Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis
Jae Young Choi, Nam Soo Joo, Mauri E. Krouse, Jin V. Wu, Robert C. Robbins, Juan P. Ianowski, John W. Hanrahan, Jeffrey J. Wine
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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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 6

Analysis of synergy in pig airway glands.

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Analysis of synergy in pig airway glands. (A) Synergy depended on CFTR a...
(A) Synergy depended on CFTR and was not inhibited by niflumic acid (Nifl). The mean response to a 20-minute exposure to 20 nM carbachol plus 10 nM VIP was set to 100%. For inhibitor studies, glands were pretreated with either niflumic acid or CFTRinh-172 for 1–5 minutes prior to exposure to the combined agonists: CFTRinh-172, but not niflumic acid, significantly inhibited the response. (B) Mucus secretion in response to suprathreshold carbachol displayed a different pharmacology. In these experiments the secretory response to a 20-minute exposure to 100 nM carbachol was set to 100%; this concentration was selected to produce a rate of mucus secretion similar to that observed with 20 nM carbachol plus 10 nM VIP. To assess the inhibitors, the glands were pretreated as above with either niflumic acid or CFTRinh-172 followed by 100 nM carbachol. In contrast with the synergy condition, both niflumic acid and CFTRinh-172 significantly inhibited the response compared with carbachol alone, and the combination of inhibitors was additive. For each condition the number of subjects and number of glands (in parentheses) is shown. *P < 0.05; **P < 0.01.