Hemin ameliorates indomethacin-induced small intestinal injury in mice through the induction of heme oxygenase-1.

Abstract

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 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: Hiroyuki Yoriki, Yuji Naito, Tomohisa Takagi, Katsura Mizusima, Yasuko Hirai, Akihito Harusato, Shinya Yamada, Toshifumi Tsuji, Munehiro Kugai, Akifumi Fukui, Yasuki Higashimura, Kazuhiko Katada, Kazuhiro Kamada, Kazuhiko Uchiyama, Osamu Handa, Nobuaki Yagi, Hiroshi Ichikawa, Toshikazu Yosikawa
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 28 Issue 4 Pg. 632-8 (Apr 2013) ISSN: 1440-1746 [Electronic] Australia
• PMID: 23216607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Chemical References

• Chemokines
• Cytokines
• DNA Primers
• Enzyme Inhibitors
• Metalloporphyrins
• Protoporphyrins
• RNA, Messenger
• Hemin
• tin protoporphyrin IX
• Heme Oxygenase-1
• Indomethacin

Topics

• Animals
• Blotting, Western
• Chemokines (genetics)
• Cytokines (genetics)
• DNA Primers (chemistry)
• Disease Models, Animal
• Enteritis (chemically induced, enzymology, pathology, prevention & control)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation
• Heme Oxygenase-1 (antagonists & inhibitors, metabolism)
• Hemin (administration & dosage, therapeutic use)
• Immunohistochemistry
• Indomethacin (toxicity)
• Intestine, Small (drug effects)
• Male
• Metalloporphyrins (pharmacology)
• Mice
• Mice, Inbred C57BL
• Protoporphyrins (pharmacology)
• RNA, Messenger (metabolism)
• Real-Time Polymerase Chain Reaction