Administration of endotoxin to humans allows a unique way to evaluate the early inflammatory reactions that occur during infection. Characterizing these responses and the mechanisms that control them is important because these inflammatory responses contribute to the development of septic shock and organ failure. Protocol 92-CC-0141 is evaluating acute inflammatory responses to endotoxin. The development of tolerance to inflammatory stimuli during critical illness has important implications for the application of antiinflammatory therapies and the prevention of organ failure during sepsis. To evaluate mechanisms of cell priming and endotoxin tolerance in vivo, subjects will be given two doses of intravenous endotoxin separated by a 3- to 6-hour interval. Systemic hemodynamics and inflammatory responses will be assessed. By using this method of endotoxin administration, we hope to gather information regarding control of Inflammatory responses induced by endotoxin and gain insight into mechanisms of tolerance. In addition to measurements of circulating inflammatory mediators (e.g., tumor necrosis factor, interleukin-1) peripheral blood cells will be evaluated to assess the changes in cell surface receptors for acute phase cytokines as well as endotoxin.
