Inflammatory responses in a new mouse model of prolonged hepatic cold ischemia followed by arterialized orthotopic liver transplantation.
The current models of liver ischemia/reperfusion injury (IRI) in mice are largely limited to a warm ischemic component. To investigate the mechanism of hepatic "cold" IRI, we developed and validated a new mouse model of prolonged cold preservation followed by syngeneic orthotopic liver transplantation (OLT). Two hundred and forty-three OLTs with or without rearterialization and preservation in University of Wisconsin solution at 4 degrees C were performed in Balb/c mice. The 14-day survivals in the nonarterialized OLT groups were 92% (11/12), 82% (9/11), and 8% (1/12) after 1-hour, 6-hour and 24-hour preservation, respectively. In contrast, hepatic artery reconstruction after 1-hour, 6-hour, and 24-hour preservation improved the outcome as evidenced by 2-week survival of 100% (12/12), 100% (10/10), and 33% (4/12), respectively, and diminished hepatocellular damage (serum alanine aminotransferase /histology). Moreover, 24-hour (but not 1-h) cold preservation of rearterialized OLTs increased hepatic CD4+ T-cell infiltration and proinflammatory cytokine (tumor necrosis factor-alpha, interleukin 2, interferon-gamma) production, as well as enhanced local apoptosis, and Toll-like receptor 4/caspase 3 expression. These cardinal features of hepatic IRI validate the model. In conclusion, we have developed and validated a new mouse model of IRI in which hepatic artery reconstruction was mandatory for long-term animal survival after prolonged (24-h) OLT preservation. With the availability of genetically manipulated mouse strains, this model should provide important insights into the mechanism of antigen-independent hepatic IRI and help design much needed refined therapeutic means to combat hepatic IRI in the clinics.
Shen
Xiu-Da
XD
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Gao
Feng
F
Ke
Bibo
B
Zhai
Yuan
Y
Lassman
Charles R
CR
Tsuchihashi
Sei-Ichiro
S
Farmer
Douglas G
DG
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
D000241:Adenosine; D000493:Allopurinol; D000818:Animals; D017209:Apoptosis; D018791:CD4 Lymphocyte Count; D004195:Disease Models, Animal; D005978:Glutathione; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology*; D007328:Insulin; D007511:Ischemia; D008099:Liver / Q000098:blood supply*; D016031:Liver Transplantation / Q000276:immunology / Q000379:methods* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019188:Organ Preservation Solutions; D011183:Postoperative Complications / Q000209:etiology; D011887:Raffinose; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome
D007328:Insulin; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose