Lay Angelina J, Donahue Deborah, Tsai Meng-Ju, Castellino Francis J
W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA.
Blood. 2007 Mar 1;109(5):1984-91. doi: 10.1182/blood-2006-07-037945. Epub 2006 Oct 17.
The anticoagulant, activated protein C (aPC), possesses antithrombotic, profibrinolytic, anti-inflammatory, and antiapoptotic properties, and the level of this protein is an important marker of acute inflammatory responses. Although infusion of aPC improves survival in a subset of patients with severe sepsis, evidence as to how aPC decreases mortality in these cases is limited. Because a total deficiency of PC shows complete neonatal lethality, no animal model currently exists to address the mechanistic relationships between very low endogenous aPC levels and inflammatory diseases. Here, we show for the first time that novel genetic dosing of PC strongly correlates with survival outcomes following endotoxin (LPS) challenge in mice. The data provide evidence that very low endogenous levels of PC predispose mice to early-onset disseminated intravascular coagulation, thrombocytopenia, hypotension, organ damage, and reduced survival after LPS challenge. Furthermore, evidence of an exacerbated inflammatory response is observed in very low PC mice but is greatly reduced in wild-type cohorts. Reconstitution of low-PC mice with recombinant human aPC improves hypotension and extends survival after LPS challenge. This study directly links host endogenous levels of PC with various coagulation, inflammation, and hemodynamic end points following a severe acute inflammatory challenge.
抗凝剂活化蛋白C（aPC）具有抗血栓形成、促纤溶、抗炎和抗凋亡特性，该蛋白的水平是急性炎症反应的重要标志物。尽管输注aPC可提高部分严重脓毒症患者的生存率，但关于aPC在这些病例中降低死亡率的机制的证据有限。由于蛋白C完全缺乏会导致新生儿完全致死，目前尚无动物模型来研究极低内源性aPC水平与炎症性疾病之间的机制关系。在此，我们首次表明，在小鼠内毒素（LPS）攻击后，新型基因剂量的蛋白C与生存结果密切相关。数据表明，极低的内源性蛋白C水平使小鼠易患早期弥散性血管内凝血、血小板减少、低血压、器官损伤，并在LPS攻击后生存率降低。此外，在极低蛋白C小鼠中观察到炎症反应加剧的证据，但在野生型群体中炎症反应大大减轻。用重组人aPC重建低蛋白C小鼠可改善低血压并延长LPS攻击后的生存期。本研究直接将宿主内源性蛋白C水平与严重急性炎症攻击后的各种凝血、炎症和血流动力学终点联系起来。
