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Molecular Medicine

, Volume 21, Issue 1, pp 1011–1024 | Cite as

GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis

  • Heba Abdel-Aziz
  • Mathias Schneider
  • Winfried Neuhuber
  • Abdel Meguid Kassem
  • Saleem Khailah
  • Jürgen Müller
  • Hadeel Gamal Eldeen
  • Ahmed Khairy
  • Mohamed T. Khayyal
  • Anastasiia Shcherbakova
  • Thomas Efferth
  • Gudrun Ulrich-Merzenich
Research Article

Abstract

Gastro-esophageal reflux disease (GERD) is one of the most common disorders in gastroenterology. Patients present with or without increased acid exposure indicating a nonuniform etiology. Thus, the common treatment with proton pump inhibitors (PPIs) fails to control symptoms in up to 40% of patients. To further elucidate the pathophysiology of the condition and explore new treatment targets, transcriptomics, proteomics and histological methods were applied to a surgically induced subchronic reflux esophagitis model in Wistar rats after treatment with either omeprazole (PPI) or STW5, a herbal preparation shown to ameliorate esophagitis without affecting refluxate pH. The normal human esophageal squamous cell line HET-1A and human endoscopic biopsies were used to confirm our findings to the G-protein-coupled receptor (GPR) 84 in human tissue. Both treatments reduced reflux-induced macroscopic and microscopic lesions of the esophagi as well as known proinflammatory cytokines. Proteomic and transcriptomic analyses identified CINC1-3, MIP-1/3α, MIG, RANTES and interleukin (IL)-1β as prominent mediators in GERD. Most regulated cyto-/chemokines are linked to the TREM-1 signaling pathway. The fatty acid receptor GPR84 was upregulated in esophagitis but significantly decreased in treated groups, a finding supported by Western blot and immunohistochemistry in both rat tissue and HET-1A cells. GPR84 was also found to be significantly upregulated in patients with grade B reflux esophagitis. The expression of GPR84 in esophageal tissue and its potential involvement in GERD are reported for the first time. IL-8 (CINC1-3) and the TREM-1 signaling pathway are proposed, besides GPR84, to play an important role in the pathogenesis of GERD.

Notes

Acknowledgements

We would like to thank EJ Verspohl (Münster, Germany) for hosting this work in his laboratory and for his support in planning and execution of the study and A Hegazy (Cairo, Egypt) for helping in establishing the animal model, as well as D Rohr (Mainz, Germany) and F Hartbrod (Bonn, Germany) for their technical assistance. We also thank the German Academic Exchange Service (DAAD) and the Egyptian Ministry of Higher Education for supporting this study with a short-term research scholarship and Steigerwald Arzneimittelwerk GmbH (Darmstadt, Germany) for financial support.

Supplementary material

10020_2015_21011011_MOESM1_ESM.pdf (2.1 mb)
Supplementary material, approximately 2.07 MB.

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Copyright information

© The Author(s) 2015

Authors and Affiliations

  • Heba Abdel-Aziz
    • 1
    • 8
  • Mathias Schneider
    • 2
  • Winfried Neuhuber
    • 3
  • Abdel Meguid Kassem
    • 4
  • Saleem Khailah
    • 4
  • Jürgen Müller
    • 5
  • Hadeel Gamal Eldeen
    • 4
  • Ahmed Khairy
    • 4
  • Mohamed T. Khayyal
    • 6
  • Anastasiia Shcherbakova
    • 7
  • Thomas Efferth
    • 2
  • Gudrun Ulrich-Merzenich
    • 7
  1. 1.Department of Pharmacology, Institute of Pharmaceutical ChemistryWestfalian Wilhelms UniversityMünsterGermany
  2. 2.Department of Pharmaceutical Biology, Institute of Pharmacy and BiochemistryJohannes Gutenberg UniversityMainzGermany
  3. 3.Institute of AnatomyUniversity of Erlangen-NürnbergErlangenGermany
  4. 4.Tropical Medicine Department and Gastrointestinal Endoscopy Unit, Faculty of MedicineCairo UniversityCairoEgypt
  5. 5.Scientific DepartmentSteigerwald Arzneimittelwerk GmbHDarmstadtGermany
  6. 6.Department of Pharmacology, Faculty of PharmacyCairo UniversityCairoEgypt
  7. 7.Medical Clinic III, University Clinic CentreRheinische Friedrich-Wilhelms UniversityBonnGermany
  8. 8.Scientific DepartmentSteigerwald Arzneimittelwerk GmbHDarmstadtGermany

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