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Plast Reconstr Surg. 2009 Feb;123(2 Suppl):65S-75S. doi: 10.1097/PRS.0b013e318191bdf4.

SDF-1 alpha expression during wound healing in the aged is HIF dependent.

Author information

  • 1Department of Surgery, Division of Plastic Surgery, 257 Campus Drive, GK-201, Stanford, CA 94305-5148, USA.

Abstract

BACKGROUND:

Age-related impairments in wound healing are associated with decreased neovascularization, a process that is regulated by hypoxia-responsive cytokines, including stromal cell-derived factor (SDF)-1 alpha. Interleukin-1 beta is an important inflammatory cytokine involved in wound healing and is believed to regulate SDF-1 alpha expression independent of hypoxia signaling. Thus, the authors examined the relative importance of interleukin (IL)-1 beta and hypoxia-inducible factor (HIF)-1 alpha on SDF-1 alpha expression in aged wound healing.

METHODS:

Young and aged mice (n = 4 per group) were examined for wound healing using a murine excisional wound model. Wounds were harvested at days 0, 1, 3, 5, and 7 for histologic analysis, immunohistochemistry, enzyme-linked immunosorbent assay, and Western blot. An engineered wild-type and mutated SDF luciferase reporter construct were used to determine HIF transactivation.

RESULTS:

Aged mice demonstrated significantly impaired wound healing, reduced granulation tissue, and increased epithelial gap compared with young controls. Real-time polymerase chain reaction demonstrated reduced SDF-1 alpha levels in aged wounds that correlated with reduced CD31+ neovessels. Western blots revealed decreased HIF-1 alpha protein in aged wounds. However, both IL-1 beta and macrophage infiltrate were unchanged between young and aged animals. Using the wild-type and mutated SDF luciferase reporter construct in which the hypoxia response element was deleted, only young fibroblasts were able to respond to IL-1 beta stimulation, and this response was abrogated by mutating the HIF-binding sites. This suggests that HIF binding is essential for SDF-1 transactivation in response to both inflammatory and hypoxic stimuli.

CONCLUSIONS:

SDF-1 alpha deficiency observed during aged wound healing is attributable predominantly to decreased HIF-1 alpha levels rather than impaired IL-1 beta expression.

PMID:
19182665
[PubMed - indexed for MEDLINE]
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