Research and Development Headquarters, Lion Corporation, Kanagawa, Japan (E.F., N.M., S.M., Y.H., T.S., K.A., M.K., M.O., M.M.); and Organization for Interdisciplinary Research Projects, University of Tokyo, Tokyo, Japan (H.K.).
J Pharmacol Exp Ther. 2014 Apr;349(1):165-73. doi: 10.1124/jpet.113.210021. Epub 2014 Feb 4.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause gastric mucosal damage as a side effect. Acetaminophen, widely used as an analgesic and antipyretic drug, has gastroprotective effects against gastric lesions induced by absolute ethanol and certain NSAIDs. However, the mechanisms that underlie the gastroprotective effects of acetaminophen have not yet been clarified. In the present study, we examined the role and protective mechanism of acetaminophen on ibuprofen-induced gastric damage in rats. Ibuprofen and acetaminophen were administered orally, and the gastric mucosa was macroscopically examined 4 hours later. Acetaminophen decreased ibuprofen-induced gastric damage in a dose-dependent manner. To investigate the mechanisms involved, transcriptome analyses of the ibuprofen-damaged gastric mucosa were performed in the presence and absence of acetaminophen. Ingenuity pathway analysis (IPA) software revealed that acetaminophen suppressed the pathways related to cellular assembly and inflammation, whereas they were highly activated by ibuprofen. On the basis of gene classifications from the IPA Knowledge Base, we identified the following five genes that were related to gastric damage and showed significant changes in gene expression: interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), matrix metalloproteinase-10 (MMP-10), MMP-13, and FBJ osteosarcoma oncogene (FOS). Expression of these salient genes was confirmed using real-time polymerase chain reaction. The expression of MMP-13 was the most reactive to the treatments, showing strong induction by ibuprofen and suppression by acetaminophen. Moreover, MMP-13 inhibitors decreased ibuprofen-induced gastric damage. In conclusion, these results suggest that acetaminophen decreases ibuprofen-induced gastric mucosal damage and that the suppression of MMP-13 may play an important role in the gastroprotective effects of acetaminophen.
非甾体抗炎药（NSAIDs）已知会引起胃黏膜损伤作为副作用。对乙酰氨基酚，广泛用作镇痛药和退烧药，具有胃保护作用，可抵抗绝对乙醇和某些 NSAIDs 引起的胃损伤。然而，对乙酰氨基酚的胃保护作用的机制尚未阐明。在本研究中，我们研究了对乙酰氨基酚在布洛芬诱导的大鼠胃损伤中的作用和保护机制。布洛芬和对乙酰氨基酚口服给药，4 小时后宏观检查胃黏膜。对乙酰氨基酚以剂量依赖的方式降低布洛芬引起的胃损伤。为了研究涉及的机制，在存在和不存在对乙酰氨基酚的情况下对布洛芬损伤的胃黏膜进行了转录组分析。IPA 软件揭示了对乙酰氨基酚抑制了与细胞组装和炎症相关的途径，而这些途径被布洛芬高度激活。基于 IPA 知识库中的基因分类，我们确定了与胃损伤相关且基因表达明显变化的以下五个基因：白细胞介素-1β（IL-1β）、趋化因子（C-C 基序）配体 2（CCL2）、基质金属蛋白酶-10（MMP-10）、MMP-13 和 FBJ 骨肉瘤癌基因（FOS）。使用实时聚合酶链反应证实了这些显著基因的表达。MMP-13 的表达对治疗反应最敏感，布洛芬强烈诱导，对乙酰氨基酚抑制。此外，MMP-13 抑制剂降低了布洛芬引起的胃损伤。总之，这些结果表明，对乙酰氨基酚可降低布洛芬引起的胃黏膜损伤，抑制 MMP-13 可能在对乙酰氨基酚的胃保护作用中发挥重要作用。
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