Neuropeptide regulation of secretion and inflammation in human airway gland serous cells

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.

Getting neural about airway gland secretion

“…Pharmacological inhibition of CFTR blunted the anti-inflammatory effects of VIP, supporting the notion that CFTR dysfunction contributes to sterile inflammation [3]. Notably, MCMAHON et al [11] also reported that CFTR activity inversely correlated with the secretion of IL-1β by serous cells. These findings have implications for the pathophysiology of CF airway disease associated with inflammation and mucus production.…”

“…The studies by MCMAHON et al [11] also suggest that imbalances in the functional properties of VIP and NPY on serous cells may be extended to the pathogenesis of other airway diseases. For example, it has been proposed that patients with COPD may suffer from acquired CFTR dysfunction due to the effects of smoking [13].…”

“…In this issue of the European Respiratory Journal, MCMAHON et al [11] conducted an extensive study on secretory properties of serous cells in response to VIP and NPY, which advanced our understanding of how imbalances in neuropeptide activities may contribute to chronic airway diseases, particularly CF. By using freshly excised serous cells and serous cell monolayers cultured under air-liquid interface (ALI) conditions, MCMAHON et al [11] have shown that VIP induced chloride and bicarbonate transport in serous cells, resulting in increased fluid secretion and regulation of fluid pH. Both responses were absent in serous cells from CF patients or upon pharmacological inhibition of CFTR in non-CF cells, demonstrating the importance of CFTR in serous cell secretory function.…”

“…While additional studies are needed to determine whether NPY contributes to CF or COPD airway disease, MCMAHON et al [11] have shown that NPY enhanced pro-inflammatory responses in serous cells induced by the asthma-relevant Th2 cytokines IL-4 and IL-13. Their findings are in agreement with earlier studies demonstrating similar effects of NPY on inflammatory responses resulting from allergy-induced asthma in mice [9,10].…”

Polarization of protease-activated receptor 2 (PAR-2) signaling is altered during airway epithelial remodeling and deciliation

“…Imaging of ASL height was performed as described (69,70). Briefly, cultures were first washed twice with 25 µM DTT (5 min prewash) to remove large clumps of airway mucus, followed by at least 5-7 washes with PBS alone to remove residual DTT.…”