Distal Lung Inflammation Effect on Asthma Exacerbations

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增加以及在接受最大标准治疗的患者亚组中持续存在症状和肺活量下降。尽管哮喘被经典地描述为大气道疾病，但过去30年收集的大量数据强调了远端肺在疾病病理生理学中的重要性。持续性小气道炎症，由每日暴露于小参与抗原和吸入皮质类固醇（ICS）的标准制剂无法到达远端肺引起，可能在复发性急性加重的频率和严重程度中发挥作用，但缺乏前瞻性数据。关于小气道在哮喘急性发作（AE）的急性反应（早期和晚期）和缓解期间的作用的数据很少，尽管有证据表明小气道炎症在AE临床缓解后仍持续存在。拟定研究的目的是表征小气道在猫房激发（CRC）诱导的AE消退过程中的作用，该AE导致自然暴露于费尔德-1抗原，其粒径足够小，可穿透远端肺。本研究将分3个阶段在未接受过类固醇治疗的轻度至中度哮喘受试者中进行，并记录猫过敏。第一阶段将描述小气道到自然CRC的急性期和消退期。第二阶段将评估初始CRC后持续的小气道炎症是否影响由第二个CRC诱导的反复哮喘加重的急性反应和消退。III期研究将评价使用超细ICS与粗ICS靶向远端与近端气道的治疗对CRC后小气道炎症和功能变化的影响。将通过以下措施评价小气道：1）小气道空气滞留的新放射学措施（在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FEF 25 - 75%，RV，FRC，RV/TLC，闭合容积），3）不同频率的脉冲振荡，4）呼出的一氧化氮的肺泡部分，和5）在支气管镜获得的远端肺刷检物中评估的哮喘炎症的免疫学生物标志物（IL-13受体α、IL-4受体α、嗜酸性粒细胞趋化因子、RANTES和诱导型一氧化氮）。这项研究有可能澄清的贡献，“沉默区”的持续发病率遇到哮喘。

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.