Mechanisms by which human filarial parasites cause disease and modulate the host's immune response are poorly understood. Although the pathways and products of arachidonic acid metabolism in mammalian cells have been intensely studied, the presence and function of pathways of arachidonic acid metabolism in helminthic parasites are largely undefined. Parasite elaboration of bioactive arachidonate derivatives, such as prostaglandins, thromboxanes, leukotrienes, or hydroxyeicosatetraenoic acids, with their known potent activities; including effects on platelet aggregation, vascular permeability, and inflammatory and immunological responses, would represent a novel means of regulating the microenvironment surrounding helminthic parasites. Utilizing adults and microfilariae of the human lymphatic filarial parasite Brugia malayi, this project will investigate the biochemical pathways of arachidonic acid metabolism in these filarial nematodes. The ability of adults or microfilariae to incorporate 3H-arachidonic acid in vitro into parasite neutral and phospholipids has been assessed utilizing thin layer chromatography and reverse phase high performance liquid chromatography (HPLC). Mechanisms of parasite incorporation of arachidonate will be further evaluated and compared with those for other saturated and unsaturated fatty acids. Pathways of parasite metabolism of arachidonic acid to cyclooxygenase (e.g., prostaglandins) or lipoxygenase (e.g., leukotrienes) products will be defined utilizing reverse phase HPLC and radioimmunoassays. Possible actions of the antifilarial agent, diethylcarbamazine, on the pathways of parasite arachidonic acid metabolism will be determined. The potential roles of filarial parasite-derived arachidonic acid metabolites as mediators of pathogenicity and as modulators of host immunity will be examined. The effects of filarial arachidonate derivatives on human eosinophil, neutrophil, lymphocyte and platelet functions will be assessed. These investigations may document the existence within multicellular metazoan parasites of biochemical pathways heretofore appreciated only in mammalian cells. Further, by characterizing the biological activities of any filarial arachidonate derivatives, these studies may provide insights into novel mechanisms of parasite pathogenicity and may suggest rational approaches to the development of antifilarial agents.
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