miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-beta Receptor II.
miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-beta Receptor II.
复制标题
miR-18a-5p 通过靶向 TGF-β 受体 II 抑制胸膜下肺纤维化。
DOI：
10.1016/j.ymthe.2016.12.017
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发表时间：
2017
影响因子：
12.4
通讯作者：
Ma Wan-Li
中科院分区：
文献类型：
--
作者：
Zhang Qian;Ye Hong;Xiang Fei;Song Lin-Jie;Zhou Li-Ling;Cai Peng-Cheng;Zhang Jian-Chu;Yu Fan;Shi Huan-Zhong;Su Yunchao;Xin Jian-Bao;Ma Wan-Li
特发性肺纤维化（IPF）是一种慢性进行性肺部疾病，通常在诊断后3-5年内导致呼吸衰竭和死亡。胸膜下肺纤维化是IPF的病理学标志。博莱霉素治疗的小鼠是一种建立的肺纤维化模型。我们最近发现，博莱霉素诱导的上皮-间质转化（EMT）有助于胸膜间皮细胞（PMC）迁移和胸膜下肺纤维化。最近发现微小RNA（miRNA）表达与特发性肺纤维化的发病机制有关。然而，在PMC和胸膜下纤维化中miRNA表达的变化尚未报道。使用培养的PMC和肺纤维化动物模型，我们发现miR-18 a-5 p在用博来霉素处理的PMC中减少，并且miR-18 a-5 p的下调有助于PMC的EMT。此外，我们确定miR-18 a-5 p与转化生长因子β受体II（TGF-βRII）mRNA的3′ UTR区域结合，这与TGF-βRII表达减少和TGF-β-Smad 2/3信号转导抑制有关。miR-18 a-5 p过表达可预防博莱霉素诱导的PMC EMT，并抑制博莱霉素诱导的小鼠胸膜下纤维化。总之，我们的数据表明，下调的miR-18 a-5 p通过上调其靶点TGF-βRII介导胸膜下肺纤维化，因此，miR-18 a-5 p的过表达可能为IPF的治疗提供一种新方法。
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease that typically leads to respiratory failure and death within 3–5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of IPF. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition (EMT) contributes to pleural mesothelial cell (PMC) migration and sub-pleural pulmonary fibrosis. MicroRNA (miRNA) expression has recently been implicated in the pathogenesis of IPF. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3′ UTR region of transforming growth factor β receptor II (TGF-βRII) mRNA, and this is associated with reduced TGF-βRII expression and suppression of TGF-β-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, TGF-βRII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF.