EOSINOPHILS, EICOSANOID BIOSYNTHESIS AND METABOLISM

哮喘的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类等多种介质的刺激。嗜酸性粒细胞在过敏性哮喘的病因学中起核心作用，嗜酸性粒细胞和嗜酸性粒细胞具有不同的合成二十烷类化合物的能力，也是对脂质介质有反应的细胞。花生四烯酸通过5-脂氧合酶(5-LO)途径代谢，形成多种不同的生物活性代谢物，包括白三烯C4和B4，它们被认为在介导过敏反应方面起着重要作用。此外，5-LO还可导致5-氧代二十碳四烯酸(5-oxo-eicosatraenoic acid，5-oxo-ETE)的形成，该物质尚未被广泛研究，但最近被认为是一种有效的嗜酸性细胞趋化因子。基本问题仍然是关于完整描述5-oxo-ETE和相关二十烷类化合物的生物合成和代谢，特别是完整描述5-oxo-ETE和相关二十烷类化合物的生物合成和代谢，特别是在对这种花生四烯酸代谢物反应的细胞中，包括嗜酸性粒细胞和巨噬细胞。最近的研究发现了另一个碳-7上的5-氧代谷胱甘肽加合物(FOG7)，它也对嗜酸性粒细胞和中性粒细胞具有趋化作用。跨细胞生物合成也在通过细胞-细胞生化合作生产具有生物活性的二十烷类化合物中发挥着重要作用。关于5-氧代-ETE二十烷类化合物在体内的形成，特别是在驻留的细胞中的形成，人们知之甚少。由于哮喘呼吸道中有大量的嗜酸性粒细胞，这项提案的一个主要焦点将涉及在动物和人类模型中详细研究5-氧代二十烷酸和FOG7的产生。这一类或二十烷类化合物的生化途径或合成和代谢也将被研究。高灵敏的质谱学技术将被用来进行这些基本的生物合成和代谢研究，以及对参与生物合成和代谢事件的酶进行表征和鉴定。

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.