CIRCADIAN REGULATION OF AIRWAY INFLAMMATION IN ASTHMA

哮喘气道炎症的昼夜节律调节

• 批准号: 2210599
• 负责人: NIZAR N JARJOUR
• 金额: $ 8.66万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2210599
• 关键词: CD antigens; asthma; biomarker; circadian rhythms; cortisol; cytokine; diagnostic respiratory lavage; eosinophil; epinephrine; histamine; human subject; in situ hybridization; inflammation; leukocyte count; lung alveolus; northern blottings; respiratory airflow disorder; respiratory function; serine proteinases; sleep; spirometry; superoxides; young adult human (21-34)

Nocturnal wheezing is an important feature of asthma. For many patients, nighttime exacerbations of asthma are frequent and often serious. Yet to be determined, however, are the mechanisms that cause nocturnal asthma. The goal of this proposal is to establish the causes of sleep-related airflow obstructions and the critical factors which are involved in this process. To achieve this goal, evidence has been obtained that circadian variations(epinephrine and, possibly, cortisol) and sleep are important factors for nighttime airflow obstruction and airway inflammation. Therefore, it is hypothesized that a mechanism of nocturnal asthma is the circadian fall in epinephrine and cortisol which promotes airway inflammation through the release or generation of cytokines. Furthermore, it is hypothesized that sleep is an independent contributor to this process but also through enhanced release of pro- inflammatory cytokines. Specific aims of this proposal are designed to determine the separate contributions of circadian patterns (epinephrine and cortisol) and sleep to nocturnal asthma. To accomplish these goals, asthma patients will be studied on four different hospitalized (General Clinical Research Unit) occasions. The four study periods are designed to determine the individual, and potentially interactive, influences of circadian rhythms (as measured by plasma epinephrine and cortisol) and sleep on pulmonary physiology, airway inflammation and airway and blood cell function. The effect of these variables on pulmonary physiology will be confirmed by spirometry. In addition, bronchoalveolar lavage (BAL) will be performed on each study occasion. BAL fluid will be used to quantitate airway inflammation by cell counts, lymphocyte markers(e.g. CD4, CD8, CD25), mediators (histamine and tryptase) and protein. Airway cell function, e.g. generation of superoxide, presence of eosinophil granular proteins (representing activation and release), concentrations of cytokines (IL-1, IL-4, IL-5, GM-CSF, TNF-alpha, and INF-gamma), and expression of mRNA for these cytokines, will be measured. Furthermore, to ascertain whether changes in cell function in nocturnal asthma are compartmentalized to the airway, peripheral blood cells will be used for lymphocytes surface markers, lymphocyte release and expression of cytokine mRNA, and eosinophil generation of superoxide. The independent, and interactive, influences of circadian patterns and sleep to changes in physiology, inflammation and cell function will then be determined. These observations, will provide new information on the mechanisms of nocturnal asthma and insight into regulation of pulmonary inflammation.

夜间喘息是哮喘的重要特征。对于许多人 患者，哮喘的夜间加重很常见，经常 严肃的。然而，要确定是导致的机制 夜间哮喘。该提议的目的是建立原因 与睡眠相关的气流障碍物和关键因素 参与了此过程。为了实现这一目标，证据已经 获得了昼夜节律的变化（肾上腺素，可能是皮质醇） 睡眠是夜间气流阻塞和 气道炎症。因此，假设 夜间哮喘是昼夜节律的肾上腺素和皮质醇 通过发行或产生来促进气道炎症 细胞因子。此外，假设睡眠是独立的 为此过程的贡献者，以及通过增强的释放 炎症细胞因子。该提案的具体目的旨在 确定昼夜节律的单独贡献（肾上腺素 和皮质醇）并睡到夜间哮喘。为了实现这些目标， 哮喘患者将在四个不同的住院治疗中研究 临床研究单位）场合。设计了四个研究期 确定个人，并有可能互动的影响 昼夜节律（通过血浆肾上腺素和皮质醇测量）和 睡在肺部生理学，气道炎症和气道和血液上 细胞功能。这些变量对肺部生理的影响 将通过肺活量测定法确认。另外，支气管肺泡灌洗 （BAL）将在每个研究场合进行。 BAL液将使用 为了通过细胞计数定量气道炎症，淋巴细胞 标记（例如CD4，CD8，CD25），介体（组胺和胰蛋白酶）和 蛋白质。气道细胞功能，例如产生超氧化物，存在 嗜酸性粒细胞颗粒蛋白（代表激活和释放）， 细胞因子的浓度（IL-1，IL-4，IL-5，GM-CSF，TNF-Alpha和 这些细胞因子的inf-gamma）和mRNA的表达将是 测量。此外，要确定细胞功能是否在 夜间哮喘被划分为气道，外周血 细胞将用于淋巴细胞表面标记，淋巴细胞释放 和细胞因子mRNA的表达和嗜酸性粒细胞的产生 超氧化物。昼夜节律的独立和互动的影响 模式和睡眠与生理学，炎症和细胞的变化 然后将确定功能。这些观察结果将提供新的 有关夜间哮喘机制和洞察力的信息 调节肺部炎症。