Department of Gastroenterology and Hepatology, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People's Republic of China.
PLoS One. 2011;6(11):e27282. doi: 10.1371/journal.pone.0027282. Epub 2011 Nov 3.
Ulcerative colitis is a gastrointestinal disorder characterized by local inflammation and impaired epithelial barrier. Previous studies demonstrated that CXC chemokine receptor 4 (CXCR4) antagonists could reduce colonic inflammation and mucosal damage in dextran sulfate sodium (DSS)-induced colitis. Whether CXCR4 antagonist has action on intestinal barrier and the possible mechanism, is largely undefined. In the present study, the experimental colitis was induced by administration of 5% DSS for 7 days, and CXCR4 antagonist AMD3100 was administered intraperitoneally once daily during the study period. For in vitro study, HT-29/B6 colonic cells were treated with cytokines or AMD3100 for 24 h until assay. DSS-induced colitis was characterized by morphologic changes in mice. In AMD3100-treated mice, epithelial destruction, inflammatory infiltration, and submucosal edema were markedly reduced, and the disease activity index was also significantly decreased. Increased intestinal permeability in DSS-induced colitis was also significantly reduced by AMD3100. The expressions of colonic claudin-1, claudin-3, claudin-5, claudin-7 and claudin-8 were markedly decreased after DSS administration, whereas colonic claudin-2 expression was significantly decreased. Treatment with AMD3100 prevented all these changes. However, AMD3100 had no influence on claudin-3, claudin-5, claudin-7 and claudin-8 expression in HT-29/B6 cells. Cytokines as TNF-α, IL-6, and IFN-γ increased apoptosis and monolayer permeability, inhibited the wound-healing and the claudin-3, claudin-7 and claudin-8 expression in HT-29/B6 cells. We suggest that AMD3100 acted on colonic claudin expression and intestinal barrier function, at least partly, in a cytokine-dependent pathway.
溃疡性结肠炎是一种以局部炎症和上皮屏障受损为特征的胃肠道疾病。先前的研究表明，CXC 趋化因子受体 4（CXCR4）拮抗剂可减少葡聚糖硫酸钠（DSS）诱导的结肠炎中的结肠炎症和黏膜损伤。CXCR4 拮抗剂是否对肠道屏障有作用以及可能的机制，在很大程度上还不清楚。在本研究中，通过给予 5% DSS 7 天来诱导实验性结肠炎，在研究期间每天一次腹腔内给予 CXCR4 拮抗剂 AMD3100。对于体外研究，用细胞因子或 AMD3100 处理 HT-29/B6 结肠细胞 24 小时，直至测定。DSS 诱导的结肠炎表现为小鼠的形态学改变。在 AMD3100 治疗的小鼠中，上皮破坏、炎症浸润和黏膜下水肿明显减少，疾病活动指数也明显降低。AMD3100 还显著降低了 DSS 诱导的结肠炎中的肠道通透性增加。DSS 给药后，结肠紧密连接蛋白-1、紧密连接蛋白-3、紧密连接蛋白-5、紧密连接蛋白-7 和紧密连接蛋白-8 的表达明显减少，而结肠紧密连接蛋白-2 的表达明显减少。用 AMD3100 治疗可预防所有这些变化。然而，AMD3100 对 HT-29/B6 细胞中紧密连接蛋白-3、紧密连接蛋白-5、紧密连接蛋白-7 和紧密连接蛋白-8 的表达没有影响。细胞因子如 TNF-α、IL-6 和 IFN-γ 增加了细胞凋亡和单层通透性，抑制了 HT-29/B6 细胞的伤口愈合以及紧密连接蛋白-3、紧密连接蛋白-7 和紧密连接蛋白-8 的表达。我们认为，AMD3100 至少部分地通过细胞因子依赖途径作用于结肠紧密连接蛋白表达和肠道屏障功能。
