期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 172, 期 4, 页码 1136-1147出版社
WILEY
DOI: 10.1111/bph.13006
关键词
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资金
- Japanese Ministry of Education [24248050, 25660224, 25252055]
- Grants-in-Aid for Scientific Research [25860395, 25660224, 24590118, 15K08150, 15K07968, 25460947, 25252055, 26860926] Funding Source: KAKEN
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-HT(3)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-HT(3)A receptor null mice. Ondansetron inhibited expression of the chemokine CCL2, IL-1, IL-6, TNF- 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.
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