Weijer Sebastian, Schoenmakers Saskia H H F, Florquin Sandrine, Levi Marcel, Vlasuk George P, Rote William E, Reitsma Pieter H, Spek C Arnold, van der Poll Tom
Laboratory of Experimental Internal Medicine and Department of Infectious Diseases, Tropical Medicine, and AIDS, University of Amsterdam, The Netherlands.
J Infect Dis. 2004 Jun 15;189(12):2308-17. doi: 10.1086/421031. Epub 2004 May 25.
Anticoagulants have gained increasing attention for the treatment of sepsis. Inhibition of the tissue factor (TF)/factor (F) VIIa pathway has been shown to attenuate the activation of coagulation and to prevent death in a primate model of sepsis caused by gram-negative bacteria.
To determine the role of the TF/FVIIa complex in the host response to peritonitis, mice received an intraperitoneal injection of live Escherichia coli with or without concurrent treatment with recombinant nematode anticoagulant protein c2 (rNAPc2), a selective inhibitor of the TF/FVIIa pathway.
Peritonitis was associated with an increase in the expression of TF at the tissue level and activation of coagulation, as reflected by elevated levels of thrombin-antithrombin complexes and by increased fibrin(ogen) deposition in the liver and lungs. rNAPc2 strongly attenuated this procoagulant response but did not influence the inflammatory response (histopathology, leukocyte recruitment to the peritoneal cavity, and cytokine and chemokine levels). Moreover, rNAPc2 did not alter bacterial outgrowth locally or dissemination of the infection, and survival was not different between rNAPc2-treated mice and control mice.
These data suggest that TF/FVIIa activity contributes to the activation of coagulation during E. coli peritonitis but does not play a role in the inflammatory response or antibacterial host defense.
抗凝剂在脓毒症治疗中受到越来越多的关注。在革兰氏阴性菌引起的脓毒症灵长类动物模型中，抑制组织因子（TF）/因子（F）VIIa途径已被证明可减弱凝血激活并预防死亡。
为了确定TF/FVIIa复合物在宿主对腹膜炎反应中的作用，小鼠腹腔注射活的大肠杆菌，同时或不同时给予重组线虫抗凝蛋白c2（rNAPc2），一种TF/FVIIa途径的选择性抑制剂。
腹膜炎与组织水平TF表达增加和凝血激活相关，表现为凝血酶 - 抗凝血酶复合物水平升高以及肝脏和肺中纤维蛋白（原）沉积增加。rNAPc2强烈减弱了这种促凝反应，但不影响炎症反应（组织病理学、白细胞向腹腔募集以及细胞因子和趋化因子水平）。此外，rNAPc2不改变局部细菌生长或感染的播散，rNAPc2治疗的小鼠和对照小鼠的存活率没有差异。
这些数据表明，TF/FVIIa活性在大肠杆菌腹膜炎期间有助于凝血激活，但在炎症反应或抗菌宿主防御中不起作用。
