Southwest Hospital and Institute of Hepatobilitary Surgery, Third Military Medical University, Chongqing, China.
Southwest Hospital and Institute of Hepatobilitary Surgery, Third Military Medical University, Chongqing, China.
J Surg Res. 2014 Jun 15;189(2):213-21. doi: 10.1016/j.jss.2014.03.008. Epub 2014 Mar 12.
Hepatic ischemia-reperfusion (IR) injury, an unfavorable complication of hepatectomy, could be prevented by hypothermic ischemia and ischemic preconditioning (IPC). However, the effects of these two approaches on hepatocarcinogenesis have not been examined. The aim of the study was to investigate roles of hypothermic ischemia and IPC in a chemically induced rat liver tumor model.
Twenty-four Sprague-Dawley rats were treated with diethylnitrosamine and phenobarbital to induce hepatocellular carcinoma. Rats underwent hepatic ischemic injury, hypothermic ischemia, and IPC. Twenty-eight-wk-old rats were sacrificed to evaluate the morbidity and growth of liver tumor. Cytokines were measured at the protein and messenger RNA level.
IR injury significantly promoted liver tumor development. Intriguingly, hypothermic ischemia, but not IPC, delayed liver carcinogenesis, although both of them suppressed the hepatic IR injury. IPC-treated rats showed elevated interleukin (IL)-6 concentration in the serum and messenger RNA expression in liver. In addition, higher levels of IL-6 activated signal transducer and activator of transcription 3 in the liver of IPC-treated rats. The hepatic expression of target genes of signal transducer and activator of transcription 3 signaling, cyclin D1, c-myc, c-fos, and c-jun, all of which might participate in tumor progression, increased in IPC group, compared with that of IR group.
These data indicated hypothermic ischemia could ameliorate both IR injury and liver tumor development. However, IPC, another effective method to prevent hepatic IR injury, might exacerbate liver tumor growth. The elevated level of IL-6 was one of the reasons for the different effects of hypothermic ischemia and IPC on hepatocarcinogenesis in rats.
肝缺血再灌注（IR）损伤是肝切除术的一种不利并发症，可以通过低温缺血和缺血预处理（IPC）来预防。然而，这两种方法对肝癌发生的影响尚未得到检验。本研究旨在探讨低温缺血和 IPC 在化学诱导的大鼠肝肿瘤模型中的作用。
24 只 Sprague-Dawley 大鼠用二乙基亚硝胺和苯巴比妥诱导肝细胞癌。大鼠接受肝缺血损伤、低温缺血和 IPC。28 周龄大鼠被处死以评估肝肿瘤的发病率和生长情况。在蛋白质和信使 RNA 水平上测量细胞因子。
IR 损伤显著促进了肝肿瘤的发展。有趣的是，低温缺血，而不是 IPC，延迟了肝癌的发生，尽管它们都抑制了肝 IR 损伤。IPC 治疗的大鼠血清中白细胞介素（IL）-6 浓度升高，肝内信使 RNA 表达升高。此外，IPC 治疗的大鼠肝脏中信号转导和转录激活因子 3（STAT3）的激活水平升高，IL-6 水平较高。IPC 组大鼠肝脏中信号转导和转录激活因子 3 信号的靶基因，如细胞周期蛋白 D1、c-myc、c-fos 和 c-jun 的表达均升高，这些基因均可能参与肿瘤进展。
这些数据表明低温缺血可改善 IR 损伤和肝肿瘤的发展。然而，IPC 是另一种预防肝 IR 损伤的有效方法，可能会加重肝肿瘤的生长。IL-6 水平升高是低温缺血和 IPC 对大鼠肝癌发生的不同影响的原因之一。
