URINARY AND EXCRETION OF LTR AS AN INDEX OF AIRWAY RESPONSES

LTR 的尿液和排泄作为气道反应的指标

• 批准号: 3769573
• 负责人: JEFFREY M DRAZEN
• 金额: --
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3769573
• 关键词: asthma; cellular immunity; enzyme linked immunosorbent assay; excretion; human subject; leukotrienes; methacholine; respiratory disorder diagnosis; respiratory function; respiratory hypersensitivity; spirometry; urine

There are 5 lines of evidence indicating that the cysteinyl leukotrienes may be involved in the asthmatic response: 1) they are produced by constitutive (mast cells/macrophages) and infiltrating (eosinophils) cells implicated in the asthmatic response, 2) they are potent bronchoconstrictors, 3) asthma is somewhat ameliorated by agents capable of interfering with their synthesis or action, 4) LTC4 is metabolized in humans into LTD4 and LTE4, allowing LTE4 (which can be recovered in the urine) to serve as a marker for all three and 5) the formation of the cysteinyl leukotrienes may not only trigger bronchospasm, but LTE4 may also sensitize the airways to the effects of irritants and/or mediators, leading to bronchial hyperreactivity. Based on these data we tender the following hypothesis: Leukotriene E4 (LTE4), the biometabolic product derived from LTC4 and LTD4, is produced during asthmatic responses. The LTE4 so produced can cause both airway narrowing and hyperresponsiveness. Since a fraction of the LTE4 produced is excreted in the urine, the quantitative urinary excretion of LTE4 provides a possible chemical index of pulmonary obstruction and responsiveness which may be of diagnostic and therapeutic value. This hypothesis will be tested in two specific aims. In this first specific aim, urinary LTE4 excretion will be measured before and after induction of airway hyperresponsiveness by exposure to platelet activating factor (PAF) or ozone in normal subjects. If the transient induction of a hyperresponsive state is associated with the endogenous production of LTE4, then we expect the amounts of LTE4 in the urine to increase in relation to altered airway responsiveness. Three experiments, all in asthmatic subjects, are proposed in the second specific aim. First the relationship between urinary LTE4 excretion and airway responsiveness will be compared in asthmatic subjects with minimal and marked airway responsiveness. Second, the relationship between urinary LTE4 excretion and spontaneous alterations in airway responsiveness that occur during allergen season will be investigated in a group of asthmatic subjects with a documented allergic diathesis. Third the relationship between urinary LTE4 excretion and the variations in airway function that occur during treatment as an acute asthmatic attack resolves will be determined in a group of acutely ill patients.

有 5 条证据表明半胱氨酰白三烯 可能与哮喘反应有关：1）它们是由 组成细胞（肥大细胞/巨噬细胞）和浸润细胞（嗜酸性粒细胞） 与哮喘反应有关，2）它们是有效的 支气管收缩药，3) 能够通过以下药物在一定程度上改善哮喘： 干扰它们的合成或作用，4) LTC4 的代谢 人类分为LTD4和LTE4，允许LTE4（可以在 尿液）作为所有三个和 5）形成的标记 半胱氨酰白三烯不仅可能引发支气管痉挛，LTE4也可能 使气道对刺激物和/或介质的影响敏感，导致 支气管高反应性。 根据这些数据，我们提出以下要求 假设： 白三烯 E4 (LTE4)，源自 LTC4 和 LTD4 的生物代谢产物， 是在哮喘反应期间产生的。 如此产生的LTE4可能会导致 气道狭窄和高反应性。 由于一小部分 产生的LTE4通过尿液排泄，定量尿中排泄 LTE4 提供了可能的肺阻塞化学指数 反应性可能具有诊断和治疗价值。 该假设将在两个具体目标中得到检验。 在这第一 具体目标，前后测量尿中LTE4排泄量 通过暴露于血小板活化诱导气道高反应性 正常受试者中的因子（PAF）或臭氧。 如果瞬态感应 高反应状态与 LTE4 的内源性产生相关， 那么我们预计尿液中 LTE4 的含量会相对增加 气道反应性改变。 三个实验，全部针对哮喘患者 主题，在第二个具体目标中提出。 首先是关系 将比较尿液 LTE4 排泄和气道反应性 气道反应性极小或显着的哮喘受试者。 二、尿LTE4排泄与自发性的关系 过敏原季节期间发生的气道反应性的改变将 在一组有过敏记录的哮喘受试者中进行研究 素质。 三、尿液中LTE4排泄量与 急性呼吸道疾病治疗期间发生的气道功能变化 哮喘发作的缓解将在一组急性病患者中确定 患者。