Bleomycin-enhanced alternative splicing of fibroblast growth factor receptor 2 induces epithelial to mesenchymal transition in lung fibrosis
Bleomycin-enhanced alternative splicing of fibroblast growth factor receptor 2 induces epithelial to mesenchymal transition in lung fibrosis
复制标题
博莱霉素增强的成纤维细胞生长因子受体2选择性剪接诱导肺纤维化中的上皮细胞向间质细胞转变
DOI：
10.1042/bsr20180445
复制
发表时间：
2018-12-21
影响因子：
4
通讯作者：
Wang, Jian-Min
中科院分区：
文献类型：
--
作者：
Chen, Kui-Jun;Li, Qing;Wang, Jian-Min
特发性肺纤维化（IPF）是一个重要的公共卫生问题，鉴于其病因学知之甚少，治疗选择很少;然而，肺细胞的上皮间质转化（EMT）已被认为是一个因素。本研究旨在利用博莱霉素（BLM）诱导的肺纤维化和转基因小鼠模型，探讨EMT介导的肺纤维化的潜在机制，重点研究成纤维细胞生长因子受体2（FGFR 2）的选择性剪接。我们采用BLM诱导和表面活性蛋白C（SPC）-Cre和LacZ双转基因小鼠模型。结果表明，EMT发生于肺纤维化过程中。BLM抑制上皮细胞剪接调节蛋白1（ESRP 1）的表达，导致FGFR 2选择性剪接增强间充质异构体IIIc。BLM诱导的肺纤维化也与TGF-β/Smad信号通路的激活有关。这些发现对合理制定治疗IPF的靶向策略具有意义。
Idiopathic pulmonary fibrosis (IPF) is an important public health problem, and it has few treatment options given its poorly understood etiology; however, epithelial to mesenchymal transition (EMT) of pneumocytes has been implicated as a factor. Herein, we aimed to explore the underlying mechanisms of lung fibrosis mediated by EMT, with a focus on the alternative splicing of fibroblast growth factor receptor 2 (FGFR2), using bleomycin (BLM)-induced lung fibrotic and transgenic mouse models. We employed BLM-induced and surfactant protein C (SPC)-Cre and LacZ double transgenic mouse models. The results showed that EMT occurred during lung fibrosis. BLM inhibited the expression of epithelial splicing regulatory protein 1 (ESRP1), resulting in enhanced alternative splicing of FGFR2 to the mesenchymal isoform IIIc. BLM-induced lung fibrosis was also associated with the activation of TGF-β/Smad signaling. These findings have implications for rationally targetted strategies to therapeutically address IPF.