title: Toll-like receptor 4 knockout mice are protected from endothelial overactivation in the absence of Kupffer cells after total hepatic ischemia/reperfusion.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Ellett
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Evans
authors.forename: Zainab
authors.initials: Z
authors.lastname: Amani
authors.forename: Edward
authors.initials: E
authors.lastname: Balish
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schmidt
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Chavin
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002448:Cell Adhesion; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D042783:Endothelial Cells / Q000378:metabolism*; D007511:Ischemia / Q000473:pathology; D007728:Kupffer Cells / Q000166:cytology*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal / Q000379:methods; D009336:Necrosis; D015427:Reperfusion Injury / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D016207:Cytokines; D051197:Toll-Like Receptor 4; D000410:Alanine Transaminase