A novel murine model of inflammatory bowel disease and inflammation-associated colon cancer with ulcerative colitis-like features.
A novel murine model of inflammatory bowel disease and inflammation-associated colon cancer with ulcerative colitis-like features.
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DOI：
10.1371/journal.pone.0041797
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Greer PK
中科院分区：
文献类型：
--
作者：
Hale LP;Greer PK
已经在人类和小鼠的许多基因中发现了增加对炎症性肠病（IBD）易感性的突变，但是控制这些突变如何促进IBD发病机制并导致溃疡性结肠炎（UC）或克罗恩病（CD）表型表现的因素尚不清楚。在这项研究中，发现TNF和IL-10均缺乏的小鼠（T/I小鼠）在断奶后不久自发发展为严重结肠炎，无需外源性触发。T/I小鼠的结肠炎具有与人类UC相似的临床和组织学特征，包括发生炎症相关结肠癌的风险显著增加。重要的是，抗生素治疗可以预防这些小鼠自发性结肠炎的发生。与已知的th17驱动炎症在细菌应答中的作用一致，T/I小鼠在发生自发性结肠炎和通过非甾体抗炎药诱导的粘膜屏障降解的系统性细菌攻击后，血清th17型细胞因子升高。虽然TNF的产生被广泛认为是IBD的致病因素，但这些数据表明，产生正常水平TNF的能力实际上可以防止肠道细菌定植引起的结肠炎的自发发展。T/I小鼠模型将有助于开发新的基于合理的治疗方法来预防和/或治疗IBD和炎症相关结肠癌，并可能进一步为人类UC的发病机制提供重要见解。
Mutations that increase susceptibility to inflammatory bowel disease (IBD) have been identified in a number of genes in both humans and mice, but the factors that govern how these mutations contribute to IBD pathogenesis and result in phenotypic presentation as ulcerative colitis (UC) or Crohn disease (CD) are not well understood. In this study, mice deficient in both TNF and IL-10 (T/I mice) were found to spontaneously develop severe colitis soon after weaning, without the need for exogenous triggers. Colitis in T/I mice had clinical and histologic features similar to human UC, including a markedly increased risk of developing inflammation-associated colon cancer. Importantly, development of spontaneous colitis in these mice was prevented by antibiotic treatment. Consistent with the known role of Th17-driven inflammation in response to bacteria, T/I mice had elevated serumTh17-type cytokines when they developed spontaneous colitis and after systemic bacterial challenge via NSAID-induced degradation of the mucosal barrier. Although TNF production has been widely considered to be be pathogenic in IBD, these data indicate that the ability to produce normal levels of TNF actually protects against the spontaneous development of colitis in response to intestinal colonization by bacteria. The T/I mouse model will be useful for developing new rationally-based therapies to prevent and/or treat IBD and inflammation-associated colon cancer and may further provide important insights into the pathogenesis of UC in humans.
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影响因子：
3.7
作者：
Chichlowski M;Westwood GS;Abraham SN;Hale LP
通讯作者：
Hale LP
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
4.8
作者：
Ericsson, Aaron C.;Myles, Matthew;Franklin, Craig
通讯作者：
Franklin, Craig
影响因子：
64.8
作者：
Malaviya, R;Ikeda, T;Abraham, SN
通讯作者：
Abraham, SN
影响因子：
4.9
作者：
Hale, LP;Gottfried, MR;Swidinski, A
通讯作者：
Swidinski, A