title: GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis.
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.org.
authors.affiliation: Department of Pharmacology, Institute of Pharmaceutical Chemistry, Westfalian Wilhelms University, Münster, Germany.
authors.forename: Heba
authors.initials: H
authors.lastname: Abdel-Aziz
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Institute of Anatomy, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Neuhuber
authors.affiliation: Tropical Medicine Department and Gastrointestinal Endoscopy Unit, Faculty of Medicine, Cairo University, Cairo, Egypt.
authors.forename: Abdel
authors.initials: A
authors.lastname: Meguid Kassem
authors.affiliation: Tropical Medicine Department and Gastrointestinal Endoscopy Unit, Faculty of Medicine, Cairo University, Cairo, Egypt.
authors.forename: Saleem
authors.initials: S
authors.lastname: Khailah
authors.affiliation: Scientific Department, Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Müller
authors.affiliation: Tropical Medicine Department and Gastrointestinal Endoscopy Unit, Faculty of Medicine, Cairo University, Cairo, Egypt.
authors.forename: Hadeel
authors.initials: H
authors.lastname: Gamal Eldeen
authors.affiliation: Tropical Medicine Department and Gastrointestinal Endoscopy Unit, Faculty of Medicine, Cairo University, Cairo, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Khairy
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: T Khayyal
authors.affiliation: Medical Clinic III, University Clinic Centre, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Anastasiia
authors.initials: A
authors.lastname: Shcherbakova
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
authors.affiliation: Medical Clinic III, University Clinic Centre, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Ulrich-Merzenich