title: T-5224, a selective inhibitor of c-Fos/activator protein-1, attenuates lipopolysaccharide-induced liver injury in mice.
abstract: The effect of T-5224, a selective inhibitor of c-Fos/activator protein (AP)-1, on lipopolysaccharide (LPS) induced liver injury was examined in mice. Administration of LPS (10 mg kg(-1), i.p.) markedly increased serum levels of tumor necrosis factor-alpha (TNFα), high mobility group box 1 (HMGB1), alanine aminotransferase/aspartate aminotransferase (ALT/AST), liver tissue levels of macrophage-inflammatory protein-1 alpha (MIP-1α) and monocyte chemoattractant protein-1 (MCP-1), as well as hepatic necrosis and inflammation, leading to 67 % lethality. Administration of T-5224 (300 mg kg(-1), p.o.) after intraperitoneal injection of LPS imparted appreciable protection against acute elevations in serum levels of TNFα, HMGB1, ALT/AST as well as in liver tissue levels of MIP-1α and MCP-1, and reduced the lethality (27 %). These data indicate that T-5224 ameliorates liver injury and improves survival through decreasing production of proinflammatory cytokines and chemokines in endotoxemic mice.
authors.affiliation: Division of Intensive Care Medicine, Kobe University Hospital, Chuo-ku, Kobe, Japan. izuta@med.kobe-u.ac.jp
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Izuta
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ueki
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.forename: Kahoru
authors.initials: K
authors.lastname: Nishina
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shiozawa
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Maekawa
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000008:administration & dosage* / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004798:Enzymes / Q000097:blood; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000494:pharmacology; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000517:prevention & control; D007555:Isoxazoles / Q000008:administration & dosage* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D016019:Survival Analysis
chemical_list: C568912:3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxy-1,2-benzisoxazol-6-yl)methoxy)phenyl)propionic acid; D001577:Benzophenones; D016207:Cytokines; D004798:Enzymes; D005765:Gastrointestinal Agents; D007555:Isoxazoles; D008070:Lipopolysaccharides