Oxygenated derivatives of fatty acids such as leukotrienes (LT), thromboxane (TX), and prostaglandins (PG's) play critical roles in hemostasis, inflammation, immune responses and cellular regulation. Therefore, complete knowledge of their biosynthesis, the enzymes involved and their regulation, interactions, and modes of activities are essential. This proposal is based, in part, on the recent isolation and structural characterization of a novel series of biologically active oxygenated derivatives of arachidonic acid, termed lipoxins (LX). Formed via interactions of the 5- and 15-lipoxygenases, lipoxins display stereospecific activities on human neutrophils (PMN), protein kinase C, microcirculation, and lung strips different than those of PG, TX, or LT's.
The aims of this proposal include the extension of ongoing studies utilizing human PMN as a model to systematically investigate intermediates in the biosynthesis of LX, mechanisms of formation, and to identify their relationship to the formation of other eicosanoids (leukotrienes). Biological activities and products of further transformations of LX will be identified. Stimuli which provoke the oxygenation of both endogenous and exogenous substrates by PMN will be identified, their cellular origins located, and """"""""balanced sheets"""""""" of product formation will be monitored to determine the relationships between PMN functional responses and the generation of mono, di, and trihydroxy fatty acids. Focus will be directed toward evaluating cellular events in the activation of 15-lipoxygenase (LO) and regulation of both the 5- and 15-LO activities of PMN. These PMN activities will be studied in the presence of serum proteins, albumin and other cell types. Cell-cell interactions along the eicosanoid axis will be evaluated in conincubation of PMN with either platelets or vascular cells. These events will also be examined in whole blood. To gain insight into the modes of action of oxygenated fatty acids, PMN functional responses (lysosomal enzyme release, generation of active oxygen species, and Ca2+ mobilization) will be studied. Focus will be on identification of novel products which can regulate cellular activities and the balance of fatty acid remodeling and its temporal relationship to cellular events in the oxygenation of fatty acids and shed light on the interactions between both individual lipoxygenases and cell types. The results of this project should provide a basis for more critical evaluations of the role(s) of oxygenated fatty acids (LT, LX) in complex biological processes.
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