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

Abstract

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-alpha; 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.

• Authors: M T Goova, J Li, T Kislinger, W Qu, Y Lu, L G Bucciarelli, S Nowygrod, B M Wolf, X Caliste, S F Yan, D M Stern, A M Schmidt
• Journal: The American journal of pathology (Am J Pathol) Vol. 159 Issue 2 Pg. 513-25 (Aug 2001) ISSN: 0002-9440 [Print] United States
• PMID: 11485910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytokines
• Endothelial Growth Factors
• Glycation End Products, Advanced
• Lymphokines
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Becaplermin
• Matrix Metalloproteinase 3
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Animals
• Becaplermin
• Binding Sites
• Cytokines (biosynthesis)
• Diabetes Mellitus, Type 1 (genetics, pathology, physiopathology)
• Endothelial Growth Factors (metabolism)
• Gene Expression Regulation
• Glycation End Products, Advanced (physiology)
• Granuloma (pathology, physiopathology)
• Lymphokines (metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 3 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Models, Biological
• Neovascularization, Physiologic
• Platelet-Derived Growth Factor (metabolism)
• Proto-Oncogene Proteins c-sis
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic (antagonists & inhibitors, physiology, therapeutic use)
• Time Factors
• Tumor Necrosis Factor-alpha (biosynthesis)
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Wound Healing (genetics, physiology)
• Wounds and Injuries (pathology, physiopathology)