ARACHIDONATE METABOLITES AND NEUTROPHIL FUNCTION

花生四烯酸代谢物和中性粒细胞功能

• 批准号: 3338532
• 负责人: JOSEPH O'FLAHERTY
• 金额: $ 15.69万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-12-01 至 1988-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3338532
• 关键词: antimetabolites; arachidonate; blood tests; cell adhesion; cell aggregation; cellular pathology; corticosteroids; cyclic nucleoside monophosphate; cytochalasins; disease /disorder model; electron microscopy; fatty acid metabolism; gas chromatography; high performance liquid chromatography; human tissue; inflammation; isolation perfusion; isomer; leukocyte disorder; leukopenia; mass spectrometry; neutrophil; platelet activating factor; prostaglandins; radiotracer; respiratory toxin; thin layer chromatography

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.

我们提出了一个统一的脂质产生模型，其中激活了 细胞形成蛛形代谢物是血小板激活因子（PAF） 同时来自共同的前体。 产品脂质然后与 彼此a）促进自己的形成； b）引起功能 父细胞的响应； c）退出细胞以激活其他 组织。 因此，这些脂质在生化和功能上链接 一种介导细胞刺激作用的复杂机制。 它们在原点单元中运行，它们是刺激之间的联系 和回应。 作为分泌产品，它们是潜在的毒素 破坏组织，例如肺。 因此，我们将测量：a）并发 通过可变刺激的人和兔子生产这些脂质 多形核中性粒细胞（PMN）； b）PAF和选择的能力 蛛形代谢产物影响自己的生产； c）确切的 与磷脂的磷脂来源 PAF的来源； d）整个脂质家族在测定中的生物活性 PMN聚集，脱粒和氧化代谢；兔子 血小板聚集和5-羟色胺释放；兔肺收缩；和 使用兔子模型肺损伤。 这些研究试图定义一些 PMN功能的分子碱基，天然脂质的肺毒性 产物和某些疾病的潜在机制（例如，过敏反应， 成人呼吸窘迫综合征，过敏性支气管疾病） 人类。 我们通过临床和生物学来处理这个项目 透视，但要借鉴生理学，生物化学和 有机化学。 我们使用肺功能技术和 形态计量学（采用光，扫描和电子显微镜）；测定 PMN，血小板和平滑肌功能；和脂质化学 涉及高性能液相色谱，质谱和 有机合成。