Fluid secretion by submucosal glands of the tracheobronchial airways

Abstract

Submucosal glands of the tracheobronchial airways provide the important functions of secreting mucins, antimicrobial substances, and fluid. This review focuses on the ionic mechanism and regulation of gland fluid secretion and examines the possible role of gland dysfunction in the lethal disease cystic fibrosis (CF). The fluid component of gland secretion is driven by the active transepithelial secretion of both Cl(-) and HCO(3)(-) by serous cells. Gland fluid secretion is neurally regulated with acetylcholine, substance P, and vasoactive intestinal peptide (VIP) playing prominent roles. The cystic fibrosis transmembrane conductance regulator (CFTR) is present in the apical membrane of gland serous cells and mediates the VIP-induced component of liquid secretion whereas the muscarinic component of liquid secretion appears to be at least partially CFTR-independent. Loss of CFTR function, which occurs in CF disease, reduces the capacity of glands to secrete fluid but not mucins. The possible links between the loss of fluid secretion capability and the complex airway pathology of CF are discussed.

FIGURE 1

Schema of a tracheobronchial submucosal gland. The gland consists of a ciliated duct, a collecting duct, and numerous secretory tubules. The secretory tubules are populated by serous and mucous cells. The serous cells are most plentiful in the distal and acinar regions of the tubules whereas the mucous cells populate the more proximal regions. This arrangement allows the secreted mucins to be easily flushed from the ducts of the tubules by the fluid secreted from the serous cells. See text for details.

FIGURE 2

Cell model for anion and liquid secretion by submucosal gland cells. Anion secretion is generally attributed to serous cells. Cl⁻ is the dominant anion that is secreted and it enters the cell across the basolateral membrane through the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC) and exits across the apical membrane through anion channels. CFTR mediates secretion induced by VIP and forskolin whereas an alternate anion channel, perhaps a Ca⁺²-activated anion channel, likely participates in the secretion induced by muscarinic agonists. HCO₃⁻ secretion is mediated through two potential pathways. HCO₃⁻ generated intracellularly results from the actions of carbonic anhydrase, which catalyzes the synthesis of HCO₃⁻ and H⁺ from CO₂ and H₂O. Removal of H⁺ from the cytoplasm by Na⁺/H⁺ exchange (NHE) results in the net synthesis of intracellular HCO₃⁻ that exits the cell through apical membrane anions channels. This pathway is induced by both forskolin and muscarinic agonists. It is likely that forskolin also induces transepithelial HCO₃⁻ secretion where HCO₃⁻ enters cells across the basolateral membrane via a Na⁺-nHCO₃⁻ cotransporter (NBC) and exits across the apical membrane through anion channels. The mechanisms for forskolin- and VIP-induced secretion are probably very similar and require CFTR. Transepithelial secretion of anions creates an electrical gradient for cations (mostly Na⁺) to follow through the paracellular pathway and the resultant osmotic gradient pulls water across the barrier. For convenience, water is shown moving through the paracellular pathway, but, due to the presence of AQP5 in the apical membrane, a significant fraction of water movement is transcellular. See text for details.