It is estimated that septic shock causes 175,000 deaths annually in the United States. Gram-negative sepsis is a major cause of septic shock; the endotoxin (LPS) of Gram-negative bacteria is believed to be responsible for initiating the cellular responses leading to septic shock. The long term goal of the research proposed here is to define the pathogenic mechanisms of septic shock at the molecular level thereby identifying potential new targets for therapeutics. Cells of the myeloid lineage play a key role in the pathogenesis of septic shock because these cells are directly stimulated by LPS to express a multiplicity of new genes encoding proteins that include cytokines and other secreted proteins, cell surface proteins and enzymes that regulate the synthesis of small molecules participating in systemic inflammation. Our discoveries of LPS binding protein (LBP), of membrane-bound CD14 as a receptor on myeloid cells for LPS-LBP complexes and of a newly recognized MAP kinase family member, p38, activated after LPS binds to CD14 provides a new basis for understanding how LPS-induced myeloid cell activation occurs. Here we will test two hypotheses stemming from these discoveries; HYPOTHESIS 1: That the LPS receptor of myeloid cells is comprised of CD14 and (an) unidentified transmembrane protein(s) that after binding LPS (LBP-LPS complexes) enables cell stimulation by the activation of intracellular kinase cascades. HYPOTHESIS 2: That LPS binding to CD14 is a key event in vivo leading the production of mediators that cause septic shock. The first hypothesis will be addressed by in vitro experiments to identify the independent structural domains of mCD14 that are involved in binding LPS or in steps involved in cell activation after LPS binds to CD14 at the cell surface, to identify and characterize the function of additional proteins of the LPS receptor and to identify components the kinase cascade activated after LPS binds to CD14. These experiments will utilize approaches relying on immunologic, biochemical and recombinant DNA techniques. The second hypothesis will be tested by using anti-CD14 antibodies to evaluate the importance of LPS-CD14 interactions in several animal models of LPS-induced cellular and organ injury with direct relevance to septic shock. Implicit in all of these studies is the potential for development of new therapies to intervene in septic shock in man.
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