从mTOR信号通路探讨健脾益气法改善Treg细胞功能与“扶正祛伏痰”防治哮喘的机制

Spleen-fortifying (SF) is an important therapy in Traditional Chinese Medicine (TCM) for asthma prevention. Our previous study found that astragalus, a classical SF medicine in TCM, increased Treg cells, strengthened the expression of Foxp3 and thus improved airway inflammation in asthma. It has been confirmed that Treg cells function is adjusted by mTOR signaling pathway which can be regulated by Astragaloside. Can Astragalus improve Treg cells function through mTOR signaling pathway? Does the effects of Astragalus only relate to its "personality", or belong to method of SF? We believe that method of SF can strengthen Qi to remove retained phlegm in lung of asthma, which may be a rule of asthma treatment by TCM. Is the Mechanism of SF to remove retained phlegm associated with the improvement of Treg cell function? In this study, we use a mouse model of asthma in vivo, with Treg cells from patients of asthma remission as a vitro model. Effects of interventions with Granular formulation of SF recipe and astragalus or drug serum will be observed on Treg cell function through mTORCl/S6k1 and mTORC2/Akt (S473) pathways. The study is to explore the common immunomodulatory mechanism between SF recipe and astragalus mainly focused on the regulation of Treg cell function, thus partially explaining the method of SF to remove retained phlegm and attenuate airway inflammation in asthma.

健脾益气法是中医防治哮喘的重要治法。课题组前期研究发现黄芪可上调Treg细胞比例，增加Foxp3表达水平，改善哮喘气道炎症。研究证实mTOR信号通路可影响Treg细胞功能，黄芪甲苷可调节mTOR信号通路。黄芪可否基于mTOR信号通路改善Treg细胞功能？黄芪的作用仅与该药的“个性”有关，还是健脾益气法的“共性”体现？课题组认为“健脾益气以扶正，扶正以祛伏痰”是哮喘的治则。健脾益气法“扶正祛伏痰”的机制内涵是否与改善Treg细胞功能相关？本研究以哮喘小鼠为体内模型，以哮喘缓解期患者Treg细胞为体外模型，分别以健脾益气方及黄芪颗粒或含药血清干预，观察其对Treg细胞功能和mTORCl/S6k1及mTORC2/Akt(S473)通路的影响。本项目以调节Treg细胞功能为切入点，通过探讨健脾益气方及黄芪“共性”免疫调节机理，部分阐释健脾益气法“扶正祛伏痰”的防治哮喘内涵。

健脾益气法是中医防治哮喘的重要治法。持续性气道慢性炎症是哮喘重要的发病机制，而Treg细胞功能下降是哮喘气道慢性炎症持续的重要机制。mTOR信号通路可通过调节Treg细胞功能，从而参与哮喘气道炎症的发生机制。本项目以mTORCl/S6k1及mTORC2/Akt(S473)信号通路调节Treg细胞功能为切入点，部分阐释健脾益气法防治哮喘的机制。结果发现，（1）健脾益气方，健脾益气要药黄芪及黄芪甲苷在体内研究可显著改善哮喘模型气道炎症，抑制mTORCl/S6k1信号通路，从而抑制效应性T细胞。（2）健脾益气方及黄芪含药血清在体外研究可显著促进Treg细胞增殖，改善Treg细胞抑制功能，其机制是通过同时抑制mTORCl/S6k1及mTORC2/Akt(S473)信号通路。这些研究结果支持健脾益气法是哮喘切实可行的治疗方法，其机制可能包括通过抑制mTOR信号通路，从而抑制效应性T细胞，及上调Treg细胞功能。本研究进一步证实健脾益气法对哮喘缓解期治疗作用，为推动哮喘缓解期的中医药防治提供线索。