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©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Hypothermic machine perfusion with metformin-University of Wisconsin solution for ex vivo preservation of standard and marginal liver grafts in a rat model
Yi-Chao Chai, Guo-Xin Dang, Hai-Qi He, Jian-Hua Shi, Hong-Ke Zhang, Rui-Tao Zhang, Bo Wang, Liang-Shuo Hu, Yi Lv
Yi-Chao Chai, Hai-Qi He, Jian-Hua Shi, Hong-Ke Zhang, Bo Wang, Liang-Shuo Hu, Yi Lv, Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Yi-Chao Chai, Guo-Xin Dang, Hai-Qi He, Jian-Hua Shi, Hong-Ke Zhang, Liang-Shuo Hu, Yi Lv, Institute of Advanced Surgical Techniques and Engineering, Regenerative Medicine and Surgery Engineering Research Center of Shaanxi Province, Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Guo-Xin Dang, Rui-Tao Zhang, Department of Hepatobiliary and Vascular Surgery, the 521 Hospital of Ordnance Industry, Xi’an 710065, Shaanxi Province, China
Author contributions: Chai YC and Dang GX contribute equally to this study; Dang GX and Hu LS conceived and designed the experimental study; Chai YC and Dang GX performed the surgical procedure; Chai YC and Zhang HK collected the data; Zhang HK provided statistical analysis; Dang GX and Zhang RT contributed to data interpretation; He HQ and Shi JH reviewed all histopathological specimens and performed morphometric measurements; Chai YC wrote the article; Hu LS, LvY and Wang B critically revised the article; all authors participated in the revision of the manuscript, read and approved the final manuscript.
Supported by the National Natural Science Foundation, No. 81470896; the Project of Development and Innovation Team of Ministry of Education, No. IRT_16R57.
Institutional review board statement: The animal experiment protocol of this paper was approved by the Laboratory Animal Administration Committee of Xi’an Jiaotong University (approval No. XJTULAC 2013001), carried out according to the Guidelines for Animal Experimentation of Xi’an Jiaotong University and Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication number 85-23, revised 2011).
Conflict-of-interest statement: All the authors declare no conflict of interest related to this publication.
Data sharing statement: No additional data are available.
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: Liang-Shuo Hu, MD, Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, No. 277, West Yanta Road, Xi’an 710061, Shaanxi Province, China.
huliangshuo1983@hotmail.com
Telephone: +86-29-85323900 Fax: +86-29-85252580
Received: August 18, 2017
Peer-review started: August 19, 2017
First decision: August 29, 2017
Revised: September 10, 2017
Accepted: September 20, 2017
Article in press: September 19, 2017
Published online: October 28, 2017
Processing time: 71 Days and 14.7 Hours
AIM
To compare the effect of University of Wisconsin (UW) solution with or without metformin, an AMP-activated protein kinase (AMPK) activator, for preserving standard and marginal liver grafts of young and aged rats ex vivo by hypothermic machine perfusion (HMP).
METHODS
Eighteen young (4 mo old) and 18 aged (17 mo old) healthy male SD rats were selected and randomly divided into three groups: control group, UW solution perfusion group (UWP), and UW solution with metformin perfusion group (MUWP). Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), interleukin-18 (IL-18), and tumor necrosis factor-alpha (TNF-α) in the perfused liquid were tested. The expression levels of AMPK and endothelial nitric oxide synthase (eNOS) in liver sinusoidal endothelial cells were also examined. Additionally, microscopic evaluation of the harvested perfused liver tissue samples was done.
RESULTS
AST, ALT, LDH, IL-18 and TNF-α levels in the young and aged liver-perfused liquid were, respectively, significantly lower in the MUWP group than in the UWP group (P < 0.05), but no significant differences were found between the young and aged MUWP groups. Metformin increased the expression of AMPK and eNOS protein levels, and promoted the extracellular release of nitric oxide through activation of the AMPK-eNOS mediated pathway. Histological examination revealed that in the MUWP group, the extent of liver cells and tissue damage was significantly reduced compared with the UWP group.
CONCLUSION
The addition of metformin to the UW preservative solution for ex vivo HMP can reduce rat liver injury during cold ischemia, with significant protective effects on livers, especially of aged rats.
Core tip: Metformin can activate the AMP-activated protein kinase pathway that could enhance the activity of endothelial nitric oxide synthase and finally increase the generation of nitric oxide, which plays an important role in the protection of liver sinusoidal endothelial cells. Hence, our study was designed to evaluate the protective effect of University of Wisconsin storage solution with metformin for preserving standard and marginal liver grafts of young and aged rats ex vivo by hypothermic machine perfusion (HMP). According to the results, HMP with metformin plays a significant protective role for liver grafts during cold ischemia, with significant effects especially for aged-marginal donors.
