Investigations on pathomechanism, diagnosis and treatment in bacterial shock-For preposal of new padadigm

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Bacterial septic shock has been one of the most crucial clinical problems in all over the world. In this project, we investigated pathomechanism of septic shock based on the underlying mediators. We first showed that endocannabinoids, anandamide and 2-arachidonylgycerol(2-AG) are produced by the macrophages and platelets stimulated with endotoxin and peptidoglycan. The produced endocannabinoids act on their specific receptors, CB1,CB2 and VR1, and exert diverse physiologic activities including hypotension, immune depression and psychomotor actions. However too increased endocannabinoids in the circulation result and cause hypotensive shock, and act as an early mediator.For the late mediator, we identified HMGB1, high molecular group protein 1.HMGB1 has been known as a DNA-binding nuclear factor. However, the protein is released from most of necrotic cells and activated macrophages, and acts on RAGE(receptor for advanced glycation endproducts), which is expressed variety types of cells. HMGB1/RAGE signaling causes production of radicals, activations of NF-kB, Rac, and CDC42, resulting barrier dysfunction in many organs, and may result hemorrhages, inflammation and edema. Thus we proposed that the protein may act as a late phase mediator in septic shock. We established specific assay method of HMGB1 by ELISA. Using this, we confirmed that protein is increased in fatal septic shock patients. In experimental animal models, removal of HMGB1 from the circulation dramatically improved the shock and lethality. We also confirmed that HMGB1 is involved the acute lung injury and ARDS. Thus HMGB1 may mediate organ dysfunctions and act as a late lethal factor in septic shock.