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）：哮喘是慢性 实际上由广泛临床定义的疾病 亚组，而不是单个疾病实体。哮喘的特征是 影响气道刚度的结构和形态变化。这 气道重塑，气道刚度和气道的关系可扩展性 这些亚型中的每一个都可能不同。尽管所有亚型都遭受 气道高反应性，急性加重，有很大的重大反应性 中度至重度哮喘患者的亚组，患有慢性病 尽管经常进行药物调整，但持续的阻塞；即 疾病对治疗无反应。该提议的目的是 确定这种慢性持续阻塞的机制 中度至重度哮喘患者。正常受试者的气道随着 每个灵感。这种正常的扩张对于扩大气道平稳至关重要 肌肉并保持气道通畅。然而，在哮喘学科中，这个正常 灵感的扩张效果可能会受到损害，导致急性和 慢性气流阻塞。调查人员假设这是 无反应性是由于导致气道墙的结构变化引起的 增加气道的刚度。可能会增加气道刚度 由于几个原因。一种解释包括增厚和缩短 相对不可固定的粘膜基底膜。即使是轻度哮喘患者 在疾病的早期，地下室发生了变化 膜和粘膜。这些更改包括特定的结构性改变 气道壁细胞外基质与胶原蛋白的沉积， 纤连蛋白和Tenascin。这些变化的可逆性都不 功能后果已被充分理解。这项研究将确定并 表征由结构性导致的气道降低性降低性的降低性 气道墙的变化，这可能是导致的重要机制 无反应性哮喘。为了衡量气道的可扩展性，调查人员将 使用高分辨率计算机断层扫描（HRCT），这是一种独特的非侵入性放射学 技术，这将允许使用肺的气道大小的变化测量 体内通货膨胀。另外，导电道的结构组成 粘膜和特定的炎症介质可能导致 随后的结构变化，从支撑架活检中获得的结构变化将是 评估。此外，口服临床相关干预的影响 气道可扩张性的糖皮质激素以及结构的变化 细胞外基质和特定的炎症介质的 测量。这些研究将提供有关有关的重要新信息 气道墙的结构变化之间的相互作用，气道腔尺寸， 中等至重度哮喘患者的体内壁厚。此外，这些 研究将针对气道炎症和细胞外的特定产品 矩阵以确立导致慢性的过程的参与 可防止气道扩张性并引起无反应性哮喘的变化。