miR-21 敲除通过抑制炎症和组织损伤改善 DSS 诱导的致命结肠炎的生存率。

BACKGROUND: MicroRNA-21 (miR-21) is overexpressed in most inflammatory diseases, but its physiological role in gut inflammation and tissue injury is poorly understood. The goal of this work is to understand the role of miR-21 in colitis and damage progression of intestine in a genetically modified murine model. METHODS: Experimental colitis was induced in miR-21 KO and wild-type (WT) mice by 3.5% dextran sulphate sodium (DSS) administration for 7 days. Disease activity index(DAI), blood parameters, intestinal permeability, histopathologic injury, cytokine and chemokine production, and epithelial cells apoptosis were examined in colons of miR-21 KO and WT mice. RESULTS: miR-21 was overexpressed in intestine of inflammatory bowel diseases (IBD) and acute intestinal obstruction (AIO) patients when compared with normal intestinal tissues. Likewise, miR-21 was up-regulated in colon of IL-10 KO mice when compared with control mice. WT mice rapidly lost weight and were moribund 5 days after treatment with 3.5% DSS, while miR-21 KO mice survived for at least 6 days. Elevated leukocytes and more severe histopathology were observed in WT mice when compared with miR-21 KO mice. Elevated levels of TNF-α and macrophage inflammatory protein-2(MIP-2) in colon culture supernatants from WT mice exhibited significant higher than miR-21 KO mice. Furthermore, CD3 and CD68 positive cells, intestinal permeability and apoptosis of epithelial cells were significantly increased in WT mice when compared with miR-21 KO mice. Finally, we found that miR-21 regulated the intestinal barrier function through modulating the expression of RhoB and CDC42. CONCLUSION: Our results suggest that miR-21 is overexpressed in intestinal inflammation and tissue injury, while knockout of miR-21 in mice improve the survival rate in DSS-induced fatal colitis through protecting against inflammation and tissue injury. Therefore, attenuated expression of miR-21 in gut may prevent the onset or progression of inflammatory bowel disease in patients.

背景：MicroRNA-21（miR-21）在大多数炎症性疾病中过度表达，但它在肠道炎症和组织损伤中的生理作用知之甚少。本研究的目的是在基因修饰的小鼠模型中了解 miR-21 在结肠炎和肠道损伤进展中的作用。

方法：通过给予 3.5%葡聚糖硫酸钠（DSS）7 天诱导 miR-21 KO 和野生型（WT）小鼠实验性结肠炎。在 miR-21 KO 和 WT 小鼠的结肠中检查疾病活动指数（DAI）、血液参数、肠道通透性、组织病理学损伤、细胞因子和趋化因子产生以及上皮细胞凋亡。

结果：与正常肠组织相比，炎症性肠病（IBD）和急性肠梗阻（AIO）患者的肠道中 miR-21 过度表达。同样，与对照小鼠相比，IL-10 KO 小鼠的结肠中 miR-21 上调。WT 小鼠在 3.5%DSS 治疗后 5 天迅速减重并濒死，而 miR-21 KO 小鼠至少存活 6 天。与 miR-21 KO 小鼠相比，WT 小鼠白细胞升高，组织病理学更严重。WT 小鼠结肠培养上清液中 TNF-α和巨噬细胞炎症蛋白-2（MIP-2）水平升高，明显高于 miR-21 KO 小鼠。此外，与 miR-21 KO 小鼠相比，WT 小鼠 CD3 和 CD68 阳性细胞、肠道通透性和上皮细胞凋亡明显增加。最后，我们发现 miR-21 通过调节 RhoB 和 CDC42 的表达来调节肠道屏障功能。

结论：我们的结果表明，miR-21 在肠道炎症和组织损伤中过度表达，而在 DSS 诱导的致命结肠炎中敲除 miR-21 可通过防止炎症和组织损伤来提高小鼠的生存率。因此，肠道中 miR-21 的表达减弱可能会预防患者炎症性肠病的发作或进展。