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. Under protocol 92-CC-0141, the effects of direct instillation of endotoxin into lung subsegments will be evaluated. Sequential bronchoalveolar lavage will be performed at 2, 6, 24, or 48 hours after endotoxin instillation. Analyses will include the following: (1) bronchoalveolar lavage for acute phase cytokines (e.g., tumor necrosis factor, interleukin-1 (IL-1), IL-8 and activated proteases (e.g., elastase, plasminogen, metalloproteases); (2) flow cytometry of neutrophils and lymphocytes to assess changes in the expression of cell surface markers as well as changes in lymphocyte subpopulations; (3) determination of cytokine receptors including type I and II tumor necrosis factor receptors and IL-1 receptors in lavage and on elicited neutrophils; (4) apoptosis of neutrophils following their recruitment into the distal airways; and (5) systemic effects including acute phase cytokine release, recruitment of cells from the marrow and the initiation of acute phase protein release. These observations will be useful in defining important events in the initiation and resolution of acute lung inflammation to bacterial endotoxin.
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