SINUSOIDAL ENDOTHELIAL-CELL AND PARENCHYMAL-CELL INJURY DURING ENDOTOXEMIA AND HEPATIC ISCHEMIA-REPERFUSION - PROTECTION BY THE 21-AMINOSTEROID TIRILAZAD MESYLATE

The early vascular injury in the liver was characterized in an experim ental model of multiple organ failure (MOF). Significant increases of hyaluronic acid levels (660%) and plasma alanine aminotransferase acti vities (1050%) were observed after 20 min hepatic ischemia followed by 4 h reperfusion and injection of 0.5 mg/kg Salmonella enteritidis end otoxin at 30 min reperfusion. Morphological evaluation of sinusoids wi th transmission electron microscopy indicated neutrophil and Kupffer c ell activation as well as damage or loss of sinusoidal endothelial cel ls. Hepatocellular injury was evident from fused microvilli and blebbe d plasma membranes. Treatment with the 21-aminosteroid tirilazad mesyl ate (U-74006F) (2 x 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. Thi s was confirmed by morphology. Our data provide morphological and func tional evidence for severe injury to sinusoidal endothelium and the va scular pole of hepatocytes in this model of MOF. U-74006F significantl y protected the liver against this Kupffer cell- and neutrophil-mediat ed injury. Thus, U-74006F may be a promising therapeutic for liver dys function and failure during a local or systemic inflammatory response. (C) 1997 Elsevier Science Ireland Ltd.