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Toll‐like receptor 4 knockout mice are protected from endothelial overactivation in the absence of Kupffer cells after total hepatic ischemia/reperfusion
Author(s) -
Ellett Justin D.,
Atkinson Carl,
Evans Zachary P.,
Amani Zainab,
Balish Edward,
Schmidt Michael G.,
Schnellmann Rick G.,
Chavin Kenneth D.
Publication year - 2011
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.22333
Subject(s) - tlr4 , medicine , lipopolysaccharide , reperfusion injury , proinflammatory cytokine , knockout mouse , ischemia , receptor , kupffer cell , cytokine , toll like receptor , endocrinology , inflammation , tumor necrosis factor alpha , immunology , innate immune system
Kupffer cells (KCs) have been shown to be critical mediators of ischemia/reperfusion (I/R) injury in the murine liver. Using liposomal clodronate (LC), we found that KCs were protective in models of total hepatic ischemia with bowel congestion. We investigated the role of toll‐like receptor 4 (TLR4) in the damage that occurs after I/R in KC‐depleted livers. We injected 8‐week‐old C57BL/10J mice and C57BL/10ScN [toll‐like receptor 4 knockout (TLR4KO)] mice with LC 48 hours before 35 minutes of warm hepatic ischemia with bowel congestion, which was followed by either 6 or 24 hours of reperfusion. The KC‐depleted animals had increased mortality as well as a 10‐fold increase in their aminotransferase levels that correlated with increases in centrilobular necrosis. These changes were absent in the TLR4KO animals. Lipopolysaccharide was bound extensively to endothelial cells after I/R, and this binding was diminished in the TLR4KO animals. In conjunction with this, there was an up‐regulation of endothelial cell adhesion molecules in the LC‐treated animals that was absent in the TLR4KO animals. Finally, there was a dramatic increase in the proinflammatory cytokine levels of the LC‐treated animals, and the TLR4KO animals were protected against this increase. In conclusion, TLR4 promotes endothelial overactivation after I/R in the absence of KCs. Liver Transpl 17:1089–1098, 2011. © 2011 AASLD.