title: The role of HMGB-1 on the development of necrosis during hepatic ischemia and hepatic ischemia/reperfusion injury in mice.
abstract: BACKGROUND
  High-mobility group 1 (HMGB-1) is a late mediator of endotoxin lethality in mice. The release of HMGB-1 is delayed compared to other proinflammatory cytokines that mediate shock and tissue injury. The purpose of this study was to investigate the role of HMGB-1 levels in response to hepatic ischemia, hepatic I/R injury, and the relationship between changes in HMGB-1 and other cytokines.
  
  
  METHODS
  Three murine models were employed: our robust model of segmental hepatic warm ischemia (SHWI), a model of partial hepatic ischemia/reperfusion injury (PHIRI), and a model of total hepatic ischemia/reperfusion injury (THIRI). Over a 48-h period following ischemic insult and reperfusion using these models, serum HMGB-1 concentrations, concentrations of HMGB-1 in ischemic and nonischemic lobes, and serum concentrations of TNF-alpha and IL-6 levels were determined in mice. An anti-HMGB-1 antibody treatment was used in SHWI and THIRI to evaluate what aspects of response to ischemia and reperfusion were potentially mediated by HMGB-1.
  
  
  RESULTS
  Hepatic HMGB-1 tissue concentrations exhibited biphasic changes in SHWI mice, which were increased in the ischemic lobes relative to nonischemic lobes at 12 h but decreased relative to nonischemic lobes at 24 h after ischemic insult. These results suggested that HMGB-1 was released into the systemic circulation by necrotic cells over the first 12 h but this process may be complete by 24 h postischemia. By 6 to 12 h after SHWI, serum TNF-alpha began to increase significantly and continued to increase for 18 h, followed by a sudden decline. Similarly, serum IL-6 increased over 1-3 h after SHWI and then decreased over the next 6 h. Treatment with an anti-HMGB-1 antibody significantly prolonged survival time in SHWI and THIRI.
  
  
  CONCLUSIONS
  HMGB-1 plays a significant role in the response to hepatic ischemia and hepatic ischemia/reperfusion injury. The present study demonstrated a time-dependent production of HMGB-1 following hepatic warm ischemia in mice. The inherent HMGB-1 in ischemic areas was exhausted and HMGB-1 may be released by necrotic cells. HMGB-1 activation is involved in immediate proinflammatory stress response to I/R and anti-HMGB-1 antibody treatment remarkably improved survival. We demonstrated that systemic HMGB-1 accumulation was measured at an earlier phase of the hepatic ischemia and ischemia/reperfusion injury model than LPS-induced endotoxemia.
authors.affiliation: Department of General Surgery, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan. taiji_watanabe@marianna-u.ac.jp
authors.forename: Taiji
authors.initials: T
authors.lastname: Watanabe
authors.forename: Sunao
authors.initials: S
authors.lastname: Kubota
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagaya
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ozaki
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagafuchi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Akashi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Taira
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsukikawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Oowada
authors.forename: Suehiro
authors.initials: S
authors.lastname: Nakano
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology; D016207:Cytokines / Q000502:physiology; D024243:HMGB1 Protein / Q000502:physiology*; D015850:Interleukin-6 / Q000097:blood; D007511:Ischemia / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D008099:Liver / Q000098:blood supply* / Q000473:pathology*; D017093:Liver Failure / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009336:Necrosis; D015427:Reperfusion Injury / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D024243:HMGB1 Protein; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha