HIF-1 expression in healing wounds: HIF-1α induction in primary inflammatory cells by TNF-α

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Abstract
The expression of the hypoxia-responsive transcription factor hypoxia-inducible factor (HIF)-1 during acute inflammation was investigated in experimental wounds. HIF-1α mRNA was maximally expressed in wound cells 6 h after injury. HIF-1α protein was detectable in wound cells 1 and 5 days after injury. Cells from 1-day-old wounds were not hypoxic, as determined by lack of pimonidazole hydrochloride adduct formation. Tumor necrosis factor (TNF)-α, but not interleukin-1β, increased the HIF-1α protein content of cells isolated 1 and 5 days after injury, and also of glycogen-elicited peritoneal cells, but not HIF-1α mRNA. HIF-1α did not accumulate in TNF-α-treated HeLa, NIH/3T3, NR8383, or RAW 264.7 cells. Nitric oxide fromS-nitrosoglutathione did not induce HIF-1α accumulation or modulate the response to TNF-α. TNF-α did not increase oxygen consumption or result in the production of reactive oxygen intermediates by day 1 wound cells. Vascular endothelial growth factor mRNA in wound cells peaked 24 h after wounding. HIF-1 expression in early wounds may contribute to the regulation of inducible nitric oxide synthase and vascular endothelial growth factor, two HIF-1-responsive genes intimately related to the process of repair.