title: Effect of necrosis modulator necrox-7 on hepatic ischemia-reperfusion injury in beagle dogs.
abstract: OBJECTIVE
  The liver is susceptible to ischemia-reperfusion (IR) injury during inflow occlusion for hepatectomy. There is no effective pharmacologic agent available to prevent the release of high-mobility-group box 1 (HMGB1) or to ameliorate IR injury. This pilot study sought to develop a model in beagle dogs for the purpose of testing the efficacy of a necrosis modulator, necrox-7, to prevent hepatic IR injury in beagle dogs.
  
  
  METHODS
  Six male beagle dogs were randomly assigned to the control group (group A; n = 3) or the treatment group (group B; n = 3). Under general anesthesia, group B received intravenous infusion of necrox-7 (13 mg/kg over 20 minutes) followed by 60 minutes of left hepatic inflow occlusion and 60 minutes of reperfusion. Both groups were tested for serum biochemicals, hematology values, liver biopsies, and plasma HMGB1 levels over a 48-hour period.
  
  
  RESULTS
  The maximum alanine transferase (ALT), aspartate transferase (AST), and lactate dehydrogenase (LDH) levels among group A versus group B were: ALT 868.3 ± 337.4 IU/L vs 274.3 ± 72.6 IU/L (P = .041); AST 1,024.7 ± 246.5 IU/L vs 505.3 ± 66.7 IU/L (P = .024); and LDH 962.7 ± 226.2 IU/L vs 552.7 ± 62.4 IU/L (P = .039). Liver biopsy demonstrated marked necrosis and inflammatory infiltrates in group A, whereas group B showed little evidence of IR injury. The plasma HMGB1 concentration was significantly lower among group B versus A.
  
  
  CONCLUSIONS
  This pilot study developed a hepatic IR injury model, demonstrating that necrox-7 reduced hepatic necrosis secondary to IR injury in a large animal setting.
authors.affiliation: Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors.forename: J M
authors.initials: JM
authors.lastname: Choi
authors.forename: K M
authors.initials: KM
authors.lastname: Park
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: D W
authors.initials: DW
authors.lastname: Hwang
authors.forename: S H
authors.initials: SH
authors.lastname: Chon
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: S Y
authors.initials: SY
authors.lastname: Lee
authors.forename: Y J
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D004195:Disease Models, Animal; D004285:Dogs; D024243:HMGB1 Protein / Q000097:blood; D007262:Infusions, Intravenous; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009336:Necrosis; D009930:Organic Chemicals / Q000008:administration & dosage / Q000494:pharmacology*; D010865:Pilot Projects; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; D009930:Organic Chemicals; D020011:Protective Agents; C556282:necrox-7; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase