Idiopathic pulmonary fibrosis (IPF), a progressive disorder of unknown etiology, is characterized by pathological lung fibroblast activation and proliferation resulting in abnormal deposition of extracellular matrix proteins within the lung parenchyma. The pathophysiological roles of exosomal microRNAs in pulmonary fibrosis remain unclear; therefore, we aimed to identify and characterize fibrosis-responsive exosomal microRNAs. We used microRNA array analysis and profiled the expression of exosome-derived miRNA in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. The effect of microRNAs potentially involved in fibrosis was then evaluated in vivo and in vitro. The expression of exosomal microRNA-16 was increased by up to 8.0-fold on day 14 in bleomycin-treated mice, compared to vehicle-treated mice. MicroRNA-16 mimic administration on day 14 after bleomycin challenge ameliorated pulmonary fibrosis and suppressed lung and serum expression of secreted protein acidic and rich in cysteine (SPARC). Pretreatment of human lung fibroblasts with the microRNA-16 mimic decreased the expression of rapamycin-insensitive companion of mTOR (Rictor) and TGF-β1–induced expression of SPARC. This is the first study reporting the anti-fibrotic properties of microRNA-16 and demonstrating that these effects occur via the mTORC2 pathway. These findings support that microRNA-16 may be a promising therapeutic target for IPF.

特发性肺纤维化（IPF）是一种病因不明的进行性疾病，其特征是病理性肺成纤维细胞活化和增殖，导致肺实质内细胞外基质蛋白异常沉积。外泌体microRNA在肺纤维化中的病理生理作用尚不清楚。因此，我们旨在鉴定和表征纤维化反应性外泌体微小RNA。我们使用微RNA阵列分析，并分析了表现出博来霉素诱导的肺纤维化的C57BL / 6小鼠血清中外源性miRNA的表达。然后在体内和体外评价可能参与纤维化的microRNA的作用。外来体的表达的微RNA - 16与媒介物处理的小鼠相比，博来霉素处理的小鼠在第14天的TNF-α升高高达8.0倍。微RNA - 16对博莱霉素攻击后14天模拟给药改善肺纤维化和分泌蛋白酸性和富含半胱氨酸（SPARC）抑制肺和血清表达。用microRNA - 16模拟物预处理人肺成纤维细胞可降低雷帕霉素不敏感的mTOR（Rictor）伴侣的表达和TGF-β1诱导的SPARC的表达。这是第一项报道microRNA - 16的抗纤维化特性并证明这些作用是通过mTORC2途径发生的研究。这些发现支持microRNA- 16可以是用于IPF有希望的治疗靶标。