LPS initiates an immunoinflammatory cascade characterized by activation of macrophages and other leukocytes, endothelial cells and parenchymal cells of liver, heart etc. Macrophages are central to this process because they release important mediators of tissue damage (i.e. TNF, ILl, PAF, free radicals) and initiate coagulation by synthesis of tissue factor. Attempts to inhibit this process by blocking the deleterious effects of endotoxin with for example antibodies have met with limited success. Inhibitors of major mediators such as TNF (eg. alphaTNF monoclonals), PAF (receptor antagonists), ILl (ILl receptor antagonist, ILlra), and inducible nitric oxide synthase (N-methyl arginine and other compounds) have had disappointing clinical results. This is because the immunoinflammatory cascade involves a complex web of mediators unlikely to be inhibited by targetting a single mediator. We have identified a unique compound, EsA, derived from the roots of a Chinese medicinal herb that inhibits generation of multiple mediators of the immunoinflammatory cascade. In vitro EsA inhibits LPS- induced macrophage synthesis of nitrogen radicals and inflammatory cytokines such as ILl and TNF as well as release of platelet activating factor. Limited in vivo testing demonstrates that EsA inhibits acute inflammation in the absence of toxic effects. In phase l EsA will be evaluated for its activity in rodent sepsis models. It is likely that EsA will have therapeutic potential for conditions associated with LPS induced tissue injury and activation of mononuclear phagocytes such as sepsis, ARDS burns, autoimmune diseases and AIDS. PROPOSED COMMERCIAL APPLICATIONS: Development of an anti-inflammatory inhibitor of multiple mediators released by macrophages has significant therapeutic potential in sepsis, ARDS, and chronic inflammatory conditions.