The pathogenesis of airways reactivity in asthma is thought to involve a complex interaction between multiple cells stimulated by a diverse array of mediators from cytokines to lipids derived from arachidonic acid. The infiltration of eosinophils into the asthmatic lung has been through to play a central role in the etiology in the etiology of allergic asthma and eosinophils and eosinophils have a diverse capacity for eicosanoid biosynthesis as well as being cells which respond to lipid mediators. The metabolism of arachidonic acid by the 5-lipoxygenase (5-LO) pathway leads to the formation of several different biologically active metabolites including leukotrienes C4 and B4 which are thought to play important roles in terms of mediating allergic reactions. In addition, 5-LO also leads to the formation of 5-oxo-eicosatetraenoic acid (5-oxo-ETE) which has not been extensively studied, but recently recognized as a potent chomatactic factor for the human eosinophil. Fundamental questions remain concerning a complete description of the biosynthesis and metabolism of 5-oxo-ETE and related eicosanoids, in particular a complete description of the biosynthesis and metabolism of 5-oxo-ETE and related eicosanoids, in particular in cells which respond to this arachidonate metabolite including the eosinophil and macrophage. Recent investigations have led to the discovery of an additional 5-oxo glutathione adduct at carbon-7 (FOG7) which is also chemotactic for eosinophils and neutrophils. Transcellular biosynthesis also plays a major role in the production of biologically active eicosanoids through cell-cell biochemical cooperation. Little is known about the formation of 5-oxo-ETE eicosanoids in vivo, in particular within cells resident. Since the eosinophil is abundant in the asthmatic airways, a major focus of this proposal will involve detail investigations of the production of 5-oxo- eicosanoids and FOG7 in both animal and human models. The biochemical pathways or synthesis and metabolism of this class or eicosanoid will also be investigated. Highly sensitive mass spectrometric techniques will be employed to carry out these basic biosynthetic and metabolism studies as well as characterization and identification of enzymes involved in the biosynthetic and metabolic events.
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