ALTERATIONS IN THROMBOXANE SYNTHASE AND THROMBOXANE A(2) RECEPTORS INEXPERIMENTAL ALCOHOLIC LIVER-DISEASE

We have previously shown that hepatic thromboxane production is increa sed in experimental alcoholic liver disease. The present study was des igned to investigate the cell type in liver responsible for increased thromboxane synthesis and the role of the thromboxane receptor system in the pathogenesis of liver injury. Male Wistar rats were divided int o four groups and fed a liquid diet with dextrose or ethanol for 2, 4 and 8 weeks. Medium chain triglycerides or corn oil provided the dieta ry fatty acids. Kupffer cells, endothelial cells and hepatocytes were isolated from rats fed the different diets for 4 weeks. Liver histopat hology, thromboxane synthase mRNA and protein, thromboxane levels and thromboxane receptor mRNA were evaluated in each group. In rats fed co rn oil and ethanol, an increase in thromboxane synthase and liver leve ls of thromboxane metabolites were significantly higher than in the co rn oil-dextrose-fed group and were correlated with the presence of pat hological changes in the liver. Kupffer cells showed increased express ion of thromboxane synthase. In rats fed medium chain triglycerides an d ethanol, the levels of thromboxane synthase mRNA and protein were si gnificantly lower than in the corn oil-ethanol-fed groups (P<.01) and liver injury was absent. However, the levels of thromboxane synthase m RNA, protein and thromboxane were significantly higher in the medium c hain triglyceride-ethanol-fed rats than in the respective dextrose-fed controls. Among the different cell types, thromboxane A(2)-receptor m RNA levels were highest in the Kupffer cells in corn oil-ethanol-fed r ats. The increase in thromboxane synthase in Kupffer cells together wi th an increase in thromboxane receptor levels suggests than thromboxan es may contribute to liver injury in ethanol-fed rats.