An orally active matrix metalloproteinase inhibitor, ONO-4817, reduces dextran sulfate sodium-induced colitis in mice
An orally active matrix metalloproteinase inhibitor, ONO-4817, reduces dextran sulfate sodium-induced colitis in mice
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DOI：
10.1007/s00011-004-1281-1
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发表时间：
2004-09-01
影响因子：
6.7
通讯作者：
Yoshikawa, T
中科院分区：
文献类型：
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作者：
Naito, Y;Takagi, T;Yoshikawa, T
目的：基质金属蛋白酶（MMPs）的过表达可加速组织破坏并破坏随后的组织修复。建立葡聚糖硫酸钠（DSS）结肠炎模型，观察口服活性MMP抑制剂ONO-4847对结肠炎症的抑制作用。材料与方法：用8% DSS灌胃饮水，连续7 d诱导BALB/c雌性小鼠急性结肠炎。随机分为不同浓度ONO-4847组和对照组，每天灌胃。采用RT-PCR方法检测DSS给药后小鼠肠组织中4种MMPs和一种MMP组织抑制剂（TIMP-1）的mRNA水平。对结肠粘膜损伤和炎症进行临床、生化和组织学评价。检查临床疾病活动指数（DAI），包括体重减轻、粪便一致性和粪便中带血。免疫分析法检测粘膜肿瘤坏死因子(TNF)- α和干扰素(IFN)- γ。结果：DSS给药后，肠道中MMP-3、-7、9、-12和TIMP-1 mRNA表达上调。ONO-4847在剂量为30 mg/kg时可显著逆转结肠缩短。与对照小鼠相比，ono -4847处理小鼠的dss处理小鼠DAI明显降低。组织学研究还显示，与对照组小鼠相比，ono -4847处理小鼠的炎症细胞（尤其是中性粒细胞）浸润减少，粘膜细胞破坏减少。与ONO-4847共给药后，DSS给药后组织相关髓过氧化物酶活性和硫代巴比妥酸活性物质的增加均被显著抑制。ONO-4847也抑制DSS给药后粘膜tnf - α和ifn - γ含量的增加。结论：ONO-4847对DSS结肠炎的改善表明，MMPs的激活通过氧化损伤和增强炎症细胞因子释放等机制参与了结肠炎症损伤的启动/扩增。
Objective: Over-expression of matrix metalloproteinases (MMPs) can accelerate tissue destruction and disrupt subsequent tissue repair. A dextran sulfate sodium (DSS) colitis model was established to examine the effects of MMP inhibition, by an orally active MMP inhibitor ONO-4847, on colonic inflammation.Materials and methods: Acute colitis was induced in female BALB/c mice by giving 8% DSS orally in drinking water for 7 days. The animals were randomized into groups receiving different concentrations of ONO-4847 or vehicle by oral gavage every day. mRNA levels of 4 MMPs and a tissue inhibitor of MMP (TIMP-1) were measured by RT-PCR in intestinal tissue isolated from mice after DSS administration. Colonic mucosal injury and inflammation were evaluated clinically, biochemically, and histologically. The clinical disease activity index (DAI), including body weight loss, stool consistency, and blood in feces, was examined. Moreover, mucosal tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were determined by immunoassay.Results: The intestinal expression of MMP-3, -7, 9, and -12 and TIMP-1 mRNA was upregulated after DSS administration. Shortening of the colon was significantly reversed by ONO-4847 at a dose of 30 mg/kg. DAI in DSS-treated mice was significantly lower in the ONO-4847-treated mice compared with the control mice. Histological study also showed a reduced infiltration of inflammatory cells, especially neutrophils, and reducedmucosal cell disruption in ONO-4847-treated mice compared with the control mice. The increases in tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances after DSS administration were both significantly inhibited by co-administration with ONO-4847. ONO-4847 also inhibited increases in the mucosal TNF-alpha and IFN-gamma content after DSS administration.Conclusion: Improvements in DSS colitis in response to ONO-4847 suggest that activation of MMPs contributes to the initiation/amplification of colonic inflammatory injury by mechanisms including oxidative damage as well as enhancement of inflammatory cytokine release.