Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis
Jae Young Choi, … , John W. Hanrahan, Jeffrey J. Wine
Jae Young Choi, … , John W. Hanrahan, Jeffrey J. Wine
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):3118-3127. https://doi.org/10.1172/JCI31992.
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Research Article Pulmonology

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

Abstract

Cystic fibrosis (CF) is caused by dysfunction of the CF transmembrane conductance regulator (CFTR), an anion channel whose dysfunction leads to chronic bacterial and fungal airway infections via a pathophysiological cascade that is incompletely understood. Airway glands, which produce most airway mucus, do so in response to both acetylcholine (ACh) and vasoactive intestinal peptide (VIP). CF glands fail to secrete mucus in response to VIP, but do so in response to ACh. Because vagal cholinergic pathways still elicit strong gland mucus secretion in CF subjects, it is unclear whether VIP-stimulated, CFTR-dependent gland secretion participates in innate defense. It was recently hypothesized that airway intrinsic neurons, which express abundant VIP and ACh, are normally active and stimulate low-level gland mucus secretion that is a component of innate mucosal defenses. Here we show that low levels of VIP and ACh produced significant mucus secretion in human glands via strong synergistic interactions; synergy was lost in glands of CF patients. VIP/ACh synergy also existed in pig glands, where it was CFTR dependent, mediated by both Cl– and HCO3–, and clotrimazole sensitive. Loss of “housekeeping” gland mucus secretion in CF, in combination with demonstrated defects in surface epithelia, may play a role in the vulnerability of CF airways to bacterial infections.

Authors

Jae Young Choi, Nam Soo Joo, Mauri E. Krouse, Jin V. Wu, Robert C. Robbins, Juan P. Ianowski, John W. Hanrahan, Jeffrey J. Wine

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Figure 9

A minimal gland cell model for synergistic interactions between nanomolar carbachol and VIP on submucosal gland fluid secretion.

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A minimal gland cell model for synergistic interactions between nanomola...
(A) Low levels of ACh do not produce effective fluid secretion because they activate K+ channels (K2) but not apical Cl– channels. (B) Low levels of VIP do not produce effective fluid secretion because they activate CFTR but not K+ channels. (C) When combined at low levels, ACh (i) activates Ca2+-activated K+ channels (K2) to increase the driving force through CFTR; it may also increase activity of basolateral transporters. VIP opens CFTR (ii), allowing electrogenic, anion-mediated fluid secretion. (D) At higher levels of ACh, apical Ca2+-activated chloride channels (CaCC) are activated (iii); at higher levels of VIP, cAMP-activated K+ channels (K1) are activated (iv). Thus, at higher rates of stimulation each pathway alone can produce enough fluid to support mucus secretion. Major unresolved points are the types of gland mucus secretory cells that express Ca2+-activated chloride channels (serous, mucous, or both) and the relative magnitudes of the apical conductances mediated by each type of channel. The apical K+ channel is based on single channel recordings in Calu-3 cells (61) and gland cells (J.V. Wu, unpublished observations).