Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse.
Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse.
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DOI：
10.1136/gut.2008.150888
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发表时间：
2009-01
期刊：
影响因子：
24.5
通讯作者：
Meddings, J.
中科院分区：
文献类型：
--
作者：
Arrieta, M. C.;Madsen, K.;Doyle, J.;Meddings, J.
小肠上皮屏障的缺陷与炎症性肠病有关，但其在疾病病因中的作用仍存在争议。在一些疾病模型中，通透性增加似乎是一个非常早期的事件。白细胞介素10（IL10）基因缺陷小鼠在12周龄后会自发患上结肠炎。已表明这些小鼠在生命早期就出现小肠通透性增加的情况。此外，结肠炎的发生取决于肠腔内的物质，因为如果在无菌条件下饲养，动物不会患病。
为了确定是否可以预防小肠通透性升高，以及这样做是否能预防或减轻结肠疾病。
用AT - 1001（一种连蛋白肽抑制剂，一种先前已证明可降低小肠通透性的小肽）对IL10基因缺陷（IL10 - / -）小鼠进行治疗。从4周龄到17周龄每周在体内测量小肠通透性。在8周龄时用尤斯灌流室评估结肠疾病，并在17周龄时测量结肠中的炎症细胞因子和髓过氧化物酶。结肠通透性和组织学也是检测指标。
接受治疗的动物小肠通透性显著降低。乳果糖/甘露醇时间曲线下的平均面积：对照组为5.36（标准误0.08），高剂量AT - 1001组为3.97（标准误0.07），p < 0.05。在8周龄时，结肠黏膜通透性显著降低，电阻增加。到17周龄时，治疗组结肠外植体肿瘤坏死因子α（TNFα）的分泌量显著降低（25.33（标准误4.30）pg/mg，对照组为106.93（标准误17.51）pg/ml，p < 0.01）。所有其他指标也表明治疗动物的结肠炎明显减轻。进行的其他实验表明AT - 1001仅在小肠中有功能活性。
这项工作表明，肠道通透性增加可能是IL10 - / -小鼠发生结肠炎的一个重要病因事件。
Defects in the small intestinal epithelial barrier have been associated with inflammatory bowel disease but their role in the causation of disease is still a matter of debate. In some models of disease increased permeability appears to be a very early event. The interleukin 10 (IL10) gene-deficient mouse spontaneously develops colitis after 12 weeks of age. These mice have been shown to have increased small intestinal permeability that appears early in life. Furthermore, the development of colitis is dependent upon luminal agents, as animals do not develop disease if raised under germ-free conditions. To determine if the elevated small bowel permeability can be prevented, and if by doing so colonic disease is prevented or attenuated. IL10 gene-deficient (IL10−/−) mice) were treated with AT-1001 (a zonulin peptide inhibitor), a small peptide previously demonstrated to reduce small intestinal permeability. Small intestinal permeability was measured, in vivo, weekly from 4 to 17 weeks of age. Colonic disease was assessed at 8 weeks in Ussing chambers, and at 17 weeks of age inflammatory cytokines and myeloperoxidase were measured in the colon. Colonic permeability and histology were also endpoints. Treated animals showed a marked reduction in small intestinal permeability. Average area under the lactulose/mannitol time curve: 5.36 (SE 0.08) in controls vs 3.97 (SE 0.07) in the high-dose AT-1001 group, p<0.05. At 8 weeks of age there was a significant reduction of colonic mucosal permeability and increased electrical resistance. By 17 weeks of age, secretion of tumour necrosis factor α (TNFα) from a colonic explant was significantly lower in the treated group (25.33 (SE 4.30) pg/mg vs 106.93 (SE 17.51) pg/ml in controls, p<0.01). All other markers also demonstrated a clear reduction of colitis in the treated animals. Additional experiments were performed which demonstrated that AT-1001 was functionally active only in the small intestine. This work suggests that increased intestinal permeability may be an important aetiological event in the development of colitis in IL10−/− mice.
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DOI：
10.1084/jem.20050407
发表时间：
2006-03-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Olson TS;Reuter BK;Scott KG;Morris MA;Wang XM;Hancock LN;Burcin TL;Cohn SM;Ernst PB;Cominelli F;Meddings JB;Ley K;Pizarro TT
通讯作者：
Pizarro TT
DOI：
10.1152/ajpgi.1999.276.4.g951
发表时间：
1999-04-01
影响因子：
4.5
作者：
Meddings, JB;Jarand, J;Gall, DG
通讯作者：
Gall, DG
影响因子：
29.4
作者：
KATZ, KD;HOLLANDER, D;ROTTER, JI
通讯作者：
ROTTER, JI
影响因子：
--
作者：
ATISOOK, K;CARLSON, S;MADARA, JL
通讯作者：
MADARA, JL
影响因子：
--
作者：
CLARKSON, TW;TOOLE, SR
通讯作者：
TOOLE, SR