Asthma is a disease of increasing incidence that already affects more than 17 million people in the United States alone. It is therefore of major importance to understand the mechanisms responsible for the underlying mechanical and physiological changes that occur during asthma exacerbations. The long-term objective of this project is to expand the understanding of these mechanisms and provide the foundations upon which to develop improved methods for diagnosing, monitoring and managing asthma. Specifically, this proposal will study the phenomenon of airway closure and gas trapping (GT) during bronchoconstriction (BC). Total closure of pulmonary airways resulting in distal GT has long been suspected to occur in asthma and has been proposed as a major mechanism contributing to the impairment of gas exchange and increased work of breathing during severe BC. Unfortunately, until recently, there has only been indirect evidence about airway closure and direct observation of closed airways during whole-lung BC has remained elusive. Using Positron Emission Tomography (PET) we demonstrated the development of large contiguous areas of pulmonary GT in broncho-constricted animals and in an asthmatic subject. These data are consistent with segment-size ventilation defects recently visualized with MRI in asymptomatic asthmatics. The main hypotheses guiding this proposal are: 1) the changes in pulmonary mechanics during severe BC in asthma can be explained in great part by airway closure and distal gas trapping and 2) the pattern of heterogeneity in ventilation (VA) and GT during asthmatic BC should be considerably affected by heterogeneous constriction of large pulmonary airways. Our novel PET imaging technique measures the local elimination kinetics of an IV injected saline solution bolus of the isotope gas Nitrogen-13 (13 NN) and yields three- dimensional data on the topographic distribution of pulmonary perfusion (Q) and VA, and on the location and extent of gas trapped regions within the lung. We plan to use this technique, in combination with sophisticated oscillatory mechanics measurements, in normal subjects and in symptomatic and asymptomatic asthmatics, in order to achieve the following specific aims: 1) Assess the relationship between changes in global lung mechanics and in the topographic distribution of VA, and the length scale and extent of GT, during agonist-induced BC. And 2) Quantify the contribution of factors affecting the temporal and spatial constancy of these local effects such as the heterogeneous distribution of the agonist and the history of lung expansion. The experimental data to be gathered is expected to provide unique insights in the process of BC in asthma and this will serve to validate and refine the theoretical models of gas exchange and lung mechanics required to develop advanced methodologies for the diagnosis, monitoring and management of asthma.
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