Abstract 836: Coagulation Factor VII Contributes to Lethal Endotoxemia in Mice in Association with Regulation of Egr-1
Since the Factor (F) VIIa/Tissue Factor (TF) pathway is a main contributor to the coagulopathy associated with acute inflammation, the potential protective effects of a genetic-based reduction in FVII levels have been investigated in a murine model of lipopolysaccharide (LPS)-induced lethal endotoxemia. Very low-expressing FVII (FVIItTA/tTA) mice, constructed by gene targeting technology, were employed to investigate in vivo pathways involved in the crosstalk between coagulation, inflammation, and survival, consequent to administration of a lethal dose of LPS. These low-FVII (FVIItTA/tTA) mice presented with reduced mortality, coagulation, and inflammatory responses compared to similarly-treated wild-type (WT) mice after administration of LPS. The attenuated inflammatory responses were related to down-regulation of the transcription factor, egr-1. Specific inhibitors to FXa and thrombin were administered to mice in an effort to distinguish mechanistically the function of FVIIa from that of downstream coagulation factors. The results demonstrated that the inflammatory responses, while not dependent on fibrin formation, were unaltered in WT mice but further reduced in FVIItTA/tTA mice. This indicates that FVII sustains a lethal response, which masks the functions of FXa and thrombin in inflammation. Thus, a FVII insufficiency enhances survival from lethal endotoxemia mainly through attenuation of inflammatory responses that result from reduced coagulation protease levels, the latter of which are known to be involved in signal transduction and inflammatory cell migration.