Therapeutic action of 5-HT3 receptor antagonists targeting peritoneal macrophages in post-operative ileus.
OBJECTIVE
Post-operative ileus (POI) is induced by intestinal inflammation. Here, we aimed to clarify the effects of 5-HT3 receptor antagonists against POI.


METHODS
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.


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.


CONCLUSIONS
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.
Department of Veterinary Pharmacology, University of Tokyo, Tokyo, 113-8657, Japan.
Toko
T
Maehara
Kenjiro
K
Matsumoto
Kazuhide
K
Horiguchi
Makoto
M
Kondo
Satoshi
S
Iino
Shunji
S
Horie
Takahisa
T
Murata
Hirokazu
H
Tsubone
Shoichi
S
Shimada
Hiroshi
H
Ozaki
Masatoshi
M
Hori
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics; D005772:Gastrointestinal Transit / Q000187:drug effects; D045823:Ileus / Q000188:drug therapy* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects; D017294:Ondansetron / Q000494:pharmacology / Q000627:therapeutic use; D000077924:Palonosetron; D011183:Postoperative Complications / Q000188:drug therapy* / Q000378:metabolism; D011812:Quinuclidines / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000077526:Tropisetron
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007211:Indoles; D007546:Isoquinolines; D011812:Quinuclidines; D012333:RNA, Messenger; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012701:Serotonin; D017294:Ondansetron; D000077924:Palonosetron; D000077526:Tropisetron