Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Am J Pathol. 2012 Dec;181(6):2217-24. doi: 10.1016/j.ajpath.2012.08.023. Epub 2012 Nov 5.
Impaired wound healing is a major complication of diabetes. Recent studies have reported reduced lymphangiogenesis and angiogenesis during diabetic wound healing, which are thought to be new therapeutic targets. Statins have effects beyond cholesterol reduction and can stimulate angiogenesis when used systemically. However, the effects of topically applied statins on wound healing have not been well investigated. The present study tested the hypothesis that topical application of simvastatin would promote lymphangiogenesis and angiogenesis during wound healing in genetically diabetic mice. A full-thickness skin wound was generated on the back of the diabetic mice and treated with simvastatin or vehicle topically. Simvastatin administration resulted in significant acceleration of wound recovery, which was notable for increases in both angiogenesis and lymphangiogenesis. Furthermore, simvastatin promoted infiltration of macrophages, which produced vascular endothelial growth factor C in granulation tissues. In vitro, simvastatin directly promoted capillary morphogenesis and exerted an antiapoptotic effect on lymphatic endothelial cells. These results suggest that the favorable effects of simvastatin on lymphangiogenesis are due to both a direct influence on lymphatics and indirect effects via macrophages homing to the wound. In conclusion, a simple strategy of topically applied simvastatin may have significant therapeutic potential for enhanced wound healing in patients with impaired microcirculation such as that in diabetes.
伤口愈合受损是糖尿病的一个主要并发症。最近的研究报告称，糖尿病伤口愈合过程中的淋巴管生成和血管生成减少，这被认为是新的治疗靶点。他汀类药物除了降低胆固醇外，还可以通过全身使用来刺激血管生成。然而，局部应用他汀类药物对伤口愈合的影响尚未得到充分研究。本研究旨在检验以下假设：局部应用辛伐他汀可促进遗传性糖尿病小鼠伤口愈合过程中的淋巴管生成和血管生成。在糖尿病小鼠的背部制造全层皮肤伤口，并局部给予辛伐他汀或载体治疗。辛伐他汀给药导致伤口恢复明显加速，这在血管生成和淋巴管生成方面都有明显增加。此外，辛伐他汀促进了巨噬细胞的浸润，巨噬细胞在肉芽组织中产生血管内皮生长因子 C。在体外，辛伐他汀直接促进毛细血管形态发生，并对淋巴管内皮细胞发挥抗凋亡作用。这些结果表明，辛伐他汀对淋巴管生成的有利影响既归因于对淋巴管的直接影响，也归因于通过归巢到伤口的巨噬细胞的间接影响。总之，局部应用辛伐他汀的简单策略可能对改善糖尿病等微循环受损患者的伤口愈合具有重要的治疗潜力。
