Regardless of the origin of the infection, septic shock continues to be a serious complication for burn and trauma patients. Most investigators acknowledge the importance of bacterial products like endotoxin (LPS) in responses of the innate immune system that contribute to septic shock. Members of this Program Grant have provided seminal findings that led to the appreciation of the importance of two proteins, LPS binding protein (LBP) and CD14, in the initiation of these host responses to LPS. LBP functions as a transfer protein delivering LPS to CD14, a 55-kDa glycoprotein found in two forms; a membrane protein (mCD14) of myeloid lineage cells and a soluble plasma protein (sCD14). mCD14 is important in activation of myeloid lineage cells while sCD14 participates in activation of non-myeloid cell types. Cellular responses to LPS are initiated at the cell membrane and culminate with intracellular kinase cascades which regulate changes in gene expression and promote other cellular responses. A full understanding of intracellular signalling pathways used by LPS still represents a substantial gap in our knowledge. Here we focus on bridging what we believe to be the most significant gaps in our knowledge about LPS/CD14-dependent pathways of cell activation. These studies will combine approaches involving structural, molecular and cell biology to address key questions regarding the regulation of LBP biosynthesis, the structure and function of CD14, the earliest steps of LPS induced signal transduction, the basic mechanisms involved in LPS-induced activation of oxidant production and the role of the LBP/CD14 dependent pathway in animal models of septic shock and in clinical disease in man. Collectively these projects promise to provide advances in our understanding of this pathway that are likely to yield new approaches to treating septic shock in man.
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