TRANSCELLULAR LEUKOTRIENE BIOSYNTHESIS AND INFLAMMATION

白三烯（LT）是衍生自 花生四烯酸的细胞氧化代谢。 这些 物质在自动冷却介质中是突出的， 引发、加重或维持炎症性疾病。 的 硫肽白三烯，以LTC 4及其代谢物为代表， 在呼吸道过敏反应中起重要作用 因为它们具有强有力的支气管收缩作用。 白三烯 B4（5S，12 R）-5，12-二羟基-6，14-顺式-8，10-反式-二十碳四烯酸 酸）具有与炎症相关的多种作用，包括 趋化作用、促肌生长作用和痛觉过敏作用 效果 最近的研究表明，酶和 红细胞和嗜中性粒细胞之间的细胞合作是一种 白三烯B4形成的新机制。 三个特征 描述这种跨细胞生物合成过程。 第一、 中性粒细胞产生并分泌LTA 4， 在白三烯生物合成中。 其次，红细胞同化， 通过其LTA 4环氧化物作用将LTA 4转化为LTB 4 水解酶。 第三，LTA 4水解酶的自杀失活， 反应性底物伴随LTB 4形成。 我们建议 研究LTB 4的调节，调节和后果 通过红细胞-中性粒细胞相互作用形成。 我们的目标是： I. 表征影响红细胞-中性粒细胞的因素 相互作用和形成的白三烯B4的跨细胞 生物合成 二. 表征白三烯A4的自杀失活 水解酶，催化白三烯B4形成的酶。 三. 开发针对自杀灭活和天然抗体 白三烯A4环氧化物水解酶作为免疫化学探针 跨细胞生物合成 这是一项新的研究提案的初始阶段， 假设：i）白三烯B4通过以下途径跨细胞生物合成 红细胞-嗜中性粒细胞相互作用是一种生理学和 病理相关过程;和ii）该过程可以是 通过LTA 4环氧化物水解酶的状态进行检测和监测 在红细胞内。 如果成功，直接应用于人类 疾病将被调查。

Leukotrienes (LT) are biologically active lipids derived from cellular oxidative metabolism of arachidonic acid. These substances are prominent among the autocoid mediators that initiate, aggravate, or sustain inflammatory disorders. The sulfidopeptide leukotrienes, typified by LTC4 and its metabolites, have been attributed a significant role in respiratory anaphylaxis because of their potent bronchoconstrictive actions. Leukotriene B4 (5S,12R)-5,12-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid) has multiple actions relevant to inflammation including a chemotactic effect, a myotropic effect, and an hyperalgesic effect. Recent investigations indicate that enzymatic and cellular cooperation between erythrocytes and neutrophils is a novel mechanism for leukotriene B4 formation. Three features characterize this transcellular biosynthetic process. First, neutrophils produce and secrete LTA4, the pivotal, intermediate in leukotriene biosynthesis. Second, erythrocytes assimilate and convert that LTA4 into LTB4 via the action of their LTA4 epoxide hydrolase. Third, suicide inactivation of LTA4 hydrolase by its reactive substrate accompanies LTB4 formation. We propose to investigate the regulation, modulating and consequences of LTB4 formation by erythrocyte-neutrophil interactions. We aim to: I. Characterize factors that influence erythrocyte-neutrophil interactions and formation of leukotriene B4 by transcellular biosynthesis. II. Characterize the suicide inactivation of leukotriene A4 hydrolase, the enzyme that catalyzes leukotriene B4 formation. III. Develop antibodies against suicide inactivated and native leukotriene A4 epoxide hydrolase as immunochemical probes for transcellular biosynthesis. This is the initial stage in a new research proposal based on the hypothesis that: i) transcellular biosynthesis of leukotriene B4 via erythrocyte-neutrophil interactions is a physiologically and pathologically relevant process; and ii) this process can be detected and monitored via the status of LTA4 epoxide hydrolase within erythrocytes. If successful, a direct application to human disease will be investigated.