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的增加以及在接受最大标准治疗的一部分患者中持续存在症状和肺活量下降。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病病理生理学中的重要性。由于每天暴露于小参与抗原和吸入皮质类固醇（ICS）的标准配方无法到达肺远端而引起的持续性小气道炎症，可能在复发性恶化的频率和严重程度中发挥作用，尽管缺乏前瞻性数据。关于小气道在急性反应（早期和晚期）和哮喘发作（AE）缓解中的作用的数据很少，尽管有证据表明小气道炎症持续时间远远超过AE的临床缓解时间。本研究的目的是表征小气道在猫室攻击（CRC）引起的AE的解决过程中的作用，CRC导致自然暴露于Feld-1抗原，其粒径足够小，可以穿透远端肺。该研究将分三个阶段在类固醇初治、轻度至中度哮喘、有猫过敏记录的受试者中进行。第一阶段将表现为小气道急性期和消退期到自然型结直肠癌。II期将评估初始结直肠癌后持续的小气道炎症是否影响由第二次结直肠癌引起的反复哮喘加重的急性反应和缓解。III期将评估针对远端和近端气道的治疗，使用超细和粗ICS，对结直肠癌后小气道炎症和功能的改变的影响。小气道将通过以下措施进行评估：1)新的小气道空气捕获的影像学测量（呼气末进行的高分辨率计算机断层扫描定量图像分析），2)小气道的经典生理学测量（等容积FEF25-75%， RV， FRC, RV/TLC，关闭体积），3)不同频率的脉冲振荡，4)呼出一氧化氮的肺泡部分，5)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)评估在支气管镜下获得远端肺刷。这项研究有可能阐明“沉默区”对哮喘持续发病的贡献。

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.