Wu Yakun, Zhang Wenfeng, Li Min, Cao Ding, Yang Xiaoli, Gong Jianping
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, PR China.
Department of Hepatobiliary Surgery, Suining Central Hospital, Suining 629000, Sichuan, PR China.
Biomed Pharmacother. 2017 May;89:732-741. doi: 10.1016/j.biopha.2017.02.087. Epub 2017 Mar 6.
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 24h 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 (50mg/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 24h 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.
本研究旨在探讨橙皮素对肝移植后肝脏缺血再灌注（IR）损伤的保护作用。体外激活库普弗细胞（KCs）并与不同浓度的橙皮素共培养24小时，检测炎症产物及TLR4/NF-κB信号通路的活性。选取Sprague-Dawley大鼠进行原位肝移植。供体在手术前1周每天静脉注射橙皮素（50mg/kg）或生理盐水。受体随机配对，并在指定时间点（手术后3、6和24小时）处死，收集移植肝脏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、KCs及CD4+ T淋巴细胞浸润情况。结果显示，橙皮素在体外可剂量依赖性地抑制激活的KCs中炎症介质的表达及TLR4/NF-κB信号通路的活性。此外，橙皮素可减轻体内IR诱导的肝损伤，显著降低血清丙氨酸转氨酶、天冬氨酸转氨酶、炎症细胞因子水平，并减轻组织病理学变化。此外，橙皮素治疗组术后肝脏的KCs和CD4+淋巴细胞浸润较少，肝细胞凋亡较低。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。总体而言，橙皮素可改善肝移植后的IR损伤，可能是预防肝脏IR损伤的一种有前景的新策略。
