Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, China.
Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China.
FASEB J. 2018 Oct;32(10):5285-5297. doi: 10.1096/fj.201800055R. Epub 2018 Apr 23.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic parenchymal lung disease of unknown etiology and lacks an effective intervention. Long noncoding RNAs (lncRNAs) participate in organ fibrosis and various pulmonary diseases, but the role of lncRNAs in lung fibrosis is not fully understood. In the present study, we identified that lncRNA NONMMUT021928, designated as pulmonary fibrosis-associated lncRNA (PFAL), was up-regulated in the lungs of mice with experimental lung fibrosis, and in TGF-β1-induced fibrotic lung fibroblasts. Further study showed that overexpression of PFAL promoted cell proliferation, migration, and fibroblast-myofibroblast transition. Overexpression further resulted in extracellular matrix deposition and fibrogenesis in lung fibroblasts through regulation of microRNA-18a (miR-18a). Importantly, knockdown of PFAL alleviated lung fibrosis both in vitro and in vivo. Mechanistically, our study showed that PFAL promoted lung-fibroblast activation and fibrogenesis by acting as a competing endogenous RNA for miR-18a: forced expression of PFAL inhibited the expression and activity of miR-18a, whereas silencing of PFAL had the opposite effect. Furthermore, we found that miR-18a was decreased during lung fibrosis in vitro and in vivo, as well as in patients with IPF. Moreover, knockdown of miR-18a led to fibrogenesis in lung fibroblasts, whereas enhanced expression of miR-18a attenuated TGF-β1-induced lung fibrosis by directly targeting the regulation of connecting tissue growth factor. Taken together, these results revealed the effect and mechanism of lncRNA PFAL in pulmonary fibrosis and suggested that PFAL depletion may provide a novel strategy for the treatment of lung fibrosis.-Li, X., Yu, T., Shan, H., Jiang, H., Sun, J., Zhao, X., Su, W., Yang, L., Shan, H., Liang, H. lncRNA PFAL promotes lung fibrosis through CTGF by competitively binding miR-18a.
特发性肺纤维化（IPF）是一种病因不明的慢性、进行性、纤维性肺实质疾病，缺乏有效干预措施。长链非编码 RNA（lncRNA）参与器官纤维化和各种肺部疾病，但 lncRNA 在肺纤维化中的作用尚不完全清楚。在本研究中，我们发现 lncRNA NONMMUT021928（命名为肺纤维化相关 lncRNA，PFAL）在实验性肺纤维化小鼠的肺部和 TGF-β1 诱导的纤维化肺成纤维细胞中上调。进一步研究表明，PFAL 的过表达促进了细胞增殖、迁移和成纤维细胞向肌成纤维细胞的转化。过表达进一步通过调节 microRNA-18a（miR-18a）导致肺成纤维细胞外基质沉积和纤维化。重要的是，PFAL 的敲低在体外和体内均减轻了肺纤维化。机制上，我们的研究表明，PFAL 通过作为 miR-18a 的竞争性内源性 RNA 促进肺成纤维细胞的激活和纤维化：强制表达 PFAL 抑制了 miR-18a 的表达和活性，而沉默 PFAL 则产生相反的效果。此外，我们发现 miR-18a 在体外和体内以及 IPF 患者的肺纤维化过程中均减少。此外，miR-18a 的敲低导致肺成纤维细胞纤维化，而增强表达 miR-18a 通过直接靶向连接组织生长因子的调节减轻 TGF-β1 诱导的肺纤维化。总之，这些结果揭示了 lncRNA PFAL 在肺纤维化中的作用和机制，并表明 PFAL 耗竭可能为肺纤维化的治疗提供一种新策略。
