Introduction and Objective: Septic shock is a highly lethal syndrome initiated by severe, overwhelming infection. This condition is the leading cause of death in Intensive Care Units in the U.S. The underlying mechanisms that cause this syndrome remain incompletely understood despite more than a half century of scientific investigation. These studies seek to examine septic shock pathogenesis and to explore the potential of novel therapeutic strategies using both small and large models of the syndrome, patients with sepsis, and normal volunteers challenged with endotoxin. progress: Early studies focused on pathophysiology comparing gram positive and gram negative organisms, the role of endotoxemia, and the efficacy of anti-endotoxin therapies such as lipid A analogs and antibodies. Nitric oxide was examined as an important mediator of septic shock. Non-selective nitric oxide synthase inhibitors were sometimes toxic and never beneficial. Normal volunteers challenged with endotoxin were found to release increased amounts of nitric oxide. Although ibuprofen blocked endotoxin-induced increases in nitric oxide production, blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation. More recent work has found that severity of illness (risk of death) influences the therapeutic efficacy of anti-inflammatory agents in septic shock. Proposed Course of Work: Ongoing comparative survival study of commonly used vasopressors in septic shock including epinephrine, norepinephrine and vasopressin. Protocols under development for lymphocyte adoptive transfer, and intra-aortic balloon pump support in septic shock. Develop and validate new canine pneumonia model with mechanical ventilation and physiology driven protocols. Validate and apply information on biomarkers and pathogenic pathways obtained from functional genomic investigations.