Therapeutic action of 5‐ HT 3 receptor antagonists targeting peritoneal macrophages in post‐operative ileus

Background and Purpose Post‐operative ileus ( POI ) is induced by intestinal inflammation. Here, we aimed to clarify the effects of 5‐HT 3 receptor antagonists against POI . Experimental Approach We administered three 5‐ HT 3 receptor antagonists, ondansetron, tropisetron and palonosetron, to a mouse model of POI induced by surgical intestinal manipulation ( IM ). Immunohistochemistry, intestinal transit, inflammatory mediator m RNA expression and 5‐ HT content were measured. In some experiments, 5‐ HT 3 A receptor null mice were used. Key Results Three 5‐ HT 3 receptor antagonists reduced IM ‐induced infiltration of inflammatory CD 68‐positive macrophages and myeloperoxidase‐stained neutrophils. Ondansetron exhibited no anti‐inflammatory actions in 5‐ HT 3 A receptor null mice. Ondansetron inhibited expression of the chemokine CCL2, IL ‐1 β , IL ‐6, TNF ‐ α and i NOS m RNA s up‐regulated by IM , and also ameliorated the delayed gastrointestinal transit. Peritoneal macrophages, but not most infiltrating monocyte‐derived macrophages, expressed 5‐ HT 3 receptors. IM stimulation increased the 5‐ HT content of peritoneal lavage fluid, which up‐regulated m RNA expression of proinflammatory cytokines in peritoneal macrophages. Immunohistochemical localization of 5‐ HT 3 receptors suggests that ondansetron suppressed expression of these m RNA s in activated peritoneal macrophages, adhering to the serosal region of the inflamed intestinal wall. Conclusion and Implications 5‐ HT 3 receptor antagonists were anti‐inflammatory, mainly targeting peritoneal macrophages expressing these receptors. They also restored the delayed gastrointestinal transit by IM . 5‐ HT 3 receptor antagonists should be therapeutically useful agents against POI .