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

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...

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Bibliographic Details
Published in:	Molecular medicine (Cambridge, Mass.) Vol. 21; no. 1; pp. 1011 - 1024
Main Authors:	Abdel-Aziz, Heba, Schneider, Mathias, Neuhuber, Winfried, Meguid Kassem, Abdel, Khailah, Saleem, Müller, Jürgen, Gamal Eldeen, Hadeel, Khairy, Ahmed, T Khayyal, Mohamed, Shcherbakova, Anastasiia, Efferth, Thomas, Ulrich-Merzenich, Gudrun
Format:	Journal Article
Language:	English
Published:	England BioMed Central 01-01-2015 Feinstein Institute for Medical Research
Subjects:	Acids Animals Biopsy Edema Endoscopy Esophagus Gastroesophageal reflux Gene expression Inflammation Pathogenesis Proteins Tumor necrosis factor-TNF Ulcers
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1076-1551 1528-3658
DOI:	10.2119/molmed.2015.00098