Center of Neuroscience Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Am J Pathol. 2011 Oct;179(4):1780-91. doi: 10.1016/j.ajpath.2011.06.026. Epub 2011 Aug 10.
Impaired macrophage functions imposed by diabetic complications and the suppressed formation of 14S,21R-dihydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA) in wounds contribute significantly to deficient wound healing in diabetics, but how are macrophage functions and 14S,21R-diHDHA formation associated? We studied 14S,21R-diHDHA generation from macrophages using liquid chromatography/mass spectrometry. The role in macrophage-mediated wound healing functions was determined using a murine splinted excisional wound healing model and in vitro assays. 14S,21R-diHDHA acts as a macrophage-generated autacoid, and its attenuated formation in macrophages of diabetic db/db mice was accompanied by impairment of macrophage prohealing functions. 14S,21R-diHDHA restored db/db macrophage-impaired prohealing functions by promoting wound re-epithelialization, formulation of granulation tissue, and vascularization. Additionally, 12/15-lipoxygenase-deficient macrophages, which are unable to produce 14S,21R-diHDHA, exhibited impaired prohealing functions, which also were restored by 14S,21R-diHDHA treatment. The molecular mechanism for 14S,21R-diHDHA-induced recovery of impaired prohealing functions of db/db macrophages involves enhancing their secretion of vascular endothelial growth factor and platelet-derived growth factor BB, decreasing hyperglycemia-induced generation of reactive oxygen species, and increasing IL-10 expression under inflammatory stimulation. Taken together, these results indicate that deficiency of 14S,21R-diHDHA formation by diabetic macrophages contributes to their impaired prohealing functions. Our findings provide mechanistic insights into wound healing in diabetics and suggest the possibility of using autologous macrophages/monocytes, treated with 14S,21R-diHDHA, or related compounds, to promote diabetes-impaired wound healing.
糖尿病并发症导致巨噬细胞功能受损，以及伤口中 14S,21R-二羟基二十二碳六烯酸（14S,21R-diHDHA）形成减少，这对糖尿病患者伤口愈合不良有重要影响，但巨噬细胞功能和 14S,21R-diHDHA 形成如何相关？我们使用液相色谱/质谱法研究了巨噬细胞中 14S,21R-diHDHA 的生成。使用小鼠夹板切创愈合模型和体外测定法，确定了其在巨噬细胞介导的伤口愈合功能中的作用。14S,21R-diHDHA 作为巨噬细胞产生的自分泌物质，其在糖尿病 db/db 小鼠巨噬细胞中的形成减少伴随着巨噬细胞前愈合功能受损。14S,21R-diHDHA 通过促进伤口再上皮化、肉芽组织形成和血管化，恢复了 db/db 巨噬细胞受损的前愈合功能。此外，不能产生 14S,21R-diHDHA 的 12/15-脂氧合酶缺陷型巨噬细胞表现出受损的前愈合功能，这种功能也可以通过 14S,21R-diHDHA 治疗得到恢复。14S,21R-diHDHA 诱导 db/db 巨噬细胞受损前愈合功能恢复的分子机制涉及增强其血管内皮生长因子和血小板衍生生长因子 BB 的分泌，减少高血糖诱导的活性氧生成，以及在炎症刺激下增加 IL-10 表达。综上所述，这些结果表明糖尿病巨噬细胞中 14S,21R-diHDHA 形成的缺乏导致其前愈合功能受损。我们的发现为糖尿病患者的伤口愈合提供了机制上的见解，并表明使用自体巨噬细胞/单核细胞，用 14S,21R-diHDHA 或相关化合物处理，可能促进糖尿病受损的伤口愈合。
