Nobiletin ameliorates ischemia-reperfusion injury by suppressing the function of Kupffer cells after liver transplantation in rats
Nobiletin ameliorates ischemia-reperfusion injury by suppressing the function of Kupffer cells after liver transplantation in rats
复制标题
川陈皮素通过抑制库普弗细胞功能改善大鼠肝移植后缺血再灌注损伤
DOI：
10.1016/j.biopha.2017.02.087
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发表时间：
2017
影响因子：
7.5
通讯作者：
Gong Jianping
中科院分区：
文献类型：
--
作者：
Wu Yakun;Zhang Wenfeng;Li Min;Cao Ding;Yang Xiaoli;Gong Jianping
本研究旨在探讨川陈皮素对肝移植术后肝缺血再灌注（IR）损伤的保护作用。体外激活库普弗细胞（KCs），与不同浓度川陈皮素共培养24 h，检测炎症产物和TLR4/NF-κB信号通路活性。选择 Sprague-Dawley 大鼠并进行原位肝移植。手术前，供体静脉注射川陈皮素 (50 mg/kg) 或盐水溶液，每天一次，持续 1 周。受体被随机配对并在指定时间点（手术后 3、6 和 24 小时）处死，收集移植肝组织和血液样本进行分析。评估肝功能、炎症介质、肝细胞凋亡、组织学变化、KC 和 CD4+ T 淋巴细胞浸润。结果显示川陈皮素剂量依赖性地抑制活化 KC 中炎症介质的表达和 TLR4/NF-κB 信号通路的活性。此外，川陈皮素可减轻体内IR引起的肝损伤，显着降低血清丙氨酸转氨酶、天冬氨酸转氨酶、炎症细胞因子的水平，减轻组织病理学变化。此外，川陈皮素治疗组的肝脏术后KCs和CD4+淋巴细胞浸润较少，肝细胞凋亡也较低。此外，KCs中TLR4/NF-κB信号通路的活性也受到抑制，与体外结果一致。总的来说，川陈皮素可以改善肝移植后的 IR 损伤，并且可能是一种有前途的预防肝 IR 损伤的新策略。
This study aims to explore the protective effects of nobiletin against hepatic ischemia–reperfusion (IR) injury after liver transplantation. Kupffer cells (KCs) were activated and co-cultured with different concentration of nobiletin for 24 h in vitro, inflammatory products and activity of TLR4/NF-κB signaling pathway were detected. Sprague–Dawley rats were selected and underwent orthotopic liver transplantation. Donors were injected intravenously with nobiletin (50 mg/kg) or saline solution, once a day for 1 week before the surgery. Recipients were randomly paired and sacrificed at the indicated time points (3, 6, and 24 h after the surgery), the graft liver tissues and blood samples were collected for analysis. Hepatic function, inflammatory mediators, apoptosis of hepatocytes, histological changes, KCs and CD4+ T-lymphocyte infiltration were assessed. Results showed nobiletin dose-dependently suppressed the expression of inflammatory mediators and the activity of TLR4/NF-κB signaling pathway in activated KCs. Furthermore, nobiletin alleviated liver damage induced by IR in vivo, significantly decreased the serum levels of alanine aminotransferase, aspartate transaminase, inflammatory cytokines and alleviated the histopathology changes. Moreover, liver in the nobiletin treated group exhibited less KCs and CD4+ lymphocyte infiltration and lower hepatocyte apoptosis after operation. In addition, activity of TLR4/NF-κB signaling pathway in KCs was also suppressed, consistent with the results in vitro. Collectively, Nobiletin can ameliorate IR injury after liver transplantation and may be a promising new strategy to protect against liver IR injury.