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Hemin ameliorates indomethacin‐induced small intestinal injury in mice through the induction of heme oxygenase‐1
Author(s) -
Yoriki Hiroyuki,
Naito Yuji,
Takagi Tomohisa,
Mizusima Katsura,
Hirai Yasuko,
Harusato Akihito,
Yamada Shinya,
Tsuji Toshifumi,
Kugai Munehiro,
Fukui Akifumi,
Higashimura Yasuki,
Katada Kazuhiko,
Kamada Kazuhiro,
Uchiyama Kazuhiko,
Handa Osamu,
Yagi Nobuaki,
Ichikawa Hiroshi,
Yosikawa Toshikazu
Publication year - 2013
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.12074
Subject(s) - hemin , heme oxygenase , myeloperoxidase , pharmacology , medicine , chemokine , tumor necrosis factor alpha , heme , inflammation , proinflammatory cytokine , immunology , chemistry , biochemistry , enzyme
Background and Aim 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 C 57 BL /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.