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.


METHODS
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).


METHODS
Skin wound tensile strength and PVA sponge collagen metabolism were determined using tensiometric, spectrosphotometric, 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 wound tensile strength, PVA sponge hydroxyproline content, and the levels of mRNA transcripts for type I and III 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.


CONCLUSIONS
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 wound repair under hypercortisolemic conditions including diabetes and Cushing's syndrome.
Bitar
M S
MS
Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, 13110 Safat, Kuwait.
Farook
T
T
Wahid
S
S
Francis
I M
IM
D000315:Adrenalectomy; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D005938:Glucocorticoids / Q000502:physiology*; D006727:Hormone Antagonists / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D015735:Mifepristone / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000293:injuries; D014945:Wound Healing / Q000187:drug effects; D014950:Wounds, Penetrating / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000601:surgery
D005938:Glucocorticoids; D006727:Hormone Antagonists; D007004:Hypoglycemic Agents; D007328:Insulin; D015735:Mifepristone