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

Abstract 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.)