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PMID: 11485910 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The American journal of pathology ·Vol. 159 ·No. 2 ·2001-08-00 ·Pages 513-25

Goova MT, Li J, Kislinger T, Qu W, Lu Y, Bucciarelli LG, Nowygrod S, Wolf BM, Caliste X, Yan SF, Stern DM, Schmidt AM

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.

MeSH Terms
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
Chemicals
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
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Goova M T
Department of Surgery, College of Physicians & Surgeons, Columbia University, 630 W. 168th St., New York, NY 10032, USA.
Li J
Kislinger T
Qu W
Lu Y
Bucciarelli L G
Nowygrod S
Wolf B M
Caliste X
Yan S F
Stern D M
Schmidt A M
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)61723-3
Published
2001-08-00
Pages
513-25
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1850533
Subset
IM
Grants
NHLBI NIH HHS · P01 HL060901 · United States
NHLBI NIH HHS · HL60901 · United States
Corrections
CommentIn
PMID: 11485896
External Links
PubMed source DOI: 10.1016/S0002-9440(10)61723-3 PMC Full Text View journal details
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