PT  - JOURNAL ARTICLE
AU  - Derek B. McMahon
AU  - Ryan M. Carey
AU  - Michael A. Kohanski
AU  - Charles C.L. Tong
AU  - Peter Papagiannopoulos
AU  - Nithin D. Adappa
AU  - James N. Palmer
AU  - Robert J. Lee
TI  - Neuropeptide regulation of secretion and inflammation in human airway gland serous cells
AID  - 10.1183/13993003.01386-2019
DP  - 2020 Jan 01
TA  - European Respiratory Journal
PG  - 1901386
4099  - http://erj.ersjournals.com/content/early/2020/01/16/13993003.01386-2019.short
4100  - http://erj.ersjournals.com/content/early/2020/01/16/13993003.01386-2019.full
AB  - Airway submucosal gland serous cells are sites of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and are important for fluid secretion in conducting airways. To elucidate how neuropeptides regulate serous cells, we tested if human nasal turbinate serous cells secrete bicarbonate (HCO3−), important for mucus polymerisation and antimicrobial peptide function, during stimulation with cAMP-elevating vasoactive intestinal peptide (VIP) and if this requires CFTR. Serous cells stimulated with VIP exhibited a ∼15–20% cAMP-dependent decrease in cell volume and a ∼0.15 unit decrease in intracellular pH (pHi), reflecting activation of Cl− and HCO3− secretion, respectively. HCO3− secretion was directly dependent on CFTR and was absent in cells from CF patients. In contrast, neuropeptide Y (NPY) reduced VIP-evoked cAMP increases, CFTR activation, and Cl−/HCO3− secretion. Culture of primary serous cells in a model that maintained a serous phenotype confirmed the activating and inhibiting effects of VIP and NPY, respectively, on fluid and HCO3− secretion. Moreover, VIP enhanced antimicrobial peptide secretion and antimicrobial efficacy of secretions while NPY reduced antimicrobial efficacy. In contrast, NPY enhanced cytokine release while VIP reduced cytokine release through a mechanism requiring CFTR. As levels of VIP and NPY are up-regulated in diseases like allergy, asthma, and chronic rhinosinusitis, the balance of these two peptides in the airway may control mucus rheology and inflammatory responses in serous cells. Furthermore, the loss of CFTR conductance in serous cells may contribute to CF pathophysiology by increasing serous cells inflammatory responses in addition to directly impairing Cl− and HCO3− secretion.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. McMahon has nothing to disclose.Conflict of interest: Dr. Carey has nothing to disclose.Conflict of interest: Dr. Kohanski has nothing to disclose.Conflict of interest: Dr. Tong has nothing to disclose.Conflict of interest: Dr. Papagiannopoulos has nothing to disclose.Conflict of interest: Dr. Adappa has nothing to disclose.Conflict of interest: Dr. Palmer has nothing to disclose.Conflict of interest: Dr. Lee reports grants from NIH/National Institute of Allergy and Infections Disease, grants from NIH/National Institute of Deafness and Other Communication Disorders, grants from Cystic Fibrosis Foundation, during the conduct of the study.