Early Wound Healing Exhibits Cytokine Surge Without Evidence of Hypoxia

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Abstract
To ascertain the spatial and temporal relation of wound hypoxia to the cell types involved, expression of selected angiogenic cytokines, the proliferative status of cells in the wound site, and angiogenesis. Hypoxia is considered to drive the angiogenic response by upregulating angiogenic cytokines observed during wound healing. But this correlation has not been shown on a cell-to-cell basis in vivo because of limitations in measuring tissue PO2 at the cellular level. Using punch biopsy wounds in rats as a wound healing model, the distributions of vascular endothelial growth factor, transforming growth factor-beta, tumor necrosis factor-alpha, and pimonidazole adducts (as a hypoxia marker) were followed immunohistochemically during the healing process. Hypoxia was absent on day 1 after wounding, even though angiogenesis and maximal expression of cytokines were observed in the wounds. Hypoxia peaked in the granulation tissue stage at day 4 and correlated with increased cellularity and cellular proliferation. Hypoxia started to decrease after day 4 and was limited to the remnant blood vessels and epithelial layer in the scar tissue. Induction of angiogenic cytokines early during wound healing may be due to triggering mechanisms other than hypoxia. Alternatively, the unique pattern of development and decline of cellular hypoxia as wound cellularity and proliferation regress suggest its involvement in initiating vascular regression during the later stages of healing.