Inhibition of stromal cell-derived factor-1α further impairs diabetic wound healing.
Inhibition of stromal cell-derived factor-1α further impairs diabetic wound healing.
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DOI：
10.1016/j.jvs.2010.10.056
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发表时间：
2011-03
影响因子：
4.3
通讯作者：
Liechty, Kenneth W.
中科院分区：
文献类型：
--
作者：
Bermudez, Dustin M.;Xu, Junwang;Herdrich, Benjamin J.;Radu, Antoneta;Mitchell, Marc E.;Liechty, Kenneth W.
糖尿病伤口愈合受损与SDF-1α产生异常、血管生成减少和慢性炎症相关。慢病毒介导的SDF-1α过表达可纠正糖尿病伤口血管生成和愈合的损伤。我们假设SDF-1α是正常伤口愈合反应的关键组分，抑制SDF-1α将进一步延迟伤口愈合过程。Db/Db糖尿病小鼠和Db/+非糖尿病小鼠用8 mm穿刺活检受伤，并用含有GFP或SDF-1α抑制剂转基因的慢病毒载体处理伤口。抑制剂转基因是SDF-1α的突变形式，其结合但不激活CXCR 4受体。每天使用计算机面积测量法测量伤口大小。在第3天和第7天通过组织学分析伤口，并使用实时PCR分析炎症标志物的产生。还评估了SDF-1α抑制剂对细胞迁移的影响。SDF-1α的抑制导致糖尿病伤口愈合率显著降低（3.8 cm 2/天vs 6.5 cm 2/天，GFP治疗伤口p=0.04），并且还损害了非糖尿病伤口愈合的早期阶段。SDF-1α抑制还导致糖尿病伤口中小口径血管减少，肉芽组织形成减少，促炎基因表达（IL-6和MIP-2）增加。创面中SDF-1α的相对水平在创面愈合反应中起着关键作用。如糖尿病或SDF-1α抑制中所见，SDF-1α伤口水平的改变通过减少细胞迁移和血管生成而损害愈合，导致炎性细胞因子和炎症的产生增加。
Impaired diabetic wound healing is associated with abnormal SDF-1α production, decreased angiogenesis, and chronic inflammation. Lentiviral-mediated overexpression of SDF-1α can correct the impairments in angiogenesis and healing in diabetic wounds. We hypothesized that SDF-1α is a critical component of the normal wound healing response and that inhibition of SDF-1α would further delay the wound-healing process. Db/Db diabetic mice and Db/+ non-diabetic mice were wounded with an 8mm punch biopsy and the wounds treated with a lentiviral vector containing either the GFP or SDF-1α inhibitor transgene. The inhibitor transgene is a mutant form of SDF-1α that binds, but does not activate, the CXCR4 receptor. Computerized planimetry was used to measure wound size daily. Wounds were analyzed at 3 and 7 days by histology and for production of inflammatory markers using real-time PCR. The effect of the SDF-1α inhibitor on cellular migration was also assessed. Inhibition of SDF-1α resulted in a significant decrease in the rate of diabetic wound healing, (3.8 cm2/day versus 6.5 cm2/day in GFP-treated wounds p=0.04), and also impaired the early phase of non-diabetic wound healing. SDF-1α inhibition also resulted in fewer small-caliber vessels, less granulation tissue formation, and increased proinflammatory gene expression (IL-6 and MIP-2) in the diabetic wounds. The relative level of SDF-1α in the wound plays a key role in the wound healing response. Alterations in the wound level of SDF-1α, as seen in diabetes or by SDF-1α inhibition, impair healing by decreasing cellular migration and angiogenesis, leading to increased production of inflammatory cytokines and inflammation.
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