Effect of anion secretion inhibitors on mucin content of airway submucosal gland ducts

Abstract

In porcine bronchi, inhibition of both Cl− and[Formula: see text] transport is required to block the anion secretion response to ACh and to cause mucus accumulation within ACh-treated submucosal gland ducts [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]. In this previous study, a combination of three potential [Formula: see text] transport inhibitors [1 mM acetazolamide, 1 mM DIDS, and 0.1 mM dimethylamiloride (DMA)] was used to block carbonic anhydrase, Cl−/[Formula: see text]exchange, and Na+/H+exchange, respectively. The aim of the present study was to obtain a better understanding of the mechanism of ACh-induced[Formula: see text] secretion in airway glands by determining which of the three inhibitors, in combination with bumetanide, is required to block anion secretion and so cause ductal mucin accumulation. Gland duct mucin content was measured in distal bronchi isolated from domestic pigs. Addition of either bumetanide alone, bumetanide plus acetazolamide, or bumetanide plus DIDS had no significant effect on ACh-induced mean gland duct mucin content. In contrast, glands treated with bumetanide plus DMA as well as glands treated with all four anion transport blockers were almost completely occluded with mucin after the addition of ACh. These data suggest that mucin is cleared from the ducts of bronchial submucosal glands by liquid generated from Cl−- and DMA-sensitive [Formula: see text] transport.

Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis

“…Fluid secretion by pig airway glands is driven by anion secretion (10,(30)(31)(32)(33)(34), and the lack of synergy in tissues from humans with CF indicated that synergy in humans requires CFTR. We next sought to determine the relative contributions of CFTR and Ca 2+ -activated chloride channels to the synergistic effect in pig glands.…”

Parasympathetic control of airway submucosal glands: Central reflexes and the airway intrinsic nervous system

“…Gland secretion in response to pharmacological mediators has been extensively studied in the tracheas and isolated airways of pigs Inglis, Corboz et al 1998;Trout, Gatzy et al 1998;Trout, King et al 1998;Ballard, Trout et al 1999;Crews, Taylor et al 2001;Trout, Corboz et al 2001;Phillips, Hey et al 2003;Trout, Townsley et al 2003;Ballard and Inglis 2004;Ballard, Trout et al 2006). Control experiments establish that secretions studied in this way are virtually all from the submucosal glands.…”

Airway surface pH in subjects with cystic fibrosis

“…Optimal ciliary function is favoured by an alkaline rather than an acidic environment [12]. Additionally, mucin solubility is enhanced by a high pH [15] and inhibition of bicarbonate secretion has been shown in an animal model to result in total occlusion of the submucosal glands by mucin [14]. Such occlusion, with associated glandular hypertrophy, is one of the first signs of lung pathology in newborn children with CF [16], although this has not been a consistent finding in all studies [17].…”

“…CFTR mutations could thus alter ASL pH which in turn could alter a number of innate defence processes. For example, both ciliary function [12,13] and mucus viscosity have been shown to be pH dependent [14]. Optimal ciliary function is favoured by an alkaline rather than an acidic environment [12].…”