Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase
Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase
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DOI：
10.1182/blood.v87.6.2337.bloodjournal8762337
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发表时间：
1996-03-15
期刊：
影响因子：
20.3
通讯作者：
Colman, RW
中科院分区：
文献类型：
--
作者：
Jansen, PM;Pixley, RA;Colman, RW
在先前的研究中，我们已经表明，对受致死性大肠杆菌攻击的狒狒施用抗人因子XII单克隆抗体（MoAb） C6B7可消除接触系统的激活并调节继发性低血压。为了评估激活的接触蛋白酶对脓毒症实验模型中其他炎症介质外观的贡献，我们研究了给予MoAb C6B7对补体和纤维蛋白溶解级联的激活以及中性粒细胞脱颗粒的刺激的影响。以及促炎细胞因子、肿瘤坏死因子- α (tnf - α)和白细胞介素-6 （IL-6）的释放。激活补体系统。正如循环C3b/c和C4b/c水平所反映的那样，在大肠杆菌致死剂量前接受MoAb C6B7的5只动物中，与只接受致死剂量的5只对照动物相比，C3b/c和C4b/c水平显著降低。接触活化的抑制也调节了纤溶反应，因为在抗因子XII MoAb预处理后，组织型纤溶酶原激活剂（t-PA）的释放和纤溶酶α(2)-抗纤溶酶（PAP）复合物进入循环的出现显着减弱。相比之下，治疗组血浆纤溶酶原激活物抑制剂（PAI）水平略有提高。通过循环弹性酶- α(1)-蛋白酶抑制剂复合物评估，中性粒细胞的脱粒和IL-6的释放在抗因子xii处理的动物中减少，但不减少tnf - α。观察到的实验组和对照组之间炎症反应的差异不太可能是由于不同的刺激，因为注射了大肠杆菌的数量，以及刺激后内毒素的循环水平。两组的结果相似。这些数据表明，接触系统的激活直接或间接地调节了非人类灵长类动物严重败血症期间参与炎症反应的各种介质系统。(C) 1996年由美国血液病学会出版。
In previous studies, we have shown that administration of monoclonal antibody (MoAb) C6B7 against human factor XII to baboons challenged with a lethal dose of Escherichia coli abrogates activation of the contact system and modulates secondary hypotension. To evaluate the contribution of activated contact proteases to the appearance of other inflammatory mediators in this experimental model of sepsis, we studied the effect of administration of MoAb C6B7 on activation of complement and fibrinolytic cascades, stimulation of neutrophil degranulation. and release of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Activation of the complement system. as reflected by circulating C3b/c and C4b/c levels, was significantly reduced in five animals that had received MoAb C6B7 before a lethal dose of E coli as compared with five control animals that had been given a lethal challenge only. Inhibition of contact activation also modulated the fibrinolytic response, since the release of tissue-type plasminogen activator (t-PA) and the appearance of plasmin-alpha(2)-antiplasmin (PAP) complexes into the circulation was significantly attenuated upon pretreatment with anti-factor XII MoAb. In contrast, plasma levels of plasminogen activator inhibitor (PAI) were modestly enhanced in the treatment group. Degranulation of neutrophils, as assessed by circulating elastase-alpha(1)-protease inhibitor complexes, and release of IL-6 but not of TNF-alpha was decreased in anti-factor XII-treated animals. Observed differences in the inflammatory response between treatment and control groups were not likely due to different challenges, since the number of E coli that had been infused, as well as circulating levels of endotoxin after the challenge. were similar for both groups. These data suggest that activation of the contact system modulates directly or indirectly various mediator systems involved in the inflammatory response during severe sepsis in nonhuman primates. (C) 1996 by The American Society of Hematology.