Bronchial asthma afflicts more than 5% of the U.S. population, and the incidence and prevalence are on the rise. A critical feature of the disease is structural changes in the wall of the airways, which become more prominent as the disease progresses, and are correlated with disease severity and symptoms. It is not clear whether these changes are a normal response to an abnormal injury, or whether the response itself is abnormal. In addition, there is inadequate information describing the mechanisms of airway remodeling to determine whether the structural changes are reversible. The bronchial epithelial cell and the subepithelial fibroblast as well as several chemical mediators have been identified as critical players in the remodeling process. However, a study that addresses the interaction amongst these specific cells and mediators in response to injuries or insults that mimic an asthmatic exacerbation has not been undertaken. The goal of the project is to develop a more comprehensive understanding of the bronchial epithelium and the fibroblast as a key system underlying airway remodeling in bronchial asthma.
Our specific aims are structured to address: 1) the integration of molecular events with changes in the extracellular matrix as probed with novel non-invasive optical techniques, 2) the impact of a physical denudation wound, and 3) the impact of a compressive stress (pressure) wound. The proposal will combine conventional biological techniques (i.e., RT-PCR) with non-traditional non-invasive optical techniques (multi-photon laser scanning microscopy) to dynamically determine the concentrations and spatial orientation of several key chemical mediators and extracellular matrix proteins in response to an epithelial injury. The research design and methods are unique as they: 1) utilize a tissue engineered model of the airway wall that consists of bronchial epithelial cells and lung fibroblasts in the normal anatomical arrangement and 2) an injury protocol that includes chronic repetitive insults in a fashion that mimics asthma. Completion of the specific aims will provide answers to key questions related to airway remodeling in bronchial asthma, and bring us closer to not only halting, but also reversing the structural changes. ? ?
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