Administration of endotoxin to humans represents a unique means of evaluating the early inflammatory reactions that occur during infection. Characterizing these responses and mechanisms that control them are important because these inflammatory responses contribute to the development of septic shock and organ failure. Protocol 92-CC-0141 is composed of seven individual studies: 1) Bronchoalveolar lavage and bronchial brushings will be performed in normal subjects to obtain alveolar and epithelial pulmonary cells for use in in vitro assays of respiratory cell function. This will establish techniques necessary for the second part of the protocol where 2) the effects of direct instillation of endotoxin into a lobe of the lung will be studied. Sequential bronchoalveolar lavage with epithelial cell brushings will be used to evaluate the control of early pulmonary inflammatory responses including neutrophil lung influx and mucin gene expression. 3) No studies have characterized the initial alterations in respiratory neuromuscular function during infection. Following intravenous endotoxin, measurements of respiratory drive and muscle strength will be evaluated. Subjects will be evaluated with and without antipyretics prior to endotoxin. 4) In order to evaluate mechanisms of cell priming and endotoxin tolerance, subjects will be given two doses of intravenous endotoxin separated by three hours. Systemic hemodynamics will be measured and inflammatory responses will be assessed. 5) Human recombinant interleukin-1 (rh IL-1r) has been evaluated in a phase I safety and phase II study is being completed to assess the ability of rh IL-1r to ameliorate acute inflammatory responses following endotoxin. 6) Human recombinant dimeric tumor necrosis factor receptor (rhTNFR:Fc) has been evaluated in a phase I safety study and a phase II study is being completed to assess the ability of rhTNFR:Fc to ameliorate inflammatory responses following intravenous endotoxin. 7) The role of nitric oxide in the acute inflammatory response to endotoxin will be evaluated in two phases. The elimination of expired nitric oxide measured using a chemiluminescence method, will be studied following an infusion of sodium nitroprusside, a nitric oxide donor. In the second phase of the study changes in expired nitric oxide following intravenous endotoxin administration will be assessed.
