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 2

Synergistic stimulation of human airway gland mucus secretion by carbachol in combination with VIP.

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Synergistic stimulation of human airway gland mucus secretion by carbach...
(A) Raw data of the type used for analysis; 7 glands from a donor trachea supplied part of the data plotted in B. Each image shows the same airway region after being cleaned and oiled (see Methods). Mucus secretion from individual glands formed spherical bubbles in the oil, whose volume was measured optically. The top image was taken 40 minutes after sequential exposure to 10 nM carbachol and VIP (20 minutes each) and the bottom image after 30 minutes exposure to the combined agonists. Arrows show corresponding gland openings. Exposure to 20 nM of either agonist was ineffective (see Figure 1). Scale bar: 0.5 mm. (B) Plot of mucus volume versus time for 10 single glands stimulated sequentially with 10 nM carbachol, 10 nM VIP, and the combination. The tissue was washed for 1 minute with Krebs-Ringer buffer after carbachol. (C) Plot of 10 bronchial glands from a single patient with CF stimulated with the identical protocol as the donor trachea. Unlike donor glands, no synergy occurred, but when the carbachol concentration was increased 100-fold to 1 μM, the CF glands secreted mucus vigorously, indicating that they were still viable (not shown).