Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
Langenbecks Arch Surg. 2011 Dec;396(8):1245-53. doi: 10.1007/s00423-011-0838-z. Epub 2011 Sep 2.
Epoxyeicosatrienoic acids (EETs) are known to modulate proliferation and angiogenesis in vitro. Tissue levels of EETs are regulated by the cytochrome P450 (CYP) epoxygenases that generate them as well as by the soluble epoxide hydrolase metabolizes them to their less active diols. The aim of this study was to determine the effect of locally administered EETs (11,12- and 14,15-EETs) and the selective sEH inhibitor (sEHI) trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB) on wound healing in vivo.
Standardized full thickness dermal wounds were created on the dorsum of hairless mouse ears. Wound epithelialization was directly viewed and measured using intravitalmicroscopy and computerized planimetry every second day until healing was complete. Wound sections were analyzed by immunostaining for endothelial lineage marker CD31, vascular endothelial growth factor (VEGF), and angiogenic cytokine stromal cell-derived factor (SDF) 1α on days 2, 4, and 13.
Treatment with EETs and t-AUCB, respectively, significantly accelerated wound epithelialization and neovascularization by synergistic upregulation of SDF1α and VEGF in vivo.
These findings demonstrated that exogenous CYP-derived EETs and globally decreased EET hydrolysis by sEH inhibition significantly accelerated wound epithelialization and neovascularization in unimpaired healing wounds. Given that hypoxia induces CYP expression and subsequently EET-dependent angiogenesis, EETs and sEHIs provide a promising new class of therapeutics for ischemic non-healing wounds.
环氧二十碳三烯酸（EETs）已知可调节体外增殖和血管生成。EETs 的组织水平受细胞色素 P450（CYP）环氧合酶调节，该酶生成 EETs，以及可溶性环氧化物水解酶将其代谢为活性较低的二醇。本研究旨在确定局部给予 EETs（11,12-和 14,15-EETs）和选择性 sEH 抑制剂（sEHI）trans-4-[4-(3-金刚烷-1-基脲基)-环己氧基]-苯甲酸（t-AUCB）对体内伤口愈合的影响。
在无毛鼠耳朵的背部创建标准化的全厚度真皮伤口。使用活体显微镜和计算机定标仪每隔一天直接观察和测量伤口上皮化，并在愈合完成之前进行测量。在第 2、4 和 13 天通过免疫染色分析内皮谱系标记物 CD31、血管内皮生长因子（VEGF）和血管生成细胞因子基质细胞衍生因子（SDF）1α的伤口切片。
EETs 和 t-AUCB 的治疗分别通过协同上调 SDF1α 和 VEGF 在体内显著加速了伤口上皮化和新生血管形成。
这些发现表明，外源性 CYP 衍生的 EETs 和 sEH 抑制作用下整体降低 EET 水解显著加速了未受损愈合伤口的上皮化和新生血管形成。鉴于缺氧诱导 CYP 表达，随后依赖 EET 的血管生成，EETs 和 sEHIs 为缺血性非愈合伤口提供了一种有前途的新型治疗方法。
