ACUTE-, LATE- AND RESOLUTION PHASE OF THE ASTHMATIC RESPONSE IN THE SMALL AIR

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 具体目标： 主要目的：本研究的总体目的是通过新的放射学技术和生理学测量来表征急性加重消退期间的小气道功能，并将这些发现与小气道炎症标志物的消退相关联。哮喘急性发作（AE）将通过猫抗原（Fel d I）的自然激发实验诱导，已知猫抗原可穿透远端气道。轻度至中度、类固醇初治哮喘受试者将在猫房中暴露足够长的时间，以引起FEV 1下降20%，猫房中含有已知浓度的Fel d I/m3空气（来自居住的活猫）。将在基线和猫房激发后的不同时间使用以下指标评估远端气道反应：1）新的放射学技术（定量分析在残余体积下获得的肺部高分辨率计算机断层扫描[HRCT]图像）2）生理学研究（吸气量[IC]、等容中流速[FEF 25 - 75%，iso]和不同频率下的脉冲振荡[IOS]呼吸阻力和IOS电抗），3）呼出一氧化氮（FENO），包括FENO的计算肺泡成分，和4）生物免疫学标记物（通过支气管镜远端肺刷获得的远端肺炎症的免疫学标记物）。一旦确定了小气道放射学、生理学和炎症变化消退的时间进程，将在未来的研究中解决以下次要目标。 次要目的：a）在标准化的FEV 1和症状的情况下，在初始猫房攻击后，确定未解决的小气道炎症是否倾向于在二次猫房攻击后更明显的恶化; B）评估用靶向小气道的抗炎疗法治疗或未治疗的个体中小气道炎症机制的改变，即，使用超细吸入皮质类固醇（ICS）与粗吸入皮质类固醇（ICS）;以及c）使用本研究中采用的小气道异常的非侵入性测量来开发用于缓解急性哮喘恶化的预测模型，其更接近地平行于自然急性哮喘恶化的炎症缓解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SPECIFIC AIMS: Primary Objective: The overall objective of this study is to characterize small airways function during the resolution of an acute exacerbation by novel radiographic techniques and physiologic measures and correlate those findings with the resolution of small airways inflammatory markers. The asthma exacerbation (AE) will be experimentally induced by a naturalistic challenge with cat antigen (Fel d I), which is known to penetrate the distal airways. Mild to moderate, steroid na¿ve asthmatic subjects will be exposed in a cat room, containing a known concentration of Fel d I per m3 of air from resident, live cats, for a sufficient period of time to provoke a 20% decline in FEV1. Distal airways response will be assessed at baseline and at various times following a cat room challenge using the following measures: 1) novel radiographic techniques (quantitative analysis of high-resolution computerized tomographic [HRCT] images of the lung acquired at residual volume) 2) physiologic studies (inspiratory capacity [IC], isovolume mid flow rate [FEF25-75%, iso], and impulse oscillation [IOS] respiratory resistance at different frequencies and IOS reactance), 3) exhaled nitric oxide (FENO), including the computed alveolar component of FENO, and 4) bioimmunologic markers (immunologic markers of distal lung inflammation obtained via bronchoscopic distal lung brushings). Once the time course to resolution of the radiographic, physiologic and inflammatory changes in the small airways is ascertained, the following secondary objectives will be addressed in future studies. Secondary Objectives: a) establish if unresolved small airways inflammation, after an initial cat room challenge, in the setting of normalized FEV1 and symptoms, predisposes to a more pronounced exacerbation after a secondary cat room challenge; b) evaluate alterations in mechanisms of small airways inflammation in individuals treated or not treated with anti-inflammatory therapy targeted to the small airways, i.e., with an extra-fine vs. a coarse inhaled corticosteroid (ICS); and c) to use the non-invasive measures of small airways abnormalities employed in this study to develop a predictive model for resolution of acute asthma exacerbations which more closely parallels the inflammatory resolution of natural acute asthma exacerbations.