Distal Lung Inflammation Effect on Asthma Exacerbations

远端肺部炎症对哮喘加重的影响

• 批准号: 6913825
• 负责人: DONALD P TASHKIN
• 金额: $ 54.08万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6913825
• 关键词: allergens; asthma; biomarker; bronchoscopy; cats; clinical research; computed axial tomography; human subject; inflammation; lung; lung alveolus; pathologic process; patient oriented research; respiratory hypersensitivity; respiratory imaging /visualization

DESCRIPTION (provided by applicant): Our limited understanding of asthma is reflected in its increasing morbidity as well as the continued presence of symptoms and spirometric decline in a subset of patients treated with maximum standard therapy. Although asthma is classically described as a large airways disease, substantial data collected over the past 3 decades underscore the importance of the distal lung in the pathophysiology of the disease. Persistent small airways inflammation, caused by daily exposure to small participate antigens and the inability of the standard formulations of inhaled corticosteroids (ICS) to reach the distal lung, may play a role in the frequency and severity of recurrent exacerbations, although prospective data is lacking. Little data is available on the role of the small airways during the acute response (early and late phase) and resolution of asthma exacerbations (AE) although there is evidence to suggest that small airways inflammation persists well beyond the time of clinical resolution of an AE. The purpose of the proposed study is to characterize the role of the small airways during the resolution of an AE induced by a cat room challenge (CRC) that results in a naturalistic exposure to Feld-1 antigen, the particle size of which is sufficiently small to penetrate the distal lung. The study will be performed in 3 phases in steroid naive, mild to moderate asthmatic subjects with documented cat allergy. Phase I will characterize the acute phase and resolution phase of the small airways to a naturalistic CRC. Phase II will evaluate whether persistent small airways inflammation, after an initial CRC, affects the acute response and resolution of a repeated asthma exacerbation, induced by a second CRC. Phase III will evaluate the impact of therapy targeted to the distal vs. proximal airways, using an extra-fine vs. a coarse ICS, on alterations in inflammation and function of small airways after a CRC. The small airways will be evaluated by the following measures: 1) novel radiographic measures of small airways air-trapping (quantitative image analysis of high resolution computed tomography performed at end-expiration), 2) classic physiologic measures of the small airways (isovolume FEF25-75%, RV, FRC, RV/TLC, closing volume), 3) impulse oscillation at different frequencies, 4) the alveolar portion of exhaled nitric oxide, and 5) immunologic biomarkers of asthma inflammation (IL-13 receptor alpha, IL-4 receptor alpha, eotaxin, RANTES, and inducible nitric oxide) assessed in bronchoscopically-obtained distal lung brushings. This study has the potential to clarify the contribution of the "silent zone" to the persistent morbidity encountered with asthma.

描述（由申请人提供）：我们对哮喘的了解有限，反映在其发病率的增加以及持续存在症状和肺活量测定下降的患者中，该子集接受了最大的标准治疗。尽管哮喘经典地描述为一种大型气道疾病，但在过去的30年中收集的大量数据强调了远端肺在该疾病的病理生理学中的重要性。持续的小气道炎症是由每天暴露于小型参与抗原以及吸入皮质类固醇（ICS）的标准配方到达远端肺部引起的，尽管缺乏前瞻性数据，但仍可能在复发性加重的频率和严重性中发挥作用。在急性反应（早期和晚期）和哮喘病情加重（AE）中，小气道的作用的数据很少，尽管有证据表明，小气道炎症仍然超出了AE的临床分辨率。拟议的研究的目的是表征小气道在猫室挑战（CRC）诱导的AE解析过程中的作用，该AE会导致自然主义暴露于Feld-1抗原，其粒径足够小，可以穿透远端肺。这项研究将在类固醇天真，轻度至中度哮喘患者的情况下以猫过敏的形式进行3阶段进行。第一阶段将表征小气道与自然主义CRC的急性相和分辨率阶段。第二阶段将评估持续的小气道炎症在初始CRC后是否会影响第二个CRC诱导的重复哮喘加重的急性反应和分辨率。第三阶段将评估针对远端和近端气道的治疗的影响，使用超细胞与粗糙IC，对CRC后小气道的炎症和功能的改变。小气道将通过以下措施进行评估：1）小型气道空气捕获的新型射线照相测量（对末期爆发时进行的高分辨率计算机断层层造影的定量图像分析），2）小型气道经典的生理测量值呼出的一氧化氮的肺泡部分和5）哮喘炎症的免疫学生物标志物（IL-13受体α，IL-4受体α，eotaxin，eotaxin，crantes和可诱导的一氧化氮）在支气管镜远端远端肠肺肺中评估。这项研究有可能阐明“沉默区”对哮喘持续的发病率的贡献。