5-lipoxygenase modulates the alteration of paracellular barrier function in mice ileum during experimental colitis
5-lipoxygenase modulates the alteration of paracellular barrier function in mice ileum during experimental colitis
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DOI：
10.1097/01.shk.0000209530.30564.22
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发表时间：
2006-04-01
期刊：
影响因子：
3.1
通讯作者：
Cuzzocrea, S
中科院分区：
文献类型：
--
作者：
Mazzon, E;Sautebin, L;Cuzzocrea, S
小肠通透性在炎症性肠病中经常发生改变，可能是由于肠道毒素通过渗漏的小肠紧密连接 (TJ) 和粘附而易位所致。最近，研究表明 5-脂氧合酶 (5-LO) 在炎症性肠病等各种炎症性疾病的发展中发挥着重要作用。在本研究中，通过比较野生型小鼠 (5-LOWT) 与缺乏 5-脂氧合酶 (5-LOKO) 的小鼠的反应，我们研究了该酶在实验性结肠炎动物模型中小肠 TJ 的通透性和结构中所起的作用。为了解决这个问题，我们使用了由二硝基苯磺酸（DNBS）诱导的结肠炎实验模型。 DNBS 诱导结肠炎四天后，通过使用硝酸镧的透射电子显微镜以及 occludin 和 ZO-1 的免疫组织化学研究回肠 TJ。与 DNBS 处理的 5-LOWT 小鼠相比，DNBS 处理的 5-LOKO 小鼠结肠损伤的组织学迹象的程度和严重程度降低。给予 DNBS 后，与假手术小鼠 (5.6% +/- 0.5%) 相比，5-LOWT 小鼠的回肠通透性显着增加 (88.3% +/- 1.2%)。在结肠炎中，回肠末端“渗漏”连接的百分比与宏观结肠损伤评分呈正相关。 5-LOWT 小鼠的远端结肠炎会导致整个小肠 TJ 通透性增加，并且改变的程度与结肠损伤相关。相反，在 5-LOKO 小鼠中观察到结肠中 DNBS 引起的 (1) 结肠损伤程度、(2) ZO-1 和 occludin 定位的改变（免疫组织化学）和 (3) 回肠通透性 (8.1% +/- 0.7%) 显着降低。同样，用 5-LO 抑制剂齐留通（每次口服 50 mg/kg，每天两次）治疗 5-LOWT 导致所有先前描述的参数显着降低。综上所述，我们的结果清楚地表明，5-LO 通过调节 TJ 蛋白来调节实验性结肠炎的小肠通透性。
Small intestine permeability is frequently altered in inflammatory bowel disease and may be caused by the translocation of intestinal toxins through leaky small intestine tight junctions (TJs) and adherence. Recently, it has been shown that 5-lipoxygenase (5-LO) plays an important role in the development of various inflammatory conditions like inflammatory bowel disease. In the present study, by comparing the responses in wild-type mice (5-LOWT) with those of mice lacking the 5-lipoxygenase (5-LOKO), we investigated the role played by this enzyme in the permeability and structure of small intestine TJs in an animal model of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). Four days after colitis induction by DNBS, the ileal TJs were studied by means of transmission electron microscopy using lanthanum nitrate and immunohistochemistry of occludin and ZO-1. When compared with DNBS-treated 5-LOWT mice, DNBS-treated 5-LOKO mice experienced a reduced rate of the extent and severity of the histological signs of colon injury. After administration of DNBS, 5-LOWT mice showed a significant increase of ileal permeability (88.3% +/- 1.2%) compared with sham (5.6% +/- 0.5%). In colitis, the percentage of "leaky" junctions in terminal ilea correlated positively with the macroscopic colon damage score. Distal colitis in 5-LOWT mice induces an increase of TJ permeability throughout the entire small intestine, and the extent of alterations correlates with colonic damage. On the contrary, a significant reduction of (1) the degree of colon injury, (2) the alteration of ZO-1 and occludin localization (immunohistochemistry), and (3) ileal permeability (8.1% +/- 0.7%) caused by DNBS in the colon was observed in 5-LOKO mice. Similarly, the treatment of 5-LOWT with zileuton (50 mg/kg per oral gavage twice a day), a 5-LO inhibitor, resulted in a significant reduction of all the previously described parameters. Taken together, our results clearly demonstrate that 5-LO modulates small intestinal permeability in experimental colitis through the regulation of TJ protein.