title: A Topical Mitochondria-Targeted Redox-Cycling Nitroxide Mitigates Oxidative Stress-Induced Skin Damage.
abstract: Skin is the largest human organ, and it provides a first line of defense that includes physical, chemical, and immune mechanisms to combat environmental stress. Radiation is a prevalent environmental stressor. Radiation-induced skin damage ranges from photoaging and cutaneous carcinogenesis caused by UV exposure, to treatment-limiting radiation dermatitis associated with radiotherapy, to cutaneous radiation syndrome, a frequently fatal consequence of exposures from nuclear accidents. The major mechanism of skin injury common to these exposures is radiation-induced oxidative stress. Efforts to prevent or mitigate radiation damage have included development of antioxidants capable of reducing reactive oxygen species. Mitochondria are particularly susceptible to oxidative stress, and mitochondrial-dependent apoptosis plays a major role in radiation-induced tissue damage. We reasoned that targeting a redox cycling nitroxide to mitochondria could prevent reactive oxygen species accumulation, limiting downstream oxidative damage and preserving mitochondrial function. Here we show that in both mouse and human skin, topical application of a mitochondrially targeted antioxidant prevents and mitigates radiation-induced skin damage characterized by clinical dermatitis, loss of barrier function, inflammation, and fibrosis. Further, damage mitigation is associated with reduced apoptosis, preservation of the skin's antioxidant capacity, and reduction of irreversible DNA and protein oxidation associated with oxidative stress.
authors: Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Rhonda M
authors: RM
authors: Brand
authors: Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Michael W
authors: MW
authors: Epperly
authors: Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: J Mark
authors: JM
authors: Stottlemyer
authors: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Erin M
authors: EM
authors: Skoda
authors: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Xiang
authors: X
authors: Gao
authors: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Song
authors: S
authors: Li
authors: Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Saiful
authors: S
authors: Huq
authors: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Peter
authors: P
authors: Wipf
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Valerian E
authors: VE
authors: Kagan
authors: Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Joel S
authors: JS
authors: Greenberger
authors: Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Electronic address: lof2@pitt.edu.
authors: Louis D
authors: LD
authors: Falo
mesh_terms: D000818:Animals; D000975:Antioxidants; D017209:Apoptosis; D003094:Collagen / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D007249:Inflammation; D015603:Keratinocytes / Q000166:cytology / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D012871:Skin Diseases / Q000378:metabolism / Q000473:pathology*
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D003094:Collagen