LEUKOTRIENES AND SLOW REACTING SUBSTANCE OF ANAPHYLAXIS

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Leukotrienes (LTs) are lipid substances derived from the oxidative metabolism of arachidonic acid following the 5-lipoxygenase pathway. The sulfidopeptide leukotrienes, LTC4, LTD4, and LTE4, were structurally characterized 10 years ago as the active principles of slow reacting substance of anaphylaxis. Therefore, a major interest has centered around the role these molecules play as lipid mediators of acute hypersensitivity reactions as well as bronchoconstricting substances mediating various lung disorders including asthma. Leukotriene B4 has a multiple actions relevant to inflammation including its potent biological activity as a chemotactic factor for the polymorphonuclear leukocyte. Major questions remain to be answered concerning the role that leukotrienes play in health and disease. In large part, this lack of definitive information is due to the difficulties in assessing total production at the site of synthesis. Leukotrienes are thought to act in the microenvironment rather than circulating; furthermore, they are rapidly metabolized and eliminated from the organism as inactive metabolites. Secondly, there is a great deal of biochemical complexity involved in the regulation of LT biosynthesis as well as complexity in the interaction between cells that produce as well as respond to these mediators. A long term objective of the proposed work is to directly address these two areas. The structure of the metabolites of LTE4 and LTB4 in various models of metabolism will be deduced using mass spectrometric and ancillary spectroscopic techniques. The goal is to identify those major urinary metabolites of leukotrienes in animals as well as man and develop quantitative mass spectrometric assays to measure the appearance of these compounds in fluids such as urine. The appearance of metabolites in normal human beings and normal animals will be determined as well as their appearance in patients with chronic lung disease and animals challenged to activate the 5-lipoxygenase pathway. A second major goal of the proposed research program, is to testy the hypothesis that leukotriene A4 serves as a transcellular mediator itself, accounting for physiologically relevant concentrations of sulfidopeptide leukotrienes in vivo. Recently, the potential role of the platelet as a site of LTC4 production was discovered. By this mechanism of neutrophil-platelet interaction, an initial signal stimulating the neutrophil which contains LTA synthase but no LTC synthase could be transduced into a signal which leads to LTC4 biosynthesis. Thus, it is felt that transcellular metabolism might be an important mechanism explaining the acute versus chronic inflammatory response. Little is known about the process by which LTA4 is taken up into the platelet and furthermore, it is felt that inhibition of this process may be a novel therapeutic strategy for drug development.