Abstract
Submucosal glands (SMGs) are a prominent structure that lines human cartilaginous airways. Although it has been assumed that SMGs contribute to respiratory defense, that hypothesis has gone without a direct test. Therefore, we studied pigs, which have lungs like humans, and disrupted the gene for ectodysplasin (EDA-KO), which initiates SMG development. EDA-KO pigs lacked SMGs throughout the airways. Their airway surface liquid had a reduced ability to kill bacteria, consistent with SMG production of antimicrobials. In wild-type pigs, SMGs secrete mucus that emerges onto the airway surface as strands. Lack of SMGs and mucus strands disrupted mucociliary transport in EDA-KO pigs. Consequently, EDA-KO pigs failed to eradicate a bacterial challenge in lung regions normally populated by SMGs. These in vivo and ex vivo results indicate that SMGs are required for normal antimicrobial activity and mucociliary transport, two key host defenses that protect the lung.
Highlights
A thin layer of airway surface liquid (ASL) is the initial point of contact when inhalation and aspiration carry potential pathogens into the lung
Trimerization of the collagen domain is a prerequisite for trimerization of the C-terminal TNF motif that binds to the receptor EDAR inducing signaling through EDARADD, which is required for proper gland development (Schneider et al, 2001; Swee et al, 2009)
In all the piglets, we found indels in exon 4 that predicted a loss of function
Summary
A thin layer of airway surface liquid (ASL) is the initial point of contact when inhalation and aspiration carry potential pathogens into the lung. ASL serves an important protective function against infection by killing microorganisms with secreted antimicrobial peptides/proteins and by facilitating their removal with mucins and mucociliary transport (MCT) (Widdicombe and Wine, 2015; Wine and Joo, 2004; Ganz, 2002; Whitsett, 2018; Knowles and Boucher, 2002). ASL is comprised of secretions from two sources: surface epithelia lining airways and submucosal glands (SMGs) in the underlying submucosa.
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