title: Recombinant human soluble thrombomodulin improved lipopolysaccharide/d-galactosamine-induced acute liver failure in mice.
abstract: The effect of recombinant human soluble thrombomodulin (TM-α) on acute liver failure (ALF) is unclear, and we elucidated the effect of TM-α in lipopolysaccharide (LPS)/d-galactosamine (GalN)-induced ALF in mice. Placebo (saline) or TM-α (100 mg/kg) was administered 1 h after LPS/GalN administration. Survival rates were evaluated for 24 h after LPS/GalN administration. Plasma and liver samples were evaluated 1, 3, and 7 h after LPS/GalN administration. Survival rates were significantly higher in the TM-α-treated group than in the placebo group. A significant augmentation of plasma high-mobility group box 1 protein (HMGB1) was observed 7 h after LPS/GalN administration. In the TM-α-treated mice, plasma HMGB1 was significantly lower than in the placebo group. A significant augmentation of hepatic nuclear factor (NF)-κB p65 was observed in the placebo-treated group, whereas a significant reduction, relative to placebo, was observed in the TM-α-treated group. Hepatic expression of tumor necrosis factor (TNF)-α and myeloperoxidase were significantly increased in the placebo group, and were similarly significantly attenuated in the TM-α-treated group. TM-α treatment also produced a significant attenuation of liver neutrophil accumulation after LPS/GalN administration. Thus, TM-α may become a useful treatment strategy for reducing the symptoms of ALF via the attenuation of LPS/GalN-induced HMGB1 levels.
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Osumi
authors.affiliation: Department of Pharmacology, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Denan
authors.initials: D
authors.lastname: Jin
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Tashiro
authors.affiliation: Department of Anatomy and Cell Biology, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Zhong-Lian
authors.initials: ZL
authors.lastname: Li
authors.affiliation: Department of Anatomy and Cell Biology, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Otsuki
authors.affiliation: Department of Anatomy and Cell Biology, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Maemura
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Komeda
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Hirokawa
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Laboratory for Innovative Medicine, Graduate School of Medicine, Osaka Medical College, Takatsuki 569-8686, Japan. Electronic address: pha010@art.osaka-med.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki 569-8686, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Uchiyama
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D004195:Disease Models, Animal; D005688:Galactosamine / Q000633:toxicity; D024243:HMGB1 Protein / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000473:pathology; D009195:Peroxidase / Q000097:blood; D011994:Recombinant Proteins / Q000008:administration & dosage; D012995:Solubility; D015996:Survival Rate; D018180:Thrombomodulin / Q000008:administration & dosage*; D051996:Transcription Factor RelA / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; C546931:THBD protein, human; D018180:Thrombomodulin; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D009195:Peroxidase
keywords: Acute liver failure; High-mobility group box 1 protein; Nuclear factor-κB; Thrombomodulin; Tumor necrosis factor-α