title: Generating and reversing chronic wounds in diabetic mice by manipulating wound redox parameters.
abstract: By 2025, more than 500 M people worldwide will suffer from diabetes; 125 M will develop foot ulcer(s) and 20 M will undergo an amputation, creating a major health problem. Understanding how these wounds become chronic will provide insights to reverse chronicity. We hypothesized that oxidative stress (OS) in wounds is a critical component for generation of chronicity. We used the db/db mouse model of impaired healing and inhibited, at time of injury, two major antioxidant enzymes, catalase and glutathione peroxidase, creating high OS in the wounds. This was necessary and sufficient to trigger wounds to become chronic. The wounds initially contained a polymicrobial community that with time selected for specific biofilm-forming bacteria. To reverse chronicity we treated the wounds with the antioxidants α-tocopherol and N-acetylcysteine and found that OS was highly reduced, biofilms had increased sensitivity to antibiotics, and granulation tissue was formed with proper collagen deposition and remodeling. We show for the first time generation of chronic wounds in which biofilm develops spontaneously, illustrating importance of early and continued redox imbalance coupled with the presence of biofilm in development of wound chronicity. This model will help decipher additional mechanisms and potentially better diagnosis of chronicity and treatment of human chronic wounds.
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA ; Bioengineering Interdepartmental Graduate Program, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dhall
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Danh C
authors.initials: DC
authors.lastname: Do
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Department of Botany and Plant Sciences, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Computer Science and Engineering, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: Seyed H
authors.initials: SH
authors.lastname: Mirebrahim
authors.affiliation: Bioengineering Interdepartmental Graduate Program, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Lyubovitsky
authors.affiliation: Department of Computer Science and Engineering, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Department of Botany and Plant Sciences, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Nothnagel
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Schiller
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA ; Bioengineering Interdepartmental Graduate Program, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Manuela
authors.initials: M
authors.lastname: Martins-Green
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002908:Chronic Disease; D048909:Diabetes Complications / Q000209:etiology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects; D014946:Wound Infection / Q000209:etiology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000900:Anti-Bacterial Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; D002374:Catalase; D005979:Glutathione Peroxidase