Center of Neuroscience Excellence, Health Science Center, Louisiana State University, New Orleans, LA 70112, USA.
J Lipid Res. 2010 May;51(5):923-32. doi: 10.1194/jlr.M000059. Epub 2009 Nov 5.
Chronic wounds remain a medical challenge, where well-coordinated cellular and molecular processes required by optimal healing are impaired by diabetes, aging, or other diseases. In determining mechanisms that regulate wound healing, we found that wounding induced formation of novel endogenous 14S,21S-dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acids (14S,21S-diHDHA);14R,21R-diHDHA; 14S,21R-diHDHA; and/or 14R,21S-diHDHA. 12-lipoxygenase and cytochrome P450 catalysis in tandem converted docosahexaenoic acid to 14S,21R-diHDHA and 14S,21S-diHDHA through the intermediacy of 14S-HDHA; P450 also converted 14R-HDHA to novel 14R,21R-diHDHA and 14R,21S-diHDHA. Macrophages function as the combination of 12-lipoxgenase and P450 to generate these 14,21-diHDHA stereoisomers, as well as their intermediates 14S-HDHA, 14R-HDHA, and 21-HDHA. The structure and formation pathways of 14,21-diHDHA stereoisomers were further confirmed by macrophage biosynthesis of 14,21-diHDHA-21,22,22,22-d(4) stereoisomers, 14S-HDHA-d(5), 14R-HDHA-d(5), and 21-HDHA-d(4) from DHA-21,21,22,22,22-d(5). We found that 14S,21-diHDHA and 14R,21-diHDHA enhanced wound closure, reepithelialization, granulation tissue growth, and capillary vasculature formation of murine wounds. 14S,21-diHDHA and 14R,21-diHDHA produced by macrophages may partially represent the molecular mechanisms for macrophage pro-healing function. Taken together, 14,21-dihydroxy-DHA stereoisomers and their formation pathways may represent a novel mechanism in the orchestration of wound healing processes, which may provide new insight for developing novel therapeutic modalities that counteract impairments to wound healing.
慢性伤口仍然是一个医学挑战，在糖尿病、衰老或其他疾病的影响下，最佳愈合所需的细胞和分子过程受到损害。在确定调节伤口愈合的机制时，我们发现创伤诱导形成新型内源性 14S，21S-二羟基二十二碳六烯酸（14S，21S-二 HDHA）；14R，21R-二 HDHA；14S，21R-二 HDHA；和/或 14R，21S-二 HDHA。12-脂氧合酶和细胞色素 P450 催化串联反应通过 14S-HDHA 中间体将二十二碳六烯酸转化为 14S，21R-二 HDHA 和 14S，21S-二 HDHA；P450 还将 14R-HDHA 转化为新型 14R，21R-二 HDHA 和 14R，21S-二 HDHA。巨噬细胞作为 12-脂氧合酶和 P450 的组合，生成这些 14,21-二 HDHA 立体异构体，以及它们的中间体 14S-HDHA、14R-HDHA 和 21-HDHA。通过巨噬细胞生物合成 DHA-21,21,22,22,22-d(4) 立体异构体、14S-HDHA-d(5)、14R-HDHA-d(5)和 21-HDHA-d(4)，进一步证实了 14,21-二 HDHA 立体异构体的结构和形成途径。我们发现 14S，21-二 HDHA 和 14R，21-二 HDHA 增强了小鼠伤口的闭合、上皮化、肉芽组织生长和毛细血管血管形成。巨噬细胞产生的 14S，21-二 HDHA 和 14R，21-二 HDHA 可能部分代表巨噬细胞促愈合功能的分子机制。总之，14,21-二羟基-DHA 立体异构体及其形成途径可能代表了伤口愈合过程协调的新机制，这可能为开发对抗伤口愈合受损的新型治疗方法提供新的见解。
