FVII stands on the crossroads of coagulation and inflammation

Upregulation of the activated Factor VII (FVIIa)/Tissue Factor (TF) complex, downregulation of natural anticoagulation pathways, and inhibition of fibrinolysis, are major contributors to coagulopathies associated with acute inflammation. Provision of FVIIa, and consequent downstream coagulation-related proteases, also stimulates further inflammatory changes. Thus, the potential protective effects in vivo of a genetic-based reduction in FVII levels have been investigated in a murine model of acute inflammation, viz., lipopolysaccharide (LPS)-induced lethal endotoxemia. Since mice with a total FVII deficiency do not survive the neonatal period, very low-expressing FVII (FVIItTA/tTA) mice, producing sufficient amounts of FVII for survival (ca., 1% of WT FVII), 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. The FVIItTA/tTA mice presented with reduced mortality, coagulation, and inflammatory responses when compared to similarly-treated wild-type (WT) mice after administration of LPS. The attenuated inflammatory responses in FVIItTA/tTA mice were associated with downregulation of Egr-1 signaling. Administration, in vivo, of specific inhibitors of FXa and thrombin demonstrated that the inflammatory responses were unaltered in WT mice, but further reduced in FVIItTA/tTA mice. Therefore, a FVII deficiency enhances survival from lethal endotoxemia both through attenuation of inflammatory responses that result directly from reduced FVIIa levels, and, indirectly, from downregulation of coagulation proteases downstream of the FVII-dependent cascade. Keratinocytes from skin tissue are rich sources of tissue factor and are highly associated with skin wound healing. However, studies of the involvement of extrinsic coagulation factors during skin wound healing are still lacking. Here we demonstrated that low FVII mice exhibited impaired skin wound healing. These gene-deficiency mice showed delayed re-epithelialization and reduced inflammatory cell infiltration at wound sites compared with control mice. The reduced inflammatory response in low FVII mice was also demonstrated using a thioglycollate induced inflammatory model. The delayed re-epthelialization in low FVII mice was associated with regulation of Egr-1 as demonstrated by the increased expression level of Egr-1 by FVIIa stimulation in keratinocytes. In vitro, Egr-1 was shown to be essential for FVIIa induced keratinocytes migration and inflammation. In vivo, Egr-1 deficient mice displayed a significant delay of skin wound healing.