BACKGROUND: Recent advances in surgical procedures and perioperative managements have made it possible to facilitate aggressive, extended hepatectomy for radical treatment of malignant liver tumors. However, the management of post-operative liver failure is still one of the most challenging problems. Overproduction of heat shock protein 70 (HSP70) in the liver is known to protect hepatocytes under various pathological conditions. Oral administration of a non-toxic HSP70 inducer, geranylgeranylacetone (GGA), was shown to enhance the heat shock response and protect rat livers against ischemia-repurfusion injury. Based on these informations, in this study, we examined whether GGA could exert protection against acute, lethal hepatic failure after 95% hepatoctomy in rats.
METHODS: Different doses of GGA (1-500 mg/kg) or vehicle was given intragastrically to rats 4 hours prior to 95% hepatectomy, and their survival was monitored up to one week. Serum levels of GOT, GPT, tumor necrosis factor-a(TNF-a), and interleukin-6 (IL-6) were measured during 24 hours of post-operative period. The levels of HSP70 mRNA and protein were measured by Northern and Western blot analyses, respectively. Residual tissues were subjected to histological and immunohistochemical analysis with an anti-HSP70 antibody.
RESULTS: All of 25 rats pretreated with vehicle died within 60 hours after 95% hepatectomy. Pre-adiministration of GGA dose-dependently improved the survival rate after 95% hepatectomy, and 10 of 25 rats pretreated with 100 mg/kg GGA completely recovered. GGA significantly suppressed the release of transaminases and IL-6 and completely inhibited TNF-aproduction. Histological examinations showed that GGA pretreatment suppressed the development of hemorrhagic necrosis. GGA enhanced the HSP70 mRNA expression and HSP70 accumulation in the residual tissues, and residual viable hepatocytes contained abundant HSP70 in their nuclei.
CONCLUSIONS: Our results suggest that GGA may prevent acute hepatic failure after massive hepatectomy, at least in part, by enhancing HSP70 induction in the residual tissues. The safety of GGA is well evidenced by the fact that this compound has been widely used in Japan for more than 15 years without any severe adverse effect. The premedication of this non-toxic HSP70 inducer may provide a potential benefit for massive surgical resection of the liver.
