Stress activates the hypothalamic-pituitary-adrenal (HPA) axis resulting in increased serum glucocorticoids (GCs); GCs are used clinically for their potent anti-inflammatory actions. Thus, because the stress-induced increase in GC is anti-inflammatory, stress predictably suppresses the inflammatory phase of wound healing and slows closure of cutaneous wounds. Previous studies from this laboratory suggest that the steroid hormone dehydroepiandrosterone (DHEA) and its metabolites androstenediol (AED) and androstenetriol (AET) counter-regulate the immune-suppressive functions of GCs. Thus we hypothesized that pharmacological treatment of animals with AED would diminish the health adverse effects of elevated GCs. It is further hypothesized that by counterbalancing the GC-mediated transcriptional regulation of cytokine gene expression through interactions with the transcriptional activator NF-κB, AED will restore inflammation and improve wound healing in stressed animals.
A murine model of cutaneous wound healing was used. Male CD-1 mice underwent daily cycles of restraint stress (RST), which began three days prior to wounding. Animals were treated with AED at 3 timepoints, while control animals received vehicle treatment. Photoplanimetry was utilized to assess healing kinetics of the wounds. Wounds were harvested at various times and processed for real time PCR analysis, or the TransAM™ assay.
The results show that RST delayed wound closure and altered the kinetics of inflammatory gene expression compared to control animals and did so by modulating NF-κB activation. Treatment with AED prevented the anti-inflammatory effects of RST and augmented NF-κB driven gene expression above control levels. Preliminary data suggest the effects of AED are manifest at the level of transcription initiation complex formation, and future studies will test this hypothesis. In conclusion, the data indicate that AED may be a viable pharmacological approach to functionally antagonize the effects of stress and presumably glucocorticoids, thereby improving wound healing.