EOSINOPHIL, 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: 6263126
• 负责人: ROBERT Carl MURPHY
• 金额: $ 9.61万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-10 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6263126
• 关键词: asthma; bronchomotion; cell migration; eicosanoid metabolism; eicosanoids; electrospray ionization mass spectrometry; eosinophil; glutathione; laboratory mouse; leukotrienes; lipoxygenase; mass spectrometry; molecular pathology; respiratory hypersensitivity

DESCRIPTION (Copied from Applicant Abstract): The pathogenesis of airways reactivity in asthma is thought to involve a complex interaction between multiple cells stimulated by a variety of mediators from cytokines to lipids derived from arachidonic acid called eicosanoids. The infiltration of eosinophils into the asthmatic lung has been thought to play a central role in allergic asthma and these cells have a diverse capacity for eicosanoid biosynthesis as well as being cells which respond to eicosanoids. The metabolism of arachidonic acid by the 5-lipoxygenase (5-LO) pathway leads to the formation of several different biologically active metabolites which include leukotrienes C4 and B4 which have been widely studied in terms of their role as mediating allergic reactions. In addition, 5-LO is thought to be involved in the formation of 5-oxo-eicosatetraenoic acid (5-oxo-ETE) which has been recently recognized as chemotactic factor for the human eosinophil and human neutrophil. Fundamental questions remain concerning the biosynthesis and metabolism of the 5-oxo-eicosanoids, in particular its synthesis by the eosinophil and macrophage. The results of preliminary investigations have identified for the first time the formation of 5-oxo-ETE in the lung through its appearance in bronchoalveolar lavage fluid of mice. Furthermore, studies of the metabolism of 5-oxo-ETE in the peritoneal macrophage has revealed the formation of an abundant metabolite which has also been found to be a potent chemotactic factor for the human eosinophil and neutrophil. This metaboilte is a unique glutathione product of 5-oxo-ETE and may likely itself be an important biologically active eicosanoid. Little is known about the formation of 5-oxo-ETE within cells or its metabolism. Since the eosinophil is abundant in the asthmatic airways, a major focus of this proposal will involve detail investigations of the biochemical pathways involved which can lead to the recruitment of eosinophils into the lung and the formation of critical lipid mediators relevant to the asthmatic airways. Highly sensitive mass spectrometric techniques will be employed to carry out these basic biochemical and pharmacological studies.

描述（复制自申请人摘要）：气道的发病机制 哮喘的反应性被认为涉及以下因素之间的复杂相互作用： 多种细胞受到从细胞因子到脂质的多种介质的刺激 衍生自花生四烯酸，称为类花生酸。的渗透 嗜酸性粒细胞进入哮喘肺被认为在 过敏性哮喘，这些细胞具有不同的类花生酸能力 生物合成以及作为响应类花生酸的细胞。的 花生四烯酸通过5-脂氧合酶（5-LO）途径的代谢导致 形成几种不同的生物活性代谢物， 包括白细胞三烯C4和B4，它们已经在其 作为过敏反应的媒介。此外，5-LO被认为是 参与形成5-氧代-二十碳四烯酸（5-氧代-ETE）， 最近被认为是人类嗜酸性粒细胞的趋化因子， 人嗜中性粒细胞。关于生物合成的基本问题仍然存在， 5-氧代-类二十烷酸的代谢，特别是其通过 嗜酸性粒细胞和巨噬细胞。初步调查结果显示， 首次发现肺中5-氧代-ETE的形成， 在小鼠支气管肺泡灌洗液中出现。此外，研究 5-氧代-ETE在腹腔巨噬细胞中的代谢揭示了 形成丰富的代谢物，也被发现是一种有效的 人嗜酸性粒细胞和中性粒细胞的趋化因子。这种代谢物是 5-氧代-ETE的独特谷胱甘肽产物，其本身可能是一种重要的 具有生物活性的类二十烷酸。人们对它的形成知之甚少 5-oxo-ETE在细胞内或其代谢。由于嗜酸性粒细胞在 哮喘气道，该提案的主要重点将涉及细节 调查所涉及的生化途径，这可能导致 嗜酸性粒细胞向肺中的募集和临界脂质的形成 与哮喘气道相关的介质。高灵敏度质量 光谱技术将被用来进行这些基本的生化 和药理学研究。