Thrombin and factor Xa enhance neutrophil chemoattractant production afterischemia/reperfusion in the rat liver

Background. Clotting proteases may affect leukocyte effector function. Acti vation of the coagulation cascade after ischemia/reperfusion stimulates cyt okine production by activated macrophages. Cytokine-induced neutrophil chem oattractant (CINC) may also be important in the pathophysiology of liver is chemia/reperfusion injury. We investigated the effects of a selective facto r Xa inhibitor, DX-9065a, on CINC expression after ischemia/reperfusion in the rat liver. Methods, Liver ischemia was induced in rats by occluding the portal vein fo r 30 min. DX-9065a (9 mg/kg) was injected intravenously 5 min before vascul ar clamping. Serum CINC concentrations were measured by enzyme-linked immun osorbent assay, Levels of CLNC mRNA in the liver were determined by Norther n blot analysis. We also examined in vitro CINC production by peritoneal ma crophages in response to alpha-thrombin or factor Xa. Results, Serum CINC concentrations increased and peaked 6 h after reperfusi on, However, pretreatment of animals with DX-9065a resulted in significantl y smaller increases in CINC after reperfusion, Pretreatment with DX-9065a a lso significantly reduced CINC mRNA levels in the liver after ischemia/repe rfusion. In vitro CINC production by peritoneal macrophages was enhanced by Lu-thrombin, as well as factor Xa. Conclusions. Thrombin and factor Xa stimulate CINC production by macrophage s. A selective inhibitor of factor Xa, DX-9065a, attenuates neutrophil chem oattractant production after ischemia/reperfusion injury of the rat liver, (C) 2000 Academic press.