白芍通过调控M2巨噬细胞极化有效缓解何首乌引发的特异质肝损伤

Paeoniae Radix Alba effectively attenuates Polygonum multiflorum Thunb.-induced idiosyncratic liver injury by modulating M2 macrophage polarization

特异质药物性肝损伤(IDILI)是一种因药物引起的严重不良反应,通常发生在少数易感人群中。何首乌(PM)虽是一个常用的补益药,但许多临床数据已证明PM会引发IDILI。大多数IDILI的发生与机体免疫应激相关,然而对于PM导致IDILI的内在机制仍尚未被阐明。白芍(PRA)在临床上常与其他中药配伍,具有增效减毒缓解炎症等功效。但PRA是否能够缓解PM引发的肝损伤及内在机制仍未可知。在本研究中,通过网络药理学分析预测了PRA配伍PM在天然免疫中的相关靶点可能与巨噬细胞极化相关。同时采用非肝毒性剂量的LPS复制免疫应激模型,通过肝功能指标及病理等结果显示,当PM与PRA联用后,肝损伤的程度有所改善,相关促炎因子TNF-α和IL-6下降,M2巨噬细胞相关因子也有所上升。在体外,PM抑制了小鼠骨髓来源巨噬细胞(BMDMs)中IL-4诱导的Arg1及M2巨噬细胞标记物的表达,PRA则能够促进M2巨噬细胞极化,当二者配伍时,PRA可以改善PM对M2巨噬细胞极化的抑制作用。总之,这些研究结初步表明PRA能够通过促进M2巨噬细胞极化,降低炎症因子的表达,从而缓解PM引发的肝损伤,为解决何首乌引发的IDILI提供了新的思路和方案。

Objective:Polygonum multiflorum Thunb.(PM)is a commonly used tonic herb known to cause idiosyncratic drug-induced liver injury(IDILI).This study explored the detoxification effects and potential mechanisms of action of Paeoniae Radix Alba(PRA)on PM-induced IDILI.Methods:Network pharmacology analysis was utilized to predict the related targets of“PRA-PM-innate immunity.”A non-hepatotoxic lipopolysaccharide(LPS)and PM-induced IDILI model was used to evaluate the detoxification effects of PRA by measuring liver function indicators,pathological examinations,and macrophage-related factors.Bone marrow-derived macrophages(BMDMs)were stimulated with IL-4 to differentiate into M2 macrophages,and the effects of PM and PRA on M2 macrophage polarization were explored.Results:Target screening of“PRA-PM-innate immunity”identified 21 intersecting targets,most of which were closely associated with macrophage polarization.In rat models of IDILI induced by PM,the combined use of PRA significantly reduced the extent of liver damage and the levels of inflammatory factors,while promoting the expression of M2 macrophage-related factors such as interleukin(IL)-4,IL-10,arginase 1(Arg1),and CD206.In vitro,PM dose-dependently inhibited the expression of the Arg1 protein and M2 macrophage-related genes,whereas PRA exhibited the opposite effect.When used in combination,PRA ameliorated the inhibitory effect of PM on M2 macrophage polarization.Conclusions:Our results demonstrate that PRA has a therapeutic effect on PM-induced IDILI;its mechanism may involve alleviating liver injury by promoting M2 macrophage polarization,thus reducing the expression of inflammatory factors.