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In Vivo Imaging of Reactive Oxygen Species in a Murine Wound Model
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Xanthine Oxidoreductase Function Contributes to Normal Wound Healing.

Michael C Madigan1,2, Ryan M McEnaney1,2, Ankur J Shukla1,2

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Molecular Medicine (Cambridge, Mass.)
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Xanthine oxidoreductase (XOR) produces reactive oxygen species (ROS) and nitric oxide (NO) essential for wound repair. Inhibiting XOR impairs healing, while topical hydrogen peroxide (H2O2) can restore it, highlighting XOR's role in wound recovery.

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Area of Science:

  • Biochemistry
  • Wound Healing Research
  • Cell Biology

Background:

  • Chronic wounds cause significant patient morbidity and disability.
  • Normal wound repair requires reactive oxygen species (ROS) and nitric oxide (NO), with disruptions leading to impaired healing.
  • Xanthine oxidoreductase (XOR) is an enzyme capable of producing both ROS and NO.

Purpose of the Study:

  • To investigate the hypothesis that XOR contributes to normal wound healing.
  • To determine the role of XOR in wound repair processes.
  • To assess the impact of XOR inhibition and modulation on wound closure and cellular behavior.

Main Methods:

  • Cutaneous wounds were induced in C57Bl6 mice.
  • XOR activity was inhibited using dietary tungsten or allopurinol.
  • Topical treatments included hydrogen peroxide (H2O2) or allopurinol.
  • Wound closure, XOR expression/activity, cell proliferation, and histology were assessed.
  • In vitro studies examined the effects of XOR, nitrite, H2O2, and allopurinol on keratinocyte (KC) and endothelial cell (EC) behavior.

Main Results:

  • XOR expression and activity were identified in skin, wound edges, and granulation tissue, as well as in cultured human KCs.
  • Dietary tungsten significantly inhibited XOR activity, impaired wound healing, reduced ROS production, angiogenesis, and KC proliferation.
  • Topical allopurinol reduced XOR activity and delayed healing, whereas oral allopurinol had no significant effect.
  • Topical H2O2 successfully restored wound healing in mice fed tungsten.
  • In vitro, both nitrite and H2O2 stimulated KC and EC proliferation and EC migration.

Conclusions:

  • Xanthine oxidoreductase (XOR) is abundantly present in wound tissues.
  • XOR plays a crucial role in normal wound healing, primarily through its effects on ROS production.
  • Modulating ROS levels, for instance with H2O2, can be a therapeutic strategy for impaired wound healing.