A fulminant hepatic failure model in the rat: involvement of interleukin-1beta and tumor necrosis factor-alpha.

Abstract

The development of a fulminant hepatic failure (FHF) model is necessary for evaluating the efficacy of extracorporeal liver support systems. Recognizing the multifaceted functions of the liver, including synthesis and degradation, we investigated blood chemistry, histological findings, and survival rate in D-galactosamine (GalN)-intoxicated rats. The pathophysiologic response of inflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), was also measured. Sprague-Dawley rats (200-300 g) were divided into two groups: GalN and saline injection. Rats were killed at 1, 3, 6, 12, 24, 36, 48, 72, and 168 hr after intraperitoneal injection of GalN (1.4 g/kg) or saline. In both groups, liver-specific markers, liver histology, and IL-1beta and TNF-alpha levels in blood and liver tissue were analyzed. In a second series of experiments, the survival rates were examined after two administrations of GalN at 1.0, 1.4 or 2.0 g/kg, at a 12-hr interval. In the GalN injection group, the liver-specific markers reached peak levels between 36 and 48 hr after injection. Histologically, hepatocellular necrosis was seen at 6-48 hr, followed by a regenerative phase occurring between 72 and 168 hr. IL-1beta and TNF-alpha levels in liver tissue peaked at 12 hr and 1 hr, respectively. The levels of these cytokines in blood, however, did not change significantly. The survival rates at day 7 for 1.0, 1.4 or 2.0 g/kg GalN injected twice were 77.8%, 16.7%, and 0%, respectively. These results suggest that single and double injection of GalN enable the development of reversible and irreversible FHF models. The results also indicate that IL-1beta and TNF-alpha are useful markers of liver injury.