Mechanisms of Reduced Airway Distension in Severe Asthma

减少严重哮喘气道扩张的机制

• 批准号: 7312428
• 负责人: Robert H Brown
• 金额: $ 42.37万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7312428
• 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.

严重哮喘患者存在持续性气流受限，既有可逆成分，也有固定成分。阐明这些成分的机制并得出有效治疗方法的唯一途径是研究严重哮喘患者的疾病过程。气道壁结构的改变被认为是严重哮喘的一个关键因素。然而，这些结构性变化与以下措施之间的相关性 严重程度一直是不一致的，可能是由于评估所有呼吸道的异质性变化的全球肺搏动测量的局限性。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体内一系列呼吸道大小的方法，以响应肺膨胀、痉挛以及严重哮喘受试者的治疗，如支气管扩张剂和抗炎药物。此外，利用这种成像方法，我们可以阐明重症的发病机制。 通过将不同个体的呼吸道反应与常规肺功能测试和肺阻抗测量相关联，以确定气流阻塞的成分和位置以及疾病严重程度。这些功能测量还将与支气管活检相关联，以确定呼吸道的形态变化。使用HRCT，我们发现重症哮喘的病理生理的一个主要组成部分是在最大肺充气时气道管腔面积减少。不仅在总肺充气时，呼吸道达到较小的最大气道大小，而且，正如我们在哮喘患者中所显示的那样 对于轻度疾病的受试者，肺充气后呼吸道的后续反应(一种深刻的灵感)是呼吸道高反应性的一个重要因素。基于这些初步发现，我们提出了这一建议的总体假设：在重症哮喘中，肺充气的最大气道大小受到两个不同组成部分的限制：1)可逆的支气管痉挛成分，2)固定的结构成分。此外，这两个因素的大小及其相互作用很可能决定了疾病的慢性化和间歇性恶化。我们会研究 使用非侵入性成像技术对不同疾病严重程度的哮喘受试者进行研究。我们将用HRCT测定去除气道张力前后的静息气道大小和最大气道大小的变化。肺阻抗测量结合HRCT的解剖信息，将使我们能够进一步无创性地探索呼吸道和组织力学的性质和分布，并对重症患者呼吸道和肺实质的生理变化提供更多的洞察力。 哮喘。此外，我们还将检测与重症哮喘的气道重塑有关的几种结构蛋白(胶原、肌腱蛋白和弹性蛋白)以及气道基底膜和BAL中的酶(MMPs和TIMP)的水平。这些研究将为重症哮喘患者体内气道壁结构变化与最大气道腔大小之间的相互作用提供重要的新信息。此外，这些研究将针对特定的呼吸道炎症产物和细胞外基质，以确定它们在导致慢性变化的过程中的参与，这些慢性变化随着肺充气而减小最大气道管腔尺寸，并导致持续的严重哮喘。