Recombimant TFPI (r-TFPI) reduces the LPS-induced pulmonary vascular injury by inhibiting leukocyte activation

INTRODUCTION: Tissue factor pathway inhibitor (TFPI) is a physiologic protease inhibitor, which regulates the extrinsic pathway of coagulation by inhibiting F.Xa and F.VIIa. r-TFPI has been shown to inhibit E. coli-induced coagulopathy and the lethal effects. Since activated leukocytes play an important role in such E. coli-induced events, r-TFPI may reduce the lethal effect by inhibiting leukocyte activation. The aim of this study is to examine whether r-TFPI reduces coagulation abnormalities and organ injury by leukocyte activation in rats given LPS. METHODS: LPS (5mg/kg. iv) was injected to induce coagulation abnormalities and acute lung injury. r-TFPI (1mg/kg, iv) was injected 30 minutes prior to the LPS administration. Lung injury was evaluated by measuring lung wet/dry weight ratio 6hrs after LPS injection. Results were compared using Analysis of Variance (ANOVA) and the Scheffe's post hoc test. RESULTS. Leukocytopenia and r-TFPI prevented both LPS-induced pulmonary vascular injury and TNF production, while neither DEGR-VIIa, a competitive inhibitor of F.VIIa, nor DX-9065a, a selective inhibitor of F.Xa did. Pretreatment Safne+LPS r-TFPI+LPS Leutacyts-peala+LPS DEGR-FVIIs+LPS Lung W/D weight ratie 5.11±0.09 5.04±0.06 * 4.98±0.06 * 5.12±0.10 Lung MPO (O/g tissue) 42±6 31±5 * 20±2 * 38±7 Plasma TNF (x10¹ pg/mLD 7.9±2.3 4.0±1.8 * 2.8±2 * 38±7 FDP[E] [rg/mLI] 95±32 41±8 25±6 * 24±5 * * p<0.05 vs Saline + LPS group. Mean±SD of 6 animal experiments. CONCLUSION: r-TFPI inhibits the LPS-induced coagulation abnormalities and lung injury by inhibiting leukocyte activation.