Antithrombin reduces mesenteric venular leukocyte interactions and small intestine injury in endotoxemic rats

We examined the hypothesis that recombinant human antithrombin would reduce mesenteric venule leukocyte adhesion and small intestine injury in endotox emic rats. Endotoxemic (endotoxin 10 mg/kg, intravenously) rats were treate d either with saline or recombinant human antithrombin (250 and 500 U/kg). In some rats, indomethacin (100 mg/kg, intraperitoneally) was injected 60 m in prior to endotoxin and recominant human antithrombin (500 U/kg) treatmen t. Compared to controls, intravital videomicroscopy of the mesentric venule showed an increase of leukocyte rolling (55 +/- 17 versus 70 +/- 19 leukoc ytes/min; P < 0.05) and firm adhesion (1.1 +/- 0.3 versus 5.8 +/- 0.8 leuko cytes/100 <mu>m; P < 0.05) in endotoxemic rats. Recombinant human antithrom bin attenuated endotoxin-induced venular endothelium leukocyte adhesive cas cade. The beneficial effects of recombinant human antithrombin on leukocyte adhesion were inhibited by indomethacin (100 mg/kg, intraperitoneally) in endotoxemic rats. Endotoxin treatment increased fluorescein isothiocyanate (FITC)-labeled dextran 4,000 (FD4) gut lumen to plasma ratio and wet weight /dry weight ratio. Recombinant human antithrombin (500 U/kg) attenuated end otoxin-induced gut injury. These observations suggest that recombinant huma n antithrombin reduces endothelium-leukocyte interactions in endotoxemic ra ts by interacting with local prostacyclin production.