STRUCTURAL MECHANISMS OPERATING IN UNRESPONSIVE ASTHMA

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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.