Thrombomodulin : As a regulator of multiple mediators

血栓调节蛋白：作为一种多介质调节剂？TM是一种膜蛋白，它将凝血酶从促凝血酶转化为抗凝血剂。TM的这种抗凝作用是通过第四、第五和第六类EGF结构实现的。我们先前的研究表明，TM也具有清除自由基的活性。HMGB1是一种与DNA结合的核蛋白，在维持DNA结构和转录方面发挥着至关重要的作用。然而，HMGB1还通过包括晚期糖基化终末产物受体(RAGE)和Toll样受体-2和-4在内的受体在细胞外空间发挥生理和病理作用。我们在这里发现，HMGB1不仅通过动员和增殖祖细胞，而且通过激活单核/巨噬细胞和树突状细胞，在伤口愈合中发挥诱导因子的作用。这些单核细胞系细胞的激活导致组织因子的表达和先天免疫的诱导。这些可能在…的止血中起着至关重要的作用更多和预防受伤部位的感染。因此，从坏死细胞和激活的单核/巨噬细胞释放的局部HMGB1在免疫和止血导致伤口修复方面起着多效性介质的作用。然而，已证实全身循环中的HMGB1在多器官衰竭和感染性休克中起中介作用。我们还发现，HMGB1在人和动物体内均可引起急性肺损伤、低血压休克和弥漫性血管内凝血(DIC)。基于这些描述和观察，我们打算探索对循环HMGB1的干预策略。由于我们先前发现血栓调节蛋白的N末端与HMGB 1结合并中和其促炎作用，因此我们评价了血栓调节蛋白在实验性感染性休克模型中的作用。重组血栓调节蛋白能有效改善DIC状态和脏器损害。这种作用可能不仅通过清除凝血酶，还可能通过清除HMGB1来实现。这些初步数据表明，TM可能通过清除凝血酶和HMGB1等多种介质而有益于DIC、SIRS和内毒素休克的治疗。较少

Thrombomodulin : as a multimediator modulatorThrombomodulin ? is a membrane protein which convert thrombin from a procoagulant protease to an anticoagulant.This anticoagulant effect of TM is accomplished by 4th, 5th and 6th EGF-like structure. We previously showed that TM also has a radical scavenging activity.HMGB1, a DNA binding nuclear protein, plays a crucial role for maintenance of DNA architecture and transcription. However the protein also exerts physiological and pathological roles in extracellular space through receptors including receptor for advanced glycation endprducts (RAGE) and toll like receptors-2, and -4.We identified here that HMGB1 acts as an inducing factor for wound healing through not only mobilization and proliferation of progenitor cells, but also activation of monocytes/macrophages and dendritc cells. The activation of these monocytic lineage cells results tissue factor expression and induction of innate immunity. These may have a crucial role for hemostasis a … More nd prevention of infections in injurious sites. Thus localized HMGB1 released from necrotic cells and activated monocytes/ macrophages acts as a pleiotropic mediator in immunity and hemostasis leading wound repair.However it has been identified that systemic, circulating HMGB 1 acts as a mediator of multiple organ failure and septic shock. We also showed that HMGB1 induces acute lung injury, hypotensive shock and disseminated intravasucular coasulation (DIC) both in humans and exoerimental animals. Based on these descriptions and observations, we intended to explore the intervention strategy for circulating HMGB1. Since we previously discovered that N-terminus of thrombomodulin binds HMGB 1 and neutralizes its proinflammatory action, we evaluated the effect of thromboodulin in experimental septic shock model. Recombinant thrombomodulin efficiently improved the DIC status and organ damage. This effect might be accomplished by scavenging effects not only thrombin but also HMGB1. These preliminary data show that TM might be beneficial for the treatment ofDIC, SIRS andendotoxin shock through scavenging multiple mediators including thrombin and HMGB1. Less