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This Article Full Text Full Text (PDF) All Versions of this Article: 290/1/L21    most recent 00155.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Welty-Wolf, K. E. Articles by Piantadosi, C. A. Search for Related Content PubMed PubMed Citation Articles by Welty-Wolf, K. E. Articles by Piantadosi, C. A.

Blockade of tissue factor-factor X binding attenuates sepsis-induced respiratory and renal failure

Divisions of ¹Pulmonary and Critical Care Medicine and ²Hematology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; ³Department of Specialty Care Services, University of Texas, Tyler, Texas; and ⁴Sunol Molecular, Miramar, Florida

Submitted 7 April 2005 ; accepted in final form 4 August 2005

Tissue factor expression in sepsis activates coagulation in the lung, which potentiates inflammation and leads to fibrin deposition. 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. Acute lung injury was produced in 15 adult baboons primed with killed Escherichia coli [1 x 10⁹ colony-forming units (CFU)/kg], and then 12 h later, they were given 1 x 10¹⁰ 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 h before being killed and their tissue harvested. 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 proinflammatory cytokines, e.g., IL-6 and -8 (P < 0.01), in systemic and alveolar compartments. Similar protective effects of the antibody on IL-6 and -8 expression and permeability were found in lipopolysaccharide-stimulated endothelial cells. 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.

thromboplastin; adult respiratory distress syndrome; multiple organ failure; septicemia; Papio

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