Objective
Impaired diabetic wound healing is associated with abnormal 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.
Design of study
Db/Db diabetic mice and Db/+ non-diabetic mice were wounded with an 8mm punch biopsy and the wounds treated with a lentiviral vector containing either the 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 PCR. 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 cm2/day versus 6.5 cm2/day in GFP-treated wounds p=0.04), and also impaired the early phase of non-diabetic wound healing. SDF-1α inhibition also resulted in fewer small-caliber vessels, less granulation tissue formation, and increased proinflammatory gene expression (IL-6 and MIP-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.