New models of the tracheal airway define the glandular contribution to airway surface fluid and electrolyte composition

Antibacterial defenses in the airway are dependent on multifactorial influe nces that determine the composition of both fluid and/or electrolytes at th e surface of the airway and the secretory products that aid in bacterial ki lling and clearance. In cystic fibrosis (CF), these mechanisms of airway pr otection may be defective, leading to increased colonization with Pseudomon as aeruginosa. Submucosal glands, a predominant site of cystic fibrosis tra nsmembrane conductance regulator (CFTR) protein expression in the airway, h ave been hypothesized to play an important role in protection of the airway , Furthermore, recent studies have suggested that the salt concentration at the airway surface may be a key factor in regulating the activity of antib acterial substances in the airway, To explore these issues, we have used a new model of the ferret tracheal airway to evaluate the contribution of sub mucosal glands in regulating airway surface fluid and electrolyte compositi on. Using tracheal xenograft models with and without submucosal glands, we have characterized several aspects of airway physiology that may be importa nt in defining antibacterial properties, These endpoints included the contr ibution of submucosal glands in defining bioelectric properties of the surf ace airway epithelium, airway surface fluid (ASF) chloride composition, ASF volumes, and secretion of the antibacterial factor lysozyme, Findings from these studies demonstrate a significantly elevated secreted fluid volume ( Vs) and chloride concentration ([CI],) in ASF from airways with submucosal glands (Vs = 47 +/- 4 mul; [CI](S) = 128 +/- 5 mM), as compared with xenogr aft airways without glands (Vs = 36 +/- 2 mul; [CI](S) = 103 +/- 6 mM), Fur thermore, a temperature labile factor secreted by submucosal glands appears to alter the baseline activation of 4,4'-diisothiocyanostilbene-2,2'-disul fonic acid and/or diphenylamine-2-carboxylic acid-sensitive chloride channe ls in the surface airway epithelium. Lastly, the lysozyme content of trache al airways with submucosal glands was 8.5-fold higher than were airways wit hout glands. These studies demonstrate that submucosal glands affect both t he ionic composition and bioelectric properties of the airway and suggest t hat models evaluating antibacterial properties of the airway in CF should t ake into account the contribution of glands in airway physiology.