Thromboxane inhibitors attenuate inflammatory and fibrotic changes in rat liver despite continued ethanol administrations.
BACKGROUND
Thromboxane levels are increased in rats fed ethanol (EtOH), whereas thromboxane inhibitors reduce alcoholic liver injury. The aim of this study is to determine whether thromboxane inhibitors could attenuate the already established alcoholic liver injury.


METHODS
Rats were fed EtOH and liquid diet for 6 weeks by intragastric infusion to induce liver injury after which EtOH was continued for 2 more weeks, and the rats were treated with either a thromboxane synthase inhibitor (TXSI) or a thromboxane receptor antagonist (TXRA). Liver pathology, lipid peroxidation, nuclear factor-kappa-B (NF-κB) activity, tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and transforming growth factor-beta1 (TGF-β(1) ) were evaluated.


RESULTS
Administration of fish oil and EtOH caused fatty liver, necrosis, inflammation and fibrosis accompanied by increased in lipid peroxidation, NF-κB activity, and expression of TNF-α, COX-2, and TGF-β(1) . Treatment with the thromboxane inhibitors ameliorated a certain level of the pathological and biochemical abnormalities. In particular, TXSI in addition to reducing necrosis, inflammation and fibrosis also decrease the severity of fatty liver.


CONCLUSIONS
Thromboxane inhibitors attenuated the alcoholic liver injury, inflammation and fibrotic changes despite continued EtOH administration. Inhibition of the production of thromboxane by thromboxane inhibitor and receptor antagonists may be a useful treatment strategy in clinical alcoholic liver disease.
Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, NS, Canada.
Amin A
AA
Nanji
Emily C
EC
Liong
Jia
J
Xiao
George L
GL
Tipoe
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000009:adverse effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004731:Endotoxins / Q000097:blood; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D005235:Fatty Liver, Alcoholic / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D005355:Fibrosis; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D053773:Transforming Growth Factor beta1 / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002492:Central Nervous System Depressants; D004731:Endotoxins; D016328:NF-kappa B; D010080:Oxazoles; D011725:Pyridines; D012333:RNA, Messenger; D017482:Receptors, Thromboxane; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; C049113:3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid; C078904:ifetroban; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D013930:Thromboxane-A Synthase