1] Department of General Surgery, First Hospital Affiliated to Medical School, Xi'an Jiaotong University, Xi'an, China [2] Hendrix Burn Laboratory, Section of Surgical Sciences, Department of Surgery, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Gene Ther. 2013 Nov;20(11):1070-6. doi: 10.1038/gt.2013.32. Epub 2013 Jun 20.
Impaired burn wound healing in the elderly represents a major clinical problem. Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator that orchestrates the cellular response to hypoxia. Its actions in dermal wounds promote angiogenesis and improve healing. In a murine burn wound model, aged mice had impaired wound healing associated with reduced levels of HIF-1. When gene therapy with HIF-1 alone did not correct these deficits, we explored the potential benefit of HIF-1 gene therapy combined with the intravenous infusion of bone marrow-derived angiogenic cells (BMDACs) cultured with dimethyloxalylglycine (DMOG). DMOG is known to reduce oxidative degradation of HIF-1. The mice treated with a plasmid DNA construct expressing a stabilized mutant form of HIF-1α (CA5-HIF-1α)+BMDACs had more rapid wound closure. By day 17, there were more mice with completely closed wounds in the treated group (χ(2), P=0.05). The dermal blood flow measured by laser Doppler showed significantly increased wound perfusion on day 11. Homing of BMDACs to the burn wound was dramatically enhanced by CA5-HIF-1α gene therapy. HIF-1α mRNA expression in the burn wound was increased after transfection with CA5-HIF-1α plasmid. Our findings offer insight into the pathophysiology of burns in the elderly and point to potential targets for developing new therapeutic strategies.
老年人烧伤创面愈合受损是一个主要的临床问题。缺氧诱导因子-1（HIF-1）是一种转录激活因子，可协调细胞对缺氧的反应。其在皮肤创面中的作用可促进血管生成并改善愈合。在小鼠烧伤创面模型中，老年小鼠创面愈合受损，HIF-1 水平降低。当单独使用 HIF-1 基因治疗不能纠正这些缺陷时，我们探讨了 HIF-1 基因治疗联合静脉输注用二甲草酰甘氨酸（DMOG）培养的骨髓源性血管生成细胞（BMDAC）的潜在益处。DMOG 可减少 HIF-1 的氧化降解。用表达稳定突变型 HIF-1α（CA5-HIF-1α）的质粒 DNA 构建体治疗的小鼠具有更快的创面闭合。到第 17 天，治疗组中完全闭合创面的小鼠更多（卡方检验，P=0.05）。激光多普勒测量的皮肤血流显示第 11 天创面灌注明显增加。CA5-HIF-1α 基因治疗可显著增强 BMDAC 向烧伤创面的归巢。用 CA5-HIF-1α 质粒转染后，烧伤创面中 HIF-1α mRNA 的表达增加。我们的研究结果深入了解了老年人烧伤的病理生理学，并为开发新的治疗策略提供了潜在的靶点。
