Protective Actions of Epithelial 5-Hydroxytryptamine 4 Receptors in Normal and Inflamed Colon.
Protective Actions of Epithelial 5-Hydroxytryptamine 4 Receptors in Normal and Inflamed Colon.
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DOI：
10.1053/j.gastro.2016.07.032
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发表时间：
2016-11
期刊：
影响因子：
29.4
通讯作者：
Mawe GM
中科院分区：
文献类型：
--
作者：
Spohn SN;Bianco F;Scott RB;Keenan CM;Linton AA;O'Neill CH;Bonora E;Dicay M;Lavoie B;Wilcox RL;MacNaughton WK;De Giorgio R;Sharkey KA;Mawe GM
5-羟色胺受体4（5-HT 4 R或HTR 4）在结肠上皮中表达，但对其功能知之甚少。我们研究了结肠上皮5-HT 4 R的激活是否能保护小鼠结肠免受炎症。在通过施用葡聚糖硫酸钠或三硝基苯磺酸诱导的活动性结肠炎发作时或期间，通过灌肠将5-HT 4 R激动剂替加色罗（1 mg/kg）、5-HT 4 R拮抗剂GR 113808（1 mg/kg）或载体（对照）递送至野生型或5-HT 4 R敲除小鼠。使用结肠炎疾病活动指数和肠组织的组织学分析来测量炎症。上皮细胞增殖，伤口愈合，抗氧化应激诱导的细胞凋亡进行了评估，是结肠动力。与给予载体的小鼠相比，直肠给予替加色罗降低了结肠炎的严重程度，并加速了从活动性结肠炎的恢复。直肠给药替加色罗不能改善5-HT 4 R基因敲除小鼠的结肠炎，腹膜内给药替加色罗不能保护野生型小鼠免受结肠炎的影响。替加色罗可增加隐窝上皮细胞的增殖。5-HT 4 R的刺激增加Caco-2细胞迁移和减少氧化应激诱导的细胞凋亡，这些行动被5-HT 4 R拮抗剂GR 113808的共同管理阻断。在未接受替加色罗的野生型小鼠的非炎症结肠中，5-HT 4 R的抑制在3天内导致结肠炎的体征。在这些小鼠中，上皮细胞增殖减少，并检测到细菌移位到肝脏和脾脏。每日给予替加色罗增加了豚鼠和小鼠发炎结肠的运动性，而给予GR 113808破坏了没有结肠炎的动物的运动性。5-HT 4 R激活维持小鼠健康结肠的运动性，豚鼠减少结肠炎小鼠结肠的炎症。激动剂可能被开发用于治疗炎症性肠病患者。
The 5-hydroxytryptamine receptor 4 (5-HT4R or HTR4) is expressed in the colonic epithelium but little is known about its functions there. We examined whether activation of colonic epithelial 5-HT4R protects colons of mice from inflammation. The 5-HT4R agonist tegaserod (1 mg/kg), the 5-HT4R antagonist GR113808 (1 mg/kg), or vehicle (control) were delivered by enema to wild-type or 5-HT4R knockout mice at the onset of, or during, active colitis, induced by administration of dextran sodium sulfate or trinitrobenzene sulfonic acid. Inflammation was measured using the colitis disease activity index and by histologic analysis of intestinal tissues. Epithelial proliferation, wound healing, and resistance to oxidative stress-induced apoptosis were assessed, as was colonic motility. Rectal administration of tegaserod reduced the severity of colitis, compared to mice given vehicle, and accelerated recovery from active colitis. Rectal tegaserod did not improve colitis in 5-HT4R knockout mice, and intraperitoneally administered tegaserod did not protect wild-type mice from colitis. Tegaserod increased proliferation of crypt epithelial cells. Stimulation of 5-HT4R increased Caco-2 cell migration and reduced oxidative stress-induced apoptosis; these actions were blocked by co-administration of the 5-HT4R antagonist GR113808. In non-inflamed colons of wild-type mice not receiving tegaserod, inhibition of 5-HT4Rs resulted in signs of colitis within 3 days. In these mice, epithelial proliferation decreased and bacterial translocation to the liver and spleen was detected. Daily administration of tegaserod increased motility in inflamed colons of guinea pigs and mice, whereas administration of GR113808 disrupted motility in animals without colitis. 5-HT4R activation maintains motility in healthy colons of mice and guinea pigs reduces inflammation in colons of mice with colitis. Agonists might be developed as treatments for patients with inflammatory bowel diseases.
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影响因子：
3.9
作者：
Heath, JP
通讯作者：
Heath, JP
影响因子：
4.4
作者：
Kim, Janice J.;Bridle, Byram W.;Khan, Waliul I.
通讯作者：
Khan, Waliul I.
影响因子：
6.3
作者：
Fujisawa, Masahiko;Murata, Takahisa;Ozaki, Hiroshi
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Ozaki, Hiroshi
影响因子：
5.8
作者：
Kamel, R;Eftekhari, P;Hoebeke, J
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Hoebeke, J
影响因子：
3.5
作者：
Hoffman, J. M.;Mcknight, N. D.;Mawe, G. M.
通讯作者：
Mawe, G. M.