We investigated the role of
anticoagulant in the
ischemia/reperfusion injury of the liver, using activated
protein C (APC), active human urinary
thrombomodulin (UTM), and
factor Xa blocked at the active site (
DEGR-Xa). Liver
ischemia was induced in male Wistar rats by occlusion of the portal vein with a microvascular
clip for 30 minutes. Each
anticoagulant was injected intravenously 10 minutes before clamping the portal vein. Serum concentrations of
cytokine-induced neutrophil
chemoattractant (CINC) were determined by
enzyme-linked
immunosorbent assay. The serum levels of CINC increased significantly following reperfusion, reaching a peak in 6 hours, and then decreasing gradually to control levels by 24 hours. CINC levels in rats pretreated with APC (500 U/kg), UTM (3,000 TMU/kg), or
DEGR-Xa (10 mg/kg) peaked 3 hours following reperfusion and decreased rapidly to baseline level within 6 and 12 hours, respectively. These peak values were significantly lower than those observed in untreated rats (P < .01). Expression of CINC transcripts in liver tissue of untreated rats was evaluated by Northern blot analysis and peaked 3 hours following reperfusion. Pretreatment with these
anticoagulants significantly decreased the expression of CINC
messenger RNA transcripts as compared with untreated animals.
Myeloperoxidase activity and the number of neutrophils accumulated into the liver 24 hours following
ischemia/reperfusion were also significantly decreased in animals pretreated with these
anticoagulants. In addition, correlations between the peak values of liver
enzymes and serum CINC levels were found to be significant (P < .001). The inactive derivative of
factor Xa, a selective inhibitor of
thrombin generation, inhibited
ischemia/reperfusion-induced increases in the serum concentration and
messenger RNA transcript quantities of CINC. The inactive
factor Xa also reduced hepatic accumulation of neutrophils after
ischemia/reperfusion. These results indicate that the release of CINC is likely related to the hepatic microcirculation disturbance induced by microthrombotic occlusion following
ischemia/reperfusion.