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
Abstract
AIM

To establish a simplified, reproducible D-galactosamine-induced cynomolgus monkey model of acute liver failure having an appropriate treatment window.

METHODS

Sixteen cynomolgus monkeys were randomly divided into four groups (A, B, C and D) after intracranial pressure (ICP) sensor implantation. D-galactosamine at 0.3, 0.25, 0.20 + 0.05 (24 h interval), and 0.20 g/kg body weight, respectively, was injected via the small saphenous vein. Vital signs, ICP, biochemical indices, and inflammatory factors were recorded at 0, 12, 24, 36, 48, 72, 96, and 120 h after D-galactosamine administration. Progression of clinical manifestations, survival times, and results of H&E staining, TUNEL, and Masson staining were recorded.

RESULTS

Cynomolgus monkeys developed different degrees of debilitation, loss of appetite, and jaundice after D-galactosamine administration. Survival times of groups A, B, and C were 56 ± 8.7 h, 95 ± 5.5 h, and 99 ± 2.2 h, respectively, and in group D all monkeys survived the 144-h observation period except for one, which died at 136 h. Blood levels of ALT, AST, CK, LDH, TBiL, Cr, BUN, and ammonia, prothrombin time, ICP, endotoxin, and inflammatory markers [(tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6)] significantly increased compared with baseline values in different groups (P < 0.05). Pathological results showed obvious liver cell necrosis that was positively correlated with the dose of D-galactosamine.

CONCLUSION

We successfully established a simplified, reproducible D-galactosamine-induced cynomolgus monkey model of acute liver failure, and the single or divided dosage of 0.25 g/kg is optimal for creating this model.

Keywords: Cynomolgus monkey; D-galactosamine; Acute liver failure; Artificial liver support systems; Intracranial pressure

Core tip: This is an article about a novel D-galactosamine-induced cynomolgus monkey model of acute liver failure (ALF). In this study, we used small saphenous vein puncture instead of jugular vein intubation for different doses of D-gal administration, which not only effectively avoided the trauma caused by intubation, but also significantly reduced the anesthesia time and greatly improved the convenience of operation. This study concluded that a simplified, reproducible D-gal-induced large-animal ALF model with an appropriate treatment window had been established successfully, which is suitable for assessing the safety and efficacy of artificial liver support systems, studying the pathogenesis of ALF, and developing new drugs.