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1 Medicine, Duke University Medical Center, Durham, NC, USA
* To whom correspondence should be addressed. E-mail: welty001{at}mc.duke.edu.
Rationale: Tissue factor expression in sepsis activates coagulation in the lung, which potentiates inflammation and leads to fibrin deposition. Objectives: We hypothesized that blockade of Factor X binding to the Tissue Factor-Factor VIIa complex would prevent sepsis-induced damage to the lungs and other organs. Methods: Acute lung injury was produced in 15 adult baboons primed with killed Escherichia coli (E. coli, 1 x 109 CFU/kg) and then 12 hours later given 1x1010 CFU/kg live E. coli by infusion. Two hours after live E. coli, animals received antibiotics with or without monoclonal antibody to Tissue Factor intravenously to block Tissue Factor-Factor X binding. The animals were monitored physiologically for 34 hours before euthanasia and tissue harvest. Measurements and Main Results: The antibody treatment attenuated abnormalities in gas exchange and lung compliance, preserved renal function, and prevented tissue neutrophil influx and bowel edema relative to antibiotics alone (all p<0.05). It also attenuated fibrinogen depletion (p<0.01) and decreased pro-inflammatory cytokines, e.g. interleukin-6 and -8 (p<0.01), in systemic and alveolar compartments. Similar protective effects of the antibody on interleukin-6 and -8 expression and permeability were found in lipopolysaccharide-stimulated endothelial cells. Conclusions: Blockade of Factor X binding to the Tissue Factor-Factor VIIa complex attenuates lung and organ injuries in established E. coli sepsis by attenuating the neutrophilic response and inflammatory pathways.
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