title: Protective effect of high-mobility group box 1 blockade on acute liver failure in rats.
abstract: High-mobility group box 1 (HMGB1) is a monocyte-derived inflammatory mediator that is released in some conditions including shock, tissue injury, and endotoxin-induced lethality. In this study, we determined the plasma and hepatic tissue levels of HMGB1 in a drug-induced rat acute liver failure (ALF) model and investigated the effect of HMGB1 blockade on ALF. Adult male Sprague-Dawley rats, weighing 250 to 300 g, were used for this study. d-galactosamine was injected into the penile vein to induce ALF. To determine HMGB1 levels, plasma and hepatic tissue samples were serially collected after the d-galactosamine injection. To test the effect of HMGB1 blockade, anti-HMGB1 polyclonal antibodies or control antibodies were injected into the penile vein right after injection of d-galactosamine. Levels of HMGB1 were increased in plasma and decreased in hepatic tissue after induction of ALF. Immunohistochemical examination for HMGB1 showed that liver from animals with ALF had little staining, whereas normal liver had strong staining in the nuclei. Injection of anti-HMGB1 antibodies resulted in significant suppression of plasma HMGB1 and hepatic enzymes, marked suppression of plasma inflammatory cytokines, marked improvement of histological findings, and significant improvement of survival. The decrease of hepatic HMGB1 was also significantly suppressed in the group injected with anti-HMGB1 antibodies. The present study suggests that in ALF, the liver may release HMGB1 into the plasma, and that neutralizing the released HMGB1 has a protective effect against injury.
authors.affiliation: Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kiminori
authors.initials: K
authors.lastname: Takano
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shinoda
authors.forename: Minoru
authors.initials: M
authors.lastname: Tanabe
authors.forename: Taku
authors.initials: T
authors.lastname: Miyasho
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Shigeshi
authors.initials: S
authors.lastname: Ono
authors.forename: Yohei
authors.initials: Y
authors.lastname: Masugi
authors.forename: Koichi
authors.initials: K
authors.lastname: Suda
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Tetsu
authors.initials: T
authors.lastname: Hayashida
authors.forename: Taizo
authors.initials: T
authors.lastname: Hibi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Obara
authors.forename: Hiroya
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kawachi
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Kawasako
authors.forename: Minoru
authors.initials: M
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yokota
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002645:Chickens; D005260:Female; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
chemical_list: D000906:Antibodies; D024243:HMGB1 Protein