miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence
miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence
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DOI：
10.1165/rcmb.2016-0163oc
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发表时间：
2017-02-01
影响因子：
6.4
通讯作者：
Liu, Gang
中科院分区：
文献类型：
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作者：
Cui, Huachun;Ge, Jing;Liu, Gang
细胞衰老与多种病理学有关。然而，关于这一过程在组织纤维化中的作用存在相互矛盾的证据。尽管microRNA的失调是肺纤维化发病机制中的关键机制，但目前尚不清楚microRNA是否通过调节疾病中的细胞衰老发挥作用。在这项研究中，我们发现miR-34 a在特发性肺纤维化患者和实验性肺纤维化小鼠的肺中表现出更高的表达，其主要定位于肺成纤维细胞。更重要的是，miR-34 a在人和小鼠肺肌成纤维细胞中均显著上调。我们发现，miR-34 a消融的小鼠在纤维化肺损伤后比野生型动物发生更严重的肺纤维化。从机制上讲，我们发现miR-34 a诱导肺成纤维细胞衰老表型，因为这种microRNA增加了衰老相关的β-半乳糖苷酶活性，增强了衰老标志物的表达，并降低了细胞增殖能力。一致地，我们发现与野生型动物相比，来自miR-34 a缺陷小鼠纤维化肺的原代肺成纤维细胞具有减少的衰老表型和增强的抗凋亡性。我们还鉴定了可能介导其诱导肺成纤维细胞衰老活性的多种miR-34 a靶点。总之，我们的数据表明，miR-34 a通过负反馈机制发挥作用，通过促进肺成纤维细胞的衰老来抑制肺中的纤维化反应。
Cellular senescence has been implicated in diverse pathologies. However, there is conflicting evidence regarding the role of this process in tissue fibrosis. Although dysregulation of microRNAs is a key mechanism in the pathogenesis of lung fibrosis, it is unclear whether microRNAs function by regulating cellular senescence in the disease. In this study, we found that miR-34a demonstrated greater expression in the lungs of patients with idiopathic pulmonary fibrosis and in mice with experimental pulmonary fibrosis, with its primary localization in lung fibroblasts. More importantly, miR-34a was up-regulated significantly in both human and mouse lung myofibroblasts. We found that mice with miR-34a ablation developed more severe pulmonary fibrosis than did wild-type animals after fibrotic lung injury. Mechanistically, we found that miR-34a induced a senescent phenotype in lung fibroblasts because this microRNA increased senescence-associated beta-galactosidase activity, enhanced expression of senescence markers, and decreased cell proliferative capacities. Consistently, we found that primary lung fibroblasts from fibrotic lungs of miR-34a-deficient mice had a diminished senescent phenotype and enhanced resistance to apoptosis as compared with those from wild-type animals. We also identified multiple miR-34a targets that likely mediated its activities in inducing senescence in lung fibroblasts. In conclusion, our data suggest that miR-34a functions through a negative feedback mechanism to restrain fibrotic response in the lungs by promoting senescence of pulmonary fibroblasts.