title: Effects of a novel NADPH oxidase inhibitor (S42909) on wound healing in an experimental ischemic excisional skin model.
abstract: Chronic wounds are a serious healthcare problem. As non-healing wounds involve continuous pathologic inflammatory stage, research is focused on anti-inflammatory treatments. Our objective was to analyze the effect of S42909, a potent NADPH oxidase inhibitor activity, with vascular anti-inflammatory properties. An ischemic rabbit ear ulcer model (24 New Zealand white rabbits) was used to evaluate the reepithelialization/contraction areas, anti-/pro-inflammatory cytokines mRNA (TGF-β1/IL-10/IFN-γ/VEGF) by qRT-PCR, collagen I/III deposition, and neovascularization (TGF-β1/VEGF) by morphological and immunohistochemical analyses. Three different doses were administered by gavage for 2 weeks: 10 and 30 mg/kg/d in self-microemulsion drug delivery system (SMEDDS) and 100 mg/kg/d in arabic gum. Each vehicle was used as control. No signs of infection or necrosis were found. Reepithelialization was almost complete whatever the groups reaching 95% at the dose of 100 mg/kg. Wound contraction was significantly reduced in all S42909-treated groups. A significant increase in anti-inflammatory cytokines TGF-β1 mRNA and IL-10 mRNA was observed at the dose of 100 and 30 mg/kg/d, respectively. No changes were observed in pro-inflammatory factors INF-γ and VEGF mRNA. Ischemic skin wound areas had scarce expression of collagen I/III and showed rich glycosaminoglycans content. Treatment increased the collagen deposition and TGF-β1 protein expression and decreased glycosaminoglycan content dose dependently; however, no effect in VEGF was appreciated. Therefore, our results indicate that S42909 improved healing process by dampening excessive inflammation and facilitating collagen deposition without wound contraction phenomena. S42909 might be a promising therapy to treat chronic wounds as venous leg ulcers.
authors.affiliation: Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.|Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sotomayor
authors.affiliation: Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.|Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
authors.forename: Gemma
authors.identifier: 0000-0002-1623-4384
authors.initials: G
authors.lastname: Pascual
authors.affiliation: Institut de Recherches Internationales SERVIER (I.R.I.S.), Suresnes, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Blanc-Guillemaud
authors.affiliation: Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.|Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mesa-Ciller
authors.affiliation: Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.|Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
authors.forename: Natalio
authors.initials: N
authors.lastname: García-Honduvilla
authors.affiliation: Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.|Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cifuentes
authors.affiliation: Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.|Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Buján
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000235:genetics / Q000517:prevention & control; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D007511:Ischemia / Q000150:complications; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000378:metabolism*; D011817:Rabbits; D062326:Re-Epithelialization / Q000187:drug effects*; D012883:Skin Ulcer / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D007371:Interferon-gamma; D019255:NADPH Oxidases
keywords: angiogenesis; chronic wound; inflammation; ischemia; venous ulcer