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）：我们对哮喘的有限了解反映在其发病率的增加以及在接受最大标准治疗的患者亚组中持续存在的症状和肺活量下降。尽管哮喘通常被描述为一种大气道疾病，但过去 30 年收集的大量数据强调了远端肺在该疾病病理生理学中的重要性。尽管缺乏前瞻性数据，但由于每天接触小参与抗原以及吸入皮质类固醇（ICS）标准制剂无法到达远端肺部而引起的持续性小气道炎症可能在反复发作的频率和严重程度中发挥作用。 。尽管有证据表明小气道炎症在 AE 临床缓解后仍持续存在，但关于小气道在急性反应（早期和晚期）和哮喘急性发作 (AE) 消退过程中的作用的数据很少。拟议研究的目的是表征小气道在猫室挑战 (CRC) 引起的 AE 解决过程中的作用，该 AE 导致自然暴露于 Feld-1 抗原，其颗粒尺寸足够小穿透远端肺。该研究将分三个阶段在未使用类固醇、患有猫过敏的轻度至中度哮喘受试者中进行。第一阶段将描述自然 CRC 的小气道的急性期和消退期。 II 期将评估初次 CRC 后持续的小气道炎症是否影响第二次 CRC 引起的反复哮喘恶化的急性反应和消退。 III 期将评估使用超细 ICS 与粗 ICS 进行针对远端气道和近端气道的治疗对 CRC 后炎症和小气道功能变化的影响。小气道将通过以下措施进行评估：1）小气道空气滞留的新颖放射学测量（呼气末进行的高分辨率计算机断层扫描的定量图像分析），2）小气道的经典生理测量（等容FEF25） -75%，RV、FRC、RV/TLC、闭合容积），3）不同频率下的脉冲振荡，4）呼出一氧化氮的肺泡部分，以及5) 在支气管镜获得的远端肺刷检中评估哮喘炎症的免疫生物标志物（IL-13受体α、IL-4受体α、eotaxin、RANTES和诱导型一氧化氮）。这项研究有可能阐明“沉默区”对哮喘持续发病的影响。