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.
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