The authors of this article declared they have no conflicts of interest.
A coagulation factor VII deficiency protects against acute inflammatory responses in mice
Article first published online: 20 OCT 2006
Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 210, Issue 4, pages 488–496, December 2006
How to Cite
Xu, H., Ploplis, V. and Castellino, F. (2006), A coagulation factor VII deficiency protects against acute inflammatory responses in mice. J. Pathol., 210: 488–496. doi: 10.1002/path.2073
- Issue published online: 9 NOV 2006
- Article first published online: 20 OCT 2006
- Manuscript Accepted: 30 AUG 2006
- Manuscript Revised: 9 AUG 2006
- Manuscript Received: 3 MAY 2006
- NIH. Grant Numbers: HL073750, HL019982
- Kleiderer-Pezold endowment
- coagulation factor VII.
Upregulation of the activated Factor VII (FVIIa)/Tissue Factor 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, which can result in disseminated intravascular coagulation. 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, namely lipopolysaccharide (LPS)-induced lethal endotoxaemia. Mice with a total FVII deficiency do not survive the neonatal period. Therefore mice expressing low levels of FVII (FVIItTA/tTA), producing sufficient amounts of FVII for survival (approximately 5% of wild-type (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 in comparison with similarly treated WT mice after administration of LPS. The attenuated inflammatory responses in FVIItTA/tTA mice were associated with downregulation of Egr-1 signalling. 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 endotoxaemia 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. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.