Neuronal stimulation with 5-hydroxytryptamine 4 receptor induces anti-inflammatory actions via α7nACh receptors on muscularis macrophages associated with postoperative ileus.
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Department of Veterinary Pharmacology, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. ahori@mail.ecc.u-tokyo.ac.jp
Yasuaki
Y
Tsuchida
Fumihiko
F
Hatao
Masahiko
M
Fujisawa
Takahisa
T
Murata
Michio
M
Kaminishi
Yasuyuki
Y
Seto
Masatoshi
M
Hori
Hiroshi
H
Ozaki
D000631:Aminopyridines / Q000627:therapeutic use; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005772:Gastrointestinal Transit / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D045823:Ileus / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007093:Imidazoles / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000627:therapeutic use; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009197:Myenteric Plexus / Q000187:drug effects / Q000502:physiology; D020556:Neutrophil Infiltration / Q000187:drug effects; D011183:Postoperative Complications / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000627:therapeutic use*; D046509:Tissue Culture Techniques; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000631:Aminopyridines; D001549:Benzamides; C525058:CJ 033466; C579165:Chrna7 protein, rat; D007093:Imidazoles; D018836:Inflammation Mediators; D009025:Morpholines; D011978:Receptors, Nicotinic; D058828:Serotonin 5-HT4 Receptor Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D044422:Receptors, Serotonin, 5-HT4; C062720:mosapride