engleski

Anti-thromboxane B2 antibodies protect against acetaminophen induced liver injury in mice

Prostanoids are lipid compounds that mediate variety of physiological and pathological functions in almost all body tissues and organs. Thromboxane (Tx) A2 is a powerful inducer of platelet aggregation and vasoconstriction and it shows ulcerogenic activity in the gastrointestinal tract. These observations prompted us to investigate whether TxA2 play a role in host response to toxic effect of acetaminophen (N-acetyl-p-aminophenol, APAP). Overdose or chronic use of a high dose of APAP is a major cause of acute liver failure in the western world. CBAT6T6 mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. The toxicity of APAP was determined by observing the survival of mice during 48 h, by measuring concentration of alanine-aminotransferase (ALT) in plasma 20-22 h after APAP administration and by liver histology. The results have shown that anti-TxB2 antibodies (anti-TxB2) and a selective inhibitor of thromboxane synthase, benzylimidazole (BZI), were significantly hepatoprotective, while a selective thromboxane receptor (TP) antagonist, daltroban, TxB2 was slightly protective in this model of acute liver injury. A stabile metabolite of TxA2, TxB2, and a stabile agonist of TP, U-46619, had no inffluence on APAP induced liver damage. These findings indirectly support the hypothesis that TxA2 has a pathogenic role in liver toxicity induced with APAP, which was highly abrogated by administration of anti-TxB2. According to our results, this protection is mediated, at least partially, through decreased production of TxB2 by liver fragments ex vivo.

acetaminophen; liver toxicitity; thromboxanes; anti-thromboxane B2 antibodies; U-4619; benzylimidazole; daltroban

nije evidentirano