基于NLRP3炎症小体的淫羊藿补骨脂配伍加重特异质肝损伤的作用机制研究

淫羊藿补骨脂配伍是现代组方中较为常用的补益肝肾的用药形式，但近年来含淫羊藿、补骨脂的中成药制剂致肝损伤现象屡见报道。课题组前期研究发现，在免疫应激条件下，淫羊藿补骨脂配伍可显著加重肝脏损伤，同时淫羊藿次苷I、补骨脂甲素可增强NLRP3炎症小体活性，且两者组合也可明显加重肝脏损伤。由此本项目提出“当机体处于免疫应激状态时，淫羊藿次苷I、补骨脂甲素组合可协同靶向增强NLRP3炎症小体活化，诱导细胞因子风暴加重特异质肝损伤”的科学假说。本项目以NLRP3炎症小体为切入点，明确二者组合对NLRP3炎症小体组成蛋白表达及组装活化的影响，阐释其协同增强作用靶标和协同机制，并结合NLRP3基因敲除小鼠和多种免疫相关疾病动物模型，解析两者组合与机体免疫及促进NLRP3炎症小体活化的关系。本研究可为淫羊藿补骨脂临床配伍应用及相关中成药制剂的安全合理用药等提供一定的科学依据。

Epimedii Folium (EF) and Psoraleae Fructus (PF) are common modern pair for invigorating the liver and kidney. However, liver injury caused by Chinese herb preparations, including EF and PF, is frequently reported over the years. Our research team validated that combined application of EF with PF could significantly aggravate liver injury under immunological stress condition. Plus, activation of NLRP3 inflammasome was enhanced by both Icarisid I and Bavachin, and severe liver injury was induced if the two compounds were used simultaneously. Therefore, we come up with a hypothesis that joint use of Icarisid I and Bavachin might synergistically enhance the activation of NLRP3 inflammasome under immunological stress condition, which results in a “cytokine-storm-induced” idiosyncratic hepatotoxicity. This project aims to explain molecular mechanism and targets for liver injury induced by combination of Icarisid I with Bavachin, through elucidating their effect on assembly activation of NLRP3 inflammasome, and their association with immunity, and activation of NLRP3 inflammasome, based on NLRP3 knockout mice and various immune-related animal models. The current research would provide theoretical foundation for the safe and reasonable clinical application for both “EF-PF” herb pair, and EF/PF containing herb preparations.