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A Protocol for Constructing a Rat Wound Model of Type 1 Diabetes
Published on: February 17, 2023
Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice
1Department of Surgery, College of Physicians & Surgeons, Columbia University, 630 W. 168th St., New York, NY 10032, USA.
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.
Insights
Blocking the receptor for advanced glycation end-products (RAGE) with soluble RAGE (sRAGE) accelerated wound closure in diabetic mice. This treatment reduced inflammation and promoted tissue repair, suggesting RAGE blockade as a therapeutic strategy for diabetic wound healing.
Area of Science:
- Biomedical Science
- Wound Healing Research
- Diabetic Complications
Background:
- Enhanced expression of Receptor for Advanced Glycation End-products (RAGE) and its ligands (AGEs, EN-RAGEs) is observed in diabetic wounds.
- Disordered wound healing is a significant complication of diabetes mellitus.
Purpose of the Study:
- To investigate the therapeutic potential of blocking RAGE signaling in diabetic wound healing.
- To determine if soluble RAGE (sRAGE) administration can accelerate wound closure in a mouse model of diabetes.
Main Methods:
- Utilized genetically diabetic db+/db+ mice with full-thickness excisional wounds.
- Administered soluble RAGE (sRAGE) to block RAGE activity.
- Assessed wound closure rates, inflammatory cell infiltration, cytokine levels (TNF-α, IL-6), matrix metalloproteinases (MMPs), and granulation tissue formation.
Main Results:
- sRAGE administration accelerated wound closure and normalized inflammatory responses.
- RAGE blockade significantly suppressed pro-inflammatory cytokines (TNF-α, IL-6) and MMPs (-2, -3, -9).
- Enhanced granulation tissue formation, vascularization, and increased levels of growth factors (PDGF-B, VEGF) were observed.
Conclusions:
- RAGE plays a critical role in the impaired wound healing observed in diabetes.
- Blockade of RAGE using sRAGE demonstrates a promising targeted strategy to improve wound repair in diabetic individuals.
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