基于p38MAPK信号通路探讨益气活血化痰法对支气管哮喘气道重塑的机制研究

Airway remodeling is the important pathological basis of the occurrence and development of bronchial asthma. In this process, the activation of inflammatory factors is closely related to p38MAPK signaling pathway. Blocking p38MAPK pathway is one of important strategies for the inhibition of airway remodeling, prevention and treatment of asthma. Based on our long-term clinical studies, we proposed a hypothesis: It was believed that the pathological basis of asthma are deficiency in origin and excess in superficiality. The former refers to the deficiency of lung, spleen and kidney, and the latter refers to stagnation of vital energy, blood stasis and phlegm condensation, which interacted with each other in complex ways and consisted in the process of asthma all the time.Our previous experimental results show that the method of replenishing qi, promoting blood circulation and resolving phlegm can effectively reduce the number of acute exacerbation of asthma, improve the lung tissue morphology of asthmatic guinea pig model, and play an important role in the regulation of immune and reduce airway inflammatory cells.We will regard the p38MAPK signal pathway as a breakthrough point to carry out in vivo and in vitro tests, which based on our previous researches. In vivo experiments, we investigated the lung function and lung morphology of asthmatic rats, expression levels of HSP27 and other related proteins and genes in p38MAPK pathway of airway smooth muscle tissue. In vitro experiments, we investigated the expression levels of ColⅢ and other related proteins and genes in the p38MAPK pathway of airway smooth muscle cells. Finally, we will explore the molecular mechanism of the method of replenishing qi, promoting blood circulation and resolving phlegm to interfere with airway remodeling of asthma, and provide theoretical basis for clinical application.

气道重塑是支气管哮喘发生发展的重要病理学基础，气道重塑过程中炎症因子的激活与p38MAPK信号通路关系密切，阻断p38MAPK 通路是阻抑气道重塑、防治哮喘的重要策略之一；我们根据长期临床研究观察，提出假说：哮病的病理基础为本虚标实，本虚为肺、脾、肾三脏亏虚，标实为气滞、血瘀、痰凝，气虚—血瘀—痰凝贯穿本病全过程；既往研究实验结果表明，益气活血化痰法能够有效减少哮喘患者急性发作次数，改善哮喘动物模型肺组织形态学变化，在调节免疫及减少气道炎症细胞等方面也起到重要作用。本项目拟在前期基础上，以p38MAPK信号通路为切入点，体内实验：研究哮喘大鼠模型肺功能及肺组织形态学，气道平滑肌组织p38MAPK通路中HSP27等相关蛋白和基因的表达水平，体外实验：研究气道平滑肌细胞p38MAPK通路中ColⅢ等相关蛋白和基因的表达水平。探究益气活血化痰法干预哮喘气道重塑的分子机制，为临床运用提供理论依据。

气道重塑是支气管哮喘发生发展的重要病理学基础，气道重塑过程中炎症因子的激活与p38MAPK信号通路关系密切，阻断p38MAPK通路是阻抑气道重塑、防治哮喘的重要策略之一。中医认为，哮病的病理基础为本虚标实，本虚为肺、脾、肾三脏亏虚，标实为气滞、血瘀、痰凝，气虚—血瘀—痰凝贯穿本病全过程；益气活血化痰是其基本治法。既往研究表明，益气活血化痰法能够有效减少哮喘患者急性发作次数，改善哮喘动物模型肺组织形态学变化，在调节免疫及减少气道炎症细胞等方面也起到重要作用。本项目在前期基础上，通过建立支气管哮喘大鼠模型和TNF-α刺激气道平滑肌细胞，体内外实验结合，运用ELISA、Western Blot、RT-qPCR等分子生物学技术，以p38MAPK信号通路为切入点，探讨益气活血化痰法干预哮喘气道重塑的分子机制。结果表明益气活血化痰法之代表方药哮喘平冲剂通过抑制p38MAPK信号通路，减轻气道炎症，抑制气道平滑肌细胞的异常增殖，维持正常的凋亡平衡，阻抑气道重塑，从而有效改善支气管哮喘大鼠肺功能以及肺组织结构，改善哮喘症状。为其临床应用提供科学依据，对于进一步优化中医药防治哮喘的临床策略亦具有重要意义。