Olekson Melissa Przyborowski, Faulknor Renea A, Hsia Henry C, Schmidt Ann Marie, Berthiaume François
Department of Biomedical Engineering, Rutgers University , Piscataway, New Jersey.
Department of Surgery, Robert Wood Johnson Medical School, Rutgers University , New Brunswick, New Jersey.
Adv Wound Care (New Rochelle). 2016 Dec 1;5(12):527-538. doi: 10.1089/wound.2015.0674.
In diabetes, hyperglycemia causes the accumulation of advanced glycation end products (AGEs) that trigger reactive oxygen species (ROS) generation through binding the receptor for AGEs (RAGE). Because exogenous growth factors have had little success in enhancing chronic wound healing, we investigated whether hyperglycemia-induced AGEs interfere with cellular responses to extracellular signals. We used stromal cell-derived factor-1 (SDF-1), an angiogenic chemokine also known to promote stem cell recruitment in skin wounds. Human leukemia-60 (HL-60) cells and mouse peripheral blood mononuclear cells (PBMCs), which express the SDF-1 receptor CXCR-4, were incubated for 24 h in medium supplemented with 25 mM d-glucose. Soluble RAGE (sRAGE) was used to block RAGE activation. Response to SDF-1 was measured in cellular migration and ROS assays. A diabetic murine excisional wound model measured SDF-1 liposome and sRAGE activity . Hyperglycemia led to significant accumulation of AGEs, decreased SDF-1-directed migration, and elevated baseline ROS levels; it suppressed the ROS spike normally triggered by SDF-1. sRAGE decreased the ROS baseline and restored both the SDF-1-mediated spike and cell migration. Topically applied sRAGE alone promoted healing and enhanced the effect of exogenous SDF-1 on diabetic murine wounds. While there is interest in using growth factors to improve wound healing, this strategy is largely ineffective in diabetic wounds. We show that sRAGE may restore signaling, thus potentiating the effect of exogenously applied growth factors. Blocking RAGE with sRAGE restores SDF-1-mediated cellular responses in hyperglycemic environments and may potentiate the effectiveness of SDF-1 applied .
在糖尿病中，高血糖会导致晚期糖基化终产物（AGEs）的积累，这些产物通过与AGEs受体（RAGE）结合触发活性氧（ROS）的生成。由于外源性生长因子在促进慢性伤口愈合方面成效甚微，我们研究了高血糖诱导的AGEs是否会干扰细胞对细胞外信号的反应。我们使用了基质细胞衍生因子-1（SDF-1），这是一种血管生成趋化因子，也已知可促进皮肤伤口中的干细胞募集。将表达SDF-1受体CXCR-4的人白血病-60（HL-60）细胞和小鼠外周血单个核细胞（PBMC）在补充有25 mM d-葡萄糖的培养基中孵育24小时。使用可溶性RAGE（sRAGE）来阻断RAGE的激活。在细胞迁移和ROS测定中测量对SDF-1的反应。在糖尿病小鼠切除伤口模型中测量SDF-1脂质体和sRAGE的活性。高血糖导致AGEs大量积累，SDF-1介导的迁移减少，基线ROS水平升高；它抑制了通常由SDF-1触发的ROS峰值。sRAGE降低了ROS基线，并恢复了SDF-1介导的峰值和细胞迁移。单独局部应用sRAGE可促进愈合，并增强外源性SDF-1对糖尿病小鼠伤口的作用。虽然人们对使用生长因子来改善伤口愈合感兴趣，但这种策略在糖尿病伤口中大多无效。我们表明，sRAGE可能恢复信号传导，从而增强外源性应用生长因子的效果。用sRAGE阻断RAGE可恢复高血糖环境中SDF-1介导的细胞反应，并可能增强应用SDF-1的有效性。
