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, soluble cytokine receptors and antagonists) 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 collaboration with other institution include evaluations of: a) in vivo priming of human neutrophils; b) phospholipase A2, PAF and their relation to other inflammatory responses; c) interleukin 8 and pulmonary inflammatory responses; d) activation of the contact activation system and alterations in factors that effect thrombosis; e) generation of endotoxin - detoxifying 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; h) cytokine production by neutrophils. The goal of this research is to learn more about mechanisms that control acute inflammatory responses that are relevant to human septic shock so that new therapies may be developed.
