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Neuronal Stimulation with 5-Hydroxytryptamine 4 Receptor Induces Anti-Inflammatory Actions Via A7nach Receptors on Muscularis Ma

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Neuronal Stimulation with 5-Hydroxytryptamine 4 Receptor Induces Anti-Inflammatory Actions Via A7nach Receptors on Muscularis Ma Gut Online First, published on November 29, 2010 as 10.1136/gut.2010.227546 Paper Neuronal stimulation with 5-hydroxytryptamine 4 Gut: first published as 10.1136/gut.2010.227546 on 29 November 2010. Downloaded from receptor induces anti-inflammatory actions via a7nACh receptors on muscularis macrophages associated with postoperative ileus Yasuaki Tsuchida,1,2 Fumihiko Hatao,2 Masahiko Fujisawa,3 Takahisa Murata,1 Michio Kaminishi,2 Yasuyuki Seto,2 Masatoshi Hori,1 Hiroshi Ozaki1 < Additional figures are ABSTRACT published online only. To view Background The main symptom of postoperative ileus Significance of this study these files please visit the (POI) is an intestinal motility disorder in which journal online (http://gut.bmj. monocytes/macrophages and neutrophils play crucial com). What is already known about this subject? roles. Prokinetic 5-hydroxytryptamine 4 receptor 1Department of Veterinary < The 5-HT R agonist mosapride is actually used (5-HT R) agonists and dopamine receptor 4 Pharmacology, Graduate School 4 in clinical practice as a gastrointestinal proki- antagonists are potential therapeutic agents for of Agriculture and Life Sciences, netic drug. The University of Tokyo, Tokyo, directly ameliorating the motility disorder associated with < Recent clinical trials showed that mosapride, Japan POI. 2 that is benzamide analogues of cisapride, reduce Department of Metabolic Care Aim To determine the effects of the 5-HT R agonists and Gastrointestinal Surgery 4 postoperative ileus although pharmacological mosapride citrate (MOS) and CJ-033466 on intestinal Graduate School of Medicine, mechanisms are not well understood. smooth muscle contractility relative to immune reactions The University of Tokyo, Tokyo, < Stimulation of the vagus nerve prevents post- Japan after POI. 3 operative ileus through a7nAChR in macro- Department of Veterinary Methods Intestinal manipulation (IM) was applied to the Science, Nippon Veterinary and phages. Life Science University, Tokyo, rat distal ileum. Both MOS (0.3 and 1 mg/kg, s.c.) and Japan CJ-033466 (1 mg/kg, s.c.) were administered to the What are the new findings? < animals before and after IM. At 24 h after IM, The 5-HT4R agonist mosapride dramatically Correspondence to isolated intestinal smooth muscle contractile activity in inhibits postoperative ileus through anti-inflam- Dr Masatoshi Hori, Department vitro, gastrointestinal transit in vivo, inflammatory of Veterinary Pharmacology, The matory reaction in addition to its gastrointestinal University of Tokyo, 1-1-1 Yayoi, mediator expression and leucocyte infiltration were prokinetic action. < Bunkyo-ku, Tokyo 113-8657, measured. The anti-inflammatory action is mediated by http://gut.bmj.com/ Japan; Results After IM, ileal circular muscle contractility in acetylcholine (ACh) release from cholinergic [email protected] vitro and gastrointestinal transit in vivo were reduced myenteric neurons, which subsequently acti- and the number of macrophages and neutrophils Revised 21 October 2010 vates a7nAChR on activated monocytes/macro- Accepted 25 October 2010 increased in the inflamed muscle layer, resulting in the phages to inhibit inflammation. induction of inflammatory mediators such as interleukin < For the first time, we found a new subset of 1 b (IL-1b), IL-6, tumour necrosis factor a (TNFa), activated macrophages expressed a7nAChR monocyte chemoattractant protein 1 (MCP-1) and during inflammation in small intestine. on September 25, 2021 by guest. Protected copyright. inducible nitric oxide synthase (iNOS). Both MOS and CJ-033466 significantly attenuated not only the How might it impact on clinical practice in the intestinal motility dysfunction but also the leucocyte foreseeable future? < infiltration and inflammatory mediator expression after 5-HT4R agonists, such as mosapride, could be IM. The autonomic ganglionic blocker hexamethonium clinically used not only as a gastrointestinal (1 mg/kg, i.p.) and the a7-nicotinic acetylcholine prokinetic drug but also as anti-inflammatory receptor (a7nAChR) antagonist methyl drug to prevent postoperative ileus. lycaconitine citrate (0.087 mg/kg, i.p.) blocked < Intestinal macrophages are unique immunoreac- MOS-mediated ameliorative actions. tive cells inducing a7nAChR during inflamma- Immunohistochemically, a7nAChR is expressed by tion, which give a significant impact on medical monocytes/macrophages but not by neutrophils in the sciences. < inflamed intestine. 5-HT4R could be a new therapeutic molecular Conclusion Stimulating the 5-HT4R accelerates acetyl target for anti-inflammatory gastrointestinal choline (ACh) release from cholinergic myenteric diseases. neurons, which subsequently activates a7nAChR on activated monocytes/macrophages to inhibit their inflammatory reactions in the muscle layer. In addition to their gastroprokinetic action, 5-HT4R agonists might INTRODUCTION serve as novel therapeutic agents for POI characterised Various 5-HT4R agonists, such as tegaserod, This paper is freely available by anti-inflammatory potency. cisapride and mosapride, have been clinically vali- online under the BMJ Journals dated as treatment for gastrointestinal disorders unlocked scheme, see http:// gut.bmj.com/site/about/ characterised by dysmotility. Originally, 5-HT4R unlocked.xhtml agonists were believed to induce prokinetic potency CopyrightTsuchida Y, HataoArticle F, Fujisawa author M, et (or al. Guttheir(2010). employer) doi:10.1136/gut.2010.227546 2010. Produced by BMJ Publishing Group Ltd (& BSG) under licence. 1 of 10 Paper only in the upper part of the gastrointestinal tract. Therefore, physiological saline was subcutaneously injected at 2 h before Gut: first published as 10.1136/gut.2010.227546 on 29 November 2010. Downloaded from 5-HT4R agonists are still clinically used to treat gastroparesis and at 2 and 6 h after IM; IM + MOS and IM+CJ, 5-HT4R 1e3 and functional dyspepsia. However, 5-HT4R agonists can also agonist MOS citrate (0.3, 1 mg/kg, donated by Dainippon induce prokinetic ability in the lower part of the gastrointestinal Sumitomo Pharma) or CJ-033466 (CJ; 1 mg/kg, donated by tract in experimental animals and humans,45and they are Pfizer) were similarly administered three times, respectively; IM clinically applied to treat chronic constipation and constipation- + MOS + GR, the 5-HT4R antagonist GR113808 (GR; 1 or predominant irritable bowel syndrome.67Indeed, immunohis- 3 mg/kg, Sigma Aldrich, St. Louis, Missouri, USA) was similarly fi tochemical studies have identi ed 5-HT4R in the myenteric and administered by three intraperitoneal (i.p.) injections with e submucosal ganglia of gastrointestinal tissues.8 10 MOS; IM + MOS + HEX, the non-specific autonomic gangli- Postoperative ileus (POI) is a common complication after onic blocker hexamethonium chloride (1 mg/kg; Nacalai Tesque, intra-abdominal surgery that is accompanied by increased Kyoto, Japan) was applied at 1 h before IM and MOS was morbidity and prolonged hospitalisation, increasing hospital applied at 2 h before and at 2 and 6 h after IM; IM + MOS + costs.11 Neurogenic, inflammatory and inflammatoryeneuronal MLA, the a7-nicotinic acetylcholine receptor (a7nAChR) interactive mechanisms are generally considered to induce antagonist methyl lycaconitine (MLA) citrate (0.087 mg/kg; POI.12 Sympathetic reflexes, the activation of non-adrenergic, TOCRIS, Bristol, UK) was injected i.p. at 30 min before each non-cholinergic nerves, inhibitory humoural agents and the MOS application. Both MOS and GR113808 were dissolved in influence of anaesthetics play crucial roles in the pathogenesis of 1% of lactic acid with physiological saline and other substances POI at the acute stage during and shortly after (up to 3 h) were dissolved in distilled water. laparotomy and abdominal surgery.13 14 Local inflammatory responses in the manipulated intestine additionally participate Contraction studies in disordered motility during the later stage of POI (24 h after The manipulated ileal portion was isolated from POI model rats e surgery).15 19 Many resident macrophages are distributed in the at 24 h after IM. The ileum was cut open along the mesenteric subserosal, myenteric plexus regions of the intestinal muscle attachment, and the mucosal and submucosal layers were gently layer and inside the circular smooth muscle layer under healthy removed. Circular strips were suspended along the circular axis conditions.20 21 Although these ramified forms of resident in a tissue bath filled with a normal physiological salt solution 22 23 fl macrophages normally remain inactive, in ammatory comprising (in mM) 136.9 NaCl, 5.4 KCl, 1 CaCl2, 1.5 MgCl2, stimuli and/or mechanical stress induced by IM activates them 23.8 NaHCO3, 5.5 glucose, and 0.01 EDTA (pH 7.4). Muscle fl 8 e to produce prostaglandins, nitric oxides, in ammatory cytokines strips were maintained at 37 C and aerated with 95% O2 5% fl and chemokines that cause muscularis in ammation and CO2. Responses of the strips were measured isometrically under e intestinal motility disorders.15 19 24 a resting tension of 10 mN. The magnitude of absolute force was The pharmacological management of POI is important to normalised to the wet weight of each strip. inhibit morbidity rates and reduce hospital costs and length of hospital stay. Gastrointestinal prokinetic agents might be useful Intestinal transit determination for managing or preventing POI according to some clinical After 18 h of fasting, the rats were randomly assigned to four http://gut.bmj.com/ e trials.25 28 The effects of various gastrointestinal prokinetic
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