Septic shock is a potentially lethal consequence of gram negative and positive bacterial infection and is a significant complication in victims of traumatic injury. There are multiple bacterial products implicated as pathogenic molecules including bacterial lipoproteins, lipopolysaccharide, (LPS), lipoteichoic acid, peptidoglycans, cell wall products, etc. Sepsis in experimental animals was shown to activate the intrinsic cell """"""""suicide"""""""" program leading to apoptosis in multiple cell types. Insights into the molecular basis of cellular activation/apoptosis in response to sepsis are under intense investigation in the hope of finding new approaches to therapy. Signaling by bacterial products occurs through the recently described Toll-like receptors (TLR) on the surface of cells. Intracellular pathways leading to NFkappaB activation proceed along similar pathways for TLR-2 and TLR-4 (the two receptors shown to respond to bacterial products). However, apoptosis pathways have received less attention. The investigators will examine sepsis-induced apoptosis and a novel activation pathway in vitro as well as the effect of gene alterations that lead to decreased apoptosis in monocytes, lymphocytes and endothelial cells in vivo. They have recently shown that the apoptotic pathway following stimulation with LPS proceeds through FADD dependent signaling and that blockade of NFkappaB does not sensitize endothelial cells to death. These observation lead to questions regarding the death pathway and intrinsic cyto-protective pathways. Since considerable apoptosis occurs in LPS resistant (TLR-4 deficient) mice during sepsis, we also speculate that TLR-2 provides both activation signals and death signals in TLR-4 deficient mice. Also, they have observed two pathways leading to endothelial cell activation. First, mice lacking functional Fas (lpr) or FasL (gld) have reduced responses to LPS, and they postulate that the Fas-FasL system is pro-imflammatory. Second, a specific caspase-8 inhibitor reduces LPS-induced VCAM-1 expression. They postulate that this protease also signals for endothelial cell activation.
The specific aims of this project are: 1) To determine the role of MyD88, Il-1 receptor- associated kinase and TNF receptor- associated factor-6 in sepsis-induced apoptosis of monocytes/macrophages and endothelial cells; 2) To determine the contribution of Fas-FasL and other molecules in that apoptosis pathway in LPS-induced inflammatory response of endothelial cells; and 3) To examine the effects of apoptotic gene alterations in monocytes, lymphocytes or endothelial in survival following induction of sepsis in mice.
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