Gram-negative sepsis in man often results in fatal hypotensive shock and disseminated intravascular coagulation. It is likely that the pathogenic mechanisms for these changes are initiated by mediators resulting from interactions of bacterial lipopolysaccharide (LPS) with one or more components of the host inflammatory system. It is our contention that one of the most important events is that of LPS binding to and stimulating the mononuclear phagocytes/macrophages (MO) of the host. The experiments proposed here will explore selected aspects of this interaction with in vitro and in vivo models. The proposed studies consist of three aspects; namely (i) Investigation of the biochemical mechanisms of LPS binding to and stimulation of the MO; (ii) Study of the MO product, Tumor Necrosis Factor (TNF), as a mediator of LPS-induced injury; and (iii) Determination of the role of a Ca2+ dependent, membrane bound phospholipase A2 of the MO in regulating arachiodonic acid release and therefore determining the availability of substrate for prostaglandin and leukotriene biosynthesis. Each area to be studied represents new investigations into the mechanism of action of LPS-induced injury. To accomplish this work we will utilize biochemical and immunologic approaches with the long range goal of evaluating findings from in vitro studies with in vivo models of LPS-induced hypotension and DIC. In addition to these specific goals, the data obtained from the proposed studies will be widely applicable to other human diseases that result from the stimulation of the host inflammatory system.
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