民族药白背叶楤木基于ILC2干预小鼠哮喘的作用及机制研究

In recent studies, type Ⅱ innate lymphoid cells(ILC2) is the important immune cells of asthma. IL-33, IL-25 and TSLP are the key cytokines in the activation of ILC2. IL-33/ST2 axis mediated by the interaction of IL-33 and its receptor ST2 in ILC2 is involved in the pathological process of asthma. Lisaw national medicinal plant Aralia chinensis L. var. nuda Nakai, has been used clinically for prevention and treatment of asthma, which is rich in triterpenoids. Preliminary study suggested that total saponions in Aralia chinensis L. var. nuda Nakai(TS) can significantly improve the inflammatory cell infiltration and goblet hyperplasia of asthmatic mice. In addition, it reduced the secretion of IL-33, IL-25 and TSLP in bronchoalveolar lavage fluid of asthmatic mice, which are the activation molecules of ILC2. Based on this, it is reasonable to speculate that TS may affect the pathogenesis of asthma through ILC2 and IL-33/ST2 axis. This project study the chemical composition of TS systematically，clarifying the material basis of TS for preventing asthma, clearing the anti-asthmatic effects of TS, and exploring its anti-asthmatic mechanism as the core of ILC2. Besides, this work will provide novel therapeutic strategies for asthma targeting ILC2, and provide scientific data for the development and utilization of the ethnic plant resources.

最新研究表明Ⅱ型固有淋巴细胞（ILC2）是参与哮喘发生发展的重要免疫细胞。IL-33、IL-25、TSLP为诱导ILC2活化的上游细胞因子，其中以IL-33最为关键。IL-33与ILC2表面的ST2受体相互作用形成的IL-33／ST2轴，在哮喘的病理过程中发挥重要作用。傈僳族药白背叶楤木民间用于治疗哮喘，但其活性成分和作用机制不清。我们前期研究发现，白背叶楤木总皂苷可显著改善哮喘小鼠的病理症状，同时降低哮喘小鼠肺泡灌洗液中ILC2活化的上游细胞因子IL-33、IL-25、TSLP的分泌,故推测白背叶楤木中皂苷类成分能靶向调节ILC2及IL-33／ST2轴而发挥治疗哮喘的作用。本项目拟进一步对白背叶楤木总皂苷进行化学成分研究，阐明其抗哮喘的物质基础，并探讨其以ILC2为核心的防治哮喘的作用机理，为哮喘的临床治疗提供一种靶向ILC2的新策略，也为从民族药用植物资源中开发抗哮喘药物提供科学依据。

Ⅱ型固有淋巴细胞（ILC2）是参与哮喘进程的重要免疫细胞，IL-33、IL-25、TSLP为ILC2激活因子，其中以IL-33最为关键，IL-33/ST2轴在哮喘的病理过程中发挥重要作用，因此，以ILC2为核心的机制研究对哮喘治疗有积极意义。白背叶楤木民间用于治疗哮喘，但其活性成分和作用机制不清。综合ILC2在哮喘中的关键作用及白背叶楤木的民族民间应用，本研究主要完成以下工作：（1）开展白背叶楤木药效物质基础研究，从中分离并鉴定73个化合物（AN-1~AN-73），体外活性筛选表明化合物AN-1、AN-5、AN-8具有良好的抗气道炎症活性，可显著下调IL-1β和IL-4水平；（2）白背叶楤木总苷可有效改善哮喘小鼠的气道炎症、气道黏液高分泌及气道高反应性，并抑制血清中IgE及OVA-IgE水平，明确了白背叶楤木总苷拮抗哮喘的药效；（3）进一步探究表明，白背叶楤木总苷可下调哮喘小鼠BALF中ILC2上游激活因子IL-33、IL-25、TSLP水平，抑制BALF中ILC2介导的下游2型炎症因子IL-4、IL-5、IL-9、IL-13等释放，同时减少肺组织中ILC2的数量，并抑制肺组织中IL-33/ST2轴介导相关蛋白表达，最终阐明了其以ILC2为核心干预哮喘的作用机制。本课题为哮喘的临床治疗提供一种靶向ILC2的新策略，也为从民族药用植物资源中开发抗哮喘新药物提供科学依据。