Characterisation of enterocolitis in the piroxicam-accelerated interleukin-10 knock out mouse - A model mimicking inflammatory bowel disease
Characterisation of enterocolitis in the piroxicam-accelerated interleukin-10 knock out mouse - A model mimicking inflammatory bowel disease
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DOI：
10.1016/j.crohns.2013.08.002
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发表时间：
2014-02-01
影响因子：
8
通讯作者：
Holm, Thomas Lindebo
中科院分区：
文献类型：
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作者：
Holgersen, Kristine;Kvist, Peter Helding;Holm, Thomas Lindebo
背景：在炎症性肠病中，粘膜屏障缺陷、免疫反应失调和对肠道微生物群的过度反应被认为会导致肠道内稳态的破坏并导致慢性炎症。吡罗昔康治疗是一种诱导IL-10 k.o.小鼠结肠炎的方法，它整合了肠道屏障和免疫系统的功能障碍。然而，该模型的翻译价值尚未得到彻底的阐明。目的：探讨吡罗昔康加速性结肠炎（PAC） IL-10 k.o.模型的临床特征、致病机制及其对现有疗法的反应能力。方法：以C57BL/6 J为背景，建立PAC IL-10 k.o.模型，评价氨苄西林和抗il -12/23p40治疗的临床表现、免疫学机制和疗效。结果：PAC IL-10 k.o.小鼠出现体重减轻和腹泻，结肠镜检查显示肉芽肿粘膜增厚。回肠和结肠的组织学检查显示克罗恩病样改变，伴有明显的增生和局灶性跨壁炎症。吡罗昔康治疗的野生型小鼠也出现回肠炎。与IL-10 k.o.和野生型小鼠相比，血液中中性粒细胞、单核细胞和自然杀伤细胞的总数升高，表明先天免疫系统在发病机制中的作用。这些发现得到了肠道细胞因子谱分析的支持。氨苄西林和抗il -12/23p40治疗在模型中显著抑制疾病。结论：PAC IL-10 k.o.模型与克罗恩病的几个特征相似，可作为临床前研究中有用的体内模型。(C) 2013欧洲克罗恩病和结肠炎组织。Elsevier B.V.版权所有。
Background: In inflammatory bowel disease a defective mucosal barrier, a dysregulated immune response and an excessive reactivity against the gut microbiota are assumed to cause a breakdown of the intestinal homeostasis and lead to chronic inflammation. Piroxicam treatment is a method for induction of colitis in IL-10 k.o. mice, which integrates a dysfunction of both the intestinal barrier and the immune system. However, the translational value of this model has not been thoroughly clarified.Aim: To characterise the piroxicam-accelerated colitis (PAC) IL-10 k.o. model with respect to clinical features, pathogenic mechanisms and its ability to respond to existing therapies.Methods: The PAC IL-10 k.o. model was established on a C57BL/6 J background and the clinical manifestations, immunological mechanisms and efficacy of ampicillin and anti-IL-12/23p40 treatment were assessed.Results: The PAC IL-10 k.o. mice developed weight loss and diarrhoea, and colonoscopy revealed a thickened granulomatous mucosa. Histological evaluation of ileum and colon showed Crohn's disease-like changes with pronounced hyperplasia and focal transmural inflammation. Ileitis was also observed in piroxicam treated wild type mice. The total number of neutrophils, monocytes and natural killer cells was elevated in the blood compared to IL-10 k.o. and wild type mice, indicating a role of the innate immune system in the pathogenesis. These findings were supported by analyses of the intestinal cytokine profile. Ampicillin and anti-IL-12/23p40 treatment significantly suppressed disease in the model.Conclusion: The PAC IL-10 k.o. model resembles several features of Crohn's disease and could be a useful in vivo model in preclinical research. (C) 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.