PRETREATMENT WITH ACTIVATED PROTEIN-C OR ACTIVE HUMAN URINARY THROMBOMODULIN ATTENUATES THE PRODUCTION OF CYTOKINE-INDUCED NEUTROPHIL CHEMOATTRACTANT FOLLOWING ISCHEMIA REPERFUSION IN RAT-LIVER/

We investigated the role of anticoagulant in the ischemia/reperfusion injury of the liver, using activated protein C (APC), active human uri nary thrombomodulin (UTM), and factor Xa blocked at the active site (D EGR-X alpha), Liver ischemia was induced in male Wistar rats by occlus ion of the portal vein with a microvascular clip for 30 minutes, Each anticoagulant was injected intravenously 10 minutes before clamping th e portal vein, Serum concentrations of cytokine-induced neutrophil che moattractant (CINC) were determined by enzyme-linked immunosorbent ass ay, The serum levels of CINC increased significantly following reperfu sion, reaching a peak in 6 hours, and then decreasing gradually to con trol 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 followi ng 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 transcr ipts in liver tissue of untreated rats was evaluated by Northern blot analysis and peaked 3 hours following reperfusion, Pretreatment with t hese anticoagulants significantly decreased the expression of CINC mes senger RNA transcripts as compared with untreated animals, Myeloperoxi dase activity and the number of neutrophils accumulated into the liver 24 hours following ischemia/reperfusion were also significantly decre ased in animals pretreated with these anticoagulants. In addition, cor relations between the peak values of liver enzymes and serum CINC leve ls were found to be significant (P < .001), The inactive derivative of factor Xa, a selective inhibitor of thrombin generation, inhibited is chemia/reperfusion-induced increases in the serum concentration and me ssenger RNA transcript quantities of CINC. The inactive factor Xa also reduced hepatic accumulation of neutrophils after ischemia/reperfusio n, These results indicate that the release of CINC is likely related t o the hepatic microcirculation disturbance induced by microthrombotic occlusion following ischemia/reperfusion.