Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice
Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice
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DOI：
10.1038/labinvest.2011.122
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发表时间：
2012-01-01
影响因子：
5
通讯作者：
Sandor, Zsuzsanna
中科院分区：
文献类型：
--
作者：
Tolstanova, Ganna;Deng, Xiaoming;Sandor, Zsuzsanna
内皮损伤和血管通透性增加（VP）在溃疡性结肠炎（UC）发病机制中的作用尚未得到研究。我们使用功能、形态学和分子生物学研究来检查内皮屏障功能障碍是否以及在多大程度上先于实验性 UC 早期阶段上皮通透性 (EP) 增强和粘膜病变的发展。我们发现，在碘乙酰胺 (IA) 诱导的 UC 大鼠中，结肠 VP 的增加较早发生（即 15 分钟时增加 2.6 倍，P < 0.01），先于上皮屏障通透性的变化。 EP 在 IA 给药后 15 和 30 分钟没有变化，在 IA 后 1 小时增加 1.9 倍，2 小时增加 6.7 倍（均 P < 0.001）。在右旋糖酐硫酸钠诱导的缓慢发展的UC中，结肠VP在2天内显着增加（P < 0.05），而EP仅在4天内显着增加（P < 0.05）。 IA 给药 30 分钟后，粘膜内皮损伤导致结肠表面上皮细胞缺氧（P < 0.05），这与转录因子缺氧诱导因子 1 α 和早期生长反应 1 表达增加有关。电子显微镜和光学显微镜显示，在 UC 大鼠和小鼠模型中，结肠粘膜血管周围水肿区域被完整的表面上皮细胞层覆盖。这是在四种 UC 模型中首次证明，内皮损伤、结肠 VP 增加、血管周围水肿和上皮缺氧先于上皮屏障功能障碍，随后出现 UC 中的糜烂、溃疡和炎症。实验室调查 (2012) 92, 9-21; doi：10.1038/labinvest.2011.122； 2011 年 9 月 5 日在线发布
The role of endothelial damage and increased vascular permeability (VP) in the pathogenesis of ulcerative colitis (UC) has not been investigated. We examined using functional, morphologic, and molecular biologic studies whether and to what extent the endothelial barrier dysfunction precedes enhanced epithelial permeability (EP) and the development of mucosal lesions during the early stages of experimental UC. We showed that in rats with iodoacetamide (IA)-induced UC increased colonic VP occurs early (ie, 2.6-fold increase at 15 min, P < 0.01) preceding changes in epithelial barrier permeability. EP was unchanged at 15 and 30 min after IA administration and was increased 1.9-fold at 1 h and 6.7-fold at 2 h (both P < 0.001) after IA. In the dextran sodium sulfate-induced slowly developing UC, colonic VP was significantly increased in 2 days (P < 0.05) and EP only in 4 days (P < 0.05). Mucosal endothelial injury led to hypoxia (P < 0.05) of colonic surface epithelial cells 30 min after IA administration that was associated with increased expressions of transcription factors hypoxia-inducible factor-1 alpha and early growth response-1. Electron and light microscopy demonstrated areas of colonic mucosa with perivascular edema covered by intact layer of surface epithelial cells in both rat and mouse models of UC. This is the first demonstration in four models of UC that endothelial damage, increased colonic VP, perivascular edema, and epithelial hypoxia precede epithelial barrier dysfunction that is followed by erosions, ulceration, and inflammation in UC. Laboratory Investigation (2012) 92, 9-21; doi:10.1038/labinvest.2011.122; published online 5 September 2011