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.