Abstract
Abstract Despite recent advancements in the pharmacologic and endoscopic management of gastrointestinal ulceration, it is still associated with high mortality. Therefore, it is important to understand mucosal protective mechanisms. Somatostatin, present in the endocrine cells & sensory nerves, and its analogues reduce mucosal blood flow, pepsin and gastric acid secretion. Its receptor subtype 4 (sst4) mediates anti-inflammatory & analgesic actions, as discovered by our group. Therefore, our aim was to investigate its role in gastrointestinal injury. We treated sst4 gene-deleted (sst4−/−) and wildtype mice with indomethacine (IDM; 35 mg/kg) or vehicle s.c.. Gastric & small intestine lesions were evaluated after 4 & 48 h macroscopically & microscopically. Plasma protein extravasation & myeloperoxidase (MPO) activity were assessed by ex vivo imaging, TNFα, IL-1, COX2, sst4 & somatostatin mRNA levels by qPCR. Gastric (4h) and small intestinal macroscopic (24 h) lesions, MPO activity (24, 48 h), and plasma extravasation (30 min) were significantly greater in IDM-treated sst4−/− mice, while histopathological scores & small intestinal length did not show strain difference. TNFα, IL-1, COX2 significantly upregulated after 4h in the stomach of sst4−/− mice, and the same pattern was observable in wildtype mice at later timepoint (48 h). These results provide evidence for the protective role of the sst4 receptor against IDM-induced gastrointestinal mucosal injury. This suggests the safety of sst4 agonist drug candidates in the gastrointestinal tract, and even their potential use for gastroprotective indication. Supported by: GINOP-2.3.2-15-2016-00050 – PEPSYS, GINOP-2.3.2 STAY ALIVE, EFOP-3.6.2-16-2017-00008, ÚNKP-19-3-III-PTE-211
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