Liquid secretion properties of airway submucosal glands

Abstract

The tracheobronchial submucosal glands secrete liquid that is important for hydrating airway surfaces, supporting mucociliary transport, and serving as a fluid matrix for numerous secreted macromolecules including the gel-forming mucins. This review details the essential structural elements of airway glands and summarizes what is currently known regarding the ion transport processes responsible for producing the liquid component of gland secretion. Liquid secretion most likely arises from serous cells and is principally under neural control with muscarinic agonists, substance P, and vasoactive intestinal peptide (VIP) functioning as effective secretogogues. Liquid secretion is driven by the active transepithelial secretion of both Cl(-) and HCO(3)(-) and at least a portion of this process is mediated by the cystic fibrosis transmembrane conductance regulator (CFTR), which is highly expressed in glands. The potential role of submucosal glands in cystic fibrosis lung disease is discussed.

Figure 1. Slide section of submucosal gland from porcine bronchus

The right arrow identifies dilated segment, or antrum, of the primary (collecting) duct in the submucosa. The left arrow shows numerous secretory tubules.

Figure 2. Summary of proposed cellular mechanisms for Cl⁻ and HCO₃⁻ secretion by serous submucosal gland cells

Though represented separately for clarity, it is likely that both anion secretion mechanisms exist in the same cell. See text for details. A, Cl⁻ secretion. Cl⁻ enters across the basolateral membrane by NKCC (1) and exits across the apical membrane through CFTR and possibly alternative anion channels (2). While NKCC is the major entry route for Cl⁻, AE2 (3) could theoretically support Cl⁻ entry across the basolateral membrane if the electrochemical driving forces are appropriate. Na⁺,K⁺-ATPase (4) is localized to the basolateral membrane. Agonist stimulation is likely to result in activation of apical membrane anion channel(s) (2) and a population of K⁺ channels on the basolateral membrane (5). B, HCO₃⁻ secretion. HCO₃⁻ is either transported across the basolateral membrane through electrogenic NBC (6) or AE2 (3), or it is generated intracellularly through the actions of carbonic anhydrase (CA). Intracellular generation of HCO₃⁻ also produces H⁺, which is removed from the cell interior by NHE (7). HCO₃⁻ then exits across the apical membrane through the anion channels (2). Agonist stimulation similarly controls secretion by activating apical membrane anion channels (2) and basolateral membrane K⁺ channels (5). Transepithelial secretion of either anion establishes a voltage gradient for cations, principally Na⁺, to follow through the paracellular pathway. H₂O flows across the barrier, either paracellularly (as shown) or transcellularly, in response to the resultant osmotic gradient.