Sepsis-induced coagulation in the baboon lung is associated with decreased tissue factor pathway inhibitor
Sepsis-induced coagulation in the baboon lung is associated with decreased tissue factor pathway inhibitor
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DOI：
10.2353/ajpath.2007.070104
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发表时间：
2007-09-01
影响因子：
6
通讯作者：
Lupu, Florea
中科院分区：
文献类型：
--
作者：
Tang, Haiwang;Ivanciu, Lacramioara;Lupu, Florea
脓毒症中组织因子（TF）依赖性促凝血活性的增加可能部分是由于组织因子途径抑制物（TFPI）的表达或功能降低。为了验证这一假设，狒狒被注入了5种大肠杆菌，并在2、8或24小时后处死。共聚焦显微镜和电子显微镜显示血管内和间质室中白细胞浸润和纤维蛋白沉积增加。通过免疫染色在白细胞中检测到大量TF，通过定量逆转录酶-聚合酶链反应、酶联免疫吸附测定和凝血测定记录了富含血小板的微血栓TF诱导。肺相关TFPI抗原和mRNA在脓毒症过程中下降，TFPI活性在2小时突然下降。阻断TFPI抗体可增加脓毒症狒狒肺中的纤维蛋白沉积，表明TF依赖性凝血可能因内皮TFPI减少而加重。TFPI活性降低与组织纤溶酶原激活物的释放和血浆生成高峰一致，表明TFPI可通过纤溶酶进行蛋白水解失活。通过输注针对纤溶酶原激活物抑制剂-1的阻断抗体，脓毒症狒狒产生的纤溶酶增强导致肺相关TFPI降低和不可预见的大量纤维蛋白沉积。我们的结论是，激活TF驱动的凝血没有充分反击TFPI可能是普遍的血栓并发症的败血症的基础。
Increased tissue factor (TF)-dependent procoagulant activity in sepsis may be partly due to decreased expression or function of tissue factor pathway inhibitor (TFPI). To test this hypothesis, baboons were infused with five Escherichia coli and sacrificed after 2, 8, or 24 hours. Confocal and electron microscopy revealed increased leukocyte infiltration and fibrin deposition in the intravascular and interstitial compartments. large amounts of TF were detected by immunostaining in leu kocytes and platelet-rich microthrombi TF induction was documented by quantitative reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and coagulation assays. Lung-associated TFPI an tigen and mRNA decreased during sepsis, and TFPI activity diminished abruptly at 2 hours. Blocking antibodies against TFPI increased fibrin deposition in septic baboon lungs, suggesting that TF-dependent coagulation might be aggravated by reduced endothelial TFPI Decreased TFPI activity coincided with the release of tissue plasminogen activator and the peak of plas generation, suggesting that TFPI could undergo proteolytic inactivation by plasmin. Enhanced plasmin produced in septic baboons by infusion of blocking antibodies against plasminogen activator inhibitor-1 led to decreased lung-associated TFPI and unforeseen massive fibrin deposition. We conclude that activation of TF-driven coagulation not adequately countered by TFPI may underlie the widespread thrombotic complications of sepsis.