Project 3: Contribution of Small Airways to Cystic Fibrosis Lung Disease Pathogenesis

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PROJECT 3 ABSTRACT It is often assumed that CF lung disease begins in the small airways. While a number of observations suggest this assumption is correct, we do not have direct experimental evidence. Because we have more knowledge of host defense defects in large CF airways, we might conjecture that the abnormalities in small CF airways are the same. However, differences in epithelial morphology, cell types, and lack of submucosal glands and continuous cartilages suggest that small airways are not simply “small” large airways. The small airways have been relatively inaccessible for detailed mechanistic studies. As a result, we lack answers to many key questions. What is the airway surface liquid pH in CF small airways? How is it controlled? What mechanism secretes protons into small airways? Is mucociliary transport disrupted in small airways? Is the activity of ASL antimicrobials impaired? Is CFTR in small airways sufficient to prevent CF lung disease? As CF lung disease progresses how do host defenses and disease in small airways change? Our overarching hypothesis is that lack of CFTR in the small airway is pivotal for the pathogenesis of CF lung disease. We will investigate 3 specific aims: Specific Aim 1. Does lack of CFTR in small airways result in host defense defects? Based on our preliminary data we hypothesize that newborn CF small airways will be more acidic, and will have an impairment in host defenses. Specific Aim 2. Does V-ATPase play a role in regulating small airways airway surface liquid pH? We hypothesize that V-ATPase is expressed on the apical surface of a specific cell type of small airway epithelial cells and plays a role in a feedback mechanism that regulates ASL pH. Specific Aim 3. Will CFTR expression in small airways of prevent CF pig lung disease? We will use a novel AAV vector to selectively express CFTR in the small airway epithelial cells of CF pigs. We will investigate the effect of restoration of CFTR function on manifestations of early lung. Answers to these questions, will guide the field in understanding the contribution of small airways to disease and in identifying strategies for better treatments of CF.