title: Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice.
abstract: It is well established that liver ischemia-reperfusion induces the expression of heat shock protein (HSP) 70. However, the biological function of HSP70 in this injury is unclear. In this study, we sought to determine the role of HSP70 in hepatic ischemia-reperfusion injury in mice. Male mice were subjected to 90 min of partial hepatic ischemia followed by up to 8 h of reperfusion. HSP70 was rapidly upregulated after reperfusion. To explore the function of HSP70, sodium arsenite (8 mg/kg iv) was injected before surgery. We found that this dose induced HSP70 expression within 6 h of treatment. Induction of HSP70 with arsenite resulted in a >50% reduction in liver injury as determined by serum transaminases and histology. In addition, arsenite similarly reduced liver neutrophil recruitment and liver nuclear factor-kappaB activation, and attenuated serum levels of tumor necrosis factor-alpha and macrophage inflammatory protein-2, but increased levels of interleukin (IL)-6. In HSP70 knockout mice, arsenite did not protect against liver injury but did reduce liver neutrophil accumulation. Arsenite-induced reductions in neutrophil accumulation in HSP70 knockout mice were found to be mediated by IL-6. To determine whether extracellular HSP70 contributed to the injury, recombinant HSP70 was injected before surgery. Intravenous injection of 10 microg of recombinant HSP70 had no effect on liver injury after ischemia-reperfusion. The data suggest that intracellular HSP70 is directly hepatoprotective during ischemia-reperfusion injury and that extracellular HSP70 is not a significant contributor to the injury response in this model. Targeted induction of HSP70 may represent a potential therapeutic option for postischemic liver injury.
authors.affiliation: The Laboratory of Trauma, Sepsis and Inflammation Research, University of Cincinnati, Department of Surgery, 231 Albert Sabin Way, Cincinnati, OH 45267-0558, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuboki
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schuster
authors.forename: John
authors.initials: J
authors.lastname: Blanchard
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Pritts
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
mesh_terms: D000818:Animals; D018053:Arsenites / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017670:Sodium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018053:Arsenites; D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D016328:NF-kappa B; D020011:Protective Agents; D017670:Sodium Compounds; C017947:sodium arsenite