Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2017; 23(42): 7572-7583
Published online Nov 14, 2017. doi: 10.3748/wjg.v23.i42.7572
Novel D-galactosamine-induced cynomolgus monkey model of acute liver failure
Lei Feng, Lei Cai, Guo-Lin He, Jun Weng, Yang Li, Ming-Xin Pan, Ze-Sheng Jiang, Qing Peng, Yi Gao
Lei Feng, Lei Cai, Guo-Lin He, Jun Weng, Yang Li, Ming-Xin Pan, Ze-Sheng Jiang, Qing Peng, Yi Gao, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China
Yi Gao, State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510282, Guangdong Province, China
Author contributions: Gao Y, Pan MX and Jiang ZS designed the research; Feng L, Cai L, He GL Weng J and Li Y performed the research; Feng L, Cai L and He GL analyzed the data; Feng L wrote the paper; Gao Y and Peng Q revised the paper.
Supported by The National Natural Science Foundation of China, No. 81470875; The Natural Science Foundation of Guangdong Province, China, No. 2014A030312013; The Science and Technology Planning Project of Guangdong Province, China, No. 2014B020227002, No. 2015B090903069, and No. 2015B020229002; and The Science and Technology Program of Guangzhou, China, No. 201604020002.
Institutional review board statement: The study was reviewed and approved by the Zhujiang Hospital Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Guangdong Province (IACUC protocol number: SCXK (Guangdong) 2014-0010).
Conflict-of-interest statement: No conflict of interest exists.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yi Gao, MD, Professor, Surgeon, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, Guangzhou 510280, Guangdong Province, China. drgaoy@126.com
Telephone: +86-20-62782560 Fax: +86-20-61643207
Received: August 21, 2017
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
Processing time: 83 Days and 0.8 Hours
ARTICLE HIGHLIGHTS
Research Background

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.

Research motivation

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.

Research objectives

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.

Research methods

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.

Research results

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.

Research conclusions

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.

Research perspectives

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.