Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice
Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice
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DOI：
10.1016/s0002-9440(10)61723-3
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发表时间：
2001-08-01
影响因子：
6
通讯作者：
Schmidt, AM
中科院分区：
文献类型：
--
作者：
Goova, MT;Li, J;Schmidt, AM
晚期糖基化终产物受体（RECEPTOR for Advanced Glycation End-products，简称AGEs）及其两种配体AGE和EN-RAGE（促炎细胞因子S100/钙颗粒蛋白家族成员）在遗传性糖尿病db+/db+小鼠中缓慢消退的全层切除伤口中表现出增强的表达。我们测试了使用可溶性受体的胞外配体结合结构域阻断受体的概念，将增强这些动物的伤口闭合。施用硫酸钠加速了伤口病灶中适当限制的炎性细胞浸润和活化的发展。在加速伤口闭合的同时，阻断TNF抑制了细胞因子、肿瘤坏死因子-α、白细胞介素-6和基质金属蛋白酶-2、-3和-9的水平。此外，生成厚，血管化良好的肉芽组织增强，与血小板衍生生长因子-B和血管内皮生长因子水平的增加平行。这些研究结果确定了一个核心的作用，在与糖尿病相关的伤口愈合障碍，并表明，该受体的封锁可能是一个有针对性的策略，以恢复有效的伤口修复这种疾病。
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.