Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation

Tissue factor pathway inhibitor (TFPI) is an important physiologic inhibito r of the extrinsic pathway of the coagulation system. We investigated wheth er recombinant TFPI (rTFPI) could reduce pulmonary vascular injury by inhib iting leukocyte activation in rats given lipopolysaccharide (LPS). Pre- or posttreatment of animals with rTFPI significantly inhibited LPS-induced pul monary vascular injury, as well as coagulation abnormalities. rTFPI signifi cantly inhibited increases in lung tissue levels of tumor necrosis factor ( TNF)-alpha, cytokine-induced neutrophil chemoattractant, and myeloperoxidas e. Expression of TNF-alpha messenger RNA in the lung after LPS administrati on was significantly reduced by rTFPI administration, However, neither DX-9 065a, a selective inhibitor of Factor Xa, nor recombinant Factor Vlla treat ed with dansyl-glutamylglycylarginyl-chloromethyl ketone, a selective inhib itor of Factor Vlla, had any effects on LPS-induced pulmonary vascular inju ry despite their potent anticoagulant effects. rTFPI significantly inhibite d TNF-alpha production by LPS-stimulated monocytes in vitro. rTFPI also sig nificantly inhibited several formyl-Met-Leu-Phe-induced neutrophil function s, as well as increases in the expression of CD11b and CD18 on the neutroph il cell surface in vitro. Additionally, rTFPI inhibited increases in levels of intracellular calcium, a second messenger of neutrophil activation, in formyl-Met-Leu-Phe-stimulated neutrophils in vitro. These results strongly suggested that rTFPI reduces pulmonary vascular injury by inhibiting leukoc yte activation, as well as coagulation abnormalities in rats given LPS.