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Toll‐like receptor 4 is a key mediator of murine steatotic liver warm ischemia/reperfusion injury
Author(s) -
Ellett Justin D.,
Evans Zachary P.,
Atkinson Carl,
Schmidt Michael G.,
Schnellmann Rick G.,
Chavin Kenneth D.
Publication year - 2009
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.21782
Subject(s) - medicine , liver transplantation , steatosis , reperfusion injury , tlr4 , endocrinology , transplantation , ischemia , receptor , mediator
Abstract Steatotic donors are routinely rejected for transplantation because of their increased rate of primary nonfunction. These grafts are more sensitive to ischemia/reperfusion (I/R) during transplantation. Removal of endotoxin before reperfusion improves liver performance post‐I/R. We hypothesize that the main modality of injury in steatotic livers is toll‐like receptor 4 (TLR4) signaling. We fed 4‐week‐old control and TLR4‐deficient (TLR4KO) mice a normal diet (ND) or a 60% high‐fat diet (HFD) for 4 weeks to induce steatosis. Mice were subjected to total hepatic ischemia (35 minutes) and reperfusion (1 or 24 hours). Survival improved and liver pathology decreased at 24 hours in TLR4KO HFD animals compared to control HFD animals. An investigation of infiltrates showed that neutrophils and CD4+ cells were increased at 24 hours in control HFD animals, whereas TLR4KO HFD animals were similar to ND controls. Messenger RNA levels of interleukin 6 (IL‐6), IL‐12, and interferon gamma were elevated at 1 hour in control HFD animals, whereas TLR4KO HFD animals were similar to ND controls. IL‐10 levels at 1 hour of reperfusion in control HFD and TLR4KO animals were decreased versus control ND animals. In conclusion, these improvements in liver function in TLR4KO HFD animals implicate TLR4 as a mediator of steatotic graft failure after I/R. Liver Transpl 15:1101–1109, 2009. © 2009 AASLD.