Project description:Background & Aims: Because the pathophysiology of GERD is not fully understood, presently used drug target only one or more of the known underlying mechanisms but are not fully effective in all patients. 1Identifying novel central targets may pave the way to develop more effective agents. Methods: A surgical model of sub-chronic reflux esophagitis was developed. Wistar rats were pretreated for 7days with omeprazole (standard proton pump inhibitor) or STW5 (herbal preparation of established efficacy in gastro-intestinal disorders). Treatment was continued for 10days after surgery, rats were sacrificed and esophagi excised. Histological, proteomic and transcriptomic methods were applied to identify reflux induced changes and treatment responses. Results: Protection against reflux induced inflammation was achieved by both test drugs. Both reduced macroscopic and microscopic lesions of the esophagi as well as most measured pro-inflammatory cytokines without significantly affecting NF-kB activity. Proteomic and transcriptomic analysis identified CINC1-3, MIP-1/3Î±, MIG, RANTES and IL-1Î² as highly relevant mediators in GERD. Other highly regulated genes were those of IL-6, CCL3, CCL7 and LOX-1. Many affected cyto-/chemokines were involved in the TREM-1 signaling pathway. The fatty acid receptor GPR84 was highly up-regulated in esophagitis but down-regulated by both drugs. This was confirmed by Western blot and immune-histochemical staining, showing for the first time expression of this receptor in esophageal tissue and its possible involvement in GERD. Conclusion: STW5 and omeprazole target a broad spectrum of molecules involved in immunological and inflammatory processes, of which IL-8 (CINC1-3), TREM-1 pathway and GPR84 are proposed to be most promising novel targets for the treatment of GERD. Refluxesophagitis was surgically induced. Wistar rats were pretreated for 7 days with omeprazole or STW5. Treatment was continued for 10days after surgery, rats were sacrificed and esophagi exiced. The study had 5 groups. Group 1: sham operated, Group 2: esophagitis group, untreated, Group3: esophagitis treated with STW5 0.5ml/kg. Group 4: esophagitis treated with STW5 2ml/kg. Group 5: esophagitis treated with Omeprazole (30mg/kg). 4 microarrays from esophageal tissue and blood from 4 animals of each group were performed.

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Beyond acid suppression: Novel therapeutic targets for gastro-esophageal reflux disease based on a murine model (whole blood)

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