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Heme Oxygenase-1 Is Protective Against Nonsteroidal Anti-inflammatory Drug–induced Gastric Ulcers

Uc, Aliye*; Zhu, Xiaoyan*; Wagner, Brett A.; Buettner, Garry R.; Berg, Daniel J.

Journal of Pediatric Gastroenterology and Nutrition: April 2012 - Volume 54 - Issue 4 - p 471–476
doi: 10.1097/MPG.0b013e3182334fdf
Original Articles: Gastroenterology

Objectives: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain, fever, and inflammation. Long-term use of these drugs is associated with significant gastric injury. Activated neutrophils and oxidative stress seem to play a significant role in NSAID-induced gastric mucosal damage. The objective of our study is to examine the protective effects of an antioxidant and anti-inflammatory enzyme, heme oxygenase-1 (HO-1), in NSAID-induced gastric injury.

Methods: Mice were intraperitoneally injected with indomethacin (10 mg/kg) or sham. A specific inducer of HO-1, cobalt protoporphyrin (5 mg/kg), was given 24 hours before indomethacin to allow for the expression of HO-1. Controls received sham treatment. Twenty-four hours after indomethacin injection, gastric tissue damage was examined with histology. HO-1 expression was measured with immunoblot; cytokine levels were measured with enzyme-linked immunosorbent assay. Neutrophil infiltration was quantified with myeloperoxidase assay. Using electron paramagnetic resonance and desferrioxamine, we measured the labile iron pool in the mouse stomach as a marker of oxidative stress.

Results: Indomethacin caused gastric inflammation and ulcers, neutrophil activation, and increased tissue expression of interleukin-6 and tumor necrosis factor-alpha in mice. Inducing HO-1 with cobalt protoporphyrin reduced gastric inflammation, number of stomach ulcers, tissue neutrophil activation, and proinflammatory cytokine expression caused by indomethacin.

Conclusions: These findings suggest that the induction of an anti-inflammatory and cytoprotective enzyme HO-1 may be a strategy to overcome the gastrointestinal adverse effects limiting the use of NSAIDs.

*Department of Pediatrics

Department of Radiation Oncology

Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA.

Address correspondence and reprint requests to Aliye Uc, MD, 2865 JPP Pediatrics, University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242 (e-mail:

Received 3 May, 2011

Accepted 15 August, 2011

This work was supported by a Children's Digestive Health and Nutrition Foundation/AstraZeneca Research Award for Acid Peptic Related Diseases and Children Miracle Network grants.

The authors report no conflicts of interest.

Copyright 2012 by ESPGHAN and NASPGHAN