Protective effect of high-mobility group box 1 blockade on acute liver failure in rats.
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.
Takano
Kiminori
K
Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Shinoda
Masahiro
M
Tanabe
Minoru
M
Miyasho
Taku
T
Yamada
Shingo
S
Ono
Shigeshi
S
Masugi
Yohei
Y
Suda
Koichi
K
Fukunaga
Koichi
K
Hayashida
Tetsu
T
Hibi
Taizo
T
Obara
Hideaki
H
Takeuchi
Hiroya
H
Kawachi
Shigeyuki
S
Kawasako
Kazufumi
K
Okamoto
Minoru
M
Yokota
Hiroshi
H
Maruyama
Ikuro
I
Kitagawa
Yuko
Y
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
D000906:Antibodies; D024243:HMGB1 Protein