PMID- 21115544
OWN - NLM
STAT- MEDLINE
DCOM- 20110722
LR  - 20220330
IS  - 1468-3288 (Electronic)
IS  - 0017-5749 (Print)
IS  - 0017-5749 (Linking)
VI  - 60
IP  - 5
DP  - 2011 May
TI  - Neuronal stimulation with 5-hydroxytryptamine 4 receptor induces 
      anti-inflammatory actions via alpha7nACh receptors on muscularis macrophages 
      associated with postoperative ileus.
PG  - 638-47
LID - 10.1136/gut.2010.227546 [doi]
AB  - BACKGROUND: The main symptom of postoperative ileus (POI) is an intestinal 
      motility disorder in which monocytes/macrophages and neutrophils play crucial 
      roles. Prokinetic 5-hydroxytryptamine 4 receptor (5-HT(4)R) agonists and dopamine 
      receptor antagonists are potential therapeutic agents for directly ameliorating 
      the motility disorder associated with POI. AIM: To determine the effects of the 
      5-HT(4)R agonists mosapride citrate (MOS) and CJ-033466 on intestinal smooth muscle 
      contractility relative to immune reactions after POI. METHODS: Intestinal 
      manipulation (IM) was applied to the rat distal ileum. Both MOS (0.3 and 1 mg/kg, 
      s.c.) and CJ-033466 (1 mg/kg, s.c.) were administered to the animals before and 
      after IM. At 24 h after IM, isolated intestinal smooth muscle contractile 
      activity in vitro, gastrointestinal transit in vivo, inflammatory mediator 
      expression and leucocyte infiltration were measured. RESULTS: After IM, ileal 
      circular muscle contractility in vitro and gastrointestinal transit in vivo were 
      reduced and the number of macrophages and neutrophils increased in the inflamed 
      muscle layer, resulting in the induction of inflammatory mediators such as 
      interleukin 1 beta (IL-1beta), IL-6, tumour necrosis factor alpha (TNFalpha), monocyte 
      chemoattractant protein 1 (MCP-1) and inducible nitric oxide synthase (iNOS). 
      Both MOS and CJ-033466 significantly attenuated not only the intestinal motility 
      dysfunction but also the leucocyte infiltration and inflammatory mediator 
      expression after IM. The autonomic ganglionic blocker hexamethonium (1 mg/kg, 
      i.p.) and the alpha7-nicotinic acetylcholine receptor (alpha7nAChR) antagonist methyl 
      lycaconitine citrate (0.087 mg/kg, i.p.) blocked MOS-mediated ameliorative 
      actions. Immunohistochemically, alpha7nAChR is expressed by monocytes/macrophages but 
      not by neutrophils in the inflamed intestine. CONCLUSION: Stimulating the 5-HT(4)R 
      accelerates acetyl choline (ACh) release from cholinergic myenteric neurons, 
      which subsequently activates alpha7nAChR on activated monocytes/macrophages to 
      inhibit their inflammatory reactions in the muscle layer. In addition to their 
      gastroprokinetic action, 5-HT(4)R agonists might serve as novel therapeutic agents 
      for POI characterised by anti-inflammatory potency.
FAU - Tsuchida, Yasuaki
AU  - Tsuchida Y
AD  - Department of Veterinary Pharmacology, The University of Tokyo, Bunkyo-ku, Tokyo 
      113-8657, Japan. ahori@mail.ecc.u-tokyo.ac.jp
FAU - Hatao, Fumihiko
AU  - Hatao F
FAU - Fujisawa, Masahiko
AU  - Fujisawa M
FAU - Murata, Takahisa
AU  - Murata T
FAU - Kaminishi, Michio
AU  - Kaminishi M
FAU - Seto, Yasuyuki
AU  - Seto Y
FAU - Hori, Masatoshi
AU  - Hori M
FAU - Ozaki, Hiroshi
AU  - Ozaki H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101129
PL  - England
TA  - Gut
JT  - Gut
JID - 2985108R
RN  - 0 (Aminopyridines)
RN  - 0 (Benzamides)
RN  - 0 (CJ 033466)
RN  - 0 (Chrna7 protein, rat)
RN  - 0 (Imidazoles)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Morpholines)
RN  - 0 (Receptors, Nicotinic)
RN  - 0 (Serotonin 5-HT4 Receptor Agonists)
RN  - 0 (alpha7 Nicotinic Acetylcholine Receptor)
RN  - 158165-40-3 (Receptors, Serotonin, 5-HT4)
RN  - I8MFJ1C0BY (mosapride)
SB  - IM
MH  - Aminopyridines/therapeutic use
MH  - Animals
MH  - Benzamides/therapeutic use
MH  - Cholinergic Fibers/drug effects/physiology
MH  - Disease Models, Animal
MH  - Drug Evaluation, Preclinical/methods
MH  - Gastrointestinal Transit/drug effects
MH  - Ileum/drug effects
MH  - Ileus/metabolism/physiopathology/*prevention & control
MH  - Imidazoles/therapeutic use
MH  - Inflammation Mediators/metabolism
MH  - Macrophages/drug effects/metabolism
MH  - Male
MH  - Morpholines/therapeutic use
MH  - Muscle Contraction/drug effects
MH  - Muscle, Smooth/drug effects
MH  - Myenteric Plexus/drug effects/physiology
MH  - Neutrophil Infiltration/drug effects
MH  - Postoperative Complications/metabolism/physiopathology/*prevention & control
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Nicotinic/metabolism/*physiology
MH  - Receptors, Serotonin, 5-HT4/*physiology
MH  - Serotonin 5-HT4 Receptor Agonists/*therapeutic use
MH  - Tissue Culture Techniques
MH  - alpha7 Nicotinic Acetylcholine Receptor
PMC - PMC3071096
COIS- Competing interests: HO received grant support from Dainippon Sumitomo Pharma Co. 
      Ltd. The remaining authors have declared no financial interests.
EDAT- 2010/12/01 06:00
MHDA- 2011/07/23 06:00
PMCR- 2010/11/29
CRDT- 2010/12/01 06:00
PHST- 2010/12/01 06:00 [entrez]
PHST- 2010/12/01 06:00 [pubmed]
PHST- 2011/07/23 06:00 [medline]
PHST- 2010/11/29 00:00 [pmc-release]
AID - gut.2010.227546 [pii]
AID - gutjnl227546 [pii]
AID - 10.1136/gut.2010.227546 [doi]
PST - ppublish
SO  - Gut. 2011 May;60(5):638-47. doi: 10.1136/gut.2010.227546. Epub 2010 Nov 29.