Therapeutic action of 5‐HT3 receptor antagonists targeting peritoneal macrophages in post‐operative ileus. (13th January 2015)

• Record Type: Journal Article
• Authors: Maehara, Toko; Matsumoto, Kenjiro; Horiguchi, Kazuhide; Kondo, Makoto; Iino, Satoshi; Horie, Shunji; Murata, Takahisa; Tsubone, Hirokazu; Shimada, Shoichi; Ozaki, Hiroshi; Hori, Masatoshi
• Is Part Of: British journal of pharmacology. Volume 172:Number 4(2015:Feb.)
• Page Start: 1136
• Page End: 1147
• Publication Date: 2015-01-13
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.13006
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph13006-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>Post‐operative ileus (POI) is induced by intestinal inflammation. Here, we aimed to clarify the effects of 5‐HT<sub>3</sub> receptor antagonists against POI.</p> </sec> <sec id="bph13006-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>We administered three 5‐HT<sub>3</sub> 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<sub>3</sub>A receptor null mice were used.</p> </sec> <sec id="bph13006-sec-0003" sec-type="section"> <title>Key Results</title> <p>Three 5‐HT<sub>3</sub> receptor antagonists reduced IM‐induced infiltration of inflammatory CD68‐positive macrophages and myeloperoxidase‐stained neutrophils. Ondansetron exhibited no anti‐inflammatory actions in 5‐HT<sub>3</sub>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‐HT<sub>3</sub> 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‐HT<sub>3</sub> receptors suggests that ondansetron suppressed expression of these mRNAs in activated peritoneal macrophages, adhering to the serosal region of the inflamed intestinal wall.</p> </sec> <sec id="bph13006-sec-0004" sec-type="section"> <title>Conclusion and Implications</title> <p>5‐HT<sub>3</sub> receptor antagonists were anti‐inflammatory, mainly targeting peritoneal macrophages expressing these receptors. They also restored the delayed gastrointestinal transit by IM. 5‐HT<sub>3</sub> receptor antagonists should be therapeutically useful agents against POI.</p> </sec> </abstract>