出版社：American Society for Biochemistry and Molecular Biology
摘要：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 14 S ,21 S -dihydroxy-docosa-4 Z ,7 Z ,10 Z ,12 E ,16 Z ,19 Z -hexaenoic acids (14 S ,21 S -diHDHA);14 R ,21 R -diHDHA; 14 S ,21 R -diHDHA; and/or 14 R ,21 S -diHDHA. 12-lipoxygenase and cytochrome P450 catalysis in tandem converted docosahexaenoic acid to 14 S ,21 R -diHDHA and 14 S ,21 S -diHDHA through the intermediacy of 14 S -HDHA; P450 also converted 14 R -HDHA to novel 14 R ,21 R -diHDHA and 14 R ,21 S -diHDHA. Macrophages function as the combination of 12-lipoxgenase and P450 to generate these 14,21-diHDHA stereoisomers, as well as their intermediates 14 S -HDHA, 14 R -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-d4 stereoisomers, 14 S -HDHA-d5, 14 R -HDHA-d5, and 21-HDHA-d4 from DHA-21,21,22,22,22-d5. We found that 14 S ,21-diHDHA and 14 R ,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.
关键词：14 S ,21 S -dihydroxy-docosa-4 Z ,7 Z ,10 Z ,12 E ,16 Z ,19 Z -hexaenoic acid (14 S ,21 S -diHDHA) ; 14 S ,21 R -diHDHA, 14 R ,21 S -diHDHA ; 14 R ,21 R -diHDHA ; 14,21-diHDHAs-d4 ; 14 - HDHAs-d5; 21-HDHA-d4 ; reepithelialization ; granulation tissue growth ; macrophages ; vascularization
