基于Nrf2介导的HMGB1/β-catenin途径探讨玉屏风散总苷在上皮间质转化中的调控机制

Pulmonary fibrosis (PF) is a serious lung disease with the unknown pathogenesis and lacks of effective treatment and drugs. Nrf2 is a protective transcription factor of oxidative stress, which plays an important role in regulating PF progression. It was found out that HMGB1 and β-catenin pathway are closely related to epithelial-mesenchymal transformation (EMT) in PF. However, there has rarely about the relationship among Nrf2, HMGB1 and β-catenin pathway in regulating EMT so far. Previous studies have found that total glycosides of Yupingfeng (YTG) is capable of anti-PF action through down-regulation of HMGB1, and inhibition of β-catenin can also reduce the expression of HMGB1 in vitro. Moreover, the expression of Nrf2 is up-regulated in PF model, and the inhibition of Nrf2 could increase the degree of PF. Here, we hypothesize that Nrf2 could intensify the process of PF through HMGB1 /β-catenin pathway. To verify this hypothesis, we intend to explore the expression of HMGB1 and β-catenin in Nrf2-/- and Nrf2+/+ PF model, discuss the regulation mechanism of Nrf2 and the intervention effect of YTG, find the new targets and drugs for PF, and provide new ideas for PF treatment with TCM.

肺纤维化（PF）危害严重，发病机制未明，缺乏有效的治疗手段。Nrf2是氧化应激中起保护性作用的转录因子，在肺纤维化中起关键调节作用。HMGB1以及β-catenin通路在上皮间质转化（EMT）中均发挥重要作用。但Nrf2与HMGB1及β-catenin通路在EMT进程中的关系如何，迄今国内外尚未见报道。前期研究发现，玉屏风总苷（YTG）通过下调HMGB1抗肺纤维化，体外抑制β-catenin通路可降低HMGB1的表达；大鼠PF模型中Nrf2的表达上调，细胞水平Nrf2沉默后，纤维化程度增加。结合文献和既往研究基础，我们推测Nrf2可能通过HMGB1/β-catenin通路加剧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Nrf2对HMGB1及β-catenin的调控机制和YTG的干预作用，以寻求PF的新靶点和新药物，为中医药防治PF提供新思路。

肺纤维化（PF）危害严重，发病机制未明，缺乏有效的治疗手段。Nrf2是氧化应激中起保护性作用的转录因子，在肺纤维化中起关键调节作用。HMGB1以及β-catenin通路在上皮间质转化（EMT）和成纤维细胞向肌成纤维细胞的分化(FMD)中均发挥重要作用。但Nrf2与HMGB1及β-catenin通路在EMT和FMD进程中的关系如何，迄今国内外尚未见报道。本项目利用博来霉素在Nrf2敲除小鼠上建立肺纤维化模型，并在肺泡上皮细胞和肺成纤维细胞上分别构建EMT和FMD模型，在整体、细胞和分子水平探讨Nrf2调节EMT和FMD的分子机制。结果发现，Nrf2通过抑制HMGB1蛋白表达减轻EMT进程；同时Nrf2可通过Wnt3a/β-catenin通路抑制FMD进程。以上研究进一步阐明了肺纤维化的发病机制，为临床防治肺纤维化提供新思路和新方法。