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 four 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 subsequent of the lung will be studied. Sequential bronchoalveolar lavage with endobronchial brushings and biopsies will be used to evaluate early pulmonary inflammatory responses including cytokine production, neutrophil influx, and early response gene expression. In addition, measurements of respiratory drive and muscle strength will be evaluated. 3) 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. 4) 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 or endobronchial endotoxin administration will be assessed.
