Abstract
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.
Abstract
VIP and NPY are neuropeptides up-regulated in allergy and asthma, respectively, which inversely regulate CFTR-dependent secretion and inflammation in airway submucosal gland serous cells, and which secrete much of the fluid that lines conducting airways http://bit.ly/2FWNT29
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.00466-2020
This article has supplementary material available from erj.ersjournals.com
Author contributions: D.B. McMahon, R.M. Carey, M.A. Kohanski and R.J. Lee performed experiments and analysed data. R.M. Carey, M.A. Kohanski, C.C.L. Tong, P. Papagiannopoulos, N.D. Adappa and J.N. Palmer aided with tissue procurement, primary cell acquisition and culture, maintenance of clinical records, and intellectually contributed. D.B. McMahon, R.M. Carey and R.J. Lee drafted the manuscript with critical input and approval from all authors.
Conflict of interest: D.B. McMahon has nothing to disclose.
Conflict of interest: R.M. Carey has nothing to disclose.
Conflict of interest: M.A. Kohanski has nothing to disclose.
Conflict of interest: C.C.L. Tong has nothing to disclose.
Conflict of interest: P. Papagiannopoulos has nothing to disclose.
Conflict of interest: N.D. Adappa has nothing to disclose.
Conflict of interest: J.N. Palmer has nothing to disclose.
Conflict of interest: R.J. Lee reports grants from NIH/National Institute of Allergy and Infections Disease, NIH/National Institute of Deafness and Other Communication Disorders and Cystic Fibrosis Foundation, during the conduct of the study.
Support statement: Work was funded by grants from the Cystic Fibrosis Foundation (LEER16G0, LEE19G0) and National Institutes of Health (R21AI137484, R01DC016309). Primary human monocytes were obtained from the University of Pennsylvania Human Immunology Core, supported by National Institutes of Health P30CA016520 and P30AI045008. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received July 12, 2019.
- Accepted January 13, 2020.
- Copyright ©ERS 2020