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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Cytokines / genetics
  • Gastrointestinal Transit / drug effects
  • Ileus / drug therapy*
  • Ileus / metabolism
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Isoquinolines / pharmacology
  • Isoquinolines / therapeutic use
  • Macrophages, Peritoneal / drug effects*
  • Macrophages, Peritoneal / metabolism
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / drug effects
  • Ondansetron / pharmacology
  • Ondansetron / therapeutic use
  • Palonosetron
  • Postoperative Complications / drug therapy*
  • Postoperative Complications / metabolism
  • Quinuclidines / pharmacology
  • Quinuclidines / therapeutic use
  • RNA, Messenger / metabolism
  • Receptors, Serotonin, 5-HT3 / metabolism
  • Serotonin / metabolism
  • Serotonin 5-HT3 Receptor Antagonists / pharmacology
  • Serotonin 5-HT3 Receptor Antagonists / therapeutic use*
  • Tropisetron


  • Anti-Inflammatory Agents
  • Cytokines
  • Indoles
  • Isoquinolines
  • Quinuclidines
  • RNA, Messenger
  • Receptors, Serotonin, 5-HT3
  • Serotonin 5-HT3 Receptor Antagonists
  • Serotonin
  • Ondansetron
  • Palonosetron
  • Tropisetron