NEUROENDOCRINE REGULATION OF WOUND HEALING DURING AGING

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Efficient cutaneous wound healing quickly restores the protective barrier to an injured surface. However, delayed healing can occur as a consequence of any number of processes that affect the early inflammatory stages of wound healing. For example, the physiological changes associated with aging and the immunosuppressive influences of psychological stress have been shown to slow wound healing. Pro- inflammatory cytokine, chemokine and growth factor responses are necessary for the coordinated function of polymorphonuclear leukocytes, monocytes and keratinocytes at the wound site. Therefore, the rapid expression of genes encoding immunomodulatory proteins and peptides is necessary for efficient healing. Combined with age-related immunosenescence, stress puts elderly individuals at high risk for infection after surgical or accidental wounds. With advancing age and during times of stress there is an increase in the cortisol/DHEA ration in the blood which may be responsible for catabolic effects associated with both states. DHEA (and its metabolite, AED) have been reported to have immunorestorative, anti-aging and anti-glucocorticoid properties. Therefore, in these studies we will investigate how AED counter balances age- and stress-mediated decrements in inflammatory/immune responses during cutaneous wound healing. An established murine model will be used to examine the kinetics and patterns of gene expression during the early phases. Further studies will seek to identify stress and age associated variables that modulate the expression of pro-inflammatory cytokine, chemokine and growth factor genes. The specific aims of this application are: (a) Determine the influence of stress and aging on the pattern and kinetics of pro-inflammatory cytokine, chemokine, and growth factor gene expression during the early stages of wound healing; (b) Examine the stress-induced neuroendocrine responses that impact gene expression during wound healing; (3) Determine the therapeutic efficacy of androstenediol (a metabolite of DHEA) treatment in the context stress- and age-associated slowing of wound healing.