Therapeutic action of 5-HT3 receptor antagonists targeting peritoneal macrophages in post-operative ileus
| Autor: | Maehara, Toko, Matsumoto, Kenjiro, Horiguchi, Kazuhide, Kondo, Makoto, Iino, Satoshi, Horie, Shunji, Murata, Takahisa, Tsubone, Hirokazu, Shimada, Shoichi, Ozaki, Hiroshi, Hori, Masatoshi |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Mice
Knockout Mice Inbred BALB C Quinuclidines Serotonin Indoles Neutrophils Tropisetron Anti-Inflammatory Agents Isoquinolines Research Papers Ondansetron Mice Inbred C57BL Palonosetron Ileus Postoperative Complications Macrophages Peritoneal Animals Cytokines Serotonin 5-HT3 Receptor Antagonists RNA Messenger Receptors Serotonin 5-HT3 Gastrointestinal Transit |
| Popis: | Post-operative ileus (POI) is induced by intestinal inflammation. Here, we aimed to clarify the effects of 5-HT3 receptor antagonists against POI.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.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.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. |
| Databáze: | OpenAIRE |
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