Protocol (86-CC-06) is evaluating the acute effects of endotoxin administration on human cardiac and pulmonary function. We have previously shown that endotoxin administration. 1) qualitatively reproduces the hemodynamic pattern of clinical septic shock. (2) alters alveolar epithelial permeability and following intravenous fluid administration leads to a widening of the alveolar-arterial gradient. 3) primes alveolar macrophages in vivo to produce enhanced amounts of inflammatory mediators. 4) promotes the early activation and subsequent inhibition of plasminogen. The continued research protocol will evaluate the effects of selective inhibitors of inflammation (ibuprofen and pentoxifylline) on the cardiac and pulmonary effects of endotoxin. Studies in progress using this model of endotoxin administration to normal humans by our group or in collaboratum with other institution include evaluations of; a) in vivo primary of human neutrophils; b) phospholipase Az and its relation to other inflammatory responses; c) interleukin 8 and its relation to the cytokine response to endotoxin; d) kallilasin-lamin system activation; e) the generation of endotoxin - detorifying enzymes (acycloxyacyl hydrolase) in vivo; f) control of cytokine responses by alveolar macrophages in vivo; g) the control of peripheral vascular tone using forearm blood flow measurements.
