Title

The 21-aminosteroid tirilazad mesylate protects against endotoxin shock and acute liver failure in rats

Document Type

Journal Article

Publication Date

1-1-1994

Journal

Journal of Pharmacology and Experimental Therapeutics

Volume

271

Issue

1

Abstract

The protective effect of the 21-aminosteroid tirilazad mesylate (U- 74006F) was investigated in an experimental model of endotoxin shock and acute liver failure. In male Fischer rats subjected to 20 min of hepatic 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. Treatment with U-74006F (two bolus doses of 3 mg/kg each; the first dose 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 reperfusion, improved the survival rate from 18% to 55% and decreased the degree of hepatic injury at 48 hr of reperfusion. U-74006F treatment did not affect the extent of complement activation during reperfusion, the Kupffer cell-induced oxidant stress, or tumor necrosis factor-alpha formation in this model. U-74006F did not significantly reduce superoxide formation of Kupffer cells and neutrophils in vitro or in vivo. The substantial neutrophil infiltration in the liver during the pathogenesis was not affected at 4 hr of reperfusion but was attenuated by 70% at 48 hr. It was therefore concluded that, in the sequence of pathophysiological 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 subsequent liver failure. These data were consistent with the hypothesis that U-74006F inhibits the early tissue injury directly through inhibition of lipid peroxidation and/or membrane stabilization and therefore attenuates the later neutrophil-induced injury. U-74006F may have therapeutic potential against inflammatory hepatic injury during ischemia-reperfusion and sepsis.

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