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BACKGROUND & AIMS: Thromboxane levels correlate with severity of liver injury in rats given alcohol. The aim of this study was to evaluate the effect of thromboxane inhibitors on pathological changes in experimental alcoholic liver disease. METHODS: Male Wistar rats were given a liquid diet and ethanol intragastrically for 1 month. The thromboxane inhibitors tested were a thromboxane receptor antagonist (TXRA) and a thromboxane synthase inhibitor (TXSI). Pathological changes, liver and plasma thromboxane levels, 6-ketoprostaglandin F1 alpha levels, lipid peroxidation, and messenger RNA levels for tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF) beta were evaluated. RESULTS: Treatment with thromboxane inhibitors prevented necrosis and inflammation. In the TXSI-treated group, fatty liver was also decreased. Ethanol administration led to a 3-4-fold increase in liver thromboxane levels; a reduction in thromboxane levels and lipid peroxidation was seen in the TXSI group. In all treatment groups, TNF-alpha and TGF-beta messenger RNA levels were decreased. CONCLUSIONS: The prevention of necroinflammatory changes in thromboxane- treated groups is related to a decrease in TNF-alpha levels. Inhibition of TGF-beta expression may also prevent fibrosis in ethanol-treated rats. (Gastroenterology 1997 Jan;112(1):200-7)

measurements of lipid peroxidation, tumor necrosis factor (TNF)-a, COX-1 and COX-2 messenger RNA that stimulate expression of COX-2, we hypothesized (mRNA), endotoxin, and liver and plasma thromboxane that COX-2 would be induced in experimental ALD. In were performed. Results: Increased expression of COX- the rat intragastric feeding model of ALD, we and others 2 mRNA was detected in the livers of rats showing have shown that an inverse relationship exists between necroinflammatory changes. The Kupffer cell was the the state of saturation of lipids in diet and the severity cell primarily responsible for the increase in COX-2 of alcohol-induced liver injury. 13-17 Thus, rats fed etha- mRNA level. Increased expression of COX-2 was associ- nol and diets enriched in saturated fatty acids 14 are pro- ated with increased levels of endotoxin, TNF-a mRNA, tected from liver injury, whereas diets enriched in poly- lipid peroxidation, and synthesis of thromboxane. COX- unsaturated fatty acids 15-17 promote alcoholic liver 1 mRNA was decreased in Kupffer cells in rats with the injury. Thus, the rat intragastric feeding model is useful most severe liver injury. Conclusions: Up-regulation of to elucidate the pathogenesis of ALD. In the current COX-2 in alcoholic liver injury occurred in the presence study, we used this model of liver injury to study the of proinflammatory stimuli and resulted in increased synthesis of inflammatory and vasoactive eicosanoids. relationship between liver pathology and COX expres- Down-regulation of COX-1 may result in decreased syn- sion and to attempt to identify the factors responsible thesis of cytoprotective eicosanoids and additionally for induction of COX-2 in ALD. exacerbate liver injury. Our results show that necrosis and inflammation in ALD are associated with increased expression of COX- 2 and higher levels of plasma endotoxin, liver TNF-a