INHIBITION OF ENDOTOXIN-INDUCED ACTIVATION OF COAGULATION AND FIBRINOLYSIS BY PENTOXIFYLLINE OR BY A MONOCLONAL ANTITISSUE FACTOR ANTIBODY IN CHIMPANZEES
INHIBITION OF ENDOTOXIN-INDUCED ACTIVATION OF COAGULATION AND FIBRINOLYSIS BY PENTOXIFYLLINE OR BY A MONOCLONAL ANTITISSUE FACTOR ANTIBODY IN CHIMPANZEES
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DOI：
10.1172/jci116934
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发表时间：
1994-01-01
影响因子：
15.9
通讯作者：
ROSENBERG, RD
中科院分区：
文献类型：
--
作者：
LEVI, M;TENCATE, H;ROSENBERG, RD
了解内毒素血症相关凝血系统激活的发病机制，对于开发更好的预防和治疗方法非常重要。我们分析了正常黑猩猩静脉输注内毒素后血浆中TNF、IL-6以及凝血和纤溶系统激活指数的变化。通过对凝血酶原激活片段F-1+2、凝血酶-抗凝血酶III复合物、和纤维蛋白肽A。纤溶机制的激活通过纤溶酶原激活物活性和纤溶酶-α（2）-抗纤溶酶复合物的测定来监测。为了潜在地干预由内毒素引起的分子途径，在内毒素前不久输注戊茶碱，一种中断单核细胞的“立即早期”基因激活的试剂，或一种中和组织因子介导的凝血起始的强效单克隆抗体。喷替福林显著抑制TNF和IL-6水平的增加，以及对凝血和纤溶的影响。相反，组织因子单克隆抗体完全消除了凝血酶生成的增加，但对细胞因子水平或纤溶没有影响。我们得出结论，内毒素诱导的凝血激活似乎是由组织因子依赖性途径介导的，内毒素触发的纤溶反应不依赖于凝血酶的生成，并且细胞因子的释放在介导体内凝血和纤溶机制的激活中可能是重要的。
Knowledge of the pathogenetic mechanisms responsible for the activation of the coagulation system associated with endotoxemia is important for the development of improved modalities for prevention and treatment. We analyzed the appearance in plasma of TNF, IL-6, and indices of coagulation and fibrinolytic system activation in normal chimpanzees after intravenous infusion of endotoxin.Endotoxin infusion elicited reproducible and dose-dependent elevations in serum TNF and IL-6, as well as marked increases in thrombin generation in vivo as measured by immunoassays for prothrombin activation fragment F-1+2, thrombin-antithrombin III complexes, and fibrinopeptide A. Activation of the fibrinolytic mechanism was monitored with assays for plasminogen activator activity and plasmin-alpha(2)-antiplasmin complexes. To potentially intervene in the molecular pathways elicited by endotoxin, pentoxifylline, an agent that interrupts ''immediate early'' gene activation by monocytes, or a potent monoclonal antibody that neutralizes tissue factor-mediated initiation of coagulation, were infused shortly before endotoxin. Pentoxifylline markedly inhibited increases in the levels of TNF and IL-6, as well as the effects on coagulation and fibrinolysis. In contrast, the monoclonal antibody to tissue factor completely abrogated the augmentation in thrombin generation, but had no effect on cytokine levels or fibrinolysis.We conclude that the endotoxin-induced activation of coagulation appears to be mediated by the tissue factor-dependent pathway, the fibrinolytic response triggered by endotoxin is not dependent on the generation of thrombin, and that the release of cytokines may be important in mediating the activation of both the coagulation and the fibrinolytic mechanisms in vivo.