替格瑞洛对大鼠胃溃疡愈合的影响及其机制研究

Effect of Ticagrelor on Gastric Ulcer Healing in Rats and its Possible Mechanism

背景:新型抗血小板药物替格瑞洛对消化道有潜在损伤风险。目的:探讨替格瑞洛对大鼠胃溃疡愈合的影响及其可能机制。方法:96只雄性Sprague-Dawley大鼠随机分为对照组和替格瑞洛低剂量、高剂量组,制作乙酸胃溃疡模型,造模后第3 d开始分别予0.5%CMC-Na、21 mg/kg和42 mg/kg替格瑞洛灌胃干预。于第3、5、7、9 d分批处死大鼠,评估胃溃疡愈合和黏膜损伤情况,以免疫组化法和蛋白质印迹法检测溃疡边缘胃黏膜血管内皮生长因子(VEGF)、表皮生长因子(EGF)和增殖细胞核抗原(PCNA)表达,TUNEL法检测细胞凋亡情况。结果:第9 d时,替格瑞洛干预组胃溃疡面积和黏膜损伤指数均显著大于对照组(P<0.05),且高剂量组显著大于低剂量组(P<0.05),同时溃疡边缘胃黏膜中VEGF、EGF、PCNA表达降低,细胞凋亡增加,与对照组相比差异均有统计学意义(P<0.05),但替格瑞洛高、低剂量组在VEGF表达、细胞凋亡方面无明显差异(P>0.05)。结论:替格瑞洛可延迟大鼠胃溃疡愈合,其机制可能是通过下调胃黏膜中的VEGF、EGF表达、抑制细胞增殖、促进细胞凋亡而减缓溃疡修复过程。

Background： Ticagrelor is a novel anti-platelet agent that may cause gastrointestinal adverse events. Aims： To investigate the effect of ticagrelor on gastric ulcer healing in rats and its possible mechanism. Methods： Ninety-six male Sprague-Dawley rats were randomly divided into three groups： control group, low-dose ticagrelor group and high-dose ticagrelor group. Gastric ulcer was induced by using acetic acid and 0.5% CMC-Na, 21 mg/kg ticagrelor and 42 mg/kg ticagrelor were given intragastrically from the 3rd day of model construction, respectively. Animals were sacrificed in batches on the 3rd, 5th, 7th and 9th day. The ulcer healing and mucosal inju13~ were assessed macro- and microscopically. Immunohistochemistry and Western blotting were used to determine the expressions of vascular endothelial growth factor （VEGF）, epidermal growth factor （EGF） and proliferating cell nuclear antigen （PCNA） in nmcosal tissue at ulcer margin, and gastric cell apoptosis was detected by TUNEL assay. Results： On the 9th day, the area of gastric ulcer and mucosal injury index in ticagrelor groups were significantly higher than those in control group （ P 〈 0.05 ）, and those in high- dose ticagrelor group were significantly higher than those in low-dose group （ P 〈 0.05 ）. Meanwhile, the expressions of VEGF, EGF and PCNA in mueosal tissue at ulcer margin were decreased in ticagrelor groups, and apoptotic cells was increased （P all 〈 0.05 ）. No significant differences in VEGF expression and cell apoptosis were found between low-dose and high-dose ticagrelor groups （ P 〉 0.05 ）. Conclusions ： Ticagrelor delays gastric ulcer healing in rats possibly through reducing VEGF and EGF expression, inhibiting cell proliferation as well as promoting cell apoptosis, thus collectively hindering the ulcer healing process.