Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: Central role of epithelial-derived MMP
Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: Central role of epithelial-derived MMP
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DOI：
10.1053/j.gastro.2005.09.017
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发表时间：
2005-12-01
期刊：
影响因子：
29.4
通讯作者：
Sitaraman, SV
中科院分区：
文献类型：
--
作者：
Castaneda, FE;Walia, B;Sitaraman, SV
背景与目的：越来越多的证据表明，基质金属蛋白酶是炎症性肠病患者肠道黏膜中主要表达的蛋白酶。我们利用含有MMP-9基因靶向缺失的小鼠研究了金属蛋白酶9 （MMP-9）在结肠炎发病机制中的作用。MMP-9是一种分泌性明胶酶，在动物模型和人类炎症性肠病中均持续上调，并与疾病严重程度相关。方法：采用右旋糖酐硫酸钠致结肠炎和鼠伤寒沙门菌致小肠结肠炎动物模型进行结肠炎研究。结果：MMP-9活性和蛋白表达在正常结肠黏膜中缺失，但在实验性结肠炎中上调。暴露于葡聚糖硫酸钠或沙门氏菌的MMP-9（-/-）小鼠结肠炎的程度和严重程度显著降低。免疫组织化学研究表明，在活动性结肠炎期间，MMP-9定位于上皮细胞和粒细胞。MMP-9-/-小鼠对鼠伤寒沙门菌的免疫反应不受影响。中性粒细胞迁移研究和骨髓嵌合体表明，中性粒细胞MMP-9既不是其迁移所必需的，也不足以诱导结肠炎期间的组织损伤，上皮细胞MMP-9对组织损伤很重要。MMP-9抑制Caco2-BBE模型肠上皮细胞系的细胞附着和伤口愈合。结论：综上所述，我们的数据表明上皮细胞表达的MMP-9可能通过调节细胞-基质相互作用和伤口愈合在结肠炎的发展中发挥重要作用。因此，抑制MMP-9的策略可能具有潜在的治疗益处。
Background & Aims: There is mounting evidence that matrix metalloproteinases are the predominant proteinases expressed in the gut mucosa during active inflammatory bowel disease. We investigated the role of metalloproteinase 9 (MMP-9), a secreted gelatinase that is consistently up-regulated in both animal models and human inflammatory bowel disease and is associated with disease severity, in the pathogenesis of colitis by using mice containing a targeted deletion of the MMP-9 gene. Methods: Dextran sodium sulfate-induced colitis and Salmonella typhimurium-induced enterocolitis were used as animal models to study colitis. Results: MMP-9 activity and protein expression were absent from normal colonic mucosa but were up-regulated during experimental colitis. MMP-9(-/-) mice exposed to dextran sodium sulfate or salmonella had a significantly reduced extent and severity of colitis. Immunohistochemical studies showed that MMP-9 was localized to epithelial cells and granulocytes during active colitis. The immune response to systemic administration of Salmonella typhimurium was not affected in MMP-9-/- mice. Neutrophil transmigration studies and bone marrow chimeras showed that neutrophil MMP-9 is neither required for its migration nor sufficient to induce tissue damage during colitis and that epithelial MMP-9 is important for tissue damage. MMP-9 inhibited cell attachment and wound healing in the model intestinal epithelial cell line, Caco2-BBE. Conclusions: Taken together, our data suggest that MMP-9 expressed by epithelial cells may play an important role in the development of colitis by modulating cell-matrix interaction and wound healing. Thus, strategies to inhibit MMP-9 may be of potential therapeutic benefit.