title: Dermal wound healing is subject to redox control.
abstract: Previously we have reported in vitro evidence suggesting that that H2O2 may support wound healing by inducing VEGF expression in human keratinocytes (C. K. Sen et al., 2002, J. Biol. Chem.277, 33284-33290). Here, we test the significance of H2O2 in regulating wound healing in vivo. Using the Hunt-Schilling cylinder approach we present the first evidence that the wound site contains micromolar concentrations of H2O2. At the wound site, low concentrations of H2O2 supported the healing process, especially in p47(phox)- and MCP-1-deficient mice in which endogenous H2O2 generation is impaired. Higher doses of H2O2 adversely influenced healing. At low concentrations, H2O2 facilitated wound angiogenesis in vivo. H2O2 induced FAK phosphorylation both in wound-edge tissue in vivo and in human dermal microvascular endothelial cells. H2O2 induced site-specific (Tyr-925 and Tyr-861) phosphorylation of FAK. Other sites, including the Tyr-397 autophosphorylation site, were insensitive to H2O2. Adenoviral gene delivery of catalase impaired wound angiogenesis and closure. Catalase overexpression slowed tissue remodeling as evidenced by a more incomplete narrowing of the hyperproliferative epithelium region and incomplete eschar formation. Taken together, this work presents the first in vivo evidence indicating that strategies to influence the redox environment of the wound site may have a bearing on healing outcomes.
authors.affiliation: Laboratory of Molecular Medicine, Department of Surgery, Comprehensive Wound Center, Davis Heart & Lung Research Institute, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Sashwati
authors.initials: S
authors.lastname: Roy
authors.forename: Savita
authors.initials: S
authors.lastname: Khanna
authors.forename: Kishore
authors.initials: K
authors.lastname: Nallu
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hunt
authors.forename: Chandan K
authors.initials: CK
authors.lastname: Sen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002374:Catalase / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010084:Oxidation-Reduction; D010766:Phosphorylation; D012867:Skin / Q000098:blood supply / Q000293:injuries* / Q000473:pathology*; D014443:Tyrosine / Q000378:metabolism; D014945:Wound Healing
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D014443:Tyrosine; D006861:Hydrogen Peroxide; D002374:Catalase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse