Sepsis, a disease with increasing morbidity and mortality, results from an uncontrolled inflammatory immune response initiated by the interaction of bacteria or bacterial components with host Toll-like receptors (TLRs). Bacterial-induced sepsis is associated with production of proinflammatory cytokines, expression of cell adhesion molecules, and induction of cell apoptosis. Lipopolysaccaride (IPS) has been identified as a critical bacterial component in the pathogenesis of gram-negative sepsis. Current treatments focus on antibiotics for controlling infection and intensive care support for associated multi-organ failure. New treatment options are needed that address both the inflammatory response and the associated cell apoptosis. We have recently identified and characterized a peptide, derived from the immunoregulatory A52R vaccinia virus protein, that i) inhibits the in vitro secretion of proinflammatory cytokines in response to a variety of TLR ligands, including LPS, ii) functions in vivo to significantly reduce bacterial-induced inflammation in a mouse model of middle ear inflammation, and iii) in preliminary in vitro studies reduces LPS-induced cell apoptosis. We propose in this Phase I study to test the feasibility of this peptide as a treatment to reduce both the inflammation and cell apoptosis seen in LPS-induced sepsis. Experiments will examine in vitro the peptide effect in limiting endothelial cell activation and apoptosis in response to LPS (specific aim #1) and the in vivo effectiveness of the peptide in a mouse model of LPS-induced sepsis (specific aim #2). If successful, these studies will provide evidence for continued assessment of the peptide as a new treatment strategy for gram-negative bacterial-induced sepsis. ? New treatment options are necessary for patients with bacterial-induced sepsis, a disease with increasing morbidity and mortality. We have identified a novel therapeutic peptide that has demonstrated significant effects in the laboratory and will now be tested in an animal model of sepsis. If successful, these studies will provide the foundation for continued assessment of this peptide as a new treatment strategy for sepsis. ? ?