title: Hemin ameliorates indomethacin-induced small intestinal injury in mice through the induction of heme oxygenase-1.
abstract: OBJECTIVE
  Although non-steroidal anti-inflammatory drugs can induce intestinal injury, the mechanisms are not fully understood, and treatment has yet to be established. Heme oxygenase-1 (HO-1) has recently gained attention for anti-inflammatory and cytoprotective effects. This study aimed to investigate the effects of hemin, an HO-1 inducer, on indomethacin-induced enteritis in mice.
  
  
  METHODS
  Enteritis was induced by single subcutaneous administration of indomethacin (10 mg/kg) in male C57BL/6 mice. Hemin (30 mg/kg) was administered by intraperitoneal administration 6 h before indomethacin administration. Mice were randomly divided into four groups: (i) sham + vehicle; (ii) sham + hemin; (iii) indomethacin + vehicle; or (iv) indomethacin + hemin. Enteritis was evaluated by measuring ulcerative lesions. Myeloperoxidase activity was measured as an index of neutrophil accumulation. The mRNA expression of inflammatory cytokines and chemokines, such as tumor necrosis factor-α, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and keratinocyte chemoattractant, were analyzed by real-time polymerase chain reaction.
  
  
  RESULTS
  The area of ulcerative lesions, myeloperoxidase activity, and mRNA expression of inflammatory cytokines and chemokines were significantly increased in mice administrated with indomethacin compared with vehicle-treated sham mice. Development of intestinal lesions, increased levels of myeloperoxidase activities, and mRNA expressions of inflammatory cytokines and chemokines were significantly suppressed in mice treated with hemin compared with vehicle-treated mice. Protective effects of hemin were reversed by co-administration of tin protoporphyrin, an HO-1 inhibitor.
  
  
  CONCLUSIONS
  Induction of HO-1 by hemin inhibits indomethacin-induced intestinal injury through upregulation of HO-1. Pharmacological induction of HO-1 may offer a novel therapeutic strategy to prevent indomethacin-induced small intestinal injury.
authors.affiliation: Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoriki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Naito
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Takagi
authors.forename: Katsura
authors.initials: K
authors.lastname: Mizusima
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hirai
authors.forename: Akihito
authors.initials: A
authors.lastname: Harusato
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamada
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Tsuji
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kugai
authors.forename: Akifumi
authors.initials: A
authors.lastname: Fukui
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Higashimura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Katada
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kamada
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Uchiyama
authors.forename: Osamu
authors.initials: O
authors.lastname: Handa
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichikawa
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yosikawa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D004195:Disease Models, Animal; D004751:Enteritis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006427:Hemin / Q000008:administration & dosage / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007213:Indomethacin / Q000633:toxicity; D007421:Intestine, Small / Q000187:drug effects*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018925:Chemokines; D016207:Cytokines; D017931:DNA Primers; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D012333:RNA, Messenger; D006427:Hemin; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1; D007213:Indomethacin