Molecular and cellular basis of septic shock : Involvement of anandamide and HMG-1

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Bacterial septicemia results hypotensive shock in severe cases. Various mediators have been proposed as causative factors in this hypotensive shock. These include inflammatory cytokines, PAF, NO and so on. However the inhibitors or antibodies against the mediators failed to improve hypotensive shock in clinical studies. Thus the other mediators may exist to cause septic shock.In the present investigations, we identified that endocannabinoids, anandamide and 2-arachidonylglycerol which axe produced and secreted from stimulated macrophages and platelets induce hypotension, and act as an early hypotensive mediators. We also identified that polymyxin B selectively binds these endocannabinoids. Hemo-perfusion through polymyxin B-coated biomembrane column efficiently removed the circulating endocannabinoids and results rapid improvement of the hypotension.Then we investigated the role of HMG-1 on the pathogenesis of septic shock, and showed that HMG-1 may act as a late phase mediator in septic shock.