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,
U74006F 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.(ABSTRACT TRUNCATED AT 250 WORDS)