title: Heme oxygenase-1 is protective against nonsteroidal anti-inflammatory drug-induced gastric ulcers.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pediatrics, University of Iowa Carver College of Medicine,200 Hawkins Dr, Iowa City, IA 52242, USA. aliye-uc@uiowa.edu
authors.forename: Aliye
authors.initials: A
authors.lastname: Uc
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhu
authors.forename: Brett A
authors.initials: BA
authors.lastname: Wagner
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Berg
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007213:Indomethacin / Q000009:adverse effects* / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015850:Interleukin-6; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D007213:Indomethacin