Supp Dorothy M, Hahn Jennifer M, McFarland Kevin L, Combs Kelly A, Lee Kin Sing Stephen, Inceoglu Bora, Wan Debin, Boyce Steven T, Hammock Bruce D
Research Department, Shriners Hospitals for Children - Cincinnati, Cincinnati, Ohio; Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio; and Department of Entomology and Nematology and UCD Comprehensive Cancer Center, University of California at Davis, Davis, Calif.
Plast Reconstr Surg Glob Open. 2016 Dec 20;4(12):e1151. doi: 10.1097/GOX.0000000000001151. eCollection 2016 Dec.
Autologous engineered skin substitutes comprised of keratinocytes, fibroblasts, and biopolymers can serve as an adjunctive treatment for excised burns. However, engineered skin lacks a vascular plexus at the time of grafting, leading to slower vascularization and reduced rates of engraftment compared with autograft. Hypothetically, vascularization of engineered skin grafts can be improved by treatment with proangiogenic agents at the time of grafting. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid that are inactivated by soluble epoxide hydrolase (sEH). EETs have multiple biological activities and have been shown to promote angiogenesis. Inhibitors of sEH (sEHIs) represent attractive therapeutic agents because they increase endogenous EET levels. We investigated sEHI administration, alone or combined with EET treatment, for improved vascularization of engineered skin after grafting to mice.
Engineered skin substitutes, prepared using primary human fibroblasts and keratinocytes, were grafted to full-thickness surgical wounds in immunodeficient mice. Mice were treated with the sEHI 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which was administered in drinking water throughout the study period, with or without topical EET treatment, and were compared with vehicle-treated controls. Vascularization was quantified by image analysis of CD31-positive areas in tissue sections.
At 2 weeks after grafting, significantly increased vascularization was observed in the TPPU and TPPU + EET groups compared with controls, with no evidence of toxicity.
The results suggest that sEH inhibition can increase vascularization of engineered skin grafts after transplantation, which may contribute to enhanced engraftment and improved treatment of full-thickness wounds.
由角质形成细胞、成纤维细胞和生物聚合物组成的自体工程皮肤替代物可作为切除烧伤的辅助治疗方法。然而，工程皮肤在移植时缺乏血管丛，与自体移植相比，导致导致血管化速度较慢且移植率降低。据推测，在移植时用促血管生成剂治疗可改善工程皮肤移植的血管化。环氧二十碳三烯酸（EETs）是花生四烯酸的细胞色素P450代谢产物，可被可溶性环氧化物水解酶（sEH）灭活。EETs具有多种生物学活性，并已被证明可促进血管生成。sEH抑制剂（sEHIs）是有吸引力的治疗剂，因为它们可提高内源性EET水平。我们研究了单独给予sEHI或与EET治疗联合使用，以改善移植到小鼠身上的工程皮肤的血管化。
使用原代人成纤维细胞和角质形成细胞制备的工程皮肤替代物被移植到免疫缺陷小鼠的全层手术伤口上。在整个研究期间，小鼠通过饮用含sEHI 1-三氟甲氧基苯基-3-（1-丙酰基哌啶-4-基）脲（TPPU）的水进行治疗，无论有无局部EET治疗，并与用赋形剂处理的对照组进行比较。通过对组织切片中CD31阳性区域的图像分析来量化血管化程度。
移植后2周，与对照组相比，TPPU组和TPPU + EET组的血管化明显增加，且无毒性迹象。
结果表明，抑制sEH可增加移植后工程皮肤移植物的血管化，这可能有助于增强移植效果并改善全层伤口的治疗。
