Xanthine oxidase inhibition attenuates Kupffer cell production of neutrophil chemoattractant following ischemia-reperfusion in rat liver

We investigated the effects of the xanthine oxidase inhibitor, BOF-4272, on the production of cytokine-induced neutrophil chemoattractant (CINC) follo wing reperfusion injury in rat liver. Ischemia was induced for 30 minutes b y portal vein occlusion. Animals were pretreated with intravenous injection of BOF-4272 (1 mg/kg) or heparin (50 U/kg) 5 minutes before vascular clamp . Both BOF-4272 and heparin limited increases in the chemoattractant compar ed with nonpretreated rats. Pretreatment with BOF-4272 plus heparin resulte d in an additive effect, Most cells immunostained for chemoattractant were macrophages in sinusoids. In vitro chemoattractant production by Kupffer ce lls isolated from animals pretreated with heparin or BOF-4272 was significa ntly lower than by Kupffer cells from nonpretreated animals. Expression of transcripts in liver for chemoattractant peaked 3 hours after reperfusion i n nonpretreated animals, while pretreatment with heparin or BOF-4272 signif icantly decreased chemoattractant mRNA levels. In vitro chemoattractant tra nscription and production could be induced in naive Kupffer cells by hypoxa nthine and xanthine oxidase, but BOF-4272 prevented these increases. We con clude that Kupffer cells release chemoattractant in response to oxygen radi cals reducible by xanthine oxidase inhibition.