5-LIPOXYGENASE PRODUCTS IN ASTHMATIC IMMUNE RESPONSE

描述：5-脂氧合酶(5-LO)产物白三烯(LT)S 显然是肺部炎症过程中的重要参与者 哮喘患者。我们已经制定了一项管理协议 卵清蛋白(OVA_AS)变应原诱导晚期变应原特异性肺损伤 正常BAL：B/c和C57BL/6小鼠患病。经卵子处理的小鼠表现出 这种疾病与过敏原引起的人类哮喘惊人地相似。在我们的鼠标里 在哮喘模型中，我们发现白三烯是哮喘的关键介质。 呼吸道粘液释放，嗜酸性粒细胞浸润。与 5-LO及其两种亚型缺陷突变小鼠的可获得性 环氧合酶(COX)(连同其特定的抑制剂/拮抗剂 脂质介体)，我们将确定5-LO通路对 过敏性呼吸道炎症和AHR的诱导和消退。这些 研究将在我们的标准方案和长期方案下进行 变应原诱导的小鼠肺纤维化模型。我们的目标将是定义 白三烯影响细胞活化的免疫机制 T细胞和树突状细胞的效应器功能 过敏性呼吸道炎症的调节。我们的具体目标如下： 具体目的1.进一步表征5-LO途径在 过敏性肺部炎症和AHR。我们将研究以下问题： A)肺内5-LO通路阻断能阻止AHR吗？B)Will 5-Lo 通路阻断能解决持续的过敏性呼吸道炎症吗？和c)威尔 阻断5-LO通路可预防变应原诱导的肺纤维化？特定目标 2.确定5-LO通路与COX-2的相互关系 途径与血小板激活因子在变态反应中的中介作用 呼吸道炎症和AHR。将研究以下问题：a) 环氧合酶-2途径激活在变态反应的发生发展中重要吗 炎症和AHR？和b)将阻断分泌型磷脂酶A2 (SPLA2)和PAF抑制过敏性肺炎症和AHR？和具体的 目的3.确定白三烯抑制阻断的机制 哮喘小鼠模型中的过敏性肺部炎症和AHR。我们 我将研究以下问题：a)5-LO通路阻断能否防止 过敏原诱导的T细胞增殖和/或细胞因子的产生是必要的 用于呼吸道炎症和AHR？以及b)是否需要激活5-LO途径 用于过继转移AHR b T细胞？我们对此的了解越具体 生化和免疫学的变化越有可能发生 具体的干预措施在减少碳排放方面利大于弊 白三烯-减少炎症，将被发现。

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.