Mechanisms of Reduced Airway Distension in Severe Asthma

减少严重哮喘气道扩张的机制

• 批准号: 6967832
• 负责人: Robert H Brown
• 金额: $ 41.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967832
• 关键词: asthma; bioimaging /biomedical imaging; bronchomotion; bronchospasm; clinical research; collagen; computed axial tomography; elastin; human subject; lung; morphology; morphometry; pathologic process; patient oriented research; pulmonary respiration; respiratory airflow disorder; respiratory airflow measurement; respiratory function; respiratory imaging /visualization; tenascin; tissue inhibitor of metalloproteinases

In severe asthma there is persistent airflow limitation that has both a reversible and a fixed component. The only way to elucidate the mechanisms of these components and arrive at effective treatments is to study the disease processes in subjects with severe asthma. Changes in the structure of the airway walls are believed to be one critical factor in severe asthma. However, the correlations between these structural changes and measures of severity have been inconsistent, likely due to the limitations of global lung spirometxic measurements to assess the heterogeneous changes in all the airways. High-resolution computed tomography (HRCT) is uniquely capable of dynamically and noninvasively measuring the dimensions of a range of airways in vivo in response to lung inflation, to spasmogens, and to treatments such as bronchodilator and anti-inflammatory medications in severe asthmatic subjects. Furthermore, using this imaging method, we can elucidate the mechanisms of severe asthma by correlating the heterogeneous individual airway responses both with conventional pulmonary function tests and lung impedance measurements to define the components and sites of airflow obstruction and disease severity. These functional measurements will also be correlated with bronchial biopsies to determine the morphological changes in the airways. Using HRCT, we have found that a major component of the pathophysiology in severe asthma is decreased airway luminal area at maximum lung inflation. Not only do the airways reach a smaller maximum airway size at total lung inflation, but also, as we showed in asthmatic subjects with mild disease, the subsequent response of the airways after lung inflation (a deep inspiration) is an important factor in the etiology of airway hyperresponsiveness. Based on these preliminary findings, we have developed the overall hypothesis of this proposal: the maximum size of the airways with lung inflation is limited in severe asthma by two distinct components: 1) A reversible bronchospastic component, and 2) A fixed structural component. Furthermore, it is likely that the magnitude of these two factors and their interaction determines the chronicity along with the intermittent exacerbations of the disease. We will study asthmatic subjects with a range of disease severity using noninvasive imaging. We will determine the resting airway size and the changes in maximum airway size before and after removal of airway tone using HRCT. Lung impedance measurements, when combined with the anatomic information of HRCT, will allow us to further noninvasively probe the nature and distribution of airway and tissue mechanics, and provide far more insight into the mechanisms responsible for the physiologic changes of the airways and lung parenchyma in severe asthma. In addition, we will measure the levels of several structural proteins (collagen, tenascin, and elastin) and enzymes (MMP and TIMP) in the airway basement membrane and BAL that have been implicated in airway remodeling in severe asthma. These studies will provide important new information regarding the interaction between structural changes in the airway wall and maximum airway luminal size in vivo in severe asthmatics. Furthermore, these studies will target specific products of airway inflammation and extracellular matrix to establish their involvement in the process that leads to the chronic changes that reduce the maximum airway luminal size with lung inflation and cause persistent severe asthma.

在严重哮喘中，存在持续的气流受限，其具有可逆的和固定的成分。阐明这些成分的机制并获得有效治疗的唯一方法是研究严重哮喘受试者的疾病过程。气道壁结构的变化被认为是严重哮喘的关键因素之一。然而，这些结构性变化和措施之间的相关性 严重程度不一致，可能是由于评估所有气道异质性变化的全球肺活量测量的局限性。高分辨率计算机断层扫描 (HRCT) 具有独特的能力，能够动态、无创地测量体内一系列气道的尺寸，以响应肺膨胀、痉挛以及严重哮喘受试者的支气管扩张剂和抗炎药物等治疗。此外，使用这种成像方法，我们可以阐明严重的机制 通过将不同的个体气道反应与传统的肺功能测试和肺阻抗测量相关联来确定气流阻塞的成分和部位以及疾病的严重程度，从而诊断哮喘。这些功能测量还将与支气管活检相关联，以确定气道的形态变化。使用HRCT，我们发现严重哮喘病理生理学的一个主要组成部分是最大肺膨胀时气道腔面积的减少。不仅在肺总充气时气道达到较小的最大气道尺寸，而且正如我们在哮喘患者中所显示的那样 对于患有轻度疾病的受试者，肺充气（深吸气）后气道的后续反应是气道高反应性病因的重要因素。基于这些初步发现，我们提出了该提案的总体假设：严重哮喘中肺充气时气道的最大尺寸受到两个不同组成部分的限制：1）可逆性支气管痉挛成分，2）固定结构成分。此外，这两个因素的严重程度及其相互作用可能决定了疾病的慢性性以及间歇性恶化。我们将学习 使用无创成像对具有一系列疾病严重程度的哮喘受试者进行研究。我们将使用 HRCT 确定静息气道尺寸以及去除气道张力前后最大气道尺寸的变化。肺阻抗测量与 HRCT 的解剖信息相结合，将使我们能够进一步无创地探索气道和组织力学的性质和分布，并更深入地了解气道和肺实质生理变化的机制。严重 哮喘。此外，我们将测量气道基底膜和 BAL 中与严重哮喘气道重塑有关的几种结构蛋白（胶原蛋白、肌腱蛋白和弹性蛋白）和酶（MMP 和 TIMP）的水平。这些研究将提供有关重度哮喘患者气道壁结构变化与体内最大气道腔尺寸之间相互作用的重要新信息。此外，这些研究将针对气道炎症和细胞外基质的特定产物，以确定它们参与导致慢性变化的过程，这些变化会随着肺膨胀而减小最大气道管腔尺寸并导致持续性严重哮喘。