基于内质网应激介导XBP1/Nrf2途径探讨EMT在肺纤维化中的作用及玉屏风散总苷的调控效应

肺纤维化（PF）危害严重，其确切机制未明，缺乏有效治疗手段。肺泡上皮间质转化（EMT）在PF进程中起重要作用。内质网应激（ERS）及其信号XBP1参与EMT调控，Nrf2及Snail均可诱导EMT，但XBP1与Nrf2、Snail在EMT进程中相互关系如何，迄今尚未见报道。前期研究发现，玉屏风总苷（YTG）能抑制EMT而抗肺纤维化，PF大鼠模型中EMT发生，sXBP1、Snail表达上调，uXBP1、Nrf2表达均下调；Nrf2敲除小鼠PF模型中Snail高表达；肺泡上皮细胞中siRNA沉默XBP1能抑制Snail表达而阻断EMT。据此有理由推测，ERS介导XBP1/Nrf2可调控EMT加速PF进程。为验证假说，本项目拟在Nrf2基因敲除小鼠和细胞PF模型上，探讨ERS介导XBP1/Nrf2途径在EMT进程中的作用和YTG的调控效应，探寻PF防治新靶点和药物，为中医药防治PF提供新思路。

Pulmonary fibrosis (PF) is a serious lung disease with the unknown pathogenesis and lacks of effective treatment and drugs.Alveolar epithelial-mesenchymal transition (EMT) has become an important cause of pulmonary fibrosis (PF). Endoplasmic reticulum stress (ERS) and its signal XBP1 can be involved in EMT regulation. However, the relationship of Snail, XBP1 and Nrf2 in the PF induced by EMT is still not illuminated. Previous studies showed that EMT occurred in PF rat model, the expression of sXBP1 and Snail were up-regulated, but the expression of uXBP1 and Nrf2 were down-regulated. The high expression of Snail was found in the PF model of Nrf2 knockout mice. In alveolar epithelial cells siRNA XBP1 inhibited Snail expression and blocked EMT progression. Moreover, we found that Total glycoside Yupingfeng (YTG) alleviated pulmonary fibrosis by inhibiting EMT. It is reasonable to speculate that ERS-mediated XBP1 / Nrf2 may be involved in regulating EMT processes. To verify this hypothesis, our project will investigate the regulatory mechanism of ERS-mediated XBP1-Nrf2 pathway in EMT process and the effect of YTG intervention in the Nrf2 knockout mice and the cell PF model. This study will explore the new targets and new drugs for the prevention of PF，and provide new ideas for treating PF by Traditional Chinese medicine.