权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pathophysiological Role of Cholinergic Anti-inflammatory Pathway via Nicotinic Acetylcholine Receptors in Experimental Ulcerative Colitis

烟碱乙酰胆碱受体胆碱能抗炎途径在实验性溃疡性结肠炎中的病理生理学作用

基本信息

批准号：
18590507
负责人：
KADOWAKI Makoto
金额：
$ 2.45万
依托单位：
University of Toyama
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

It has been reported that the cholinergic anti-inflammatory pathway that is controlled by the vagus nerve inhibits local cytokine release. Epidemiologic reports suggest that smoking and nicotine may improve the symptoms of ulcerative colitis(UC. The purpose of the present study was to investigate the pathophysiological role of vagus nerve in oxazolone (OXZ)-induced Th2 type UC model. METHODS: OXZ was injected into the colon of BALB/c mice (Th2 dominant strain). OXZ colitis was assessed in the colon with the disease activity score(DAS), pathological colonic damage score(CDS) by macroscopic evaluation and MPO. RESULT: OXZ-treated mice developed colitis marked by increase of DAS, CDS and MPO in the colon of the OXZ colitis. The central stimulation of vagus nerves by 2-deoxy-d-glucose significantly improved DAS, CDS and MPO and nicotine significantly alleviated the OXZ colitis in a dose-dependent fashion. Notably, hexamethonium and α7-nicotinic acetylcholine receptor (nAChR) antagonist methyllycaconitine significantly prevented the therapeutic effects of nicotine in OXZ colitis. Transcript levels of Th2 cytokines (IL-4, IL-5, and IL-10) significantly increased in the spleen and the colon of OXZ colitis mice. On the other hand, Thl cytokine, IFN-γ mRNA significantly decreased in the spleen and significantly increased in the middle colon. Noteably, both Thl and Th2 cytokines mRNAs were significantly down-regulated in the spleen and colon of nicotine-treated mice. Moreover, to identify α7-nAChR in the colon, unfixed cryosections of colon from OXZ colitis mice were stained with FITC-labelled α-bungarotoxin (α-BTx; α7-nAChR antagonist). Α-BTx-binding cells were upregulated in the OXZ colitis colon, and nicotine pretreatment abolished the fluorescence of α-BTx. CONCLUSION: The vagal anti-inflammatory and immune pathway acts through α7-nAChR in the mucosa of the colon to alleviate inflammation in the colon.

据报道，迷走神经控制的胆碱能抗炎通路抑制局部细胞因子的释放。流行病学报告显示，吸烟和尼古丁可改善溃疡性结肠炎的症状。本研究旨在探讨迷走神经在oxazolone （OXZ）诱导的Th2型UC模型中的病理生理作用。方法：将OXZ注射到BALB/c小鼠（Th2优势株）结肠中。用疾病活动性评分（DAS）、病理性结肠损伤评分（CDS）、宏观评价和MPO对OXZ结肠炎结肠进行评价。结果：OXZ处理小鼠结肠炎后，结肠内DAS、CDS、MPO均升高。2-脱氧-d-葡萄糖中枢刺激迷走神经可显著改善DAS、CDS和MPO，尼古丁可显著缓解OXZ结肠炎，且呈剂量依赖性。六甲铵和α7-烟碱乙酰胆碱受体（nAChR）拮抗剂甲基莱卡乌碱显著抑制尼古丁对OXZ结肠炎的治疗作用。在OXZ结肠炎小鼠的脾脏和结肠中，Th2细胞因子（IL-4、IL-5和IL-10）的转录水平显著升高。另一方面，Thl细胞因子、IFN-γ mRNA在脾脏显著降低，在中结肠显著升高。值得注意的是，在尼古丁处理小鼠的脾脏和结肠中，Thl和Th2细胞因子mrna均显著下调。此外，为了鉴定结肠中的α7-nAChR，我们用fitc标记的α-bungarotoxin （α-BTx； α7-nAChR拮抗剂）染色OXZ结肠炎小鼠的未固定结肠冷冻切片。OXZ结肠炎结肠中Α-BTx-binding细胞表达上调，尼古丁预处理使α-BTx荧光消失。结论：迷走神经抗炎免疫通路通过结肠粘膜α7-nAChR起缓解结肠炎症的作用。