Welty-Wolf Karen E, Carraway Martha S, Ortel Thomas L, Ghio Andrew J, Idell Steven, Egan Jack, Zhu Xiaoyun, Jiao Jin-an, Wong Hing C, Piantadosi Claude A
Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Am J Physiol Lung Cell Mol Physiol. 2006 Jan;290(1):L21-31. doi: 10.1152/ajplung.00155.2005. Epub 2005 Aug 12.
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.
脓毒症时组织因子的表达可激活肺内凝血，进而增强炎症反应并导致纤维蛋白沉积。我们推测，阻断因子X与组织因子-因子VIIa复合物的结合可预防脓毒症所致的肺及其他器官损伤。对15只成年狒狒用灭活大肠杆菌[1×10⁹ 菌落形成单位（CFU）/kg]进行预处理以诱发急性肺损伤，12小时后，通过静脉输注给予它们1×10¹⁰ CFU/kg的活大肠杆菌。给予活大肠杆菌2小时后，动物静脉注射抗生素，部分动物同时给予抗组织因子单克隆抗体以阻断组织因子-因子X的结合。在处死动物并采集组织前，对其进行34小时的生理监测。与单纯使用抗生素相比，抗体治疗减轻了气体交换和肺顺应性的异常，保护了肾功能，预防了组织中性粒细胞浸润和肠水肿（所有P<0.05）。它还减轻了纤维蛋白原的消耗（P<0.01），并降低了全身和肺泡腔中促炎细胞因子如IL-6和IL-8的水平（P<0.01）。在脂多糖刺激的内皮细胞中也发现了该抗体对IL-6和IL-8表达及通透性的类似保护作用。阻断因子X与组织因子-因子VIIa复合物的结合，可通过减弱中性粒细胞反应和炎症途径，减轻已发生的大肠杆菌脓毒症中的肺和器官损伤。
