Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
FASEB J. 2013 Jun;27(6):2382-91. doi: 10.1096/fj.12-219493. Epub 2013 Mar 1.
The expression of smooth muscle actin-α (SMA-α) by fibroblasts defines phenotypic transition to myofibroblasts and is a primary contributor to contractile force generation by these differentiated cells. Although the regulation of SMA-α expression has been the focus of many studies, there is presently only limited information concerning miRNA regulation of lung myofibroblast differentiation and the involvement of these miRNAs in pulmonary fibrosis. To determine the role of miR-145 in regulating lung myofibroblast differentiation and pulmonary fibrosis. Wild-type and miR-145(-/-) mice were studied. Lung fibrosis models and cell culture systems were employed. miR-145 mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic and contractile activities of lung fibroblasts were determined. We found that miR-145 expression is upregulated in TGF-β1-treated lung fibroblasts. miR-145 expression is also increased in the lungs of patients with idiopathic pulmonary fibrosis as compared to in normal human lungs. Overexpression of miR-145 in lung fibroblasts increased SMA-α expression, enhanced contractility, and promoted formation of focal and fibrillar adhesions. In contrast, miR-145 deficiency diminished TGF-β1 induced SMA-α expression. miR-145 did not affect the activity of TGF-β1, but promoted the activation of latent TGF-β1. miR-145 targets KLF4, a known negative regulator of SMA-α expression. Finally, we found that miR-145(-/-) mice are protected from bleomycin-induced pulmonary fibrosis. miR-145 plays an important role in the differentiation of lung myofibroblasts. miR-145 deficiency is protective against bleomycin-induced lung fibrosis, suggesting that miR-145 may be a potential target in the development of novel therapies to treat pathological fibrotic disorders.
平滑肌肌动蛋白-α（SMA-α）在成纤维细胞中的表达定义了表型向肌成纤维细胞的转化，是这些分化细胞产生收缩力的主要贡献者。尽管 SMA-α表达的调控一直是许多研究的焦点，但目前关于 miRNA 对肺肌成纤维细胞分化的调控以及这些 miRNA 参与肺纤维化的信息非常有限。
为了确定 miR-145 在调节肺肌成纤维细胞分化和肺纤维化中的作用，研究了野生型和 miR-145（-/-）小鼠。采用肺纤维化模型和细胞培养系统。将 miR-145 模拟物或抑制剂转染到肺成纤维细胞中。测定肺成纤维细胞的纤维生成和收缩活性。
我们发现 miR-145 在 TGF-β1 处理的肺成纤维细胞中表达上调。与正常人类肺相比，特发性肺纤维化患者的肺中 miR-145 的表达也增加。肺成纤维细胞中 miR-145 的过表达增加了 SMA-α 的表达，增强了收缩力，并促进了焦点和纤维状粘连的形成。相比之下，miR-145 缺乏减少了 TGF-β1 诱导的 SMA-α 表达。miR-145 不影响 TGF-β1 的活性，但促进了潜伏 TGF-β1 的激活。miR-145 的靶标是 KLF4，KLF4 是 SMA-α 表达的已知负调节剂。最后，我们发现 miR-145（-/-）小鼠对博莱霉素诱导的肺纤维化有保护作用。
miR-145 在肺肌成纤维细胞的分化中起着重要作用。miR-145 缺乏对博莱霉素诱导的肺纤维化具有保护作用，这表明 miR-145 可能是治疗病理性纤维性疾病的新型治疗方法的潜在靶点。
