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行的证据表明白细胞三烯 可能参与哮喘反应：1）它们是由 组成型（肥大细胞/巨噬细胞）和浸润（嗜酸性粒细胞）细胞 与哮喘反应有关，2）它们是有效的 支气管收缩剂，3）哮喘有点由能够 干扰其合成或作用，4）LTC4被代谢 人类进入LTD4和LTE4，允许LTE4（可以在 尿液）作为所有三个和5）的标记 白细胞三烯不仅可能触发支气管痉挛，而且LTE4也可能 使气道对刺激物和/或介体的影响敏感 进行支气管高反应性。 基于这些数据，我们招标以下 假设： 白三烯E4（LTE4），衍生自LTC4和LTD4的生物代谢产物， 在哮喘反应期间产生。 如此生产的LTE4可能导致 气道变窄和反应性过高。 由于一小部分 产生的LTE4在尿液中排泄，定量尿液排泄 LTE4的OF提供了肺阻塞和 可能具有诊断和治疗价值的反应能力。 该假设将以两个具体的目的进行检验。 在第一个 具体目的，将在之前和之后测量尿LTE4排泄 通过暴露于血小板激活来诱导气道高反应性 正常受试者中的因子（PAF）或臭氧。 如果瞬时诱导 高反应状态与LTE4的内源性产生有关 然后，我们期望尿液中的LTE4量与 改变气道响应能力。 三个实验，全部用于哮喘 受试者是在第二个特定目标中提出的。 首先是关系 将比较尿LTE4排泄和气道响应能力之间 在哮喘患者中，气道响应能力很小和明显。 其次，尿液LTE4排泄与自发之间的关系 过敏原季节发生的气道响应能力的改变将会 可以在一组有记录的过敏的哮喘患者中进行调查 素质。 第三，尿LTE4排泄与 作为急性治疗期间发生的气道功能的变化 哮喘攻击解决方案将在一组急性病中确定 患者。