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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 157-164
Antithrombin Reduces Ischemia/Reperfusion Injury of Rat Liver by
Increasing the Hepatic Level of Prostacyclin
Naoaki Harada,
Kenji Okajima,
Shigeki Kushimoto,
Hirotaka Isobe, and
Keiichi Tanaka
From the Department of Laboratory Medicine, Kumamoto University
School of Medicine, Kumamoto, Japan; and the Department of Emergency
and Critical Care Medicine, School of Medicine, Fukuoka University,
Fukuoka, Japan.
We investigated whether antithrombin (AT) can reduce
ischemia/reperfusion (I/R)-induced injury of rat liver by promoting
prostacyclin release from endothelial cells. Although intravenous
administration of AT (250 U/kg) markedly reduced hepatic injury,
neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa
(DEGR-Xa), a selective inhibitor of thrombin generation, nor
Trp49-modified AT, which lacks affinity for heparin, had
any effect. Hepatic levels of 6-keto-PGF1 , a stable
prostacyclin (PGI2) metabolite, were increased
significantly after I/R of the rat liver. AT significantly increased
the hepatic level of 6-keto-PGF1, whereas neither
DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue
blood flow was markedly reduced after I/R. Although AT significantly
increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor
Trp49-modified AT increased the blood flow. Hepatic levels
of cytokine-induced neutrophil chemoattractant (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 Trp49-modified AT.
Pretreatment of animals 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-PGF1 levels after I/R. Iloprost, a stable analog
of PGI2, exhibited effects similar to those of AT and also
significantly inhibited the exacerbation of liver injury, the decrease
in hepatic tissue blood flow, and the increases in hepatic CINC and MPO
levels seen in rats subjected to I/R but pretreated with IM. These
findings suggest that AT may prevent I/R-induced hepatic injury by
increasing the hepatic levels of PGI2 through the
interaction of AT with cell-surface glycosaminoglycans, thus increasing
hepatic tissue blood flow and inhibiting leukocyte activation in
animals subjected to I/R.
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