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(摘自申请者摘要)：呼吸道的发病机制 哮喘的反应性被认为涉及一种复杂的相互作用 从细胞因子到脂质等多种介质刺激的多个细胞 从花生四烯酸衍生而来，称为二十碳二烯酸。……的渗透 嗜酸性粒细胞进入哮喘肺中被认为在 过敏性哮喘和这些细胞对二十烷类化合物有不同的能力 生物合成，以及对二十烷类化合物做出反应的细胞。这个 花生四烯酸通过5-脂氧合酶(5-LO)途径代谢导致 几种不同生物活性代谢物的形成 包括白三烯C4和B4，它们已经被广泛研究 起到调节过敏反应的作用。此外，5-LO被认为是 参与5-氧代二十碳四烯酸(5-oxo-ETE)的形成 最近被认为是人类嗜酸性粒细胞的趋化因子和 人类中性粒细胞。关于生物合成和生物合成的基本问题仍然存在 5-氧代二十烷类化合物的代谢，特别是它的合成 嗜酸性粒细胞和巨噬细胞。初步调查的结果是 首次鉴定了5-氧代-乙二醇醚在肺中的形成 出现在小鼠的支气管肺泡灌洗液中。此外，还研究了 5-oxo-ETE在腹膜巨噬细胞中的代谢显示 形成一种丰富的代谢物，它也被发现是一种有效的 嗜酸性粒细胞和中性粒细胞的趋化因子。这个代谢物是 5-氧代-ETE的一种独特的谷胱甘肽产物，本身可能是一种重要的 具有生物活性的二十烷类化合物。人们对它的形成知之甚少。 细胞内或其代谢中的5-氧代-ETE。因为嗜酸性粒细胞在 哮喘呼吸道，这项提案的一个主要焦点将涉及细节 对可能导致癌症的生化途径的研究 嗜酸性粒细胞在肺中的募集和临界脂质的形成 与哮喘呼吸道相关的中介物。高灵敏质量 光谱技术将被用来进行这些基本的生化 和药理学研究。