平喘方调控PI3K/AKT通路对哮喘气道炎症及气道重塑的影响及其机制研究

Airway inflammation and airway remodeling is of the main pathological mechanism of bronchial asthma which is difficult to cure.Our previous research has shown that the therapeutic method of phlegm and stasis resolving and asthma relieving have regulating action on airway inflammation and airway remodeling. Our preliminary experiment showed that treatment with Pingchuan formula (PCF)downregulates RORγt, elevates Foxp3 expression which restoring Treg/Th17 balance,reduces MIP-1α and IgE level, improving airway inflammation and reducing asthma symptoms.So via the animal experiments,we will for the first time reveal that through downregulate the signaling pathways PI3K/AKT which may promote collagen also downregulates airway inflammation synthesis and further prove that maybe the important mechanism on asthma.In conclusion, our study will clarify mechanisms of PCF used to enhance therapeutic effect in asthma.

支气管哮喘难以根治，气道炎症及气道重塑是其主要病理机制。我们前期研究发现平喘方针对“痰气瘀互结”病理环节，治疗哮喘疗效确切，能够改善气道炎症和重塑，但机制不明。我们的预实验发现平喘方能降低RORγt并升高FOXp3，从而恢复Treg/Th17细胞平衡，降低巨噬细胞炎性蛋白-1α(MIP-1α)和IgE水平。而PI3K/Akt是RORγt和FOXp3的重要上游信号通路并能促进胶原纤维合成，可能是平喘方的重要作用环节。因此本研究将从两个层面系统阐述“平喘方→PI3K/AKT↓→FOXp3↑/RORγt↓→Treg/Thl7平衡→MIP-1α↓→改善哮喘气道炎症”以及“平喘方→PI3K/AKT↓ →α-SMA↓I型胶原↓→改善哮喘气道重塑”。这有助于平喘方作用机制的阐明，为改进平喘方从而进一步提高疗效提供理论依据。

本研究发现平喘方治疗哮喘的疗效与激素接近，早期应用平喘方可以控制哮喘气道炎症，延缓气道重塑进程，且随着治疗时间延长有时间累积效应，能显著改善哮喘模型小鼠肺组织病理变化。机制研究发现平喘方与地塞米松有相似的靶点及作用机制。一方面，平喘方能抑制mTOR蛋白表达，抑制PI3K/AKT信号通路，上调CD4+CD25+Treg比率，抑制RORγt的表达，上调FOXp3的表达，进而恢复Treg/Th17平衡，减少炎症因子释放，从而改善哮喘气道炎症；另一方面，平喘方调控关键信号分子p-Akt，提高E钙粘蛋白表达水平，抑制纤维连接蛋白-1表达，抑制间质化上皮α-SMA和I型胶原沉着，从而抑制哮喘气道重塑发生，上述研究为平喘方的应用提供了实验依据。