Abstract
Epoxyeicosatrienoic acids (EET) facilitate regeneration in different tissues, and their benefit in dermal wound healing has been proven under normal conditions. In this study, we investigated the effect of 11,12 EET on dermal wound healing in diabetes. We induced diabetes by i.p. injection of streptozotocin 2 weeks prior to wound creation on the dorsal side of the mouse ear. 11,12 EET was applied every second day on the wound, whereas the control groups received only solvent. Epithelialization was monitored every second day intravitally up to wound closure. Wounds were stained for VEGF, CD31, TGF-β, TNF-α, SDF-1α, NF-κB, and Ki-67, and fibroblasts were counted after hematoxylin-eosin stain on days 3, 6, 9, and 16 after wounding. After induction of diabetes, wounds closed on day 13.00 ± 2.20 standard deviation (SD). Local 11,12 ETT application improved wound closure significantly to day 8.40 ± 1.39 SD. EET treatment enhanced VEGF and CD31 expression in wounds on day 3. It also seemed to raise TNF-α level on all days investigated as well as TGF-β level on days 3 and 6. A decrease in NF-κB could be observed on days 9 and 16 after EET application. The latter findings were not significant. SDF-1α expression was not influenced by EET application, and Ki-67 was significantly less in the EET group on day 9 after EET application. The number of fibroblasts was significantly increased on day 9 after the 11,12 EET application. 11,12 EET improve deteriorated wound healing in diabetes by enhancing neoangiogenesis, especially in the early phase of wound healing. Furthermore, they contribute to the dissolution of the initial inflammatory reaction, allowing the crucial transition from the inflammatory to proliferative phase in wound healing.
Highlights
Chronic ulcers caused by diabetes mellitus still impose an immense problem in modern medicine
We evaluated the effect of 11,12 EET on wounds of diabetic mice by measuring the day of wound closure and the process of reepithelialization throughout the wound healing process
To analyze the molecular mechanisms that caused amelioration of wound healing in diabetics caused by EET, we investigated the impact on neoangiogenesis as well as local inflammatory reaction and proliferation
Summary
Chronic ulcers caused by diabetes mellitus still impose an immense problem in modern medicine. Chronic diabetic ulcers exhibit a higher expression of TNF-α than wounds of healthy individuals in the later stages of wound healing, demonstrating that chronic wounds fail to resolve inflammation and are unable to switch to a proliferative state [8] This is supported by the fact that high concentrations of TNF-α prevent granulation tissue formation and suppress the function of transforming growth factor-β (TGF-β) [9,10,11,12]. EET can enhance tissue growth and regeneration in different organs and have anti-inflammatory properties, as well as enhancing vasodilation, cellular proliferation, and migration [23] They have been shown to enhance the expression of fibroblast growth factor 2 (FGF2), which raises fibroblast proliferation and ameliorates angiogenesis [29,30]. We evaluated local EET application in wound healing in diabetic homozygous, fully immunocompetent hairless mice and analyzed the effects on inflammation and neovascularization in wounds
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