ARACHIDONIC ACID METABOLISM BY FILARIAL PARASITES

人类丝虫性寄生虫致病和调节 对宿主的免疫反应知之甚少。尽管这些小路和 哺乳动物细胞中花生四烯酸代谢的产物 深入研究花生四烯酸途径的存在和功能 寄生虫体内的酸代谢在很大程度上是未知的。寄生虫 生物活性花生四烯酸衍生物的精制，如前列腺素， 血栓烷、白三烯或羟基二十碳四烯酸及其 已知的有效活性；包括对血小板聚集的影响， 血管通透性以及炎症和免疫反应将 代表了一种调节周围微环境的新方法 蠕虫类寄生虫。利用人的成虫和微丝虫 淋巴丝虫寄生虫马来丝虫，这个项目将调查 这些丝虫花生四烯酸代谢的生化途径 线虫。成虫或微丝虫结合的能力 ~3H-花生四烯酸体外转化成寄生虫中性和磷脂 用薄层层析法和反相高效毛细管电泳法进行鉴定 高效液相色谱分析。寄生虫的作用机制 花生四烯酸的纳入将进一步评估并与 其他饱和和不饱和脂肪酸。的途径 花生四烯酸的寄生代谢为环氧合酶(例如， 前列腺素)或脂氧合酶(例如，白三烯)产品将 采用反相高效液相色谱和放射免疫分析方法进行定义。可能的 抗丝虫病药物二乙氨基马津在丝虫病转导途径中的作用 寄生虫花生四烯酸代谢将被测定。潜力 丝虫来源的花生四烯酸代谢产物作为 致病性的介体和宿主免疫的调节器将是 检查过了。丝虫花生四烯酸盐衍生物对人体的影响 嗜酸性粒细胞、中性粒细胞、淋巴细胞和血小板功能 评估过了。这些调查可能证明存在于 迄今生化途径的多细胞后生动物寄生虫 仅在哺乳动物细胞中受到重视。此外，通过将 任何丝虫花生四烯酸盐衍生物的生物活性 研究可能为寄生虫的新机制提供见解 致病性，并可能提出合理的方法来发展 抗丝虫病药。

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.