Related Experiment Video
Updated: Apr 21, 2026
Postoperative Ileus Murine Model
Published on: July 12, 2024
Therapeutic action of 5-HT3 receptor antagonists targeting peritoneal macrophages in post-operative ileus
Toko Maehara1, Kenjiro Matsumoto, Kazuhide Horiguchi
1Department of Veterinary Pharmacology, University of Tokyo, Tokyo, 113-8657, Japan.
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.
Insights
5-HT3 receptor antagonists reduce post-operative ileus by targeting peritoneal macrophages and decreasing inflammation. These agents also improve gastrointestinal transit, suggesting therapeutic potential for post-operative ileus.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- Post-operative ileus (POI) is a common complication following abdominal surgery.
- Intestinal inflammation plays a key role in the development of POI.
- 5-HT3 receptor antagonists are a class of drugs with potential anti-inflammatory properties.
Purpose of the Study:
- To investigate the efficacy of 5-HT3 receptor antagonists in a mouse model of post-operative ileus.
- To elucidate the mechanisms by which these antagonists exert their effects on intestinal inflammation and function.
Main Methods:
- A mouse model of POI was induced by surgical intestinal manipulation (IM).
- Three 5-HT3 receptor antagonists (ondansetron, tropisetron, palonosetron) were administered.
- Measurements included inflammatory cell infiltration, mRNA expression of inflammatory mediators, 5-HT content, and intestinal transit.
- Experiments utilized 5-HT3 A receptor null mice to assess the role of the receptor.
Main Results:
- 5-HT3 receptor antagonists reduced the infiltration of macrophages and neutrophils in the manipulated intestine.
- Ondansetron demonstrated anti-inflammatory effects only in the presence of functional 5-HT3 A receptors.
- These antagonists inhibited the expression of key pro-inflammatory cytokine mRNAs (CCL2, IL-1β, IL-6, TNF-α, iNOS) and improved delayed gastrointestinal transit.
- Peritoneal macrophages, but not most infiltrating macrophages, expressed 5-HT3 receptors, and 5-HT3 receptor antagonists suppressed pro-inflammatory cytokine production in these cells.
Conclusions:
- 5-HT3 receptor antagonists possess anti-inflammatory properties, primarily by targeting peritoneal macrophages expressing 5-HT3 receptors.
- These antagonists effectively restore delayed gastrointestinal transit impaired by intestinal manipulation.
- The findings suggest that 5-HT3 receptor antagonists hold significant therapeutic promise for the management of post-operative ileus.
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