Previous studies have shown that chronically-inflamed airways have remodeled airway walls in which all layers of the wall are thickened. Evidence also exists to suggest that airways in a highly constricted state exhibit a distinctive folding or buckling pattern characterized by a relatively small number of epithelial folds. Research is proposed to examine the hypothesis that structural remodeling in chronically-inflamed airways is the primary cause of the buckling pattern with few folds. We further hypothesize that this altered buckling pattern is responsible, at least in part, for the severe state of obstruction observed in chronically-inflamed airways. The proposed research program consists of three components: (i) experiments in a rat model of chronic airway inflammation to document the differences in airway wall thickness, composition, buckling pattern and degree of lumenal obstruction, and to examine relationships among these parameters, (ii) computational modeling to predict the relationships between dimensional, compositional and structural changes observed in the airways and the altered buckling pattern, and to explore ways in which this buckling pattern might be altered, (iii) physical model experiments to validate the computational model and to examine the relationship between buckling pattern and the degree of lumenal obstruction associated with a particular level of smooth muscle activation. The primary objective of this study is to identify the importance of airway wall buckling, as distinct from alterations in smooth muscle behavior, in airway hyper-responsiveness observed in conditions with chronic airway inflammation such as asthma.
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