Mechanism of substance P-induced liquid secretion across bronchial epithelium

Abstract

The present study was undertaken to identify and determine the mechanism of noncholinergic pathways for the induction of liquid secretion across airway epithelium. Excised porcine bronchi secreted substantial and significant quantities of liquid when exposed to acetylcholine, substance P, or forskolin but not to isoproterenol, norepinephrine, or phenylephrine. Bumetanide, an inhibitor of Na(+)-K(+)-2Cl(-) cotransport, reduced the liquid secretion response to substance P by 69%. Approximately two-thirds of bumetanide-insensitive liquid secretion was blocked by dimethylamiloride (DMA), a Na(+)/H(+) exchange inhibitor. Substance P responses were preserved in airways after surface epithelium removal, suggesting that secreted liquid originated from submucosal glands. The anion channel blockers diphenylamine-2-carboxylate (DPC) and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) inhibited >90% of substance P-induced liquid secretion, whereas DIDS had no effect. DMA, DPC, and NPPB had greater inhibitory effects on net HCO(3)(-) secretion than on liquid secretion. Although preserved relative to liquid secretion, net HCO(3)(-) secretion was reduced by 39% in the presence of bumetanide. We conclude that substance P induces liquid secretion from bronchial submucosal glands of pigs through active transport of Cl(-) and HCO(3)(-). The pattern of responses to secretion agonists and antagonists suggests that the cystic fibrosis transmembrane conductance regulator mediates this process.

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

“…In healthy airways the mass of the glands is at least 20-fold greater than the mass of surface goblet cells (Lamb and Reid 1972). Furthermore, when mucus was collected from airways before and after removal of the surface epithelium, there was little difference in the amount collected (Trout, Corboz et al 2001); these results suggest that glands supply ~95% of the mucus that keeps the airways sterile. The importance of airway glands to innate defense has been shown directly by experiments in which ferret tracheal xenografts with glands were much more resistant to infections than those that lacked glands (Dajani, Zhang et al 2005).…”

“…Glands secrete well in response to VIP, not only glycoconjugates as once thought (Peatfield, Barnes et al 1983), but also fluid (Joo, Irokawa et al 2002;Joo, Saenz et al 2002). They also respond to SP (Coles, Neill et al 1984;Gashi, Borson et al 1986;Shimura, Sasaki et al 1987;Haxhiu, Haxhiu-Poskurica et al 1990;Davis and Tseng 1991;Wagner, Fehmann et al 1995;Trout, Corboz et al 2001), and at low concentrations SP greatly augments the secretory rate produced by VIP (J. Y. Choi, J. P. Ianowski, J. W. Hanrahan, J. J.Wine, unpublished observations). The effect of NO has not yet been tested on single gland secretion, but it does not release glycoconjugates from airway explants (Kim, Okamoto et al 2006), suggesting that its role in gland secretion might be to increase blood flow around the glands in support of fluid transport.…”

“…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.…”

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

“…The bacteria in CF airways reside in the mucus, which in normal airways is sterile and mobile (6), suggesting that CF mucus is abnormal both in its ability to be cleared from the airways (7) and in its antimicrobial properties (8). Most airway mucus is thought to arise from submucosal glands (9,10), and in the only direct comparisons ever made of airways with and without glands, airways with glands secreted much more lysozyme and were more resistant to bacterial infections, even though no central innervation of the glands was present (11,12). We hypothesize that abnormalities in airway gland mucus, secondary to loss of CFTR-mediated anion secretion, is a significant contributor to airways pathology in CF (13).…”

Characterisation, localisation and expression of porcine TACR1, TACR2 and TACR3 genes

“…It also has a modulatory effect on ovarian function (Pitzel et al 1991). Pigs can be useful models for the study of human cystic fibrosis as it has been shown that substance P induces liquid secretion from bronchial submucosal glands of pigs (Trout et al 2001).…”