AIRWAY REMODELING IN SEVERE ASTHMA

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。 这项建议的总体目标是更好地了解重度哮喘儿童和成人气道重塑的分子基础，以及它与轻中度哮喘的不同之处。在此背景下，我们建议研究基线和两年后严重哮喘患者的特征良好的队列，并将这些发现与中度哮喘、正常对照组和患病对照组(慢性支气管炎)进行对比。我们认为，重度哮喘患者的气道重塑和炎症比轻至中度哮喘患者和正常对照组更严重，并且重塑与较不可逆的气流阻塞有关。由于急性和慢性呼吸道炎症、对呼吸道的侮辱(由于感染/毒素/环境暴露)以及潜在的遗传易感性之间的复杂相互作用，哮喘似乎发生了气道重塑。持续的呼吸道炎症、上皮脱屑/剥脱(由于死亡或细胞凋亡)以及修复过程，如上皮增生(细胞增殖)和上皮下纤维化，导致呼吸道的异常结构变化。在患有严重哮喘的患者中，这可能在临床上表现为不可逆转的气流阻塞和哮喘控制不良，尽管进行了适当的抗炎治疗。哮喘患者这种病理过程背后的机制尚不清楚，将在该项目中得到更好的定义。此外，我们假设，使用高分辨率肺CT对气道壁厚度的非侵入性测量将与(在节段性气道水平上)重塑的生理和病理测量相关。我们将评估这些与重塑相关的因素在同一个体中如何随着时间的推移而改变。因此，为了更好地确定重度哮喘的气道重塑的分子基础以及它与轻中度哮喘的不同之处，我们建议：1)在一组特征良好的重度哮喘受试者中定义气道重塑与气流阻塞可逆性之间的关系；2)定义与重度哮喘患者的气道重塑相关的气道上皮细胞中的促和抗凋亡因子；以及3)研究重度哮喘患者的气道厚度的放射测量是否与病理和心理标记物相关；并将这些结果与轻中度哮喘患者以及疾病和正常对照组进行比较。识别与重塑和严重哮喘相关的潜在变量将有助于识别哪些高危个体将受益于特定的靶向治疗。

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. The overall goal of this proposal is to better understand the molecular basis for airway remodeling in children and adults with severe asthma and how it differs from mild-to-moderate asthma. In that context, we propose to study a well characterized cohort of subjects with severe asthma at baseline and two years later and contrast these findings to mil-moderate asthma, normal controls, and diseased controls (chronic bronchitis). We propose that individuals with severe asthma have more severe airway remodeling and inflammation than subjects with mild-to-moderate asthma and normal controls and that the remodeling is associated with less reversible airflow obstruction. Airway remodeling appears to develop in asthma due to a complex interaction between acute and chronic airway inflammation, insults to the airway (due to infections/toxins/environmental exposures), and underlying genetic susceptiblit. Ongoing airway inflammation, epithelial desquamation/denudation (due to death or apoptosis), and repair processes, such as epithelial hyperplasia (cellular proliferation) and subepithelial fibrosis, result in abnormal structural changes in the airway. In subjects with severe asthma, this may manifest clinically as irreversible airflow obtruction and poor asthma control despite appropriate ant-inflammatory therapy. The mechanism behind this pathologic processin humans with asthma is unclear and will be better defined in this project. Furthermore, we hypothesize that a noninvasive measurement of airway wall thickness using high resolution computed tomography of the lung wil lcorrelate to the physiologic and pathologic measures of remodeling (on a segmental airway level). We will evaluate how these factors associated with remodeling are modified over time in the same individual. Accordingly, in order to better define the molecular basis for airway remodeling in severe asthma and how it differs from mild-to-moderate asthma, we propose to: 1)Define the relationship between airway remodeling and reversibility of airflow obstruction in a wellcharacterized cohort of subjects with severe asthma; 2) Define the pro- and anti-apoptotic factors in airway epithelium associated with airway remodeling in subjects with severe asthma; and 3) Investigate whether radiologic measures of airway thickness correlate with pathologic and psychologic markers in subjects with severe asthma; and compare these findings to subjects with mild-to-moderate asthma and diseased and normal controls. The identification of the potential variables associated with remodeling and severe asthma will help identify individuals at risk who would benefit from specific targeted therapy.