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.

在严重的哮喘中，存在持续的气流受限，其具有可逆和固定的成分。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一个关键因素。然而，这些结构性变化与 严重程度不一致，可能是由于评估所有气道中异质性变化的整体肺呼吸量测量的局限性。高分辨率计算机断层扫描（HRCT）是唯一能够动态和非侵入性地测量气道的范围内的尺寸在体内响应于肺膨胀，痉挛，治疗，如支气管扩张剂和抗炎药物在严重哮喘受试者。此外，使用这种成像方法，我们可以阐明严重的机制， 通过将不均匀的个体气道反应与常规肺功能测试和肺阻抗测量两者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。这些功能测量也将与支气管活检相关，以确定气道的形态学变化。使用HRCT，我们发现严重哮喘的病理生理学的一个主要组成部分是最大肺充气时气道管腔面积减少。不仅气道在全肺充气时达到较小的最大气道尺寸，而且，正如我们在哮喘患者中所示， 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学中的重要因素。基于这些初步发现，我们提出了这一建议的总体假设：在严重哮喘中，肺充气的气道的最大尺寸受到两个不同成分的限制：1）可逆的支气管痉挛成分，和2）固定的结构成分。此外，很可能这两个因素的大小及其相互作用决定了疾病的慢性沿着间歇性加重。我们将研究 使用非侵入性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确定静息气道大小和去除气道张力前后最大气道大小的变化。肺阻抗测量结合HRCT的解剖学信息，将使我们能够进一步无创地探测气道和组织力学的性质和分布，并提供对严重呼吸道疾病中气道和肺实质生理变化机制的更多了解。 哮喘此外，我们还将测量气道基底膜和BAL中与重度哮喘气道重塑有关的几种结构蛋白（胶原蛋白、腱生蛋白和弹性蛋白）和酶（MMP和TIMP）的水平。这些研究将提供重要的新信息之间的相互作用，在气道壁的结构变化和最大气道管腔尺寸在体内严重哮喘。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，该慢性变化随着肺膨胀而减少最大气道管腔尺寸并导致持续严重哮喘。