Receptor for advanced glycation end-products (RAGE), and two of its ligands, AGE and EN-RAGEs (members of the S100/calgranulin family of pro-inflammatory cytokines), display enhanced expression in slowly resolving full-thickness excisional wounds developed in genetically diabetic db+/db+ mice. We tested the concept that blockade of RAGE, using soluble(s) RAGE, the extracellular ligand-binding domain of the receptor, would enhance wound closure in these animals. Administration of sRAGE accelerated the development of appropriately limited inflammatory cell infiltration and activation in wound foci. In parallel with accelerated wound closure at later times, blockade of RAGE suppressed levels of cytokines; tumor necrosis factor-α; interleukin-6; and matrix metalloproteinases-2, -3, and -9. In addition, generation of thick, well-vascularized granulation tissue was enhanced, in parallel with increased levels of platelet-derived growth factor-B and vascular endothelial growth factor. These findings identify a central role for RAGE in disordered wound healing associated with diabetes, and suggest that blockade of this receptor might represent a targeted strategy to restore effective wound repair in this disorder.
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Supported by grants from the Surgical Research Fund, Department of Surgery, College of Physicians and Surgeons, Columbia University; the United States Public Health Service grant HL60901 (to A. M. S., S. F. Y., and D. M. S.); grant JDRF4-200-945 from the Juvenile Diabetes Research Foundation International (to A. M. S. and D. M. S.); and BWC APP 2601 from the Burroughs Wellcome Fund. L. B. is a Postdoctoral Research Fellow of the Juvenile Diabetes Research Foundation International (grant JDRF 3-2000-112), and A. M. S. is a recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.
