Isoglycyrrhizinate Magnesium Enhances Hepatoprotective Effect of FK506 on Ischemia-Reperfusion Injury Through HMGB1 Inhibition in a Rat Model of Liver Transplantation
Isoglycyrrhizinate Magnesium Enhances Hepatoprotective Effect of FK506 on Ischemia-Reperfusion Injury Through HMGB1 Inhibition in a Rat Model of Liver Transplantation
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异甘草酸镁通过抑制 HMGB1 增强 FK506 对肝移植大鼠模型缺血再灌注损伤的保肝作用
DOI：
10.1097/tp.0000000000001941
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发表时间：
2017-12
期刊：
影响因子：
6.2
通讯作者：
Shusen Zheng
中科院分区：
文献类型：
--
作者：
Weichen Zhang;Feibo Li;Yufu Ye;Yuanxing Liu;Songfeng Yu;Chao Cen;Xuliang Chen;Lin Zhou;Xiaofeng Tang;Jun Yu;Shusen Zheng
背景肝移植（LT）后缺血再灌注损伤损害移植物功能并影响受者预后。异甘草酸镁（Iso）是一种通常用于肝损伤后的保肝药物。本研究旨在探讨Iso单独应用对大鼠肝移植缺血再灌注损伤是否具有保护作用。我们还旨在研究Iso是否可以增强FK506（他克莫司）的肝保护作用及其机制。方法大鼠肝移植术后给予不同浓度的FK506加或不加、Iso或低剂量FK506加Iso。在48小时、72小时和7天后测量丙氨酸转氨酶、天冬氨酸转氨酶和白蛋白水平。建立细胞缺血再灌注模型，进一步研究FK506和Iso的保肝作用机制。结果Iso对移植肝无明显影响，但在移植后48 h、72 h和7 d时，低剂量FK506 + Iso对移植肝的保护作用优于低剂量FK506。然而，FK506诱导的自噬也导致高迁移率族蛋白盒（HMGB）1从细胞核释放，通过触发p38磷酸化和趋化因子释放导致肝细胞损伤。Iso能有效抑制HMGB1及其下游炎性细胞因子的释放。结论Iso可抑制FK506释放HMGB1，增强FK506对大鼠肝移植的保护作用，Iso与FK506联合应用对肝移植后患者有较好的治疗效果。
Background Ischemia-reperfusion injury after liver transplantation (LT) impairs graft function and affects prognosis of recipients. Isoglycyrrhizinate magnesium (Iso) is a hepatoprotective drug usually used after liver injury. In this study, we intended to explore whether Iso alone have protective effect after ischemia-reperfusion injury in a rat model of liver transplantation. We also aimed to study whether Iso could enhance the hepatoprotective effect of FK506 (tacrolimus) and underlying mechanism. Methods Rats after LT were treated with different concentration of FK506 with or without, Iso or lower-dose FK506 plus Iso. Alanine transaminase, aspartate transaminase, and albumin level were measured after 48 hours, 72 hours, and 7 days. A cell ischemic/reperfusion model was established to further study the mechanism of hepatoprotective effect of FK506 and Iso. Results Iso treatment alone had no effect on liver grafts after LT, but lower-dose FK506 + Iso was better for maintenance of liver function than lower-dose FK506 alone at 48 hours, 72 hours, and 7 days after LT. In terms of mechanism, FK506 induced autophagy which resulted in significantly reduced apoptosis and maintained proliferative potential. However, autophagy induced by FK506 also lead to high-mobility group box (HMGB) 1 release from nuclei, resulting in hepatocyte injury through triggering of p38 phosphorylation and chemokine release. Iso effectively inhibited the release of HMGB1 and downstream inflammatory cytokines. Conclusions Iso could inhibit release of HMGB1 by FK506 and enhance the hepatoprotective effect of FK506 in rat LT. Combining Iso with FK506 would be promising for the patients after LT.
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影响因子：
--
作者：
Mollica, Luca;De Marchis, Francesco;Bianchi, Marco E.
通讯作者：
Bianchi, Marco E.
影响因子：
6.2
作者：
Kee-Hwan Kim;Say-June Kim;Soo-Ho Lee
通讯作者：
Kee-Hwan Kim;Say-June Kim;Soo-Ho Lee
影响因子：
64.8
作者：
Scaffidi, P;Misteli, T;Bianchi, ME
通讯作者：
Bianchi, ME
影响因子：
6
作者：
Serafin, A;Roselló-Catafau, J;Peralta, C
通讯作者：
Peralta, C
DOI：
10.1152/ajpgi.00210.2014
发表时间：
2014-12-01
影响因子：
4.5
作者：
Gupta, Nitika A.;Kolachala, Vasantha L.;Kirk, Allan D.
通讯作者：
Kirk, Allan D.