Sotomayor Sandra, Pascual Gemma, Blanc-Guillemaud Vanessa, Mesa-Ciller Claudia, García-Honduvilla Natalio, Cifuentes Alberto, Buján Julia
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.
Exp Dermatol. 2017 Feb;26(2):148-155. doi: 10.1111/exd.13099. Epub 2016 Dec 29.
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.
慢性伤口是一个严重的医疗保健问题。由于不愈合伤口涉及持续的病理性炎症阶段，研究集中在抗炎治疗上。我们的目标是分析具有血管抗炎特性的强效NADPH氧化酶抑制剂S42909的效果。使用缺血性兔耳溃疡模型（24只新西兰白兔）通过qRT-PCR评估再上皮化/收缩面积、抗炎/促炎细胞因子mRNA（TGF-β1/IL-10/IFN-γ/VEGF），通过形态学和免疫组织化学分析评估I/III型胶原蛋白沉积和新生血管形成（TGF-β1/VEGF）。通过灌胃给予三种不同剂量，持续2周：自微乳给药系统（SMEDDS）中的10和30mg/kg/d以及阿拉伯胶中的100mg/kg/d。每种赋形剂用作对照。未发现感染或坏死迹象。无论哪个组，再上皮化几乎完成，在100mg/kg剂量时达到95%。所有S42909治疗组的伤口收缩均显著降低。分别在100和30mg/kg/d剂量下观察到抗炎细胞因子TGF-β1 mRNA和IL-10 mRNA显著增加。促炎因子INF-γ和VEGF mRNA未观察到变化。缺血性皮肤伤口区域I/III型胶原蛋白表达稀少，糖胺聚糖含量丰富。治疗剂量依赖性地增加了胶原蛋白沉积和TGF-β1蛋白表达，并降低了糖胺聚糖含量；然而，未观察到对VEGF的影响。因此，我们的结果表明，S42909通过减轻过度炎症和促进胶原蛋白沉积而无伤口收缩现象，改善了愈合过程。S42909可能是治疗慢性伤口如小腿静脉溃疡的一种有前景的疗法。
