First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
J Pharmacol Exp Ther. 2011 Oct;339(1):93-8. doi: 10.1124/jpet.111.182592. Epub 2011 Jul 7.
High-mobility group box 1 (HMGB1) acts as an early mediator of inflammation and organ damage in hepatic ischemia-reperfusion (I/R) injury. Glycyrrhizin is a natural anti-inflammatory and antiviral triterpene in clinical use. The purpose of this study was to investigate the effect of glycyrrhizin on liver injury caused by I/R and production of HMGB1 by Kupffer cells in rats. In the first test period, rats were given saline or glycyrrhizin 20 min before segmental hepatic warm I/R. Serum alanine aminotransferase and HMGB1 levels and hepatic histopathological findings were evaluated after I/R. Furthermore, expression of HMGB1 in the liver was assessed by immunohistochemical staining after I/R. Kupffer cells were isolated by collagenase digestion and differential centrifugation, and production of HMGB1 was assessed. In another set of experiments, the effect of inhibition of Kupffer cells by injection of liposome-entrapped dichloromethylene diphosphonate (lipo-MDP) on liver injury and expression of HMGB1 were investigated after I/R. Liver injury was prevented in the glycyrrhizin group compared with the control group. Furthermore, serum HMGB1 levels were also significantly blunted in the glycyrrhizin group compared with the control group. Cells expressing HMGB1 were detected in the hepatic sinusoid by immunohistochemistry and recognized morphologically as Kupffer cells. Furthermore, the expression of HMGB1 was reduced in the glycyrrhizin group compared with the control group. Production of HMGB1 was reduced in Kupffer cells isolated from the glycyrrhizin group compared with the control group. It is noteworthy that treatment with lipo-MDP significantly blunted serum HMGB1 levels and prevented liver injury after I/R. These results suggest that glycyrrhizin has the therapeutic potential to prevent warm I/R-induced injury during hepato-biliary surgery.
高迁移率族蛋白 B1（HMGB1）作为炎症和肝缺血再灌注（I/R）损伤中器官损伤的早期介质。甘草酸是一种在临床上使用的天然抗炎和抗病毒三萜。本研究旨在探讨甘草酸对大鼠 I/R 引起的肝损伤和枯否细胞产生 HMGB1 的影响。在第一个测试期，大鼠在分段肝温 I/R 前 20 分钟给予生理盐水或甘草酸。I/R 后评估血清丙氨酸氨基转移酶和 HMGB1 水平以及肝组织病理学发现。此外，通过 I/R 后免疫组织化学染色评估肝中 HMGB1 的表达。通过胶原酶消化和差速离心分离枯否细胞，并评估 HMGB1 的产生。在另一组实验中，通过注射脂质体包封的二氯亚甲基二膦酸盐（lipo-MDP）抑制枯否细胞对 I/R 后肝损伤和 HMGB1 表达的影响进行了研究。与对照组相比，甘草酸组的肝损伤得到了预防。此外，与对照组相比，甘草酸组的血清 HMGB1 水平也明显降低。通过免疫组织化学检测到 HMGB1 在肝窦中的表达，并在形态上识别为枯否细胞。此外，与对照组相比，甘草酸组 HMGB1 的表达减少。与对照组相比，从甘草酸组分离的枯否细胞中 HMGB1 的产生减少。值得注意的是，lipo-MDP 的治疗显著降低了血清 HMGB1 水平并预防了 I/R 后的肝损伤。这些结果表明，甘草酸具有在肝胆手术期间预防热缺血再灌注引起的损伤的治疗潜力。
