THE 21-AMINOSTEROID TIRILAZAD MESYLATE PROTECTS AGAINST ENDOTOXIN-SHOCK AND ACUTE LIVER-FAILURE IN RATS

The protective effect of the 21-aminosteroid tirilazad mesylate (U-740 06F) was investigated in an experimental model of endotoxin shock and acute liver failure. In male Fischer rats subjected to 20 min of hepat ic no-flow ischemia followed by reperfusion and injection of 0.5 mg/kg of Salmonella enteritidis endotoxin, severe hepatic injury developed, as indicated by a histological evaluation and liver enzyme release. T reatment with U-74006F (two bolus doses of 3 mg/kg each; the first dos e was injected i.v. 30 min before ischemia and the second dose, at the time of reflow) reduced the hepatic injury by 60% at 4 hr of reperfus ion, improved the survival rate from 18% to 55% and decreased the degr ee of hepatic injury at 48 hr of reperfusion. U-74006F treatment did n ot affect the extent of complement activation during reperfusion, the Kupffer cell-induced oxidant stress, or tumor necrosis factor-alpha fo rmation in this model. U-74006F did not significantly reduce superoxid e formation of Kupffer cells and neutrophils in vitro or in vivo. The substantial neutrophil infiltration in the liver during the pathogenes is was not affected at 4 hr of reperfusion but was attenuated by 70% a t 48 hr. It was therefore concluded that, in the sequence of pathophys iological events, U-74006F acted at a site distal to inflammatory cell activation and the generation of cytotoxic mediators. The protection against the initial endotoxin-enhanced reperfusion injury in the liver strongly inhibited the progression of the inflammatory response and s ubsequent liver failure. These data were consistent with the hypothesi s that U-74006F inhibits the early tissue injury directly through inhi bition of lipid peroxidation and/or membrane stabilization and therefo re attenuates the later neutrophil-induced injury. U-74006F may have t herapeutic potential against inflammatory hepatic injury during ischem ia-reperfusion and sepsis.