594 SURGERY WOUND HEALING IS A COMPLEX phenomenon that proceeds with inflammation and granulation tissue formation, followed by extracellular matrix deposi- tion and remodeling. 1 Clinical and experimental diabetes has been reported to alter most of these processes, including a reduction in angiogenesis, collagen biosynthesis, and inflammatory cell infil- tration. 2-7 A possible mediator of diabetes-related deficit in wound repair may include an elevation in the plasma level of glucocorticoids (GCs). 8 These hormones may regulate the expression of multiple genes that are likely to influence cell ability to respond to the stress of wounding. 9 Cells derived from various organs respond to meta- bolic stress by increasing the formation of a set of highly conserved proteins termed heat-shock or stress proteins (HSPs). A certain class of these HSPs with a molecular weight of about 70 kd appears to exhibit a cytoprotective role in that it makes a cell better able to survive an acute stress or injury. 10-17 Indeed, a loss of heat stress tolerance has been demonstrated in fibroblasts and neurons after they were microin- jected with an anti-HSP 70 antibody. 18,19 The HSPs 70 are also involved in normal cellular functions includ- ing protein folding, assembly, and translocation as well as DNA replication and repair. 20-22 Heat-shock protein 72/ 73 and impaired wound healing in diabetic and hypercortisolemic states Milad S. Bitar, MSc, PhD, FCP, Thameem Farook, PhD, Bency John, BSc, and Issam M. Francis, MD, PhD, Safat, Kuwait Background. Impaired wound healing is a well-documented phenomenon in experimental and clinical diabetes. Emerging evidence favors the involvement of glucocorticoids (GCs) in the pathogenesis of this diabetic complication. Recent data indicated that a heat-shock protein (HSP) with a molecular weight of about 70 kd is expressed in wound healing and it is under the control of the hypothalamic-pituitary- adrenal axis. In view of these findings, the current study was designed to examine the influence of dia- betes and the hypercortisolemic state on the expression of HSP 72/ 73 during wound healing. Methods. Induction of diabetes was achieved by the intravenous injection of streptozotocin at a dose of 55 mg/ kg. Subcutaneously implanted polyvinyl alcohol (PVA) sponges were used as a wound healing model. Control and diabetic animals received, respectively, subcutaneous 30-day timed-release pellets of GC (200 mg) and RU 486 (25 mg). Corresponding animals received placebo pellets. Expression of HSP 72/ 73 within the PVA sponges was assayed with use of Western blotting and immunohistochemical tech- n iqu es. Results. GCs caused a Cushing-like syndrome with weight loss and adrenal atrophy. A pronounced accumulation of constitutive HSP 72/ 73 was observed in the cytoplasm of various cell types including fibroblasts, macrophages, and endothelium of nondiabetic controls. The PVA sponge contents of HSP 72/ 73 were decreased as a function of diabetes. A similar phenomenon was seen in control animals receiving high doses of GCs. Partial normalization of the associated hyperglycemic and hypercortisolemic states of diabetes with insulin (hyperglycemia) and the GC receptor block RU 486 (hypercortisolemia) ameliorated the diabetes-related decrease in PVA sponge contents of HSP 72/ 73. Conclusions. The current study provides evidence that both diabetes and the hypercortisolemic state are associated with a reduction in PVA sponge content of HSP 72/ 73. An amelioration of these changes was achieved by the institution of RU 486 therapy. Although our data may point to the possibility that the diabetes-related decrease in HSP 72/ 73 is mediated at least in part by GCs, a confirmation regarding this premise awaits further investigation. (Surgery 1999;125:594-601.) From the Departments of Pharmacology and Toxicology and Pathology, Faculty of Medicine, Kuwait University, Safat, Kuwait Accepted for publication Feb 20, 1999. Supported by Kuwait University grant No. MR033. Reprint requests: Milad S. Bitar, MSc, PhD, FCP, Department of Pharmacology, Faculty of Medicine, PO Box 24923, 13110 Safat, Kuwait. Copyright © 1999 by Mosby, Inc. 0039-6060/ 99/ $8.00 + 0 11/ 56/ 98044