Neuronal stimulation with 5-hydroxytryptamine 4 receptor induces anti-inflammatory actions via α7nACh receptors on muscularis macrophages associated with postoperative ileus
- Yasuaki Tsuchida1,2,
- Fumihiko Hatao2,
- Masahiko Fujisawa3,
- Takahisa Murata1,
- Michio Kaminishi2,
- Yasuyuki Seto2,
- Masatoshi Hori1,
- Hiroshi Ozaki1
- 1Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
- 2Department of Metabolic Care and Gastrointestinal Surgery Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- 3Department of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo, Japan
- Correspondence to Dr Masatoshi Hori, Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan;
- Revised 21 October 2010
- Accepted 25 October 2010
- Published Online First 29 November 2010
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-HT4R) 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-HT4R 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 β (IL-1β), IL-6, tumour necrosis factor α (TNFα), 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 α7-nicotinic acetylcholine receptor (α7nAChR) antagonist methyl lycaconitine citrate (0.087 mg/kg, i.p.) blocked MOS-mediated ameliorative actions. Immunohistochemically, α7nAChR is expressed by monocytes/macrophages but not by neutrophils in the inflamed intestine.
Conclusion Stimulating the 5-HT4R accelerates acetyl choline (ACh) release from cholinergic myenteric neurons, which subsequently activates α7nAChR on activated monocytes/macrophages to inhibit their inflammatory reactions in the muscle layer. In addition to their gastroprokinetic action, 5-HT4R agonists might serve as novel therapeutic agents for POI characterised by anti-inflammatory potency.
- Prokinetic agents
- motility disorder
- abdominal surgery
- motility disorders
- prokinetic agent
Funding This work was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education (to MH, no.18380173 and no. 21380178; to HO, no. 20228005; and to TM, no. 19688014).
Competing interests HO received grant support from Dainippon Sumitomo Pharma Co. Ltd. The remaining authors have declared no financial interests.
Patient consent Not needed.
Provenance and peer review Not commissioned; externally peer reviewed.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.