leukotriene-b4 and Liver-Diseases--Alcoholic

The purpose of our study is to determine if a relationship exists between the severity of injury in experimental alcoholic liver disease and hepatic levels of leukotriene B4, leukotriene C4 and lipid peroxide. Splague-Dawley rats were fed ethanol (46% of calories) with either safflower oil (SE) or beef oil (BE) (20% of calories) for 12 weeks. Control animals were fed isocaloric amounts of dextrose instead of ethanol with the same diets. The followings were evaluated in each group: hepatic levels of leukotriene B4, C4, lipid peroxide, and collagen-bound hydroxyl-proline, hepatic fatty acid composition, incorporation of 14C-L-proline into hydroxyproline of collagen protein by liver slice. Rats fed SE showed the most abundant accumulation of hepatic hydroxyproline and lipid peroxide. Hepatic leukotriene B4 and C4, hepatic levels of linoleic acid and arachidonic acid were also greater in rat livers from animals fed the SE diet. A strong positive correlation was seen between hepatic levels of leukotrien B4 as well as C4 and lipid peroxide. The hepatic level of lipid peroxide also correlated positively with hepatic levels of linoleic acid and arachidonic acid. Our study shows the importance of leukotriene derived from arachidonic acid cascade in the pathogenesis of experimental alcoholic liver disease.

Topics: Animals; Arachidonic Acids; Dietary Fats; Inflammation Mediators; Leukotriene B4; Leukotriene C4; Linoleic Acid; Lipid Peroxides; Liver; Liver Diseases, Alcoholic; Male; Plant Oils; Rats; Rats, Sprague-Dawley

The purpose of our study is to determine if a relationship exists between the severity of injury in experimental alcoholic liver disease and plasma levels of endotoxin, prostaglandin E2, leukotriene B4, and thromboxane B2. Four groups of animals (n = 4 to 8 in each group) were fed a liquid diet with corn oil (25% of calories) and ethanol over various time periods: 1 week, 2 weeks, 1 month, and 2 months. At sacrifice, liver pathology scores and plasma levels of the above were determined. Plasma levels of endotoxin were already increased after 1 week (26.6 +/- 18.6 pg/ml) and continued to increase over time, with the highest levels at 2 months (69.5 +/- 24.5 pg/ml). A strong positive correlation (r = 0.84, P < 0.001) was seen between plasma endotoxin levels and severity of liver injury. The pathology score also correlated positively with leukotriene B4 (r = 0.47, P < 0.05) and thromboxane B2 (0.66, P < 0.01). A negative correlation was obtained with prostaglandin E2 levels (r = -0.44, P < 0.05). A positive correlation was also seen between endotoxin levels and leukotriene B4 (r = 0.57, P < 0.02) and thromboxane B2 (0.64, P < 0.01); a negative correlation was obtained with prostaglandin E2 levels (r = -0.55, P < 0.02). Each metabolite was also correlated with each of the features of alcoholic liver injury, i.e., fatty liver, necrosis, and inflammation. With prostaglandin E2, the most marked decrease was seen in association with severe fatty liver (3 to 4+). Thromboxane B2 correlated best with presence of inflammation and necrosis. Our study shows the importance of endotoxin in the pathogenesis of experimental alcoholic liver disease and suggests that endotoxin modulates production of eicosanoids that contribute to the severity of liver injury.

Topics: Animals; Dinoprostone; Eicosanoids; Endotoxins; Leukotriene B4; Liver; Liver Diseases, Alcoholic; Male; Rats; Rats, Wistar; Thromboxane B2

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

Alcohol inhibits phospholipase (PL) activity in a number of animal models. We have therefore measured prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), liberated by stimulated peripheral blood mononuclear cells (PBMC) and neutrophils respectively in chronic alcoholics and in control subjects. Peripheral blood mononuclear cells from alcoholics produced less PGE2 (p less than 0.01) and neutrophils produced less LTB4 (p less than 0.025). Reduced PGE2 production by PBMC of alcoholics was corrected by the addition of exogenous arachidonic acid (p less than 0.005) whilst neutrophil LTB4 production remained lower in the alcoholics (p less than 0.01). Percutaneous liver biopsies were undertaken in the 20 alcoholics having abnormal liver function tests. Prostaglandin E2 biosynthesis was lower in PBMC from patients with alcoholic hepatitis than with alcoholic cirrhosis (p less than 0.05). Analysis of PBMC fatty acid composition demonstrated that endogenous arachidonate and linoleate contents were not significantly different in alcoholics and controls. Cells from controls and alcoholics were incubated with 0, 50 and 150 mmol/l ethanol for two hours but there was no alteration in PGE2 or LTB4 biosynthesis. In summary, we found reduced eicosanoid production by peripheral leucocytes in alcoholics, supporting the hypothesis that chronic alcohol consumption either inhibits membrane bound phospholipase activity or enhances, alternatively, catabolism of eicosanoids. This phenomenon is more marked in alcoholic patients with hepatitis than in those with cirrhosis alone.

Topics: Adult; Alcoholism; Dinoprostone; Humans; Leukocytes, Mononuclear; Leukotriene B4; Liver Diseases, Alcoholic; Middle Aged; Neutrophils