Sinusoidal endothelial cell and parenchymal cell injury during endotoxemia and hepatic ischemia-reperfusion: protection by the 21-aminosteroid tirilazad mesylate

Abstract

The early vascular injury in the liver was characterized in an experimental model of multiple organ failure (MOF). Significant increases of hyaluronic acid levels (660%) and plasma alanine aminotransferase activities (1050%) were observed after 20 min hepatic ischemia followed by 4 h reperfusion and injection of 0.5 mg/kg Salmonella enteritidis endotoxin at 30 min reperfusion. Morphological evaluation of sinusoids with transmission electron microscopy indicated neutrophil and Kupffer cell activation as well as damage or loss of sinusoidal endothelial cells. Hepatocellular injury was evident from fused microvilli and blebbed plasma membranes. Treatment with the 21-aminosteroid tirilazad mesylate (U-74006F) (2 × 3 mg/kg) reduced plasma hyaluronic acid levels by 61% and plasma transaminase activities by 69% suggesting a beneficial effect on sinusoidal endothelial cell and parenchymal cell injury. This was confirmed by morphology. Our data provide morphological and functional evidence for severe injury to sinusoidal endothelium and the vascular pole of hepatocytes in this model of MOF. U-74006F significantly protected the liver against this Kupffer cell- and neutrophil-mediated injury. Thus, U-74006F may be a promising therapeutic for liver dysfunction and failure during a local or systemic inflammatory response.