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Prevention of endotoxin-induced mortality by antitissue factor immunization
A P Dackiw1, I D McGilvray, M Woodside
1Department of Surgery, Toronto Hospital, University of Toronto, Ontario.
Archives of Surgery (Chicago, Ill. : 1960)
|December 1, 1996
Summary
An antibody targeting tissue factor reduced mortality in endotoxic shock by inhibiting coagulation and fibrin deposition. This approach improved survival without affecting the initial cytokine response, suggesting a key role for coagulation in sepsis-induced organ injury.
Area of Science:
- Immunology
- Pathophysiology
- Coagulation Science
Background:
- Microvascular thrombosis and fibrin deposition are hallmarks of endotoxic shock.
- Tissue factor expression by endothelial and monocyte/macrophage cells drives this procoagulant response.
Purpose of the Study:
- To investigate the therapeutic potential of an antitissue factor antibody in mitigating endotoxic shock.
- To assess the impact of modulating tissue factor-mediated coagulation on survival and inflammatory markers.
Main Methods:
- Developed a polyclonal antibody against murine tissue factor.
- Validated antibody efficacy in vitro by measuring inhibition of lipopolysaccharide (LPS)-induced procoagulant activity in macrophages.
- Assessed in vivo efficacy in a lethal murine endotoxemia model, evaluating mortality, fibrinogen, and tumor necrosis factor levels.
Main Results:
- The antitissue factor antibody effectively abrogated LPS-induced procoagulant activity in vitro.
- In vivo, antibody treatment significantly reduced mortality in mice subjected to lethal endotoxemia (P < .05).
- Immunized mice exhibited higher fibrinogen levels and similar tumor necrosis factor levels compared to controls, indicating reduced coagulation consumption without blunted cytokine induction.
Conclusions:
- Targeting tissue factor-mediated coagulation offers a promising therapeutic strategy for endotoxic shock.
- Inhibition of microvascular fibrin deposition improves survival in sepsis models.
- Coagulation plays a significant pathogenic role in sepsis-induced acute organ injury.