title: Inhibition of stromal cell-derived factor-1α further impairs diabetic wound healing.
abstract: OBJECTIVE
  Impaired diabetic wound healing is associated with abnormal stromal cell-derived factor (SDF)-1α production, decreased angiogenesis, and chronic inflammation. Lentiviral-mediated overexpression of SDF-1α can correct the impairments in angiogenesis and healing in diabetic wounds. We hypothesized that SDF-1α is a critical component of the normal wound-healing response and that inhibition of SDF-1α would further delay the wound-healing process.
  
  
  METHODS
  dB/Db diabetic mice and Db/+ nondiabetic mice were wounded with an 8-mm punch biopsy and the wounds treated with a lentiviral vector containing either the green fluorescent protein (GFP) or SDF-1α inhibitor transgene. The inhibitor transgene is a mutant form of SDF-1α that binds, but does not activate, the CXCR4 receptor. Computerized planimetry was used to measure wound size daily. Wounds were analyzed at 3 and 7 days by histology and for production of inflammatory markers using real-time polymerase chain reaction. The effect of the SDF-1α inhibitor on cellular migration was also assessed.
  
  
  RESULTS
  Inhibition of SDF-1α resulted in a significant decrease in the rate of diabetic wound healing, (3.8 vs 6.5 cm(2)/day in GFP-treated wounds; P = .04), and also impaired the early phase of nondiabetic wound healing. SDF-1α inhibition resulted in fewer small-caliber vessels, less granulation tissue formation, and increased proinflammatory gene expression of interleukin-6 and macrophage inflammatory protein-2 in the diabetic wounds.
  
  
  CONCLUSIONS
  The relative level of SDF-1α in the wound plays a key role in the wound-healing response. Alterations in the wound level of SDF-1α, as seen in diabetes or by SDF-1α inhibition, impair healing by decreasing cellular migration and angiogenesis, leading to increased production of inflammatory cytokines and inflammation. Inhibition of SDF-1α further impairs diabetic wound healing.
authors.affiliation: Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pa, USA.
authors.forename: Dustin M
authors.initials: DM
authors.lastname: Bermudez
authors.forename: Junwang
authors.initials: J
authors.lastname: Xu
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Herdrich
authors.forename: Antoneta
authors.initials: A
authors.lastname: Radu
authors.forename: Marc E
authors.initials: ME
authors.lastname: Mitchell
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Liechty
mesh_terms: D000818:Animals; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000235:genetics; D054426:Chemokine CXCL2 / Q000235:genetics; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005822:Genetic Vectors; D006097:Granulation Tissue / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009154:Mutation; D018919:Neovascularization, Physiologic; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D013997:Time Factors; D014945:Wound Healing
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D054426:Chemokine CXCL2; C515256:Cxcl12 protein, mouse; C404915:Cxcl2 protein, mouse; D018836:Inflammation Mediators; D015850:Interleukin-6; D012333:RNA, Messenger; D019718:Receptors, CXCR4