STRUCTURAL MECHANISMS OPERATING IN UNRESPONSIVE ASTHMA

无反应性哮喘的结构机制

• 批准号: 6129448
• 负责人: Robert H Brown
• 金额: $ 32.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6129448
• 关键词: asthma; basement membrane; bronchomotion; clinical research; computed axial tomography; disease /disorder etiology; elasticity; extracellular matrix; glucocorticoids; growth /development; human subject; inflammation; respiratory airflow disorder; respiratory airway volume; respiratory disorder chemotherapy; respiratory epithelium

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.

描述（改编自申请人的摘要）：哮喘是一种慢性病 实际上由广泛的临床定义的疾病组成 亚组，而不是单一疾病实体。哮喘的特点是 影响气道僵硬的结构和形态变化。这 气道重塑、气道僵硬度和气道扩张性的关系 这些亚型中的每一个可能都不同。尽管所有亚型都患有 气道高反应性，急性加重时，有显着的 患有慢性衰弱性哮喘的中度至重度哮喘患者亚组 尽管频繁调整药物，但仍持续梗阻；即 疾病对治疗“无反应”。该提案的目的是 确定这种慢性持续性阻塞的机制 中度至重度哮喘患者。正常受试者的气管扩张 每一个灵感。这种正常的扩张对于扩张气道顺畅至关重要 肌肉并保持呼吸道通畅。然而，在哮喘受试者中，这种正常 吸气的扩张作用可能会受到损害，导致急性和 慢性气流阻塞。研究人员推测，这 反应迟钝是由于气道壁的结构变化导致的 以增加气道的硬度。可能会出现气道僵硬增加 有几个原因。一种解释包括加厚和缩短 相对不可扩张的粘膜基底膜。即使是轻度哮喘患者 疾病发展早期，基底发生变化 膜和粘膜。这些变化包括特定结构的改变 气道壁细胞外基质沉积胶原蛋白， 纤连蛋白和生腱蛋白。这些变化的可逆性及其影响 功能后果是很好理解的。这项研究将确定并 表征结构性导致的气道扩张性下降 气道壁的变化，这可能是导致的重要机制 无反应性哮喘。为了测量气道扩张性，研究人员将 使用高分辨率计算机断层扫描 (HRCT)，这是一种独特的无创放射学技术 技术，这将允许测量肺气道尺寸的变化 体内膨胀。另外，传导气道的结构组成 粘膜和特定的炎症介质可能是导致 从支气管内活检获得的后续结构变化将 评价。此外，临床相关口腔干预的效果 糖皮质激素对气道扩张性和结构变化的影响 细胞外基质和特定炎症介质 测量。这些研究将提供有关以下方面的重要新信息： 气道壁结构变化、气道腔尺寸之间的相互作用， 和中度至重度哮喘患者的体内壁厚度。此外，这些 研究将针对气道炎症和细胞外的特定产物 矩阵来确定他们参与导致慢性病的过程 阻止气道扩张并导致无反应性哮喘的变化。