5-LIPOXYGENASE PRODUCTS IN ASTHMATIC IMMUNE RESPONSE

描述：5-脂氧合酶（5-LO）的产物，白三烯（LT）， 在肺部炎症过程中， 哮喘患者。 我们已经制定了一个方案， 卵清蛋白（OVA_）作为变应原诱导晚期变应原特异性肺 在正常BAL：B/c和C57 BL/6小鼠中的疾病。 卵清蛋白处理的小鼠表现出 这种疾病与过敏原诱发的人类哮喘惊人地相似。 在我们的老鼠 在哮喘模型中，我们发现白三烯是哮喘的关键介质， 气道的粘液释放和嗜酸性粒细胞浸润。 与 突变小鼠缺乏5-LO和两种亚型的可用性 环氧合酶（考克斯）（连同特异性抑制剂/拮抗剂） 脂质介质），我们将确定5-LO途径的贡献， 诱导和缓解过敏性气道炎症和AHR。 这些 研究将在我们的标准方案和长期方案中进行。 过敏原诱导的小鼠肺纤维化模型。 我们的目标是定义 免疫机制，其中白三烯影响激活， T细胞和树突状细胞的效应功能， 调节过敏性气道炎症。 我们的具体目标如下： 具体目标1。 为了进一步表征5-LO途径在以下方面的作用： 过敏性肺部炎症和AHR。 我们将研究这些问题： 肺内5-LO通路阻断能预防AHR吗？ B）威尔5-LO 通路阻断是否能解决持续的过敏性气道炎症？ C.意志 阻断5-LO通路可预防过敏原诱导的肺纤维化？ 具体目标 2. 确定5-LO途径与考克斯-2的相互关系 血小板活化因子（PAF）介导的过敏性紫癜 气道炎症和AHR。 将研究以下问题：a） 考克斯-2通路活化在过敏性疾病发展中是否重要 炎症和AHR？ 和B）将阻断分泌型磷脂酶A2 （sPLA 2）和PAF抑制过敏性肺炎症和AHR？ 和具体 目标3： 确定白三烯抑制阻断 过敏性肺部炎症和哮喘小鼠模型中的AHR。 我们 将研究这些问题：a）5-LO通路阻断是否会阻止 过敏原诱导的T细胞增殖和/或细胞因子产生是必需的 治疗气道炎症和AHR 和B）5-LO途径激活是必需的吗 用于AHR B T细胞的过继转移 我们越具体地了解 生物化学和免疫学的变化就越大 具体的干预措施在减少艾滋病毒/艾滋病方面利大于弊， 会发现白三烯减少的炎症。

DESCRIPTION: The 5-lipoxygenase (5-LO) products, the leukotriene (LT)s, are clearly important participants in the pulmonary inflammatory process in patients with asthma. We have developed a protocol for administration of ovalbumin (OVA_ as allergen to induce late-phase allergen-specific pulmonary disease in normal BAL:B/c and C57BL/6 mice. OVA-treated mice display a disease strikingly similar to allergen-induced human asthma. In our mouse model of asthma, we have found that leukotrienes are key mediators of the mucus release and eosinophil infiltration of the airways. With the availability of mutant mice deficient in 5-LO and both isoforms of cyclooxygenase (COX) (together wit specific inhibitors/antagonists of the lipid mediators), we will determine the contribution of the 5-LO pathway to the induction and resolution of allergic airway inflammation and AHR. These studies will be performed in both our standard protocol and a long-term model of allergen-induced lung fibrosis in mice. Our goal will be to define immune mechanisms by which leukotrienes influences the activation and effector functions of T cells and dendritic cells, key cells in the mediation of allergic airway inflammation. Our specifi aims are as follows: Specific Aim 1. To characterize further the role of the 5-LO pathway in allergic pulmonary inflammation and AHR. We will examine these questions: a) Will intrapulmonary 5-LO pathway blockade prevent AHR? b) Will 5-LO pathway blockade resolve ongoing allergic airway inflammation? and c) Wil 5-LO pathway blockade prevent allergen-induced lung fibrosis? Specific Aim 2. To determine the interrelationship of the 5-LO pathway with COX-2 pathway and platelet activating factor (PAF) in the mediation of allergic airway inflammation and AHR. The following questions will be studied: a) Is COX-2 pathway activation important in development of allergic inflammation and AHR? and b) Will blockade of secretory phospholipase A2 (sPLA2) and PAF inhibit allergic lung inflammation and AHR? and Specific Aim 3. To determine the mechanisms by which leukotriene inhibition blocks allergic pulmonary inflammation and AHR in the murine model of asthma. We will study these questions: a) Will 5-LO pathway blockade prevent allergen-induced T cell proliferation and/or cytokine generation necessary for airway inflammation and AHR? and b) Is 5-LO pathway activation required for adoptive transfer of AHR b T cells? The more specific our knowledge of the biochemical and immunological changes becomes, the more likely it is that specific interventions producing more benefit than harm in reducing leukotriene-reduced inflammation, will be found.