Testing the Contributions of Airway Submucosal Glands and Surface Epithelia to Lung Health

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PROJECT SUMMARY Our lungs are continually exposed to bacteria, viruses, and toxic particles, often complicating common pulmonary disorders such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). To protect the lungs from these challenges, mammals have evolved multiple innate airway defenses that include mucus production, antimicrobial factor secretion, and mucociliary transport (MCT). Both airway submucosal glands (SMG) and surface epithelia contribute to this first line of lung defense. However, the relative importance of their contributions or the interplay between these contributions is not well understood. Furthermore, these defenses depend on maintaining optimal pH and airway surface liquid (ASL) volume. Based on the abundance of SMG and their products, it has been hypothesized that SMG play a critical role in host defense. But that hypothesis has gone untested. We also do not know whether SMG serve host defense under basal conditions or only when they are stimulated to secrete by an airway challenge. Before we can develop novel therapeutic approaches for devastating lung diseases, we must: a) determine the contribution of airway surface epithelia and SMG to airway host defense and b) understand how pH and ASL volume regulate MCT and antimicrobial activity. In this proposal, we focus on the interplay of SMG and surface epithelia. We study pigs because they have airways and SMG like those in humans. We disrupted a gene (EDA) necessary for SMG development. Newborn EDA-KO pigs lack airway SMG, have disrupted MCT, and impaired bacterial killing. Because EDA-KO pigs lack SMG, they provide the exciting opportunity to test our overarching hypothesis that SMG are required for normal airway host defense and that their loss will lead to airway disease. We will test our hypothesis by investigating the following Specific Aims: Aim 1. What is the role of submucosal glands in ASL pH and volume regulation in the airway? Aim 2. How do submucosal glands contribute to large and small airway mucociliary transport? Aim 3. Does decreased antimicrobial peptide- mediated bacterial killing, due to lack of SMG, cause lung disease? Comparing pigs with and without SMG will provide the first direct evidence about whether and how SMG are required for respiratory host defense. The results will also lay a critical foundation for future tests of how SMG contribute to airway disease pathophysiology. Finally, increased scientific knowledge of SMG and interactions between surface epithelia/SMG will provide a better foundation for understanding how ASL is regulated, how MCT is controlled, and ultimately identify desperately needed new targets for lung diseases.