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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 具体目标： 主要目的：本研究的总体目标是通过新的放射学技术和生理测量来表征急性加重缓解过程中小气道的功能，并将这些发现与小气道炎症标志物的消退相关联。哮喘加重(AE)将由CAT抗原(FEL-I)的自然刺激诱导，已知CAT抗原可穿透远端呼吸道。轻度至中度的类固醇哮喘受试者将暴露在猫室中，该房间每立方米居住的活猫空气中含有已知浓度的FELDI，持续足够长的时间，以引起FEV1下降20%。将在基线和猫室挑战后的不同时间使用以下指标评估远端气道的反应：1)新的放射学技术(对在剩余容量下获得的高分辨率计算机断层扫描(HRCT)图像进行定量分析)2)生理学研究(吸气量[IC]、等容中段流速[FEF25-75%，iso]和脉冲振荡[IOS]不同频率下的呼吸阻力和IOS电抗)，3)呼出一氧化氮(FeNO)，包括计算出的FeNO的肺泡成分，以及4)生物免疫学标志物(通过支气管镜远端肺刷检获得的远端肺炎症的免疫标志物)。一旦确定了小气道放射学、生理学和炎症性改变的解决时间进程，将在未来的研究中处理以下次要目标。 次要目标：a)确定在最初的猫室挑战后，在正常化的FEV1和症状的背景下，如果小气道炎症未缓解，容易在二次猫室挑战后发生更明显的恶化；b)评估针对小气道的抗炎治疗或未接受抗炎治疗的个体小气道炎症机制的变化，即超细或粗吸入皮质类固醇(ICS)；以及c)使用本研究中采用的小气道异常的非侵入性措施来建立一个预测哮喘急性发作的预测模型，该模型与自然的急性哮喘恶化的炎症消退更接近。

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.