Amelioration of Sepsis by Macrophage Activation

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DESCRIPTION (provided by applicant): The critically ill patient frequently develops a complex disease spectrum that may include adult respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), sepsis syndrome and/or septic shock. At present, we do not understand the cellular and molecular mechanisms that are involved in the initiation and propagation of septic injury; nor do we understand the innate physiologic mechanisms that attempt to limit inflammation maintain homeostasis and promote survival in the septic patient. The phosphoinsitide 3-kinases/Akt (PI3K/Akt) is a conserved family of signal transduction enzymes which are involved in regulating cellular proliferation and survival. During the last grant period, we discovered that the PI3K family of signal transduction enzymes plays an important physiologic role by limiting the inflammatory response to plymicrobial sepsis. Specifically, endogenous PI3K suppresses pro-inflammatory cytokine release and apoptosis in the septic host. It also promotes survival in fulminating sepsis. Of greater significance, we discovered that a carbohydrate ligand that is bound by membrane associated pattern recognition receptors stimulates the PI3K/Akt pathway resulting in decreased morbidity and increased survival outcome in fulminating sepsis. These data suggest that stimulation of the PI3K pathway may be an effective approach for preventing and/or treating sepsis/septic shock. In the current proposal, we will extend these studies to examine the cellular and molecular mechanisms by which glucan ligands stimulate PI3K/Akt signaling. We will focus on understanding the ligand-receptor interactions that activate PI3K, the postreceptor signal transduction events that stimulate PI3K/Akt/GSK3 and the cellular changes that culminate in modulation of PI3K and induction of the protective phenotype in sepsis injury. Not only will the results of this research increase our basic science knowledge of the innate response to inflammatory/septic disease, but it may also result in the development of new treatment strategies for several important disease states.