Published online Nov 14, 2017. doi: 10.3748/wjg.v23.i42.7572
Peer-review started: August 24, 2017
First decision: September 13, 2017
Revised: September 17, 2017
Accepted: October 17, 2017
Article in press: October 17, 2017
Published online: November 14, 2017
Acute liver failure (ALF) is a serious threat to human health. Artificial liver support system (ALSS) is a novel method to deal with ALF. However, the safety and efficacy of ALSS must be verified before clinical application. Therefore, the establishment of an ALF animal model is of great significance for testing ALSS, studying the pathogenesis of ALF, and determining the comprehensive treatment of ALF. Nowadays, there have been many studies about the acute liver failure in large animals, such as pigs and dogs. However, there have been few previously reported studies of ALF models in cynomolgus monkey. Furthermore, the methods of drug administration are complex and increase the trauma to experimental animals.
In this study, our motivation was to establish an ideal animal model of ALF with an appropriate treatment window which is suitable for assessing the safety and efficacy of ALSS, studying the pathogenesis of ALF, developing new drugs, and determining the comprehensive treatment of ALF.
The primary objective of this study was to establish a simplified, reproducible D-gal-induced large-animal ALF model with an appropriate treatment window. In addition, we wanted to explore the optimal dosage of D-gal to induce ALF in cynomolgus monkey.
In this study, we used small saphenous vein puncture instead of jugular vein intubation for different doses of D-gal administration, and then observed the clinical manifestations, survival times, changes in biochemical indices, intracranial pressure changes, and resulting pathological and histological characteristics. This method not only effectively avoided the trauma caused by intubation, but also significantly reduced the anesthesia time and greatly improved the convenience of operation. All experimental data were analyzed using SPSS 21.0 statistical package.
The results showed that the experimental monkeys developed different levels of anorexia, anemia, jaundice, and coagulopathy after intravenous injection of different doses of D-gal that were similar to the various degrees of clinical ALF. The animals administered 0.30 g/kg of D-gal had the shortest survival time, and there was no significant difference in survival time after 0.25 g/kg was given as a single or divided dose. The degree of acute liver damage and the survival time of experimental animals were positively correlated with the dose of D-gal. The experimental animals given 0.25 g/kg as a single or divided dose had an appropriate treatment window. However, the number of animals used was limited, and further studies with larger experimental groups are warranted to verify our results.
The authors have successfully established a simplified, reproducible D-gal-induced cynomolgus monkey model of ALF and found that the optimal dosage to induce ALF in cynomolgus monkey is 0.25 g/kg as either a single or divided dose.
From this study, we found that drug dosages and the administration methods are important for establishing drug-induced models. The method of drug administration affects the convenience of using a model. In addition, we think small saphenous vein puncture for D-gal administration is the best method to induce ALF in cynomolgus monkey and the dosage of 0.25 g/kg as either a single or divided dose is optimal. Furthermore, we can use this method and dosage to induce ALF in cynomolgus monkey to test ALSS or study the pathogenesis of ALF in the future.