Impaired wound healing in Cushing's syndrome: the role of heat shock proteins.

Abstract

Glucocorticoids impair wound healing and cause surgical morbidity. Heat shock proteins are essential to cellular stress tolerance and are associated with glucocorticoids. The adrenal heat shock protein response is under hypothalmic-pituitary-adrenal-axis control, whereas the vascular response is associated with alpha-1 receptors. Because heat shock proteins affect cellular stress responses and are under hypothalmic-pituitary-adrenal-axis control in other tissues, we postulated an association between heat shock proteins and glucocorticoids in healing wounds. Modified Hunt-Schilling wound chambers were implanted subcutaneously in rats. They received subcutaneous time-release dexamethasone (25 mg) or placebo pellets. Wound chamber heat shock protein 25 and heat shock protein 72/73 were serially assayed for 21 days with western analysis and immunocytochemistry. Dexamethasone caused Cushing's syndrome with approximately 10% weekly weight-loss and adrenal atrophy. Total wound tissue decreased 90% with profound differences in molecular wound responses manifested by decreased heat shock protein 25, 72, and 73 in animals treated with dexamethasone despite equal protein loads. Furthermore, dexamethasone caused heat shock protein 72 redistribution by immunocytochemistry. This study represents the first description of heat shock proteins in a wound healing model and demonstrates tissue-specific decrease of heat shock proteins with glucocorticoid therapy. Thus the heat shock protein response is intimately associated with normal wound healing and is profoundly altered in subjects with Cushing's syndrome. Manipulation of this response may have clinical importance in wound healing.