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

The expression of the hypoxia-responsive transcription factor hypoxia-induc ible factor (HIF)-1 during acute inflammation was investigated in experimen tal wounds. HIF-1 alpha mRNA was maximally expressed in wound cells 6 h aft er injury. HIF-1 alpha protein was detectable in wound cells 1 and 5 days a fter injury. Cells from 1-day-old wounds were not hypoxic, as determined by lack of pimonidazole hydrochloride adduct formation. Tumor necrosis factor (TNF)-alpha, but not interleukin-1 beta, increased the HIF-1a protein cont ent of cells isolated 1 and 5 days after injury, and also of glycogen-elici ted peritoneal cells, but not HIF-1 alpha mRNA. HIF-1 alpha did not accumul ate in TNF-alpha -treated HeLa, NIH/3T3, NR8383, or RAW 264.7 cells. Nitric oxide from S-nitrosoglutathione did not induce HIF-1 alpha accumulation or modulate the response to TNF-alpha. TNF-alpha did not increase oxygen cons umption or result in the production of reactive oxygen intermediates by day 1 wound cells. Vascular endothelial growth factor mRNA in wound cells peak ed 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.