Thrombomodulin : As a regulator of multiple mediators

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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