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.