Tissue-specific role of Nrf2 in the treatment of diabetic foot ulcers during hyperbaric oxygen therapy
Tissue-specific role of Nrf2 in the treatment of diabetic foot ulcers during hyperbaric oxygen therapy
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DOI：
10.1016/j.freeradbiomed.2019.04.031
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发表时间：
2019-07-01
影响因子：
7.4
通讯作者：
Ramkumar, Kunka Mohanram
中科院分区：
文献类型：
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作者：
Dhamodharan, Umapathy;Karan, Amin;Ramkumar, Kunka Mohanram
高压氧（HBO）治疗被证明是非常成功的糖尿病足溃疡（DFU）的治疗，由于其抗菌作用，增加血管生成和增强胶原蛋白的合成。本研究探讨了高压氧治疗的分子机制，特别是Nrf 2在创伤愈合过程中的作用。此外，我们还研究了溃疡组织中血管生成标志物的水平及其与Nrf 2的相关性，并与DFU的标准治疗（非HBO）进行了比较。共招募了32名患者，并将其随机分配至单独的标准伤口护理程序（n= 17）或HBO治疗联合标准伤口护理程序（n=15），持续20天。我们的研究结果表明，与非HBO治疗相比，接受HBO治疗的患者中Nrf 2沿着其下游靶点的组织水平显著增加。此外，HBO治疗诱导血管生成，如通过组织样品中血管生成标志物如EGF、VEGF、PDGF、FGF-2和CXCL 10的水平增加来评估的。HBO治疗组eNOS表达和亚硝酸盐浓度均显著高于非HBO治疗组。此外，HBO治疗使巨噬细胞敏感以释放FGF-2和EGF，从而促进血管生成。此外，它增加了中性粒细胞引诱剂CXCL-8的水平，从而促进了趋化因子CCL 2的释放，CCL 2是一种众所周知的新血管形成介质。Pearson相关分析显示Nrf 2与EGF、VEGF、PDGF呈正相关。总之，本研究的结果表明，高压氧治疗促进伤口愈合，增加氧气供应和分布到受损组织，刺激血管生成，减少炎症，并增加亚硝酸盐水平。增加的Nrf 2水平瞬时调节伤口活检中血管生成基因的表达，这可能导致慢性伤口的加速愈合。
Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic foot ulcer (DFU) treatment due to its antimicrobial effect, increased angiogenesis and enhanced collagen synthesis. The molecular mechanism underlying HBO therapy particularly the involvement of Nrf2 in the wound healing process was investigated in the present study. In addition, we have studied the levels of angiogenic markers in ulcer tissues and their correlation with Nrf2 during HBO therapy compared with standard therapy (Non-HBO) for DFU. A total of 32 Patients were recruited and randomized to standard wound care procedure alone (n= 17) or HBO therapy in combination with standard wound care procedure (n=15) for 20 days. Our results showed that the tissue levels of Nrf2 along with its downstream targets were significantly increased in patients who underwent HBO therapy when compared to Non-HBO therapy. Further, HBO therapy induced angiogenesis as assessed by increased levels of angiogenesis markers such as EGF, VEGF, PDGF, FGF-2 and CXCL10 in the tissue samples. The expressions of eNOS and nitrite concentrations were also significantly increased in HBO therapy when compared to Non-HBO therapy subjects. Moreover, HBO therapy sensitises the macrophages to release FGF-2 and EGF thereby promotes angiogenesis. Further, it increased the levels of neutrophil attractant CXCL-8 thereby promotes the release of chemokine CCL2, a well-known mediator of neovascularization. The Pearson correlation showed that Nrf2 has a positive correlation with EGF, VEGF and PDGF. In conclusion, the findings of the present study suggest that HBO therapy promotes wound healing by increasing oxygen supply and distribution to damaged tissues, stimulating angiogenesis, decreasing inflammation, and increasing the nitrite levels. Increased levels of Nrf2 transiently regulate the expression of angiogenic genes in wound biopsies, which may result in accelerated healing of chronic wounds.