title: Soluble epoxide hydrolase disruption as therapeutic target for wound healing.
abstract: BACKGROUND
  Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) possess angiogenic effects. However, the effect of CYP-derived EETs and soluble epoxide hydrolase (sEH) deletion on wound healing in vivo has not been rigorously investigated. In this study, we measured the effect of exogenous CYP-derived EETs and targeted disruption of sEH in an in vivo wound model.
  
  
  METHODS
  Standardized full-thickness dermal wounds were created on the dorsum of mouse ears. Wound epithelialization was directly viewed and measured using intravital microscopy and computerized planimetry every second day until healing was complete. Wound sections were analyzed by immunostaining for metalloproteinase (MMP) 2, MMP7, MMP9, tissue inhibitor of metalloproteinases (TIMP) 1, and tumor necrosis factor (TNF) α on days 2, 4, and 12.
  
  
  RESULTS
  Treatment with 11,12-EETs, 14,15-EETs, and sEH deletion significantly accelerated wound closure. This effect was attenuated by the EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) in sEH(-/-) mice. Neither 11,12- nor 14,15-EETs caused significant alterations in MMP9 expression in wounds. In contrast, MMP2 and MMP7 were significantly upregulated in the EET-treated groups, whereas TIMP1 and TNF-α were downregulated.
  
  
  CONCLUSIONS
  Collectively, these data demonstrated that potentiation of the CYP epoxy-genase pathway by either exogenous CYP-derived EETs or sEH deletion significantly accelerated wound epithelialization in vivo. This beneficial effect might be due to downregulation of TNF-α production and, to a lesser degree, to the release of MMPs and could be used as a viable angiogenic therapeutic strategy.
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Frankfurt/Main, Germany. AnnaLena.Sander@kgu.de
authors.forename: Anna L
authors.initials: AL
authors.lastname: Sander
authors.forename: Katharina
authors.initials: K
authors.lastname: Sommer
authors.forename: Thomas
authors.initials: T
authors.lastname: Neumayer
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Ingo
authors.initials: I
authors.lastname: Marzi
authors.forename: John H
authors.initials: JH
authors.lastname: Barker
authors.forename: Johannes
authors.initials: J
authors.lastname: Frank
authors.forename: Heike
authors.initials: H
authors.lastname: Jakob
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D062326:Re-Epithelialization / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D004851:Epoxide Hydrolases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D015126:8,11,14-Eicosatrienoic Acid