Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan, 629000, PR China.
Biomed Pharmacother. 2017 May;89:1392-1400. doi: 10.1016/j.biopha.2017.03.022. Epub 2017 Mar 19.
We have evaluated the protective mechanism of tanshinone IIA in ischemia/reperfusion injury (IRI) induced by liver grafts, revealing novel supplementary immunotherapy for liver transplantation.
The tanshinone IIA preconditioning group (TP group) was pretreated with tanshinone IIA via intraperitoneal injection for 1 week before receiving orthotopic liver transplantation with hepatic arterial ischemia for 30min. The sham-operation group (SO group), control graft group (CG group) and IRI group were pretreated with an equivalent volume of normal saline. The IRI group and CG group received orthotopic liver transplantation with or without hepatic arterial ischemia. Rats were sacrificed at each time point, serum was collected for ELISA detection, and Kupffer cells (KCs) were isolated to extract total protein and RNA for western blotting and real-time PCR, respectively.
The levels of TNF-α and IL-4 in the TP group were significantly lower than those of in the IRI group; meanwhile the IL-10 and TGF-β levels were significantly higher than in the IRI group. The protein and mRNA expression levels of HMGB1 were significantly lower in TP group than in the IRI group at each time point. The TLR-4, Myd88, NLRP3 and p-NF-κb p65 expression levels in the TP groups were significantly lower than those in the IRI group, while the PTEN, PI3K and AKT phosphorylation levels in the TP groups were significantly higher than those in the IRI group.
Tanshinone IIA attenuates IRI caused by liver grafts via down-regulation of the HMGB1-TLR-4/NF-κb pathway in KCs and activation of PTEN/PI3K/AKT pathway, suggesting a potential role for prevention of liver cell IRI during liver transplantation.
本研究旨在探讨丹参酮Ⅱ A 预处理对肝移植缺血再灌注损伤（IRI）的保护作用，为肝移植提供新的免疫治疗策略。
丹参酮Ⅱ A 预处理组（TP 组）于肝移植术前 1 周腹腔注射丹参酮Ⅱ A，建立缺血 30min 肝移植模型。假手术组（SO 组）、对照组（CG 组）及 IRI 组给予等容量生理盐水预处理，IRI 组及 CG 组建立缺血再灌注模型。各组分别于再灌注后 6、12、24h 处死大鼠，留取血清，ELISA 法检测血清 TNF-α、IL-4、IL-10、TGF-β 水平，分离肝组织分离提取 Kupffer 细胞（KCs）总蛋白及 RNA，Western blot 及 qRT-PCR 法检测 HMGB1、TLR-4、Myd88、NLRP3、p-NF-κb p65、PTEN、PI3K、AKT 蛋白及 mRNA 表达。
与 IRI 组比较，TP 组血清 TNF-α、IL-4 水平明显降低，IL-10、TGF-β 水平明显升高；TP 组各时间点 HMGB1 蛋白及 mRNA 表达均明显降低；TP 组 TLR-4、Myd88、NLRP3、p-NF-κb p65 蛋白表达明显降低，PTEN、PI3K、AKT 磷酸化水平明显升高。
丹参酮Ⅱ A 预处理通过下调 HMGB1-TLR-4/NF-κB 信号通路，激活 PTEN/PI3K/AKT 信号通路减轻肝移植缺血再灌注损伤，为肝移植围手术期防治肝细胞 IRI 提供了新的策略。
