Effect of lazaroid U-74389G and methylprednisolone on endotoxin-induced shock in mice

• Published in: Surgery 1999-04, Vol.125 (4), p.421-430
• Main Authors: Fukuma, Kazuyuki, Marubayashi, Seiji, Okada, Kazuro, Yamada, Kazuo, Kimura, Akinori, Dohi, Kiyohiko
• Format: Article
• Language: English
• Subjects: Alanine Transaminase - analysis; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Anti-Inflammatory Agents - pharmacology; Antioxidants - pharmacology; Aspartate Aminotransferases - analysis; Biological and medical sciences; Blotting, Northern; DNA Probes; Emergency and intensive care: infection, septic shock; Enzyme Activation - drug effects; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - immunology; Intensive care medicine; L-Lactate Dehydrogenase - analysis; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lipid Peroxidation - drug effects; Lipopolysaccharides; Liver - cytology; Liver - drug effects; Liver - enzymology; Male; Medical sciences; Methylprednisolone - pharmacology; Mice; Mice, Inbred ICR; NF-kappa B - metabolism; Nitrates - blood; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nitrites - blood; Phagocytosis - immunology; Pregnatrienes - pharmacology; RNA, Messenger - analysis; Shock - chemically induced; Shock - drug therapy; Shock - mortality; Survival Analysis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/S0039-6060(99)70010-3

Background: Lazaroids are nonglucocorticoid analogs of methylprednisolone with multiple actions. We investigated whether lazaroid U-74389G could attenuate endotoxin-induced liver injury. We hypothesized that U-74389G treatment may protect against hepatic injury by suppressing proinflammatory gene up-regulation through inhibition of activation of nuclear factor κB (NF-κB). We also compared the efficacy of U-74389G with methylprednisolone in endotoxin-induced liver injury. Methods: Lipopolysaccharide ( Escherichia coli, 30 mg/kg given intraperitoneally) was administered to male ICR mice, and U-74389G (3 mg/kg intraperitoneally) or methylprednisolone (30 mg/kg intravenously) was administered simultaneously. Phosphate-buffered saline solution (0.15 mL intravenously) was administered to mice that served as a control group. Results: U-74389G and methylprednisolone treatment significantly increased survival rates 48 hours after lipopolysaccharide injection and protected against lipopolysaccharide-induced liver injury in vivo, as indicated by the decreased hepatic lipid peroxidation, tumor necrosis factor-α, and inducible nitric oxide synthase messenger RNA formation, hepatic enzyme release, and neutrophil infiltration in the liver. U-74389G and methylprednisolone also showed inhibitory effects on NF-κB activation in the liver. Conclusions: These findings suggest that U-74389G can suppress proinflammatory gene up-regulation through inhibition of NF-κB activation and that it is a promising new antioxidant drug for the treatment of endotoxin shock. (Surgery 1999;125:421-30.)