Department of Biomedical Sciences, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA.
Department of Surgery, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA.
Cells. 2021 Apr 15;10(4):908. doi: 10.3390/cells10040908.
Nonsteroidal anti-inflammatory drugs cause gastric ulcers and gastritis. No drug that treats GI injury directly stimulates mucosal healing. ZINC40099027 (ZN27) activates focal adhesion kinase (FAK) and heals acute indomethacin-induced small bowel injury. We investigated the efficacy of ZN27 in rat and human gastric epithelial cells and ongoing aspirin-associated gastric injury. ZN27 (10 nM) stimulated FAK activation and wound closure in rat and human gastric cell lines. C57BL/6J mice were treated with 300 mg/kg/day aspirin for five days to induce ongoing gastric injury. One day after the initial injury, mice received 900 µg/kg/6 h ZN27, 10 mg/kg/day omeprazole, or 900 µg/kg/6 h ZN27 plus 10 mg/kg/day omeprazole. Like omeprazole, ZN27 reduced gastric injury vs. vehicle controls. ZN27-treated mice displayed better gastric architecture, with thicker mucosa and less hyperemia, inflammation, and submucosal edema, and lost less weight than vehicle controls. Gastric pH, serum creatinine, serum alanine aminotransferase (ALT), and renal and hepatic histology were unaffected by ZN27. Blinded scoring of pFAK-Y-397 immunoreactivity at the edge of ZN27-treated lesions demonstrated increased FAK activation, compared to vehicle-treated lesions, confirming target activation in vivo. These results suggest that ZN27 ameliorates ongoing aspirin-associated gastric mucosal injury by a pathway involving FAK activation. ZN27-derivatives may be useful to promote gastric mucosal repair.
非甾体抗炎药会导致胃溃疡和胃炎。没有一种治疗胃肠道损伤的药物可以直接刺激黏膜愈合。ZINC40099027（ZN27）激活粘着斑激酶（FAK）并治愈急性吲哚美辛诱导的小肠损伤。我们研究了 ZN27 在大鼠和人胃上皮细胞以及正在进行的阿司匹林相关胃损伤中的疗效。ZN27（10 nM）刺激大鼠和人胃细胞系中的 FAK 激活和伤口闭合。C57BL/6J 小鼠每天用 300 mg/kg 阿司匹林处理五天以诱导正在进行的胃损伤。在初次损伤后的第一天，小鼠接受 900 µg/kg/6 h ZN27、10 mg/kg/天奥美拉唑或 900 µg/kg/6 h ZN27 加 10 mg/kg/天奥美拉唑。与奥美拉唑一样，ZN27 降低了胃损伤与载体对照。ZN27 处理的小鼠显示出更好的胃结构，粘膜更厚，充血、炎症和粘膜下层水肿减少，体重减轻比载体对照少。胃 pH 值、血清肌酐、血清丙氨酸氨基转移酶（ALT）以及肾脏和肝脏组织学不受 ZN27 影响。ZN27 处理病变边缘的 pFAK-Y-397 免疫反应性的盲法评分显示 FAK 激活增加，与载体处理病变相比，证实了体内的靶标激活。这些结果表明，ZN27 通过涉及 FAK 激活的途径改善正在进行的阿司匹林相关胃黏膜损伤。ZN27 衍生物可能有助于促进胃黏膜修复。
