Acetyl-3-Aminoethyl Salicylate Ameliorates Hepatic Ischemia/Reperfusion Injury and Liver Graft Survival Through a High-Mobility Group Box 1/Toll-Like Receptor 4-Dependent Mechanism
Acetyl-3-Aminoethyl Salicylate Ameliorates Hepatic Ischemia/Reperfusion Injury and Liver Graft Survival Through a High-Mobility Group Box 1/Toll-Like Receptor 4-Dependent Mechanism
复制标题
乙酰基 - 3 - 氨基乙基水杨酸盐通过 HMGB 1/ TLR 4 - 依赖性机制改善肝缺血 - 再灌注损伤和肝移植物存活
DOI：
10.1002/lt.25575
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发表时间：
2019-08-01
影响因子：
4.6
通讯作者：
Gong, Jianping
中科院分区：
文献类型：
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作者：
Lai, Xing;Gong, Junhua;Gong, Jianping
在肝移植病例中，严重的肝缺血/再灌注损伤(HIRI)是肝移植不良和整体预后的强烈预测指标。在HIRI过程中，高迁移率族蛋白1(HMGB1)通过Toll样受体4(TLR4)促进肝细胞死亡和促炎细胞因子的分泌。由于水杨酸盐抑制HMGB1/TLR4相互作用，我们推测水杨酸盐可能通过抑制HMGB1/TLR4轴的激活而减轻HIRI所致的肝损伤。在小鼠HIRI模型上，我们发现水杨酸乙酰-3-氨基乙基水杨酸(Ac3AESA)可降低HIRI后血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平，降低Suzuki评分和细胞凋亡率。Ac3AESA还下调HIRI后肝细胞HMGB1和TLR4、kappa Bα磷酸化抑制物、细胞外信号调节激酶1/2、c-jun氨基末端激酶、p38丝裂原活化蛋白激酶、裂解caspase 3和裂解caspase 1水平。Ac3AESA降低HIRI后肝脏枯否细胞促炎症介质肿瘤坏死因子α(TNF-α)、白介素6(IL)6、白介素1β(IL1β)、趋化因子(C-X-C基序)配体(CXCL)1、CXCL2和CXCL8的转录。Ac3AESA还呈剂量依赖性地减少Kupffer细胞的肿瘤坏死因子-α的体外释放。利用小鼠原位肝移植模型，我们发现每天给予ac3AESA直到移植后第10天可以改善肝移植存活，抑制同种移植肝损伤，并下调HMGB1/TLR4信号。这些对存活和移植物健康的好处在冷缺血时间为12小时和18小时时保持不变。值得注意的是，TLR4基因敲除消除了上述所有ac3AESA诱导的效应。总之，ac3AESA部分缓解了HIRI的负面影响，并以TLR4依赖的方式延长了移植肝的存活时间。
In liver transplant cases, severe hepatic ischemia/reperfusion injury (HIRI) is a strong predictor of adverse liver graft and overall outcomes. During HIRI, high-mobility group box 1 (HMGB1) promotes hepatocellular death and proinflammatory cytokine secretion by toll-like receptor 4 (TLR4). Because salicylates inhibit HMGB1/TLR4 interaction, we hypothesized that salicylates may ameliorate HIRI-induced liver damage by inhibiting HMGB1/TLR4 axis activation. Using a murine model of HIRI, we found that the salicylate acetyl-3-aminoethyl salicylic acid (ac3AESA) reduced serum alanine aminotransferase and aspartate aminotransferase as well as Suzuki scores and apoptotic cell counts after HIRI. Ac3AESA also down-regulated hepatocellular HMGB1 and TLR4 expression, phosphorylated inhibitor of kappa B alpha, extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, cleaved caspase 3, and cleaved caspase 1 levels after HIRI. Ac3AESA reduced liver Kupffer cell transcription of proinflammatory mediators tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 6, IL1 beta, chemokine (C-X-C motif) ligand (CXCL) 1, CXCL2, and CXCL8 after HIRI. Ac3AESA also dose-dependently reduced in vitro release of Kupffer cell TNF-alpha. Employing a murine orthotopic liver transplantation model, we found daily ac3AESA administration up to day 10 after transplant improved liver graft survival, suppressed allograft damage, and down-regulated HMGB1/TLR4 signaling. These benefits to survival and allograft health were maintained for cold ischemia times of 12 and 18 hours. Notably, TLR4 knockout eliminated all foregoing ac3AESA-induced effects. In conclusion, ac3AESA partially rescues the negative effects of HIRI and prolongs liver graft survival in a TLR4-dependent manner.