Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans.
Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans.
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DOI：
10.1164/rccm.200411-1483oc
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发表时间：
2005-05
影响因子：
24.7
通讯作者：
T. van der Poll;M. Levi;J. Nick;E. Abraham
中科院分区：
文献类型：
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作者：
T. van der Poll;M. Levi;J. Nick;E. Abraham
理论依据急性肺损伤和肺炎与肺凝血激活和纤维蛋白溶解抑制相关，导致肺中纤维蛋白沉积。活化蛋白C（APC）在脓毒症患者中具有全身抗凝作用。目的研究重组人APC对内毒素诱导的人支气管肺泡腔止血改变的影响。方法健康人静脉注射APC（24 μ g/kg/h; n = 8）或赋形剂（n = 7）;所有受试者在一个肺亚段中给予生理盐水，在对侧肺中给予内毒素（4 ng/kg）。给予生理盐水和内毒素后16小时进行支气管肺泡灌洗。内毒素诱导局部凝血激活，表现为凝血酶-抗凝血酶复合物水平升高（1.9 +/- 0.1 ng/ml）和可溶性组织因子（15.0 ± 0.6 pg/ml），可被APC抑制（分别为1.4 +/- 0.1 ng/ml和12.3 +/- 0.4 pg/ml;均p < 0.01）。同时，内毒素抑制纤维蛋白溶解，表现为支气管肺泡纤溶酶原激活物活性水平降低伴纤溶酶原激活物抑制剂I型活性水平升高。APC降低了纤溶酶原激活物抑制剂I型活性的升高（从3.9 +/- 0.1至3.0 +/- 0.2 ng/ml，p = 0.002），但对纤溶酶原激活物活性水平无显著影响。内毒素降低支气管肺泡蛋白C浓度，这是由APC阻止。蛋白C不影响内毒素诱导的局部可溶性血栓调节蛋白水平升高。结论APC对内毒素攻击的人肺具有抗凝作用。
RATIONALE Acute lung injury and pneumonia are associated with pulmonary activation of coagulation and suppression of fibrinolysis, resulting in fibrin deposition in the lung. Activated protein C (APC) has systemic anticoagulant effects in patients with sepsis. OBJECTIVE To determine the effect of systemic administration of recombinant human APC on endotoxin-induced hemostatic alterations in the bronchoalveolar space in humans. METHODS Healthy humans received intravenous APC (24 microg/kg/hour; n = 8) or vehicle (n = 7); all subjects were administered saline in one lung subsegment and endotoxin (4 ng/kg) into the contralateral lung. Bronchoalveolar lavage was performed 16 hours after saline and endotoxin administration. MEASUREMENTS AND MAIN RESULTS Endotoxin induced local activation of coagulation, as reflected by elevated levels of thrombin-antithrombin complexes (1.9 +/- 0.1 ng/ml) and soluble tissue factor (15.0 +/- 0.6 pg/ml) in bronchoalveolar lavage fluid, which was inhibited by APC (1.4 +/- 0.1 ng/ml and 12.3 +/- 0.4 pg/ml, respectively; both p < 0.01). Concurrently, endotoxin suppressed fibrinolysis, as indicated by reduced bronchoalveolar levels of plasminogen activator activity accompanied by elevated levels of plasminogen activator inhibitor type I activity. APC diminished the rise in plasminogen activator inhibitor type I activity (from 3.9 +/- 0.1 to 3.0 +/- 0.2 ng/ml, p = 0.002), while not significantly influencing plasminogen activator activity levels. Endotoxin reduced bronchoalveolar protein C concentrations, which was prevented by APC. Protein C did not influence the endotoxin-induced rise in local soluble thrombomodulin levels. CONCLUSION APC exerts an anticoagulant effect in the human lung challenged with endotoxin.