e-3330 and Liver-Diseases--Alcoholic

We evaluated the role of endothelial cell (EC) proliferation in experimental alcoholic liver disease (ALD) using different dietary models of ALD. Rats were divided into treatment groups to receive ethanol with either corn oil (CO + E), fish oil (FO + E), saturated fat (SF + E), and corn oil with a novel quinone derivative (E3330) and cimetidine. All ethanol-fed rats in the different groups were pair-fed with dextrose replacing the ethanol-derived calories. All ethanol-fed groups and their controls were fed for periods ranging from 1 to 4 weeks. For each animal, immunocytochemical staining for PCNA was performed on paraffin-embedded tissue sections and the number of endothelial cells staining for PCNA per 10 high-power fields (HPF) was determined. Rats fed CO + E and FO + E developed pathological changes, whereas none of the histologic features of ALD were seen in SF + E rats. The severity of injury was reduced in the quinone and cimetidine-treated groups. A higher rate of EC proliferation (6-30x) was seen in the SF + E group (no liver injury) than in the CO + E and FO + E groups (pathologic changes present). The difference was evident by 1 week, which is well before pathologic changes can be recognized (usually 4 weeks). An increase in EC proliferation was seen in the E3330 and cimetidine-treated groups. Our study indicates that the proliferative response of EC in ethanol-fed rats may be a factor in the progression to liver injury. Suppression of ethanol-induced EC proliferation in CO + E and FO + E groups occurred prior to development of liver injury; a lack of suppression of EC proliferation is associated with absence (SF + E and CO + E + cimetidine) or reduction in severity (CO + E + E3330) of liver injury.

Topics: Animals; Benzoquinones; Cell Division; Cimetidine; Corn Oil; Diet; Endothelium; Ethanol; Fish Oils; Liver; Liver Diseases, Alcoholic; Male; Proliferating Cell Nuclear Antigen; Propionates; Rats; Rats, Wistar

Chronic ethanol intake impairs several parameters of immune function. Since there is evidence that cytokine production by immune cells may contribute to the immunosuppressive effect of ethanol, we examined interleukin 1 (IL1) production by liver non-parenchymal cells (NPC) in ethanol-fed rats. Male Wistar rats (225-250 g) were fed by continuous intragastric infusion. The source of fat was either saturated fat or polyunsaturated fat. In addition, the effect of a quinone compound on IL1 production was assessed. Animals were fed for various periods: 1 week, 2 weeks, 1 month and 2 months. NPC were isolated and stimulated by lipopolysaccharide. IL1 production by NPC and the ratio of stimulated to unstimulated (S:U) IL1 production were evaluated in the different groups and related to the presence of liver injury. As expected, animals fed corn oil and ethanol (CO+E) developed pathologic liver injury, whereas animals fed saturated fat and ethanol (SF+E) had no liver injury. A progressive decrease in the S:U IL1 ratio was seen in the CO+E group over the 8-week period. The ratio in the SF+E group was higher. The quinone compound reversed the suppressive effect of ethanol on IL1 production. In summary, ethanol-induced suppression of IL1 production was modulated by diet and the presence of liver injury. This suppression of IL1 production was reversed by a quinone compound; the exact mechanism for the reversal of this inhibition is unknown.

Topics: Animals; Benzoquinones; Ethanol; Fatty Acids; Interleukin-1; Liver; Liver Diseases, Alcoholic; Male; Propionates; Rats; Rats, Wistar

The present study evaluated the possible protective effect of ((2E)-3-[5-(2,3 dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonyl-2-propanoic acid) (E3330), a newly synthesized hepatoprotective-quinone derivative, on experimental alcoholic liver injury. The intragastric feeding rat model for alcoholic liver disease was used. Eight sets of experiments were performed in which animals fed either corn oil and ethanol or corn oil, ethanol and E3330 were sacrificed at intervals of 1 week, 2 weeks, 1 month and 2 months. Nonparenchymal cell supernatant (NPCS) and plasma measurements of tumor necrosis factor, prostaglandin E2, leukotriene B4 and thromboxane B2 were evaluated in relation to the development of pathologic liver injury. Oral treatment with E3330 reduced the severity of liver injury; this was accompanied by a reduction in thromboxane B2 and leukotriene B4 levels in both NPCS and plasma and a reduction in tumor necrosis factor levels in NPCS. The difference in pathologic severity between drug- and nondrug-treated groups correlated well with the changes in the NPCS and plasma thromboxane B2/prostaglandin E2 ratio. These findings suggest that E3330 has multiple actions, such as inhibition of thromboxane, leukotriene and tumor necrosis factor generation, which contribute to its protective effect in alcoholic liver injury.

Topics: Animals; Benzoquinones; Dinoprostone; Leukotriene B4; Liver; Liver Diseases, Alcoholic; Male; Propionates; Rats; Rats, Wistar; Thromboxane B2; Tumor Necrosis Factor-alpha