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（从申请人摘要复制）：气道的发病机理 哮喘中的反应性被认为涉及复杂的相互作用 从细胞因子到脂质的多种介质刺激的多个细胞 源自蛛网膜酸，称为eicosanoids。渗透 嗜酸性粒细胞进入哮喘肺已被认为在 过敏性哮喘和这些细胞具有多种多样的类花生酸的能力 生物合成以及对类花生酸反应的细胞。这 5-脂氧合酶（5-lo）途径对蛛网膜酸的代谢，导致 形成了几种不同的生物活性代谢产物，这些代谢产物 包括白细胞C4和B4，它们已经广泛研究了 角色是介导过敏反应。此外，被认为是5-lo是 参与具有5-氧 - 二氧化碳的形成 最近被认为是人嗜酸性粒细胞的趋化因子 人类中性粒细胞。基本问题仍然与生物合成有关 5-氧气元素素的代谢，尤其是其合成的代谢 嗜酸性粒细胞和巨噬细胞。初步研究的结果 首次鉴定出肺部5-氧气的形成 它的出现在小鼠的支气管肺泡灌洗液中。此外，研究 腹膜巨噬细胞中5-氧 - 元素的代谢已揭示了 形成丰富的代谢物，也被发现是有效的 人嗜酸性粒细胞和中性粒细胞的趋化因子。这个metaboilte是 5-oxo-ete的独特谷胱甘肽产物本身可能是重要的 生物活性类花生酸。关于形成知之甚少 细胞内的5-氧 - 代谢。由于嗜酸性粒细胞丰富 哮喘气道，该提案的主要重点将涉及细节 对所涉及的生化途径的调查，这可能导致 将嗜酸性粒细胞募集到肺中和临界脂质的形成 与哮喘气道相关的调解人。高度敏感的质量 光谱技术将采用这些基本的生化技术 和药理研究。