Center of Neuroscience Excellence, Louisiana State University Health Science Center, New Orleans, Louisiana 70112, USA.
J Biol Chem. 2011 Feb 11;286(6):4443-53. doi: 10.1074/jbc.M110.100388. Epub 2010 Nov 26.
Treatment of diabetes-impaired wound healing remains a major unresolved medical challenge. Here, we identified suppressed formation of a novel reparative lipid mediator 14S,21R-dihydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA) in cutaneous wounds of diabetic db/db mice. These results indicate that diabetes impedes the biosynthetic pathways of 14S,21R-diHDHA in skin wounds. Administration of exogenous 14S,21R-diHDHA to wounds in diabetic animals rescued healing and angiogenesis. When db/db mesenchymal stem cells (MSCs) were administered together with 14S,21R-diHDHA to wounds in diabetic animals, they coacted to accelerate wound re-epithelialization, granulation tissue formation, and synergistically improved vascularization. In the pivotal cellular processes of angiogenesis, 14S,21R-diHDHA enhanced VEGF release, vasculature formation, and migration of db/db dermal microvascular endothelial cells (DMVECs), as well as remedied paracrine angiogenic functions of db/db MSCs, including VEGF secretion and the promotion of DMVEC migration and vasculature formation. Our results show that 14S,21R-diHDHA activates the p38 MAPK pathway in wounds, db/db MSCs, and DMVECs. Overall, the impeded formation of 14S,21R-diHDHA described in this study suggests that diabetes could affect the generation of pro-healing lipid mediators in wound healing. By restoring wound healing and MSC functions, 14S,21R-diHDHA is a new lead for the development of better therapeutics used in treating wounds of diabetics.
糖尿病导致的伤口愈合受损仍然是一个重大的医学难题。在这里，我们发现，糖尿病 db/db 小鼠皮肤伤口中一种新型修复性脂质介质 14S,21R-二羟基二十二碳六烯酸（14S,21R-diHDHA）的生成受到抑制。这些结果表明，糖尿病会阻碍皮肤伤口中 14S,21R-diHDHA 的生物合成途径。向糖尿病动物的伤口中给予外源性 14S,21R-diHDHA 可挽救其愈合和血管生成。当将 db/db 间充质干细胞（MSCs）与 14S,21R-diHDHA 一起给予糖尿病动物的伤口时，它们协同作用可加速伤口再上皮化、肉芽组织形成，并协同改善血管化。在血管生成的关键细胞过程中，14S,21R-diHDHA 增强了 VEGF 的释放、血管形成和 db/db 真皮微血管内皮细胞（DMVECs）的迁移，同时纠正了 db/db MSCs 的旁分泌血管生成功能，包括 VEGF 分泌以及促进 DMVEC 迁移和血管形成。我们的结果表明，14S,21R-diHDHA 在伤口、db/db MSCs 和 DMVECs 中激活了 p38 MAPK 通路。总的来说，本研究中描述的 14S,21R-diHDHA 形成受阻表明，糖尿病可能会影响伤口愈合中促愈合脂质介质的生成。通过恢复伤口愈合和 MSC 功能，14S,21R-diHDHA 为开发治疗糖尿病患者伤口的更好疗法提供了新的线索。
