The multiple physiological, pathological and immunological activities of bacterial endotoxins (lipopolysaccharides, LPS) are well documented. A primary reason for this broad spectrum of activities is the almost ubiquitous capacity of these potent bacterial products to interact with host defense systems. Because of the high affinity which LPS appears to have for membranes in general, it has been postulated that biochemical events localized to the cytoplasmic membranes of cells are sufficient to initiate cellular responses. The available data has provided evidence for both specific endotoxin receptors and non-specific perturbational events. Our hypothesis, that both of these interactions contribute to endotoxin-initiaed lymphoid cell responses, will form the primary focus of the proposed research. In this respect we will examine those elements of the LPS macromolecule which are critical for its ability to bind to and intercollate with lymphoid cell membranes and to recognized high affinity binding sites. We have also designed experiments to define the pathophysiologic and immunologic fate of endotoxins their interaction with phagocytic cells. Particular attention will focus upon neutralization and/or degradation of the biologic activities of endotoxins following their interation with lysosomal constituents. Finally we have proposed studies to examine host responses to endotoxins derived from """"""""natural"""""""" sources likely to be encountered in clinical situations. These studies are premised upon our observations that endotoxins can vary markedly in activity depending upon the method used for extraction. For some of these proposed experiments we will take advantage of the commercial availability of implantable delivery systems to examine differences in host responses under situations of chronic challenge as compared to bolus intravenous or intraperitoneal injection. Our analyses of the interaction of bacterial endotoxins with host mediation systems will provide fundamental information on the contribution of these biologically active macromolecules to the hypotension and disseminated intravascular coagulation characteristic of patients with gram negative sepsis.
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