Castaneda Florencia E, Walia Baljit, Vijay-Kumar Matam, Patel Neal R, Roser Susanne, Kolachala Vasantha L, Rojas Mauricio, Wang Lixin, Oprea Gabriela, Garg Pallavi, Gewirtz Andrew T, Roman Jesse, Merlin Didier, Sitaraman Shanthi V
Division of Digestive Diseases, Emory University, Atlanta, Georgia 30322, USA.
Gastroenterology. 2005 Dec;129(6):1991-2008. doi: 10.1053/j.gastro.2005.09.017.
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.
Dextran sodium sulfate-induced colitis and Salmonella typhimurium-induced enterocolitis were used as animal models to study colitis.
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.
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.
越来越多的证据表明，基质金属蛋白酶是活动性炎症性肠病期间肠道黏膜中表达的主要蛋白酶。我们通过使用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是一种分泌型明胶酶，在动物模型和人类炎症性肠病中均持续上调，且与疾病严重程度相关。
采用葡聚糖硫酸钠诱导的结肠炎和鼠伤寒沙门氏菌诱导的小肠结肠炎作为动物模型来研究结肠炎。
正常结肠黏膜中不存在MMP - 9活性和蛋白表达，但在实验性结肠炎期间其表达上调。暴露于葡聚糖硫酸钠或沙门氏菌的MMP - 9基因敲除小鼠的结肠炎范围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基因敲除小鼠对全身给予鼠伤寒沙门氏菌的免疫反应未受影响。中性粒细胞迁移研究和骨髓嵌合体研究表明，中性粒细胞MMP - 9在结肠炎期间对其迁移既非必需，也不足以诱导组织损伤，而上皮细胞MMP - 9对组织损伤很重要。在模型肠上皮细胞系Caco2 - BBE中，MMP - 9抑制细胞黏附和伤口愈合。
综合来看，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起重要作用。因此，抑制MMP - 9的策略可能具有潜在的治疗益处。
