Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice

Receptor for advanced glycation end-products (RAGE), and two of its ligands , AGE and EN-RAGEs (members of the S100/calgranulin family of pro-inflammat ory cytokines), display enhanced expression in slowly resolving full-thickn ess excisional wounds developed in genetically diabetic db+/db+ mice. We te sted the concept that blockade of RAGE, using soluble(s) RAGE, the extracel lular ligand-binding domain of the receptor, would enhance wound closure in these animals. Administration of sRAGE accelerated the development of appr opriately limited inflammatory cell infiltration and activation in wound fo ci. In parallel with accelerated wound closure at later times, blockade of RAGE suppressed levels of cytokines; tumor necrosis factor-alpha; interleuk in-6; and matrix metalloproteinases-2, -3, and -9. In addition, generation of thick, well-vascularized granulation tissue was enhanced, in parallel wi th increased levels of platelet-derived growth factor-B and vascular endoth elial growth factor. These findings identify a central role for RAGE in dis ordered wound healing associated with diabetes, and suggest that blockade o f this receptor might represent a targeted strategy to restore effective wo und repair in this disorder.