Establishment of acute liver failure models induced by D-galactosamine in non-human primates / 器官移植

ABSTRACT

Objective To evaluate the effect of different doses of D-galactosamine (D-Gal) on non-human primate cynomolgus monkey and to establish a monkey model with different degree of acute liver failure (ALF). Methods Twelve cynomolgus monkeys were evenly divided into the low-, medium- and high-dose groups (n=4) with a dosage of 0.23, 0.25 and 0.27 g/kg, respectively. In each group, the corresponding dose of D-Gal solution was injected into the monkeys through the forearm vein at one time in a sober state (without anesthesia). The survival time of the cynomolgus monkeys was recorded. Digestive tract and hepatic encephalopathy symptoms were observed. Vital signs were measured at 0 h before and 12, 24, 36, 48, 60, 72, 96, 120 and 144 h after D-Gal administration. Alanine transaminase (ALT), total bilirubin (TB), prothrombin time (PT), blood ammonia and other parameters were detected from the blood samples. The liver tissues were prepared for hematoxylin-eosin (HE) staining to observe the pathological changes. Results All cynomolgus monkeys in the low-dose group survived and transient liver injury was noted without the hepatic encephalopathy symptoms. At 60 h after D-Gal administration, the liver function and coagulation indexes reached the peak, gradually recovered and then basically returned to the normal range at 120 h. In the medium-dose group, the course of disease was relatively slow and gradually recovered after the appearance of severe liver damage and hepatic encephalopathy symptoms and only one animal died. All cynomolgus monkeys in the high-dose group died after developing hepatic encephalopathy symptoms and severe liver damage with a mean survival time of (72±13) h. Pathological examination of liver tissue demonstrated that scattered liver cell necrosis and inflammatory cell infiltration were observed in the liver tissues of the low-dose group. In the medium- and high-dose groups, the hepatic lobule structure was not clear, and the liver cell necrosis in flakes accompanied by evident hemorrhage were documented. Conclusions The D-Gal dosage in the medium- and high-dose groups meet the standards of the ALF model. The degree of ALF in the medium-dose group is relatively slight, which is beneficial to the implementation of liver transplantation. ALF in the high-dose group is relatively severe, which is suitable for the evaluation of the clinical efficacy of therapeutic options.