Defective wound healing in diabetes continues to be an important cause of morbidity in the postoperative period, following trauma, and in the repair of cutaneous lesions. Advanced Glycation Endproducts (AGEs) are the result of nonenzymatic glycation/oxidation of proteins/lipids. Accelerated formation and accumulation of AGEs in tissues of patients with diabetes has been linked, in certain situations, to the development of secondary complications. An important means by which AGEs perturb homeostatic processes is through their interaction with cellular binding sites; the best characterized of these is Receptor for AGE or RAGE, an immunoglobulin superfamily molecule expressed by endothelium, monocytes, and smooth muscle cells, as well as mesangial cells and neurons. AGE engagement of RAGE leads to endothelial activation, with expression of adhesion molecules, enhanced procoagulant properties, and diminished barrier function; and perturbation of monocytes, with changes in cell motility and activation, resulting in expression of proinflammatory cytokines. The hypothesis guiding our studies is that interaction of AGEs with RAGE-bearing cells, especially endothelium and mononuclear phagocytes, promotes chronic cellular activation thereby preventing optimal wound healing as reflected by formation of granulation tissue and new connective tissue. Our pilot data are consistent with this concept: using a secondary intention wound model in diabetic mice, wound closure is enhanced following administration of soluble (s) RAGE, the extracellular domain of the receptor which binds to AGEs and prevents their interaction with cell surface RAGE.
Our specific aims will examine this concept in detail using genetically diabetic (db+/db+) mice by: (1) localizing subcutaneous sites of AGE accumulation and cells expressing RAGE, and assessing endothelial/monocyte activation using a wound model; and (2) determining if blockade of AGE-RAGE interaction will accelerate wound healing. If sRAGE has substantial beneficial effects on wound healing, this could suggest a potentially novel therapeutic target, AGE- RAGE interaction, for patients with diabetes. These experiments contribute to our long-term goal, understanding the contribution of cellular interactions of AGEs in the pathogenesis of diabetic complications.
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