Levi M, van Der POLL T, ten CATE H, Kuipers B, Biemond B J, Jansen H M, ten CATE J W
Center for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Laboratory of Experimental Medicine, and Department of Pulmonology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Am J Respir Crit Care Med. 1998 Jul;158(1):92-8. doi: 10.1164/ajrccm.158.1.9709007.
Activation and inhibition of coagulation and fibrinolysis was analyzed in bronchoalveolar lavage (BAL) fluids obtained from endotoxin-challenged chimpanzees. The mediatory role of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) on endotoxin-induced changes in bronchoalveolar coagulation and fibrinolysis was investigated in experiments in which the infusion of endotoxin was combined with the administration of monoclonal anti-TNF-alpha or anti-IL-6 antibodies. Endotoxin infusion elicited a marked increase in bronchoalveolar thrombin generation as measured by levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes. Markers for intrinsic pathway activation were not detectable, suggesting that the thrombin generation was mediated by the tissue factor-dependent route. Levels of antithrombin were low before the injection of endotoxin and not detectable hereafter. The administration of anti-IL-6 antibody completely abolished the endotoxin-induced activation of bronchoalveolar coagulation, whereas treatment with anti-TNF-alpha antibody only partly inhibited this effect. Bronchoalveolar fibrinolytic activity, due to urokinase-type plasminogen activator (u-PA), was significantly depressed after endotoxin injection, mainly due to a striking increase in plasminogen activator inhibitor-2 levels in BAL fluid. The endotoxin-induced effects on bronchoalveolar fibrinolysis could be blocked by the simultaneous administration of anti- TNF-alpha antibodies. We conclude that endotoxemia results in the activation of bronchoalveolar coagulation, which is apparently mediated by the tissue factor route of coagulation activation and which may be amplified by consumption of antithrombin III. Bronchoalveolar fibrinolytic activity is significantly abolished by increased levels of mainly PAI-2 after the injection of endotoxin. The endotoxin-induced effects on bronchoalveolar coagulation appears to be mediated by IL-6, whereas TNF-alpha seems to be the pivotal mediator of the endotoxin-induced depression of bronchoalveolar fibrinolysis.
对从内毒素攻击的黑猩猩获得的支气管肺泡灌洗（BAL）液中的凝血和纤维蛋白溶解的激活与抑制进行了分析。在将内毒素输注与单克隆抗TNF-α或抗IL-6抗体给药相结合的实验中，研究了肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）对内毒素诱导的支气管肺泡凝血和纤维蛋白溶解变化的介导作用。通过凝血酶原激活片段F1 + 2和凝血酶 - 抗凝血酶复合物的水平测量，内毒素输注引起支气管肺泡凝血酶生成显著增加。未检测到内源性途径激活的标志物，表明凝血酶生成是由组织因子依赖性途径介导的。在内毒素注射前抗凝血酶水平较低，此后无法检测到。抗IL-6抗体的给药完全消除了内毒素诱导的支气管肺泡凝血激活，而抗TNF-α抗体治疗仅部分抑制了这种作用。内毒素注射后，由于尿激酶型纤溶酶原激活剂（u-PA）导致的支气管肺泡纤维蛋白溶解活性显著降低，主要是由于BAL液中纤溶酶原激活剂抑制剂-2水平显著增加。同时给予抗TNF-α抗体可阻断内毒素对支气管肺泡纤维蛋白溶解的诱导作用。我们得出结论，内毒素血症导致支气管肺泡凝血激活，这显然是由凝血激活的组织因子途径介导的，并且可能因抗凝血酶III的消耗而放大。内毒素注射后，主要是PAI-2水平升高，显著消除了支气管肺泡纤维蛋白溶解活性。内毒素对支气管肺泡凝血的诱导作用似乎由IL-6介导，而TNF-α似乎是内毒素诱导的支气管肺泡纤维蛋白溶解抑制的关键介质。
