Previous studies demonstrated that ACh-induced liquid secretion by porcine bronchi is driven by active Cl(-) and HCO(-)(3) secretion. The present study was undertaken to determine whether this process was localized to submucosal glands and mediated by the cystic fibrosis transmembrane conductance regulator (CFTR). When excised, cannulated, and treated with ACh, porcine bronchi secreted 15.6 +/- 0.6 microliter. cm(-2). h(-1). Removal of the surface epithelium did not significantly affect the rate of secretion, indicating that the source of the liquid was the submucosal glands. Pretreatment with diphenylamine-2-carboxylate, a relatively nonselective Cl(-)-channel blocker, significantly reduced liquid secretion by 86%, whereas pretreatment with DIDS, which inhibits a variety of Cl(-) channels but not CFTR, had no effect. When bronchi were pretreated with glibenclamide or 5-nitro-2-(3-phenylpropylamino)benzoic acid (both inhibitors of CFTR), the rate of ACh-induced liquid secretion was significantly reduced by 39 and 91%, respectively, compared with controls. Agents that blocked liquid secretion also caused disproportionate reductions in HCO(-)(3) secretion. Polyclonal antibodies to the CFTR bound preferentially to submucosal gland ducts and the surface epithelium, suggesting that this channel was localized to these sites. These data suggest that ACh-induced gland liquid secretion by porcine bronchi is driven by active secretion of both Cl(-) and HCO(-)(3) and is mediated by the CFTR.

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.

Tight junctions are located at the luminal aspect of adjacent epithelial cells and form a barrier that limits the paracellular diffusion of hydrophilic solutes. In recent years, evidence has accumulated to indicate that tight-junction permeability is regulated by the absorption of various nutrients. In this review, we present the physiological basis and importance of tight-junction regulation in intestinal epithelium. The molecular structure of tight junctions and their interactions with the cell cytoskeleton as well as the physical and chemical forces that influence tight junction permeability are described. Much of this review addresses the controversial Pappenheimer hypothesis, which states that a major portion of intestinal glucose absorption occurs through tight junctions and not by saturable transcellular active transport. The absorption of a significant portion of glucose through tight junctions requires increased junctional permeability, a very high intralumenal glucose concentration, and a sufficient osmotic gradient to promote volume flow.

Inhibitors of Cl− and[Formula: see text] secretion reduce acetylcholine-induced liquid, but not mucin, secretion by bronchial submucosal glands [S. K. Inglis, M. R. Corboz, A. E. Taylor, and S. T. Ballard. Am. J. Physiol. 272 ( Lung Cell. Mol. Physiol. 16): L372–L377, 1997]. The present study quantified contributions of Cl− and[Formula: see text] transport to volume and composition of acetylcholine-induced liquid secretion by airway epithelium. When distal bronchi were excised from 33 pigs and treated with 10 μM acetylcholine, the airways secreted 13.4 ± 0.7 μl ⋅ cm−2 ⋅ h−1. Bumetanide (10 μM) pretreatment reduced acetylcholine-induced liquid and Cl− secretion rates by ∼70%, but [Formula: see text] secretion fell by only 40%. Dimethylamiloride (DMA; 100 μM) pretreatment reduced Cl− secretion rates by ∼15%, but[Formula: see text] secretion fell 47%. DMA alone had little effect on liquid secretion. When airways were pretreated with both bumetanide and DMA, acetylcholine-induced liquid secretion was nearly abolished. We conclude that about three-fourths of acetylcholine-induced liquid secretion in distal bronchi is dependent on Cl− secretion. Most of the remaining response is driven by[Formula: see text] secretion. We speculate that the principal source of this liquid is submucosal glands. Crossover inhibition of bumetanide on [Formula: see text]secretion and DMA on Cl−secretion implies modulation of anion secretion secondary to changes in cell electrolyte composition.

The combination of both Cl− and[Formula: see text] secretion inhibitors causes an accumulation of mucins within the submucosal gland ducts of acetylcholine (ACh)-treated bronchi [S. K. Inglis, M. R. Corboz, A. E. Taylor, and S. T. Ballard. Am. J. Physiol. 272 ( Lung Cell. Mol. Physiol. 16): L372–L377, 1997], suggesting indirectly that these agents block airway gland liquid secretion. The present study tested the hypotheses that ACh-stimulated liquid secretion is driven by Cl−and [Formula: see text] secretion and that inhibition of this process leads to secretion of a dehydrated mucus with altered rheological properties. Excised distal bronchi from pigs were pretreated with either a combination of Cl− and[Formula: see text] secretion inhibitors (bumetanide, acetazolamide, dimethylamiloride, and 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid) or the dimethyl sulfoxide vehicle and were then treated with ACh to induce secretion. The rate of mucus liquid secretion was substantially reduced when the airways were pretreated with the anion secretion inhibitors. Mucus liquid from inhibitor-pretreated airways contained almost threefold more nonvolatile solids than the control liquid. Rheological analysis revealed that mucus liquid from inhibitor-pretreated airways expressed a significantly greater log G * (rigidity factor), whereas tangent δ (recoil factor) was significantly reduced. These results suggest that 1) ACh-induced liquid secretion in bronchi is driven by both Cl− and[Formula: see text] secretion and 2) inhibition of ACh-induced liquid secretion results in the secretion of mucus with a reduced water content and altered rheological properties.