外基质的产生、沉积和降解紊乱。目前针对 PF 仍缺乏有效的治疗策略。细胞外高迁移率族蛋白 B1 (HMGB1) 通过 NF-κB 介导的 TGF-β1 释放诱导 PF。在此，我们首先验证了 HMGB1 敲低对 TGF-β1 诱导的α-平滑肌肌动蛋白 (α-SMA) 和胶原 I 蛋白表达的抑制作用。在 PF 中，miRNAs 通过靶向各种下游靶信使 RNA 发挥不同的作用。我们在在线数据库中搜索 PF 组织中失调的 miRNAs；其中，在线工具预测 miR-627 通过靶向 HMGB1 抑制其表达。miR-627 过表达可部分逆转 TGF-β1 诱导的正常人肺成纤维细胞增殖，以及α-SMA 和胶原 I 蛋白表达。miR-627 抑制可通过直接结合 HMGB1 的 3'UTR 部分逆转 HMGB1 敲低对 TGF-β1 诱导的α-SMA 和胶原 I 蛋白表达的抑制作用。此外，miR-627/HMGB1 通过 RAGE/NF-κB 信号影响 TGF-β1 的释放；miR-627/HMGB1 和 RAGE/NF-κB 信号形成一个调控环路，以体外调节 TGF-β1 诱导的 PF。总之，miR-627 可能是一种通过靶向 HMGB1 抑制其表达从而改善体外 TGF-β1 诱导的 PF 的潜在药物。
