Winkelsett, Lukas and Malfertheiner, Peter and Wex, Thomas and Kandulski, Arne (2018) Mucosal Two-Step Pathogenesis in Gastroesophageal Reflux Disease: Repeated Weakly Acidic Stimulation and Activation of Protease-Activated Receptor-2 on Mucosal Interleukin-8 Secretion. DIGESTION, 98 (1). pp. 19-25. ISSN 0012-2823, 1421-9867
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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. (C) 2018 S. Karger AG, Basel
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ESOPHAGEAL EPITHELIAL-CELLS; MOLECULAR-CLONING; KAPPA-B; EXPRESSION; TRYPSIN; ROLES; PAR-2; IL-8; Gastroesophageal reflux disease; Interleukin-8; Inflammation; Protease-activated receptor-2; Epithelial immune response |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Mar 2020 13:41 |
| Last Modified: | 20 Mar 2020 13:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15374 |
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