Thrombomodulin : As a regulator of multiple mediators

血栓调节蛋白：作为多介质调节剂的血栓调节蛋白？是一种将凝血酶从促凝蛋白酶转化为抗凝酶的膜蛋白。TM的这种抗凝作用是由第4、第5和第6个egf样结构完成的。我们之前的研究表明，TM也具有自由基清除活性。HMGB1是一种DNA结合核蛋白，对维持DNA结构和转录起着至关重要的作用。然而，该蛋白也通过受体在细胞外空间发挥生理和病理作用，包括晚期糖基化终产物受体（RAGE）和toll样受体-2和-4。我们在这里发现HMGB1不仅通过祖细胞的动员和增殖，还通过单核/巨噬细胞和树突状细胞的激活，作为伤口愈合的诱导因子。这些单核细胞的激活导致组织因子的表达和先天免疫的诱导。这些可能对止血和预防损伤部位的感染具有至关重要的作用。因此，坏死细胞和活化的单核/巨噬细胞释放的局部HMGB1在导致伤口修复的免疫和止血中起多效介质作用。然而，已经确定全身循环hmgb1作为多器官衰竭和感染性休克的中介。我们还发现HMGB1在人和实验动物中均可诱导急性肺损伤、低血压休克和弥散性血管内凝血（DIC）。基于这些描述和观察，我们打算探索循环HMGB1的干预策略。由于我们之前发现血栓调节素的n端结合hmgb1并中和其促炎作用，因此我们在实验性感染性休克模型中评估了血栓调节素的作用。重组血栓调节蛋白能有效改善DIC状态和器官损伤。这种作用可能是通过清除凝血酶和HMGB1来实现的。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，对dic、SIRS和内毒素休克有治疗作用。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