La J-H, Gebhart G F
Center for Pain Research, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Neurogastroenterol Motil. 2014 Dec;26(12):1730-42. doi: 10.1111/nmo.12455. Epub 2014 Oct 13.
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 (postinflammatory on day 15), or acidified hypertonic saline (non-inflammatory). Colorectal sensitivity before (day 10) and after (day 15) 4-day dexamethasone (Dex) 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 postinflammatory 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 Dex-treated postinflammatory model. In the non-inflammatory model, cyclooxygenase-2 mRNA was negatively correlated with colorectal sensitivity.
CONCLUSIONS & INFERENCES: 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.
有假说认为，低度炎症介导了功能性肠病中的内脏高敏感性，这些疾病在肠道炎症消退后甚至在无肠道炎症的情况下仍持续存在。我们旨在使用两种小鼠模型测试甾体抗炎治疗的疗效，并确定介导炎症后和非炎症性结肠高敏感性的局部炎症分子。
将对结肠扩张的内脏运动反应量化，作为结肠敏感性的指标。在第1天，小鼠接受结肠内注射生理盐水（对照）、三硝基苯磺酸（第15天为炎症后模型）或酸化高渗盐水（非炎症模型）。比较了4天的地塞米松（Dex）治疗前后（第10天和第15天）的结肠敏感性，并对结肠中炎症分子的基因表达进行了定量。
地塞米松有效抑制了结肠中白细胞介素（IL）-1β和肥大细胞蛋白酶-1等炎症分子的基因表达，但在两种模型中均未减轻结肠高敏感性。对照模型和非炎症模型结肠中炎症分子的基因表达无差异，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-内啡肽前体、闭锁蛋白和黏蛋白2减少。虽然在这些模型中没有共同的分子可以解释结肠高敏感性，但在对照模型中，高敏感性与TGF-β2 mRNA呈正相关，在Dex治疗的炎症后模型中，与IL-1β、抑制素βA和前列腺素E2合酶呈正相关。在非炎症模型中，环氧化酶-2 mRNA与结肠敏感性呈负相关。
这些结果表明，持续性功能性结肠高敏感性由特定条件下的介质介导，其在结肠中的基因表达对甾体抗炎治疗不一定敏感。
