Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Mol Ther. 2012 Jun;20(6):1251-60. doi: 10.1038/mt.2012.36. Epub 2012 Mar 6.
Loss of microRNA-29 (miR-29) is known to be a mechanism of transforming growth factor-β (TGF-β)-mediated pulmonary fibrosis, but the therapeutic implication of miR-29 for pulmonary fibrosis remains unexplored. The present study investigated whether miR-29 had therapeutic potential for lung disease induced by bleomycin in mice. In addition, the signaling mechanisms that regulated miR-29 expression were investigated in vivo and in vitro. We found that miR-29 was a downstream target gene of Smad3 and negatively regulated by TGF-β/Smad signaling in fibrosis. This was evidenced by the findings that mice or pulmonary fibroblasts null for Smad3 were protected against bleomycin or TGF-β1-induced loss of miR-29 along with fibrosis in vivo and in vitro. Interestingly, overexpression of miR-29 could in turn negatively regulated TGF-β and connective tissue growth factor (CTGF) expression and Smad3 signaling. Therefore, Sleeping Beauty (SB)-mediated miR-29 gene transfer into normal and diseased lung tissues was capable of preventing and treating pulmonary fibrosis including inflammatory macrophage infiltration induced by bleomycin in mice. In conclusion, miR-29 is negatively regulated by TGF-β/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis.
已知微小 RNA-29（miR-29）的缺失是转化生长因子-β（TGF-β）介导的肺纤维化的一种机制，但 miR-29 对肺纤维化的治疗意义仍未得到探索。本研究旨在探讨 miR-29 是否对博来霉素诱导的小鼠肺部疾病具有治疗潜力。此外，还在体内和体外研究了调节 miR-29 表达的信号机制。我们发现 miR-29 是 Smad3 的下游靶基因，并且 TGF-β/Smad 信号通路负调控纤维化过程中的 miR-29 表达。这一发现的证据是，Smad3 缺失的小鼠或肺成纤维细胞在体内和体外都能抵抗博来霉素或 TGF-β1 诱导的 miR-29 缺失以及纤维化。有趣的是，miR-29 的过表达反过来又能负调控 TGF-β 和结缔组织生长因子（CTGF）的表达以及 Smad3 信号通路。因此，睡眠美人（SB）介导的 miR-29 基因转移到正常和病变的肺组织中，能够预防和治疗博来霉素诱导的小鼠肺部纤维化，包括炎症性巨噬细胞浸润。总之，miR-29 受 TGF-β/Smad3 负调控，对肺纤维化具有治疗潜力。SB 介导的 miR-29 基因治疗是一种与纤维化相关的肺部疾病的非侵入性治疗策略。
