目的 研究新癀片中药成分对吲哚美辛产生的胃肠毒性反应的减毒作用机制。方法 大鼠分别ig给予新癀片及相当剂量的吲哚美辛，每日1次，连续给予3 d，测定各组大鼠胃酸分泌量及胃蛋白酶活性；测定血清胃泌素、环氧化酶-1（COX-1）、环氧化酶-2（COX-2）等指标；大鼠分别ig给予新癀片及相当剂量的吲哚美辛，每日1次，连续给予2周，进行肝组织基因表达芯片分析，研究新癀片及吲哚美辛对胃肠毒性相关基因的影响。结果 吲哚美辛可促进大鼠胃泌素分泌，从而促进胃酸分泌及增加胃蛋白酶活性，新癀片能显著抑制胃泌素分泌，抑制胃蛋白酶活性，对胃酸分泌增加有一定的抑制作用。吲哚美辛可显著抑制COX-1活力，而与吲哚美辛比较，新癀片可以升高COX-1活性。吲哚美辛能显著下调基质金属肽酶2（Mmp2）表达，上调穿孔蛋白基因表达，显著下调免疫、凝血系统相关基因表达；与吲哚美辛比较，新癀片能显著上调Mmp2、紧密连接蛋白1（Cldn1）表达，下调穿孔蛋白基因表达，显著上调免疫相关基因、凝血因子、纤维蛋白原表达。结论 新癀片中药成分对吲哚美辛胃肠毒性的减毒作用机制可能与其抑制胃泌素分泌增加、提高被吲哚美辛抑制的COX-1活性，以及上调Cldn1表达，下调穿孔蛋白表达，增加细胞膜稳定性，上调免疫相关蛋白基因、凝血因子、纤维蛋白原表达，促进伤口修复有关。

Objective To study the mechanism of Chinese herbal ingredients in Xinhuang Tablet on attenuating gastrointestinal toxicity induced by indomethacin. Methods Xinhuang Tablet and a considerable dose of indomethacin were ig given to rats once a daily, lasted for 3 d, and then the levels of gastric acid, the activity of gastric protease, and the indexes of the serum gastrin, COX-1, COX-2, etc were determined. Xinhuang Tablet and a considerable dose of indomethacin were ig given to rats once daily, lasted for 2 weeks, and then the liver tissue gene expression microarray analysis was applicated to research the effects of Xinhuang Tablet and indomethacin on the gastrointestinal toxicity associated proteins. The mechanism of Chinese herbal ingredients in Xinhuang Tablet on attenuating the gastrointestinal toxicity induced by indomethacin was explored on the gene level. Results Indomethacin could promote gastrin secretion, thus increasing gastric acid secretion and the vitality of pepsin. Xinhuang Tablet could significantly inhibit gastrin secretion, the activity of pepsin, and gastric acid secretion. Indomethacin could significantly inhibit the vitality of COX-1, while Xinhuang Tablet could increase the COX-1 vitality and further protect the gastric mucosa. Indomethacin could significantly up-regulate the gene expression of perforin, while down-regulate the gene expression of Mmp2 as well as the related protein genes of immune system and coagulation system. Compared with indomethacin, Xinhuang Tablet could significantly lower the expression of perforin gene, and raise the expression of Mmp2, Cldn1, the immune-related protein genes, coagulation factors, and fibrinogen. Conclusion These results indicated that the attenuating mechanism of Chinese herbal ingredients in Xinhuang Tablet on the gastrointestinal toxicity of indomethacin might be ralated to the inhibition of gastrin secretion, improved vitality of inhibited COX-1 by indomethacin, down-regulate perforin, up-regulate Cldn1, immune-related protein genes, coagulation factors, fibrinogen, increase the membrane stability, and promote wound healing as well.

国家科技重大专项（2012ZX09505001-001）