STRUCTURAL MECHANISMS OPERATING IN UNRESPONSIVE ASTHMA

描述(摘自申请人的摘要)：哮喘是一种慢性疾病 这种疾病实际上由一系列临床定义的 小组，而不是单一的疾病实体。哮喘的特点是 影响呼吸道僵硬的结构和形态变化。这个 气道重塑、气道僵硬与气道扩张性的关系 对于这些子类型中的每一种可能是不同的。尽管所有子类型都患有 呼吸道高反应性，伴急性加重，有显著的 患有慢性衰弱疾病的中到重度哮喘患者亚群 持续梗阻，尽管经常调整药物；即 疾病对治疗“无反应”。这项建议的目的是 确定慢性持续性梗阻背后的机制 中度至重度哮喘患者。正常受试者的呼吸道扩张 每一次灵感。这种正常的扩张对于扩张顺畅的呼吸道是必不可少的。 肌肉和维持呼吸道通畅。然而，在哮喘受试者中，这是正常的 吸入的扩张作用可能会受到影响，导致急性和 慢性气流阻塞。调查人员推测，这是 无反应是由于导致气道壁的结构变化 导致呼吸道僵硬。可能会出现呼吸道僵硬增加 有几个原因。一种解释包括增厚和缩短 相对不扩张的粘膜基底膜。即使是轻度哮喘患者 在疾病发展的早期，基底细胞有变化。 膜和粘膜。这些变化包括特定的结构变化 气道壁细胞外基质中有胶原沉积， 纤维粘连蛋白和Tenascin。无论是这些变化的可逆性还是它们的 功能性后果是很好理解的。这项研究将确定和 描述结构性结构导致的气道扩张性降低 气道壁的改变，这可能是导致 哮喘反应迟钝。为了测量呼吸道的扩张性，研究人员将 使用高分辨率计算机断层扫描(HRCT)，一种独特的非侵入性放射学 技术，这将允许测量与肺的呼吸道大小的变化 活体内膨胀。此外，传导气道的结构组成 粘膜和特定的炎性介质可能对 随后的结构变化，从支气管内活检获得，将是 已评估。此外，一种临床相关的口服干预的效果 糖皮质激素对气道扩张性和结构变化的影响 细胞外基质和特定的炎症介质 量过了。这些研究将提供有关 气道壁结构变化、气道腔大小、 以及中、重度哮喘患者体内的室壁厚度。此外，这些 研究将针对特定的呼吸道炎症和细胞外产物 矩阵，以确定他们参与的过程，导致慢性 防止呼吸道扩张和引起无反应性哮喘的变化。

DESCRIPTION (Adapted from the applicant's abstract): Asthma is a chronic disease that is actually composed of a broad spectrum of clinically defined subgroups, rather than a single disease entity. Asthma is characterized by structural and morphologic changes that affect airway stiffness. The relationship of airway remodeling, airway stiffness, and airway distensibility may be different for each of these subtypes. Although all subtypes suffer from airway hyperresponsiveness, with acute exacerbations, there is a significant subgroup of moderate to severe asthmatics who suffer with debilitating chronic persistent obstruction despite frequent medication adjustments; i.e., the disease is "unresponsive" to treatment. The objective of this proposal is to determine the mechanisms underlying this chronic persistent obstruction in moderate to severe asthmatic patients. Airways from normal subjects dilate with each inspiration. This normal dilation is essential to distend airway smooth muscle and maintain airway patency. In asthmatic subjects, however, this normal dilating effect of inspiration may be compromised, leading to both acute and chronic airflow obstruction. The investigators hypothesize that this unresponsiveness results from structural changes in the airway wall that lead to increased stiffness of the airway. Increased airway stiffness could occur for several reasons. One explanation includes thickening and shortening of the relatively indistensible mucosal basement membrane. Even in mild asthmatics early in the development of the disease, there are changes in the basement membrane and mucosa. These changes include specific structural alterations of the airway wall extracellular matrix with the deposition of collagen, fibronectin, and tenascin. Neither the reversibility of these changes nor their functional consequences are well understood. This study will identify and characterize the decreased airway distensibility that results from structural changes in the airway wall, which may be an important mechanism that causes unresponsive asthma. To measure airway distensibility, the investigators will use high resolution computed tomography (HRCT), a unique noninvasive radiologic technique, that will allow measurement of changes in airway size with lung inflation in vivo. In addition, the structural composition of conducting airway mucosa, and specific inflammatory mediators which may be responsible for subsequent structural changes, obtained from endobronchial biopsies, will be evaluated. Further, the effects of a clinically relevant intervention of oral glucocorticoids on airway distensibility, and on the changes in the structure of the extracellular matrix and specific inflammatory mediators, will be measured. These studies will provide important new information regarding the interaction between structural changes in the airway wall, airway lumenal size, and wall thickness in vivo in moderate to 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 prevent airway distensibility and cause unresponsive asthma.