title: Mechanisms of hypothermic protection against ischemic liver injury in mice.
abstract: Hepatic hypothermia can safely prolong the duration of hepatic inflow occlusion during complex liver resectional surgeries. The mechanism(s) by which hypothermia protects against this form of liver ischemia-reperfusion injury are not completely understood. In this study, we sought to determine whether hypothermia protects against ischemia-reperfusion injury by altering the hepatic inflammatory response. Mice undergoing 90 min of partial hepatic ischemia followed by up to 8 h of reperfusion had their body temperatures regulated at 35-37 degrees C (normothermic) or unregulated, in which rectal temperature dropped as low as 25 degrees C by the end of ischemia (hypothermic). Hypothermic mice had less liver injury vs. normothermic mice, as assessed histologically, by serum transaminase levels (89% decrease), and by liver wet-to-dry weight ratios (91% decrease). Neutrophil accumulation was absent in hypothermic mice (99% reduction vs. normothermic mice). Production of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, and macrophage inflammatory protein-2 were reduced by up to 92%. Activation of the transcription factor nuclear factor-kappa B was not reduced in hypothermic mice, but activation of c-Jun NH(2)-terminal kinase (JNK) and the transcription factor activator protein (AP)-1 were greatly diminished. These data suggest that hypothermia suppresses the hepatic inflammatory response through selective inhibition of JNK and AP-1.
authors.affiliation: Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Saurabh
authors.initials: S
authors.lastname: Singh
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: McLeish
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
mesh_terms: D000818:Animals; D001833:Body Temperature Regulation; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D006505:Hepatitis / Q000517:prevention & control; D007036:Hypothermia, Induced; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000098:blood supply*; D048670:MAP Kinase Kinase 4; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases