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Mucosal Two-Step Pathogenesis in Gastroesophageal Reflux Disease: Repeated Weakly Acidic Stimulation and Activation
Lukas Winkelsett1, Peter Malfertheiner1, Thomas Wex1
1Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
Background:
Activation of protease-activated receptor-2 (PAR2) is involved in the mucosal immune pathogenesis of gastroesophageal reflux disease (GERD) that is characterized by proinflammatory cytokines such as interleukin-8 (IL-8). PAR2 activation on epithelial cells induces epithelial IL-8 secretion and initiates mucosal inflammation.
Methods:
A human primary esophageal epithelial cell model was established to investigate the effects of repeated stimulation with weakly acidic solutions and subsequent PAR2 activation. After creating a monolayer, cells were incubated under weakly acidic conditions for 7 h followed by 17 h at pH 7.4. This short-term exposure was repeated once. After weakly acidic stimulation, PAR2 activation was achieved by a synthetic agonist at pH 7.4.
Results:
After repeated weakly acidic incubation, PAR2 transcript levels were 3.6-fold upregulated (p = 0.001) and IL-8 transcripts were 2.4-fold enhanced (p = 0.034) compared to nonstimulated controls, while IL-8 protein in the cell pellet and supernatant was not increased. Only the additional PAR2 activation upon pH stimulation led to increased IL-8 secretion into the supernatant.
Conclusions:
We propose a 2-step mechanism in which repeated weakly acidic exposure leads to the upregulation of epithelial PAR2 expression. The subsequent activation of upregulated PAR2 contributes to the initiation of mucosal inflammation, which underlies the important role of esophageal epithelium in GERD pathogenesis.
Insights
Repeated acid exposure upregulates protease-activated receptor-2 (PAR2) in esophageal cells. Subsequent PAR2 activation enhances interleukin-8 (IL-8) secretion, contributing to gastroesophageal reflux disease (GERD) inflammation.
Area of Science:
- Gastroenterology
- Immunology
- Cell Biology
Background:
- Protease-activated receptor-2 (PAR2) activation is implicated in gastroesophageal reflux disease (GERD) pathogenesis.
- GERD is characterized by proinflammatory cytokines like interleukin-8 (IL-8).
- PAR2 activation on epithelial cells promotes IL-8 secretion and initiates mucosal inflammation.
Purpose of the Study:
- To investigate the effects of repeated weak acid stimulation and subsequent PAR2 activation on esophageal epithelial cells.
- To elucidate the role of esophageal epithelium in GERD pathogenesis.
Main Methods:
- Established a human primary esophageal epithelial cell model.
- Repeatedly exposed cells to weakly acidic conditions followed by neutral pH.
- Stimulated PAR2 using a synthetic agonist after acid exposure.
Main Results:
- Repeated acid exposure upregulated PAR2 and IL-8 transcripts.
- IL-8 protein levels did not increase without additional PAR2 activation.
- PAR2 activation following pH stimulation significantly increased IL-8 secretion.
Conclusions:
- A two-step mechanism is proposed for GERD pathogenesis.
- Repeated acid exposure upregulates epithelial PAR2 expression.
- Activated PAR2 contributes to mucosal inflammation initiation, highlighting the esophageal epithelium's role.
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