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We investigated the potential of dietary saturated fatty acids to decrease endotoxemia and suppress expression of cyclooxygenase 2 (Cox-2) and tumor necrosis factor alpha (TNF-alpha) in established alcohol-induced liver injury. Six groups (five rats/group) of male Wistar rats were studied. Rats in group 1 were fed a fish oil-ethanol diet for 6 weeks. Rats in groups 2, 3, and 4 were fed fish oil and ethanol for 6 weeks. Ethanol administration was stopped at this time, and the rats were switched to isocaloric diets containing dextrose with fish oil (group 2), palm oil (group 3), or medium-chain triglycerides (group 4) as the source of fat for an additional 2 weeks. Rats in groups 5 and 6 were fed fish oil-ethanol and fish oil-dextrose, respectively, for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, and levels of messenger RNA (mRNA) for Cox-2 and TNF-alpha. Concentrations of endotoxin were determined in plasma. The most severe inflammation and fibrosis were detected in groups 1 and 5, as were the highest levels of endotoxin, lipid peroxidation, and mRNA for Cox-2 and TNF-alpha. After ethanol was discontinued, there was minimal histological improvement in group 2 but near normalization of the histology, including regression of fibrosis, in groups 3 and 4. Histological improvement was associated with decreased levels of endotoxin, lipid peroxidation, and reduced expression of Cox-2 and TNF-alpha. The data indicate that a diet enriched in saturated fatty acids (groups 3 and 4) effectively reverses alcohol-induced liver injury, including fibrosis. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased levels of TNF-alpha and Cox-2.

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)

Gastrointestinal stromal tumor (GIST) is a rare, but potentially aggressive tumor. We present an asymptomatic 64-year-old man with an incidental 9-cm GIST that arose in the posterior mediastinum. Wide surgical excision was performed with rotation of an intercostal muscle flap to buttress a surgically created esophageal wall defect. The patient is now free of disease 26 months postoperative. This tumor is defined by the carcinogenic over-expression of KIT-protein, a tyrosine kinase receptor. Accurate diagnosis of gastrointestinal stromal tumor is imperative, as specific medical therapy is now available for potential control of recurrent or metastatic disease.

Based on studies that show a role for the low-density lipoprotein (LDL)-receptor in arachidonic acid delivery and eicosanoid synthesis in macrophages, the present study investigated the effect of cholesterol supplementation on pathological changes and thromboxane (TX) synthesis in alcoholic liver injury. Male Wistar rats were intragastrically fed ethanol with either corn oil or fish oil for 1 month. Control rats received isocaloric amounts of dextrose instead of ethanol. An additional group of rats fed either ethanol or dextrose with fish oil or corn oil were supplemented with 1% cholesterol. At the time of killing, all rats had the following evaluated: liver histopathology, lipid peroxidation, liver and plasma thromboxane levels, plasma endotoxin and messenger RNA (mRNA) levels of LDL-receptor, tumor necrosis factor alpha (TNF-alpha), cyclooxygenase (Cox)-1 and -2, and transforming growth factor beta (TGF-beta). Rats fed ethanol with either fish oil or corn oil developed fatty liver, necrosis, inflammation, and central vein collagen deposition. Cholesterol supplementation enhanced the degree of fibrosis but prevented necrosis and inflammation. These alterations in pathological changes by cholesterol were accompanied by absent TNF-alpha and Cox-2 mRNAs, decreased thromboxane levels, decreased lipid peroxidation, and increased TGF-beta mRNA. Cholesterol enrichment of the diet thus decreases proinflammatory components, but enhances fibrosis in ethanol-fed rats. (Hepatology 1997 Jul;26(1):90-7)

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