Pattern of ischemia reperfusion injury in a mouse orthotopic liver transplant model

• Published in: The Journal of surgical research Vol. 116; no. 2; pp. 262 - 268
• Main Authors: Que, Xingyi, Debonera, Fotini, Xie, Jinfu, Furth, Emma E., Aldeguer, Xavier, Gelman, Andrew E., Olthoff, Kim M.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.02.2004; Elsevier
• Subjects: Animals; Biological and medical sciences; Cell Division; Cryopreservation; Feasibility Studies; General aspects; Graft Survival; Interleukin-6 - biosynthesis; ischemia reperfusion; Liver - pathology; Liver Regeneration; Liver Transplantation; Male; Medical sciences; Mice; Mice, Inbred C57BL; mouse liver transplantation; rearterialization; Renal Circulation; Reperfusion Injury - pathology; Time Factors; ischemia reperfusion; rearterialization; mouse liver transplantation; liver regeneration; Animal model; Injury; Liver; Rodentia; Cardiovascular disease; Transplantation; Medicine; Regeneration; Vertebrata; Mammalia; Reperfusion; Treatment; Ischemia; Mouse; Animal; Surgery; Graft; Lesion
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2003.07.005

The molecular pathways of ischemic injury after liver transplantation are complex and difficult to dissect because of the presence of many variables. Transgenic and genetically deficient strains of mice provide ideal models for the study of the contribution of a single gene product in biological processes in vivo. Although well described in rats, prolonged preservation has not been studied in a mouse model of orthotopic liver transplantation (mOLT). The aim of this study was to establish a model of cold ischemia and reperfusion injury in mOLT and describe the pattern of the regenerative response to various lengths of cold storage. mOLT was performed using a syngeneic combination. Grafts were preserved at 4°C in University of Wisconsin (Viaspan) solution for increasing periods of cold preservation. After cold storage, the liver grafts were transplanted and recipient survival was monitored. Hepatocellular injury was determined by histology, and the regenerative response was quantitated by interleukin 6 upregulation and DNA replication. Long-term survival was 100%, 100%, 88%, and 0% for cold preservation of 1, 4, 8, and 16 h, respectively. Grafts with short preservation times (1 and 4 h) demonstrated limited injury and a weak regenerative response, with slight IL-6 early upregulation and minimal cell division. Eight hours of cold ischemia resulted in prominent injury and an intense regenerative response accompanied by significant IL-6 upregulation and DNA synthesis. Sixteen hours of storage resulted in all recipients succumbing to liver failure, with histology showing extensive hepatic necrosis. This study demonstrated the feasibility of using the mOLT model for the study of molecular mechanisms associated with recovery from cold ischemia and reperfusion injury. Increasing lengths of cold ischemia correlate with progressive tissue damage whereas recovery is associated with a regenerative response that correlates with the severity of injury.