Condition-specific role of colonic inflammatory molecules in persistent functional colorectal hypersensitivity in the mouse.
Condition-specific role of colonic inflammatory molecules in persistent functional colorectal hypersensitivity in the mouse.
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DOI：
10.1111/nmo.12455
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发表时间：
2014-12
影响因子：
3.5
通讯作者：
Gebhart GF
中科院分区：
文献类型：
--
作者：
La JH;Gebhart GF
据推测，低水平炎症介导了功能性肠道疾病中的内脏高敏感性，这些疾病在肠道炎症后甚至在没有肠道炎症的情况下持续存在。我们的目的是测试类固醇抗炎治疗的疗效，并确定局部炎症分子介导的炎症后和非炎症性结直肠过敏使用两种小鼠模型。内脏对结直肠扩张的反应被量化为结直肠敏感性的量度。在第1天，小鼠接受结肠内盐水（对照）、三硝基苯磺酸（第15天炎症后）或酸化高渗盐水（非炎症）。比较了地塞米松治疗前（第10天）和治疗后（第15天）的结肠直肠敏感性，并定量了炎症分子的结肠基因表达。地塞米松可有效抑制结肠中炎症分子（如白细胞介素（IL）-1β和肥大细胞蛋白酶-1）的基因表达，但在两种模型中均未减弱结直肠超敏反应。结肠中炎症分子的基因表达在对照和非炎症模型之间没有差异，但炎症后模型显示IL-10和紧密连接蛋白2增加，IL-6、转化生长因子（TGF）-β（β-内啡肽的前体）、闭合蛋白和粘蛋白2减少。虽然在这些模型中没有共同的分子解释结直肠超敏反应，但在对照组中，超敏反应与TGF-β2 mRNA呈正相关，在地塞米松治疗的炎症后模型中，超敏反应与IL-1β、白介素βA和前列腺素E2合酶呈正相关。在非炎症模型中，环氧合酶-2 mRNA与结直肠敏感性呈负相关。这些结果表明，持续的功能性结直肠过敏是由条件特异性介质介导的，其在结肠中的基因表达不一定对类固醇抗炎治疗敏感。
A low-level inflammation has been hypothesized to mediate visceral hypersensitivity in functional bowel disorders that persist after or even in the absence of gut inflammation. We aimed to test the efficacy of a steroidal anti-inflammatory treatment, and identify local inflammatory molecules mediating post- and non-inflammatory colorectal hypersensitivity using two mouse models. Visceromotor responses to colorectal distension were quantified as a measure of colorectal sensitivity. On day 1, mice received intracolonic saline (control), trinitrobenzenesulfonic acid (post-inflammatory on day 15), or acidified hypertonic saline (non-inflammatory). Colorectal sensitivity before (day 10) and after (day 15) four-day dexamethasone treatment was compared, and colonic gene expression of inflammatory molecules was quantified. Dexamethasone effectively inhibited gene expression of inflammatory molecules such as interleukin (IL)-1β and mast cell protease-1 in the colon, but did not attenuate colorectal hypersensitivity in either model. Gene expression of inflammatory molecules in the colon did not differ between control and the non-inflammatory model, but the post-inflammatory model showed increased IL-10 and tight junction protein 2, and decreased IL-6, transforming growth factor (TGF)-β, a precursor of β-endorphin, occludin, and mucin 2. While no common molecule explained colorectal hypersensitivity in these models, hypersensitivity was positively correlated with TGF-β2 mRNA in control, and with IL-1β, inhibin βA and prostaglandin E2 synthase in the dexamethasone-treated post-inflammatory model. In the non-inflammatory model, cyclooxygenase-2 mRNA was negatively correlated with colorectal sensitivity. These results suggest that persistent functional colorectal hypersensitivity is mediated by condition-specific mediators whose gene expression in the colon is not inevitably sensitive to steroidal anti-inflammatory treatment.
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