TRANSCELLULAR LEUKOTRIENE BIOSYNTHESIS AND INFLAMMATION

白三烯(LT)是一种生物活性脂类，来源于 花生四烯酸的细胞氧化代谢。这些 物质在自体激素的介体中是突出的 引发、加重或维持炎症性紊乱。这个 以LTC4及其代谢物为代表的硫多肽白三烯， 都被认为在呼吸道过敏中起着重要作用 因为它们有很强的支气管收缩作用。白三烯 B4(5S，12R)-5，12-dihydroxy-6，14-cis-8，10-trans-eicosatetraenoic 酸)具有多种与炎症相关的作用，包括 趋化作用、肌力作用和痛觉过敏 效果。最近的研究表明，酶和 红细胞和中性粒细胞之间的细胞协作是一种 白三烯B4形成的新机制。三大特色 描述这一跨细胞生物合成过程。第一, 中性粒细胞产生和分泌LTA4，LTA4是中性粒细胞的关键中间体 在白三烯生物合成中。第二，红细胞同化和 通过其LTA4环氧化物作用将LTA4转化为LTB4 水解酶。第三，LTA4水解酶的自杀性失活 活性底物伴随着LTB4的形成。我们建议 研究LTB4的调节、调控及其后果 由红细胞-中性粒细胞相互作用形成。我们的目标是： 一、描述影响红细胞中性粒细胞的因素 白三烯B4的跨细胞相互作用和形成 生物合成。 II.白三烯A4的自杀失活特征 水解酶，催化白三烯B4形成的酶。 三、研制抗自杀灭活抗体和天然抗体 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。 这是一项新研究提案的初始阶段，该提案基于 假设：i)白三烯B4的跨细胞生物合成 红细胞-中性粒细胞相互作用是一种生理学和 病理上相关的过程；以及ii)该过程可以是 通过LTA4环氧化物水解酶的状态进行检测和监控 在红细胞内。如果成功，直接应用于人类 将对疾病进行调查。

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.