2007 Fiscal Year Final Research Report Summary
Pathophysiological Role of Cholinergic Anti-inflammatory Pathway via Nicotinic Acetylcholine Receptors in Experimental Ulcerative Colitis
| Project/Area Number |
18590507
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | University of Toyama |
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Principal Investigator |
KADOWAKI Makoto University of Toyama, Institute of Natural Medicine, Professor (20305709)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Takeshi University of Toyama, Institute of Natural Medicine, Assistant Professor (70316181)
KURAMOTO Hirofumi University of Toyama, Deapartment of Applied Biology, Associate Professor (30153373)
SUGIYAMA Toshito University of Toyama, School of Medicine, Professor (00196768)
KADOWAKI Takashi The University of Tokyo, School of Medicine, Professor (30185889)
KAGEYAMA Natsuko University of Toyama, Institute of Natural Medicine, Assistant Professor (90342865)
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| Project Period (FY) |
2006 – 2007
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| Keywords | ulcerative Colitis / oxazolone / nicotinic acetylcholine receptor s / intestinal mucosal immune system / type-2 helper T cell / cytokine |
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| Research Abstract |
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.
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