Inhibition of stromal cell-derived factor-1alpha further impairs diabetic wound healing.

摘要

OBJECTIVE: Impaired diabetic wound healing is associated with abnormal stromal cell-derived factor (SDF)-1alpha production, decreased angiogenesis, and chronic inflammation. Lentiviral-mediated overexpression of SDF-1alpha can correct the impairments in angiogenesis and healing in diabetic wounds. We hypothesized that SDF-1alpha is a critical component of the normal wound-healing response and that inhibition of SDF-1alpha 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-1alpha inhibitor transgene. The inhibitor transgene is a mutant form of SDF-1alpha 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-1alpha inhibitor on cellular migration was also assessed. RESULTS: Inhibition of SDF-1alpha 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-1alpha 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-1alpha in the wound plays a key role in the wound-healing response. Alterations in the wound level of SDF-1alpha, as seen in diabetes or by SDF-1alpha inhibition, impair healing by decreasing cellular migration and angiogenesis, leading to increased production of inflammatory cytokines and inflammation. Inhibition of SDF-1alpha further impairs diabetic wound healing.