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Br J Pharmacol. 2015 Feb;172(4):1136-47. doi: 10.1111/bph.13006. Epub 2015 Jan 13.

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

Author information

1
Department of Veterinary Pharmacology, University of Tokyo, Tokyo, 113-8657, Japan.

Abstract

BACKGROUND AND PURPOSE:

Post-operative ileus (POI) is induced by intestinal inflammation. Here, we aimed to clarify the effects of 5-HT3 receptor antagonists against POI.

EXPERIMENTAL APPROACH:

We 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 RESULTS:

Three 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 IMPLICATIONS:

5-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.

PMID:
25377620
PMCID:
PMC4314201
DOI:
10.1111/bph.13006
[Indexed for MEDLINE]
Free PMC Article

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