Early wound healing exhibits cytokine surge without evidence of hypoxia

Objective To ascertain the spatial and temporal relation of wound hypoxia to the cell types involved, expression of selected angiogenic cytokines, the prolifera tive status of cells in the wound site, and angiogenesis. Summary Background Data Hypoxia is considered to drive the angiogenic response by upregulating angi ogenic cytokines observed during wound healing. But this correlation has no t been shown on a cell-to cell basis in vivo because of limitations in meas uring tissue Po-2 at the cellular level. Methods Using punch biopsy wounds in rats as a wound healing model, the distributio ns 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. Results Hypoxia was absent on day 1 after wounding, even though angiogenesis and ma ximal expression of cytokines were observed in the wounds. Hypoxia peaked i n the granulation tissue stage at day 4 and correlated with increased cellu larity and cellular proliferation. Hypoxia started to decrease after day 4 and was limited to the remnant blood vessels and epithelial layer in the sc ar tissue. Conclusions 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 pr oliferation regress suggest its involvement in initiating vascular regressi on during the later stages of healing.