Qiu Jing, Ma Chunlan, Dai Wenjing, Fang Enrong, Li Wancheng, Yang Fan
Chengdu Medical College, No. 783, Xindu Avenue, Xindu District, Chengdu, 610500, Sichuan, China; Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Chengdu Medical College, No. 278, Baoguang Avenue, Xindu District, Chengdu, 610500, Sichuan, China; Key Laboratory of Geriatic Respiratory Diseases of Sichuan Higher Education Institutes, No. 278, Baoguang Avenue, Xindu District, Chengdu , 610500, Sichuan, China.
Chengdu Medical College, No. 783, Xindu Avenue, Xindu District, Chengdu, 610500, Sichuan, China; Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Chengdu Medical College, No. 278, Baoguang Avenue, Xindu District, Chengdu, 610500, Sichuan, China; Key Laboratory of Geriatic Respiratory Diseases of Sichuan Higher Education Institutes, No. 278, Baoguang Avenue, Xindu District, Chengdu , 610500, Sichuan, China.
Arch Biochem Biophys. 2022 Jan 15;715:109082. doi: 10.1016/j.abb.2021.109082. Epub 2021 Nov 10.
Pulmonary fibrosis is a severe condition with limited therapeutic options and characterized by increased fibroblast activation and progressive accumulation of extracellular matrix. Ghrelin, a gastrointestinal hormone, has been reported to possess protective roles in lung diseases including pulmonary fibrosis. However, the precise mechanisms underlying the protective effects of ghrelin remain unknown. The present study was designed to investigate the effects of ghrelin on transforming growth factor-β1 (TGF-β1)-induced pulmonary fibrosis in vitro and in vivo and the possible mechanism of action. It was found that ghrelin significantly attenuated TGF-β1-induced fibrotic responses in human lung fibroblast (IMR-90) cells and bleomycin (BLM)-induced fibrotic lung tissues. Meanwhile, ghrelin decreased the expressions of miR-125a-5p and phosphorylated smad2/3 and increased protein expressions of Kruppel-like factor 13 (KLF13) in vivo and in vitro. Ghrelin-induced anti-fibrotic effects and smad2/3 downregulation in TGF-β1-stimulated IMR-90 cells were markedly reversed by miR-125a-5p mimics and KLF13 siRNA. Furthermore, miR-125a-5p directly targeted KLF13 in IMR-90 cells. Our findings suggest that ghrelin attenuates TGF-β1-induced pulmonary fibrosis via the miR-125a-5p/KLF13 axis, which supports ghrelin as a new therapeutic agent against pulmonary fibrosis by antagonizing the TGF-β1 signaling pathway.
肺纤维化是一种严重疾病，治疗选择有限，其特征为成纤维细胞活化增加和细胞外基质进行性积聚。胃饥饿素是一种胃肠激素，据报道在包括肺纤维化在内的肺部疾病中具有保护作用。然而，胃饥饿素发挥保护作用的确切机制尚不清楚。本研究旨在探讨胃饥饿素在体外和体内对转化生长因子-β1（TGF-β1）诱导的肺纤维化的影响及其可能的作用机制。研究发现，胃饥饿素可显著减轻TGF-β1诱导的人肺成纤维细胞（IMR-90）的纤维化反应以及博来霉素（BLM）诱导的肺纤维化组织的纤维化反应。同时，胃饥饿素在体内和体外均可降低miR-125a-5p的表达以及磷酸化smad2/3的水平，并增加Kruppel样因子13（KLF13）的蛋白表达。miR-125a-5p模拟物和KLF13 siRNA可显著逆转胃饥饿素在TGF-β1刺激的IMR-90细胞中诱导的抗纤维化作用和smad2/3下调。此外，miR-125a-5p在IMR-90细胞中直接靶向KLF13。我们的研究结果表明，胃饥饿素通过miR-125a-5p/KLF13轴减轻TGF-β1诱导的肺纤维化，这支持胃饥饿素作为一种通过拮抗TGF-β1信号通路来治疗肺纤维化的新型治疗药物。
