Premium
A coagulation factor VII deficiency protects against acute inflammatory responses in mice
Author(s) -
Xu H,
Ploplis VA,
Castellino FJ
Publication year - 2006
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2073
Subject(s) - downregulation and upregulation , inflammation , factor vii , tissue factor , lipopolysaccharide , proteases , immunology , in vivo , pharmacology , medicine , coagulation , disseminated intravascular coagulation , chemistry , biology , enzyme , biochemistry , microbiology and biotechnology , gene
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 (FVII tTA/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 FVII tTA/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 FVII tTA/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 FVII tTA/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.