Glucocorticoid-dependent impairment of wound healing in experimental diabetes: Amelioration by adrenalectomy and RU 486

Background. Failure of wounds to heal represents one of the major diabetic complications. Emerging evidence favors the involvement of glucocorticoids (GCs) in the pathogenesis of impaired wound healing in diabetes mellitus. Objective. The purpose of this study was to examine wound healing potential in diabetics under conditions in which the hypercortisolemic state is normalized. Design and intervention, Linear skin incision and polyvinyl alcohol (PVA) sponge were used as wound healing models. Six groups of rats matched with respect to age, sex, and strain were included in this study. Animals in groups 1 and 6 were injected with citrate buffer, whereas rats in groups 2,3,4, and 5 received streptozotocin (STZ, 55 mg/kg iv in citrate buffer). Five days later animals in groups 4,5, and 6 received insulin (group 4) and subcutaneous implantation of slow-releasing pellets containing either the GC receptor blocker RU 486 (group 5) or a high dose of GC (group 6). Main outcome measurements. Skin wound tensile strength and PVA sponge collagen metabolism were determined using tensiometric, spectrophotometric, and polymerase chain reaction-based assays. In addition, cell infiltration and granulation tissue growth were assessed using a well-established histochemical technique. Results. Wound-related parameters including fibroplasia, neovascularization, and inflammatory cell numbers were reduced as a function of diabetes. Similarly, skin mound tensile strength, PVA sponge hydroxyproline content, and the levels of mRNA transcripts for type I and LII collagen were also decreased in this disease state. This diabetes-related deficit in wound healing potential was ameliorated by subjecting diabetic animals to insulin treatment or by counteracting the excessive actions of GCs using both pharmacological (RU 486) and endocrinological (ADX) paradigms. Conclusion. The current study supports the notion that GCs are implicated in the wound healing deficit of diabetics. Moreover, it illuminates the therapeutic potential of the GC receptor blocker (e.g., RU 486) in promoting mound repair wider hypercortisolemic conditions including diabetes and Cushing's syndrome. (C) 199 Academic Press.