Blockade of tissue factor-factor X binding attenuates sepsis-induced respiratory and renal failure.
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 10(9) colony-forming units (CFU)/kg], and then 12 h later, they were given 1 x 10(10) 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.
Welty-Wolf
Karen E
KE
Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. welty001@mc.duke.edu
Carraway
Martha S
MS
Ortel
Thomas L
TL
Ghio
Andrew J
AJ
Idell
Steven
S
Egan
Jack
J
Zhu
Xiaoyun
X
Jiao
Jin-an
JA
Wong
Hing C
HC
Piantadosi
Claude A
CA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001775:Blood Circulation; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004927:Escherichia coli Infections / Q000150:complications*; D005170:Factor X / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D018836:Inflammation Mediators / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D010215:Papio; D051437:Renal Insufficiency / Q000382:microbiology* / Q000473:pathology / Q000503:physiopathology*; D012131:Respiratory Insufficiency / Q000382:microbiology* / Q000473:pathology / Q000503:physiopathology*; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007140:Immunoglobulin Fab Fragments; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D005170:Factor X; D013925:Thromboplastin