The inception and exacerbations of childhood asthma may be the result of a dysregulated airway inflammation/repair process that occurs in individuals having genetic, developmental, or acquired imbalances in their immune response to environmental airway challenges such as viral infections and allergens. We have developed a rat model of chronic airway dysfunction that shares many features with childhood asthma, and we are employing this model to study mechanisms that are potentially important to defining the host factors that make airways vulnerable to asthma pathogenesis, and the mechanisms that ultimately link immune dysregulation with airflow obstruction. Peripheral airway instability and closure may be important to the airway obstruction of asthma, but the characteristics and the mechanisms of airway closure are poorly understood. It is the overall hypothesis of this project that airway closure is a pivotal component of airway obstruction in asthma, and is the result of an interaction of pathophysiological mechanisms in the airways. The objectives of this project are to determine, using detailed physiologic and morphometric analyses in rats having an asthma-like phenotype, the relative contributions of 4 principal mechanisms to airway closure: reduced lung elastic recoil; altered airway smooth muscle dynamics; altered airway wall morphology; altered airway luminal secretions. In the first Specific Aim, studies are designed to quantify the contribution of each of the airway closure mechanisms, and determine the morphologic correlates with physiological dysfunction. In the second Specific Aim, the same mechanisms of airway closure will be characterized in the context of alterations during, and after withdrawal of, systemic corticosteroid treatment. These studies will increase our understanding of the mechanisms of airway obstruction in asthma, and will provide information that complements parallel studies in children with asthma, as well as identify hypotheses for future translational studies in children with asthma.
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