title: Xanthine Oxidoreductase Function Contributes to Normal Wound Healing.
abstract: Chronic, nonhealing wounds result in patient morbidity and disability. Reactive oxygen species (ROS) and nitric oxide (NO) are both required for normal wound repair, and derangements of these result in impaired healing. Xanthine oxidoreductase (XOR) has the unique capacity to produce both ROS and NO. We hypothesize that XOR contributes to normal wound healing. Cutaneous wounds were created in C57Bl6 mice. XOR was inhibited with dietary tungsten or allopurinol. Topical hydrogen peroxide (H2O2, 0.15%) or allopurinol (30 μg) was applied to wounds every other day. Wounds were monitored until closure or collected at d 5 to assess XOR expression and activity, cell proliferation and histology. The effects of XOR, nitrite, H2O2 and allopurinol on keratinocyte cell (KC) and endothelial cell (EC) behavior were assessed. We identified XOR expression and activity in the skin and wound edges as well as granulation tissue. Cultured human KCs also expressed XOR. Tungsten significantly inhibited XOR activity and impaired healing with reduced ROS production with reduced angiogenesis and KC proliferation. The expression and activity of other tungsten-sensitive enzymes were minimal in the wound tissues. Oral allopurinol did not reduce XOR activity or alter wound healing but topical allopurinol significantly reduced XOR activity and delayed healing. Topical H2O2 restored wound healing in tungsten-fed mice. In vitro, nitrite and H2O2 both stimulated KC and EC proliferation and EC migration. These studies demonstrate for the first time that XOR is abundant in wounds and participates in normal wound healing through effects on ROS production.
authors: Surgery Services, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America.|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Michael C
authors: MC
authors: Madigan
authors: Surgery Services, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America.|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Ryan M
authors: RM
authors: McEnaney
authors: Surgery Services, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America.|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Ankur J
authors: AJ
authors: Shukla
authors: Surgery Services, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America.|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Guiying
authors: G
authors: Hong
authors: Department of Anesthesia, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Eric E
authors: EE
authors: Kelley
authors: Surgery Services, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America.|Department of Anesthesia, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Margaret M
authors: MM
authors: Tarpey
authors: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Mark
authors: M
authors: Gladwin
authors: Surgery Services, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America.|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Brian S
authors: BS
authors: Zuckerbraun
authors: Surgery Services, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America.|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Edith
authors: E
authors: Tzeng
mesh_terms: D042931:Aldehyde Oxidase / Q000378:metabolism; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D019587:Dietary Supplements; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D015870:Gene Expression; D006097:Granulation Tissue / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014414:Tungsten / Q000378:metabolism / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology*; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D009573:Nitrites; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D052247:Nitric Oxide Synthase Type II; D014968:Xanthine Dehydrogenase; D042931:Aldehyde Oxidase; C544448:Arg1 protein, mouse; D001119:Arginase; D014414:Tungsten