MOLECULAR PATHOLOGY OF LPS HOST-PROTEIN COMPLEXES

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Endotoxic shock subsequent to gram negative sepsis is a serious medical problem, especially of burn or trauma injured patients. The hypotensive shock, coagulopathy, multiple organ failure, and consequent fatality associated with gram negative sepsis have been shown to be initialed by the cell wall lipopolysaccharides (LPS) of gram negative bacteria re?eased into the blood. Recent research has shown the existence of a newly recognized acute phase reactant in the sera of mice, rats, rabbits, and humans subsequent to several types of injury. The unique property of this acute phase reactant is that it binds to LPS. As a result, the hemodynamic and endotoxic properties oF the LPS are modifed. The proposed research has as its overall goals an understanding of the consequences and nature of the lipopolysaccharide binding protein (LBP)-LPS interaction. Thus, one specific aim is a biochemical characterization of LBP and the stoichiometry, structure, and properties of LBP-LPS complexes. This portion of the study will include amino acid sequencing studies of LBP, photochemical crosslinking of LBP and LPS to determine sites of LBP-LPS interaction, and kinetic and equilibrium studies of LBP-LPS complex formation and decomposition. An additional specific aim is to determine in what ways the endotoxicity of LPS is changed when LBP- LPS complexes are formed. These studies will include in vitro studies of the activation of cells and humoral mediation systems by LPS and LBP-LPS complexes, as well as studies of the fate of LPS in acute phase animals and studies of the ability of LPS to induce febrile and other physiological responses before and after complexation with LBP. This research may suggest therapeutic methods for intervention in the progress of gram negative septic shock at an early stage of LPS interaction with humoral components.