Remifentanil Ameliorates Liver Ischemia-Reperfusion Injury Through Inhibition of Interleukin-18 Signaling
Remifentanil Ameliorates Liver Ischemia-Reperfusion Injury Through Inhibition of Interleukin-18 Signaling
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DOI：
10.1097/tp.0000000000000737
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发表时间：
2015-10-01
期刊：
影响因子：
6.2
通讯作者：
Tian, Jie
中科院分区：
文献类型：
--
作者：
Liu, Xiaohua;Pan, Zhiying;Tian, Jie
背景。移植或肺叶切除术后缺血再灌注（I/R）引起的肝损伤是主要的临床问题。瑞芬太尼在这些肝脏手术中的潜在益处仍然未知。目前的研究调查了瑞芬太尼是否可以在大鼠模型中保护肝脏免受 I/R 损伤，以及其潜在机制是否涉及白细胞介素 (IL)-18 信号传导的调节。方法。雄性 Sprague-Dawley 大鼠经历 45 分钟的部分肝缺血，然后进行 6 小时的再灌注。然后，他们从缺血前30分钟开始接受静脉注射盐水或瑞芬太尼（每分钟0.4、2或10μg/kg）直至缺血结束，之前给予或不给予纳洛酮（一种非选择性阿片受体拮抗剂）。分析血清转氨酶、肝脏形态和肝脏中性粒细胞浸润。肝脏IL-18的表达； IL-18结合蛋白（BP）；并测量了 IL-18 信号下游的关键细胞因子。结果。瑞芬太尼显着降低血清转氨酶水平并显着减轻肝脏组织学损伤。肝缺血再灌注损伤增加了肝脏 IL-18 和 IL-18BP 的表达。尽管瑞芬太尼预处理显着降低了I/R诱导的IL-18表达，但它进一步上调了肝组织中IL-18BP的水平。瑞芬太尼还显着减少缺血再灌注引起的肝干扰素-γ、肿瘤坏死因子-a 和 IL-1β 表达的增加以及中性粒细胞浸润。纳洛酮抑制瑞芬太尼诱导的 IL-18 下调，但不抑制 IL-18BP 升高，并显着减弱其对肝 I/R 损伤的保护作用。结论。瑞芬太尼可保护肝脏免受缺血再灌注损伤。调节肝脏 IL-18/IL-18BP 平衡和抑制 IL-18 信号传导至少部分介导瑞芬太尼的保肝作用。
Background. Hepatic injury induced by ischemia-reperfusion (I/R) after transplantation or lobectomy is amajor clinical problem. The potential benefit of remifentanil in these hepatic surgeries remains unknown. The current study investigated whether remifentanil protects the liver against I/R injury in a rat model and whether the underlying mechanism involves the modulation of interleukin (IL)-18 signaling. Methods. Male Sprague-Dawley rats were subjected to 45 minutes of partial hepatic ischemia followed by 6 hours of reperfusion. Then, they received an intravenous saline or remifentanil (0.4, 2, or 10 mu g/kg perminute) infusion from 30 minutes before ischemia until the end of ischemia with or without previous administration of naloxone, a nonselective opioid receptor antagonist. Serum aminotransferase, hepatic morphology, and hepatic neutrophil infiltration were analyzed. The expression of hepatic IL-18; IL-18-binding protein (BP); and key cytokines downstream of IL-18 signaling were measured. Results. Remifentanil significantly decreased serum aminotransferase levels and profoundly attenuated the liver histologic damages. Liver I/R injury increased the expression of both hepatic IL-18 and IL-18BP. Although remifentanil pretreatment significantly decreased I/R-induced IL-18 expression, it further upregulated IL-18BP levels in liver tissues. The I/R-induced increases of hepatic interferon-gamma, tumor necrosis factor-a and IL-1 beta expression, and neutrophil infiltration were also significantly reduced by remifentanil. Naloxone inhibited the remifentanil-induced downregulation of IL-18, but not the elevation of IL-18BP, and significantly attenuated its protective effects on liver I/R injury. Conclusions. Remifentanil protects the liver against I/R injury. Modulating the hepatic IL-18/IL-18BP balance and inhibiting IL-18 signaling mediate, at least in part, the hepatoprotective effects of remifentanil.