Enhanced cyclooxygenase-2 gene expression in alcoholic liver disease in the rat.
OBJECTIVE
Inflammatory stimuli and lipid peroxidation up-regulate cyclooxygenase (COX)-2. This study evaluated the relationship between inflammatory mediators, COX expression, and pathological changes in experimental alcoholic liver disease.


METHODS
Rats (5 per group) were fed ethanol and a diet containing saturated fat, corn oil, or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in controls. In the first set of experiments, whole livers were analyzed. In the second set of experiments, Kupffer cells, endothelial cells, and hepatocytes were isolated from rats in each group. Pathological analyses and measurements of lipid peroxidation, tumor necrosis factor (TNF)-alpha, COX-1 and COX-2 messenger RNA (mRNA), endotoxin, and liver and plasma thromboxane were performed.


RESULTS
Increased expression of COX-2 mRNA was detected in the livers of rats showing necroinflammatory changes. The Kupffer cell was the cell primarily responsible for the increase in COX-2 mRNA level. Increased expression of COX-2 was associated with increased levels of endotoxin, TNF-alpha mRNA, lipid peroxidation, and synthesis of thromboxane. COX-1 mRNA was decreased in Kupffer cells in rats with the most severe liver injury.


CONCLUSIONS
Up-regulation of COX-2 in alcoholic liver injury occurred in the presence of proinflammatory stimuli and resulted in increased synthesis of inflammatory and vasoactive eicosanoids. Down-regulation of COX-1 may result in decreased synthesis of cytoprotective eicosanoids and additionally exacerbate liver injury.
Nanji
A A
AA
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Miao
L
L
Thomas
P
P
Rahemtulla
A
A
Khwaja
S
S
Zhao
S
S
Peters
D
D
Tahan
S R
SR
Dannenberg
A J
AJ
D000818:Animals; D051546:Cyclooxygenase 2; D019446:Endotoxemia / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D007527:Isoenzymes / Q000235:genetics*; D007728:Kupffer Cells / Q000201:enzymology; D015227:Lipid Peroxidation; D008108:Liver Diseases, Alcoholic / Q000201:enzymology*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013929:Thromboxane B2 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D007527:Isoenzymes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013929:Thromboxane B2; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases