The Antifibrotic Effects and Mechanisms of MicroRNA-26a Action in Idiopathic Pulmonary Fibrosis
The Antifibrotic Effects and Mechanisms of MicroRNA-26a Action in Idiopathic Pulmonary Fibrosis
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microRNA-26a 在特发性肺纤维化中的抗纤维化作用和机制。
DOI：
10.1038/mt.2014.42
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发表时间：
2014-06-01
影响因子：
12.4
通讯作者：
Du, Zhimin
中科院分区：
文献类型：
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作者：
Liang, Haihai;Xu, Chaoqian;Du, Zhimin
特发性肺纤维化(IPF)是一种慢性、进行性、高致死性纤维性肺疾病，其特征是成纤维细胞过度增殖、细胞外基质堆积，最终导致肺功能丧失。尽管一些microRNAs(MiRs)的调节失调在IPF的病理生理过程中发挥了重要作用，但miRs在纤维化肺疾病中的作用尚不清楚。在本研究中，我们发现miR-26a在实验性肺纤维化小鼠肺组织和IPF中表达下调，导致结缔组织生长因子(CTGF)转录后下调，并诱导胶原生成。更重要的是，抑制miR-26a在体内可引起肺纤维化，而miR-26a过表达则抑制转化生长因子-β1诱导的MRC-5细胞纤维化，从而减轻小鼠实验性肺纤维化。我们的研究表明，转化生长因子-β1介导的Smad3的磷酸化下调了miR-26a的表达。此外，miR-26a通过直接靶向Smad4抑制p-Smad3的核转位，Smad4决定了p-Smad2/Smad3的核转位。综上所述，我们的实验证实了miR-26a在纤维化肺疾病中的抗纤维化作用，并为应用miR-26a防治IPF提供了新的策略。目前的研究还发现了miR-26a和p-Smad3之间的一个新的正反馈环，它参与了肺纤维化。
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high-lethality fibrotic lung disease characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, loss of lung function. Although dysregulation of some microRNAs (miRs) has been shown to play important roles in the pathophysiological processes of IPF, the role of miRs in fibrotic lung diseases is not well understood. In this study, we found downregulation of miR-26a in the lungs of mice with experimental pulmonary fibrosis and in IPF, which resulted in posttranscriptional derepression of connective tissue growth factor (CTGF), and induced collagen production. More importantly, inhibition of miR-26a in the lungs caused pulmonary fibrosis in vivo, whereas overexpression of miR-26a repressed transforming growth factor (TGF)-beta 1-induced fibrogenesis in MRC-5 cells and attenuated experimental pulmonary fibrosis in mice. Our study showed that miR-26a was downregulated by TGF-beta 1-mediated phosphorylation of Smad3. Moreover, miR-26a inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4, which determines the nuclear translocation of p-Smad2/Smad3. Taken together, our experiments demonstrated the antifibrotic effects of miR-26a in fibrotic lung diseases and suggested a new strategy for the prevention and treatment of IPF using miR-26a. The current study also uncovered a novel positive feedback loop between miR-26a and p-Smad3, which is involved in pulmonary fibrosis.