Pepsin exposure in a non‐acidic environment upregulates mucin 5AC (MUC5AC) expression via matrix metalloproteinase 9 (MMP9)/nuclear factor κB (NF‐κB) in human airway epithelial cells

Abstract

Background Gastric reflux GR is a backflow of gastric content to the aerodigestive tract GR was previously found to be associated with inflammatory airway diseases and a potential cause of airway remodeling Chronic exposure to gastric content may induce damage from nose to lung because digestive enzymes and acidity are toxic to airway epithelial cells Recently the toxicity of pepsin in a non-acidic environment was found to increase proinflammatory cytokines and receptors in the epithelium of the aerodigestive tract However the effect of pepsin in non-acidic conditions on mucin expression has not been investigated in human airway epithelial cells The purpose of this study was to evaluate the effect of pepsin on mucin AC MUC AC expression in upper and lower airway epithelial cells as an important potential factor of non-acidic GR-related airway inflammation Methods In NCI-H cells and human nasal epithelial cells HNEpCs the effects and signaling pathways of pepsin on MUC AC expression were examined using reverse-transcription polymerase chain reaction RT-PCR real-time PCR enzyme immunoassay zymography Western blot and immunofluorescence staining ResultsPepsin increased MUC AC expression in non-acidic condition of NCI-H cells and HNEpCs Further pepsin activated matrix metalloproteinase MMP and phosphorylated nuclear factor κB NF-κB Moreover inhibitors of MMP and NF-κB significantly attenuated pepsin-induced MUC AC expression and the knockdown of NF-κB by small interfering RNA siRNA significantly blocked pepsin-induced MUC AC expression in human airway epithelial cells Conclusion These findings suggest that pepsin increased MUC AC expression in non-acidic conditions via the activation of MMP and NF-κB in human airway epithelial cells

Amprenavir inhibits pepsin‐mediated laryngeal epithelial disruption and E‐cadherin cleavage in vitro

“…MMP‐2,9,14 may be dysregulated by sE‐cad 52 and MMP7 by E‐cad/CTF‐related Wnt signaling 72 . MMP‐9 mediates pepsin‐induced mucin 5AC expression in airway epithelial cells contributing to hypersecretion and inflammation, 73 is induced by TGF‐β signaling in tracheal cells, a key pathway in laryngotracheal stenosis, 74 is elevated in mild and severe GERD, 75 and plays a role in the early inflammatory response in a model of Barrett's esophagus (BE) 76 . MMP‐2, 7 and 9 have been implicated in laryngeal cancer 77 .…”

SARS-CoV-2 Induces Expression of Cytokine and MUC5AC/5B in Human Nasal Epithelial Cell through ACE 2 Receptor

“…Mucus gene expression is increased by reactive oxygen species, cytokines, and inflammatory mediators of respiratory inflammatory diseases [ 3 – 5 ]. The nature and hypersecretion of the mucus change the course of the disease [ 22 ].…”

Pepsin and the Lung—Exploring the Relationship between Micro-Aspiration and Respiratory Manifestations of Gastroesophageal Reflux Disease

“…Further research on the effects of pepsin on the respiratory tract in non-acidic conditions found that it could induce mucus hypersecretion in both upper and lower airway epithelial cells [ 19 ]. This effect was due to an increase in mucin 5AC expression after exposure to pepsin via the matrix metalloproteinase 9 (MMP9) and phosphorylated nuclear factor κB (NF-κB) pathways.…”