title: Protective effect of neutralization of the extracellular high-mobility group box 1 on renal ischemia-reperfusion injury in miniature swine.
abstract: BACKGROUND
  Strategies that reduce ischemia-reperfusion injury (IRI) have the potential to expand the numbers of available organs for transplantation. Recent reports in rodent models have demonstrated that high-mobility group box 1 (HMGB1) acts as an alarm in initiating the inflammatory response resulting from ischemic injury. The aim of this study was to evaluate the cytoprotective effects of anti-HMGB1 antibodies on renal IRI in preclinical large animals.
  
  
  METHODS
  One hundred twenty minutes of warm and 60 min of cold renal ischemia were induced in 8 CLAWN miniature swine. Three of eight animals received intravenous anti-HMGB1 antibody at 1 mg/kg just before the reperfusion of renal blood flow. Renal function was assessed by serum creatinine and renal biopsy. Serum levels of interleukin (IL)-1β, IL-6, and HMGB1 were measured.
  
  
  RESULTS
  The concentration of HMGB1 increased as early as 30 min after reperfusion and before the elevation of IL-1β and IL-6. Serum creatinine levels were markedly elevated, peaking at a median of 5 days (peak creatinine levels: 11.6 ± 1.6 mg/dL) and recovering by day 14. Anti-HMGB1 antibody injection dramatically decreased renal damage as well as serum levels of HMGB1 associated with IRI. Renal function returned to near normal by day 9, and peak creatinine levels were markedly lower (7.4 ± 0.2 mg/dL), and biopsies possessed fewer pathologic changes when compared to the control group.
  
  
  CONCLUSIONS
  In this study, we demonstrated the beneficial effects of perioperative administration of anti-HMGB1 antibody in reducing renal IRI in a clinically relevant, large animal model.
authors.affiliation: 1 Division of Organ Replacement and Xenotransplantation Surgery, Center for Advanced Biomedical Science and Swine Research, Kagoshima University, Kagoshima, Japan. 2 Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 3 Address correspondence to Kazuhiko Yamada, M.D., Ph.D., Center for Advanced Biomedical Science and Swine Research, Kagoshima University 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miura
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sahara
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Sekijima
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kawai
authors.forename: Shiori
authors.initials: S
authors.lastname: Waki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimura
authors.forename: Kentaro
authors.initials: K
authors.lastname: Setoyama
authors.forename: Eric S
authors.initials: ES
authors.lastname: Clayman
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D017209:Apoptosis; D001706:Biopsy; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D004195:Disease Models, Animal; D005260:Female; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000097:blood; D007249:Inflammation; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007511:Ischemia; D007668:Kidney / Q000276:immunology / Q000473:pathology*; D007674:Kidney Diseases / Q000473:pathology* / Q000628:therapy; D008297:Male; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000473:pathology* / Q000628:therapy; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors
chemical_list: D000906:Antibodies; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D003404:Creatinine