PMID- 28293507 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240327 IS - 2169-7574 (Print) IS - 2169-7574 (Electronic) IS - 2169-7574 (Linking) VI - 4 IP - 12 DP - 2016 Dec TI - Soluble Epoxide Hydrolase Inhibition and Epoxyeicosatrienoic Acid Treatment Improve Vascularization of Engineered Skin Substitutes. PG - e1151 LID - 10.1097/GOX.0000000000001151 [doi] LID - e1151 AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. FAU - Supp, Dorothy M AU - Supp DM AD - 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. FAU - Hahn, Jennifer M AU - Hahn JM AD - 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. FAU - McFarland, Kevin L AU - McFarland KL AD - 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. FAU - Combs, Kelly A AU - Combs KA AD - 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. FAU - Lee, Kin Sing Stephen AU - Lee KS AD - 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. FAU - Inceoglu, Bora AU - Inceoglu B AD - 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. FAU - Wan, Debin AU - Wan D AD - 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. FAU - Boyce, Steven T AU - Boyce ST AD - 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. FAU - Hammock, Bruce D AU - Hammock BD AD - 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. LA - eng GR - R01 ES002710/ES/NIEHS NIH HHS/United States GR - K99 ES024806/ES/NIEHS NIH HHS/United States GR - P42 ES004699/ES/NIEHS NIH HHS/United States GR - U24 DK097154/DK/NIDDK NIH HHS/United States GR - R00 ES024806/ES/NIEHS NIH HHS/United States GR - U54 NS079202/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20161220 PL - United States TA - Plast Reconstr Surg Glob Open JT - Plastic and reconstructive surgery. Global open JID - 101622231 PMC - PMC5222652 EDAT- 2017/03/16 06:00 MHDA- 2017/03/16 06:01 PMCR- 2016/12/20 CRDT- 2017/03/16 06:00 PHST- 2016/09/16 00:00 [received] PHST- 2016/10/07 00:00 [accepted] PHST- 2017/03/16 06:00 [entrez] PHST- 2017/03/16 06:00 [pubmed] PHST- 2017/03/16 06:01 [medline] PHST- 2016/12/20 00:00 [pmc-release] AID - 10.1097/GOX.0000000000001151 [doi] PST - epublish SO - Plast Reconstr Surg Glob Open. 2016 Dec 20;4(12):e1151. doi: 10.1097/GOX.0000000000001151. eCollection 2016 Dec.