PHARMACOLOGY OF LIPOXYGENASE INHIBITORS

花生四烯酸（AA）是多种炎症介质的前体， 和过敏反应。 5-脂氧合酶途径的AA代谢物 包括白三烯LTB 4，它是一种非常有效趋化剂， 气道肌肉收缩剂，以及LTC 4，LTD 4和LTE 4，它们是活性的 SRS的组分，过敏反应和速发型过敏反应中的重要介质， 超敏反应 白细胞中产生白三烯， 淋巴细胞、巨噬细胞、RBL-1和某些肥大细胞和肥大细胞瘤细胞。 15-脂氧合酶产物15-HETE抑制PMN中的5-脂氧合酶， 淋巴细胞导致白三烯和5-HETE形成减少。 我们已经发现15-HETE可以激活细胞中的一种隐蔽的5-脂氧合酶， 培养的肥大细胞/嗜碱性细胞系PT-18，其形成来自 外源添加AA。 15-HETE诱导的5-脂氧合酶活化是 在用吲哚美辛预处理PT-18细胞后增强四倍。 在RBL-1细胞中观察到类似的15-HETE诱导LT形成 用1 μ M A23187预处理。 然而，随着这一数量的增加， 离子载体，发现15-HETE抑制LT的生物合成。最后， 15-HETE也能促进大鼠腹膜内SRS/LT的形成 用A23187刺激。 本课题旨在研究LT的调节机制 生物合成15-HETE。 体外研究将使用PT-18和RBL-1 细胞 我们将确定15-HETE的进一步代谢物或 15-HETE的结构相关类似物是生理激活剂。 我们 还将研究15-HETE是否直接作用于5-脂氧合酶，通过 受体和/或通过诱导Ca++流。 我们会尝试找出 环加氧酶代谢物，抑制总激活的 5-通过15-HETE测定PT-18细胞中的脂氧合酶。 探讨其作用机制 15-HETE对大鼠腹膜SRS/LT形成的体内调节，我们 将检查15-HETE对离体腹膜炎的体外作用。 巨噬细胞，肥大细胞和中性粒细胞，确定如何15-HETE调节， 不同免疫和非免疫诱导的体内SRS形成 刺激和研究如何预先与阿司匹林或吲哚美辛 影响15-HETE对SRS产生的体内调节。 从这些研究中获得的信息将提供新的见解， 调节5-脂氧合酶，这是一个重要组成部分，在 白三烯的形成。 希望最终这将导致 治疗某些炎症的新方法 疾病

Arachidonic acid (AA) is the precursor of various mediators of inflammatory and allergic reactions. AA metabolites of the 5-lipoxygenase pathway include leukotriene LTB4 which is a very potent chemotactic agent and airway muscle contractant, and LTC4, LTD4 and LTE4, which are the active components of SRS, an important mediator in anaphylaxis and immediate hypersensitivity reactions. Leukotrienes are produced in leukocytes, lymphocytes, macrophages, RBL-1 and certain mast and mastocytoma cells. The 15-lipoxygenase product 15-HETE inhibits the 5-lipoxygenase in PMNs and lymphocytes resulting in decreased formation of leukotrienes and 5-HETE. We have found that 15-HETE can activate a cryptic 5-lipoxygenase in the cultured mast/basophil cell line PT-18 forming LTB4 and 5-HETE from exogenously added AA. 15-HETE-induced activation of the 5-lipoxygenase was enhanced four-fold upon pretreatment of PT-18 cells with indomethacin. Similar induction of LT formation by 15-HETE was observed in RBL-1 cells pretreated with 1 MuM A23187. However, with higher amounts of this ionophore, inhibition of LT biosynthesis by 15-HETE was found. Finally, 15-HETE also potentiated SRS/LT formation in vivo in the rat peritoneum stimulated with A23187. This project is designed to investigate the mechanism of modulation of LT biosynthesis by 15-HETE. The in vitro studies will use PT-18 amd RBL-1 cells. We will determine whether a further metabolite of 15-HETE or a structurally related analog of 15-HETE is the physiological activator. We will also examine whether 15-HETE acts directly on the 5-lipoxygenase, via a receptor and/or via induction of Ca++ flux. We will attempt to identify the cyclooxygenase metabolite that inhibits the total activation of the 5-lipoxygenase in PT-18 cells by 15-HETE. To investigate the mechanism of in vivo regulation of SRS/LT formation in the rat peritoneum by 15-HETE, we will examine the in vitro effects of 15-HETE on isolated peritoneal macrophages, mast cells and neutrophils, determine how 15-HETE modulates in vivo SRS formation induced by different immunological and non-immunological stimuli and investigate how pretreatment with aspirin or indomethacin affects the in vivo regulation of SRS production by 15-HETE. The information obtained from these studies will provide new insights into regulation of the 5-lipoxygenase which is an essential component in the formation of leukotrienes. It is hoped that ultimately this will lead to new therapeutic approaches in the management of certain inflammatory diseases.