A coagulation factor VII deficiency protects against acute inflammatory responses in mice.
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.
Xu
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WM Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA.
Ploplis
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VA
Castellino
F J
FJ
D000721:Ancrod / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000990:Antithrombin III / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D001777:Blood Coagulation / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000276:immunology; D051766:Early Growth Response Protein 1 / Q000276:immunology; D019446:Endotoxemia / Q000276:immunology*; D005168:Factor VII Deficiency / Q000276:immunology*; D015951:Factor Xa / Q000276:immunology; D005340:Fibrinogen / Q000276:immunology; D000077425:Fondaparinux; D006629:Hirudins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology; D010447:Peptide Hydrolases / Q000276:immunology; D011134:Polysaccharides / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D013917:Thrombin / Q000276:immunology
D000925:Anticoagulants; D015415:Biomarkers; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006629:Hirudins; D008070:Lipopolysaccharides; D011134:Polysaccharides; D011994:Recombinant Proteins; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D005340:Fibrinogen; D010447:Peptide Hydrolases; D000721:Ancrod; D013917:Thrombin; D015951:Factor Xa; D000077425:Fondaparinux; C083544:lepirudin