Different roles of hepatic hypothermic ischemia and ischemic preconditioning in chemically induced hepatocarcinogenesis in rats.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.