• Br. J. Pharmacol. · Feb 2015

    Therapeutic action of 5-HT3 receptor antagonists targeting peritoneal macrophages in post-operative ileus.

    • Toko Maehara, Kenjiro Matsumoto, Kazuhide Horiguchi, Makoto Kondo, Satoshi Iino, Shunji Horie, Takahisa Murata, Hirokazu Tsubone, Shoichi Shimada, Hiroshi Ozaki, and Masatoshi Hori.
    • Department of Veterinary Pharmacology, University of Tokyo, Tokyo, 113-8657, Japan.
    • Br. J. Pharmacol. 2015 Feb 1; 172 (4): 1136-47.

    Background And PurposePost-operative ileus (POI) is induced by intestinal inflammation. Here, we aimed to clarify the effects of 5-HT3 receptor antagonists against POI.Experimental ApproachWe administered three 5-HT3 receptor antagonists, ondansetron, tropisetron and palonosetron, to a mouse model of POI induced by surgical intestinal manipulation (IM). Immunohistochemistry, intestinal transit, inflammatory mediator mRNA expression and 5-HT content were measured. In some experiments, 5-HT3 A receptor null mice were used.Key ResultsThree 5-HT3 receptor antagonists reduced IM-induced infiltration of inflammatory CD68-positive macrophages and myeloperoxidase-stained neutrophils. Ondansetron exhibited no anti-inflammatory actions in 5-HT3 A receptor null mice. Ondansetron inhibited expression of the chemokine CCL2, IL-1β, IL-6, TNF-α and iNOS mRNAs up-regulated by IM, and also ameliorated the delayed gastrointestinal transit. Peritoneal macrophages, but not most infiltrating monocyte-derived macrophages, expressed 5-HT3 receptors. IM stimulation increased the 5-HT content of peritoneal lavage fluid, which up-regulated mRNA expression of proinflammatory cytokines in peritoneal macrophages. Immunohistochemical localization of 5-HT3 receptors suggests that ondansetron suppressed expression of these mRNAs in activated peritoneal macrophages, adhering to the serosal region of the inflamed intestinal wall.Conclusion And Implications5-HT3 receptor antagonists were anti-inflammatory, mainly targeting peritoneal macrophages expressing these receptors. They also restored the delayed gastrointestinal transit by IM. 5-HT3 receptor antagonists should be therapeutically useful agents against POI.© 2014 The British Pharmacological Society.

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