Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin

We investigated whether antithrombin (AT) can reduce ischemia/reperfusion ( I/R)-induced injury of rat liver by promoting prostacyclin release from end othelial cells. Although intravenous administration of AT (250 U/kg) marked ly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-t reated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, n or Trp(49)-modified AT, which lacks affinity for heparin, had any effect. H epatic levels of 6-keto-PGF(1 alpha), a stable prostacyclin (PGI(2)) metabo lite, were increased significantly after I/R of the rat liver. AT significa ntly increased the hepatic level of 6-keto-PGF(1 alpha), whereas neither DE GR-Xa nor Trp(49)-modified AT increased it. Hepatic tissue blood flow was m arkedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp(49)-modified AT increa sed the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattr actant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp(49)-modified AT. Pretreatment of anima ls with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF(1 alpha) levels after I/R. Il oprost, a stable analog of PGI(2), exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the dec rease in hepatic tissue blood flow, and the increases in hepatic CINC and M PO levels seen in rats subjected to I/R but pretreated with IM. These findi ngs suggest that AT may prevent I/R-induced hepatic injury by increasing th e hepatic levels of PGI(2) through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibitin g leukocyte activation in animals subjected to I/R. (C) 1999 by The America n Society of Hematology.