EOSINOPHILS, EICOSANOID BIOSYNTHESIS AND METABOLISM

嗜酸性粒细胞、类二十烷酸生物合成和代谢

• 批准号: 6612400
• 负责人: ROBERT Carl MURPHY
• 金额: $ 24.21万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6612400
• 关键词: allergens; asthma; blood tests; cell cell interaction; cell population study; chemical structure function; chemotaxis; clinical research; diagnostic respiratory lavage; disease /disorder model; eicosanoid metabolism; eicosanoids; eosinophil; genetically modified animals; glutathione; high performance liquid chromatography; human subject; immunoregulation; inflammation; laboratory mouse; lipoxygenase; mass spectrometry; pathologic process; respiratory pharmacology; tissue /cell culture; urinalysis

The pathogenesis of airways reactivity in asthma is thought to involve a complex interaction between multiple cells stimulated by a diverse array of mediators from cytokines to lipids derived from arachidonic acid. The infiltration of eosinophils into the asthmatic lung has been through to play a central role in the etiology in the etiology of allergic asthma and eosinophils and eosinophils have a diverse capacity for eicosanoid biosynthesis as well as being cells which respond to lipid mediators. The metabolism of arachidonic acid by the 5-lipoxygenase (5-LO) pathway leads to the formation of several different biologically active metabolites including leukotrienes C4 and B4 which are thought to play important roles in terms of mediating allergic reactions. In addition, 5-LO also leads to the formation of 5-oxo-eicosatetraenoic acid (5-oxo-ETE) which has not been extensively studied, but recently recognized as a potent chomatactic factor for the human eosinophil. Fundamental questions remain concerning a complete description of the biosynthesis and metabolism of 5-oxo-ETE and related eicosanoids, in particular a complete description of the biosynthesis and metabolism of 5-oxo-ETE and related eicosanoids, in particular in cells which respond to this arachidonate metabolite including the eosinophil and macrophage. Recent investigations have led to the discovery of an additional 5-oxo glutathione adduct at carbon-7 (FOG7) which is also chemotactic for eosinophils and neutrophils. Transcellular biosynthesis also plays a major role in the production of biologically active eicosanoids through cell-cell biochemical cooperation. Little is known about the formation of 5-oxo-ETE eicosanoids in vivo, in particular within cells resident. Since the eosinophil is abundant in the asthmatic airways, a major focus of this proposal will involve detail investigations of the production of 5-oxo- eicosanoids and FOG7 in both animal and human models. The biochemical pathways or synthesis and metabolism of this class or eicosanoid will also be investigated. Highly sensitive mass spectrometric techniques will be employed to carry out these basic biosynthetic and metabolism studies as well as characterization and identification of enzymes involved in the biosynthetic and metabolic events.

哮喘气道反应性的发病机制被认为涉及多种细胞之间的复杂相互作用，这些细胞受到从细胞因子到花生四烯酸衍生的脂质的多种介质的刺激。嗜酸性粒细胞浸润到哮喘肺中已经在过敏性哮喘的病因学中发挥了中心作用，嗜酸性粒细胞和嗜酸性粒细胞具有不同的类花生酸生物合成能力以及作为响应脂质介质的细胞。花生四烯酸通过5-脂氧合酶（5-LO）途径的代谢导致几种不同的生物活性代谢物的形成，包括白三烯C4和B4，其被认为在介导过敏反应方面起重要作用。此外，5-LO还导致5-氧代-二十碳四烯酸（5-氧代-ETE）的形成，其尚未被广泛研究，但最近被认为是人嗜酸性粒细胞的有效趋化因子。 关于5-氧代-ETE和相关类二十烷酸的生物合成和代谢的完整描述，特别是5-氧代-ETE和相关类二十烷酸的生物合成和代谢的完整描述，特别是在对这种花生四烯酸代谢物有反应的细胞（包括嗜酸性粒细胞和巨噬细胞）中的生物合成和代谢，仍然存在基本问题。最近的研究发现了另外一种碳-7位的5-氧代谷胱甘肽加合物（FOG 7），它也对嗜酸性粒细胞和中性粒细胞具有趋化性。跨细胞生物合成也通过细胞-细胞生化合作在产生具有生物活性的类二十烷酸中发挥着重要作用。关于5-氧代-ETE类二十烷酸在体内的形成，特别是在驻留细胞内的形成知之甚少。由于嗜酸性粒细胞在哮喘气道中是丰富的，该建议的主要焦点将涉及在动物和人模型中5-氧代-类二十烷酸和FOG 7的产生的详细研究。也将研究这类或类花生酸的生物化学途径或合成和代谢。将采用高灵敏度质谱技术进行这些基本的生物合成和代谢研究，并对生物合成和代谢过程中涉及的酶进行表征和鉴定。