Endotoxin has been implicated in the pathogenesis of septic shock and anti- endotoxin therapy in human septic shock has been shown to possibly reduce morbidity and mortality. Lipid X, a monosaccharide precursor of Lipid A (the toxic moiety of endotoxin) has been shown in mice and sheep to prevent lethality from endotoxin challenge. In vitro, lipid X appears to directly antagonize the actions of endotoxin in a manner consistent with competitive inhibition. In this study, analogs of lipid X and lipid A are being investigated for anti-endotoxin activity using an assay based on the ability of endotoxin to prime human neutrophils for enhanced superoxide and leukotriene B4 production. These experiments are useful for defining the molecular requirements for endotoxin antagonism by lipid A part-structures. An understanding of the chemical structure required for inhibition of endotoxin activity will allow for the design of even more potent blocking agents that may have beneficial effects in the treatment of septic shock. This study is nearly complete and the 3rd manuscript from this project is being written. Current studies are examining the effect of these analogs on intracellular calcium fluxes in human neutrophils and the inhibition of LPS-induced cytokine transcription.
