We propose testing a unified model of lipid production wherein activated cells form arachidonate metabolites an platelet-activating factor (PAF) concurrently from common precursors. The product lipids then interact with one another to a) promote their own formation; b) elicit functional responses of the parent cell; and c) exit the cell to activate other tissues. Thus, these lipids are linked biochemically and functionally in an intricate mechanism mediating the effects of cell stimulation. Operating within the cell of origin, they serve as a link between stimulus and response. As secretory products, they are potential toxins that can disrupt tissues such as lung. Accordingly, we will measure: a) concurrent production of these lipids by variably stimulated human and rabbit polymorphonuclear neutrophils (PMNs); b) the ability of PAF and selected arachidonate metabolites to influence their own production; c) the exact phospholipid sources of metabolizable arachidonate in relationship to the sources of PAF; d) the bioactivity of the entire family of lipids in assays of PMN aggregation, degranulation, and oxidative metabolism; rabbit platelet aggregation and serotonin release; rabbit lung contraction; and lung injury using a rabbit model. These studies seek to define some of the molecular bases for PMN function, the pulmonary toxicity of natural lipid products, and potential mechanism of certain diseases (e.g., anaphylaxis, adult respiratory distress syndromes, allergic bronchospasms) that afflict humans. We approach this project from a clinical and biological perspective but draw upon the disciplines of physiology, biochemistry, and organic chemistry. We use techniques of pulmonary function and morphometrics (employing light, scanning, and electron microscopy); assays of PMN, platelet, and smooth muscle function; and of lipid chemistry involving high-performance liquid chromatography, mass spectroscopy, and organic synthesis.
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