title: Autacoid 14S,21R-dihydroxy-docosahexaenoic acid counteracts diabetic impairment of macrophage prohealing functions.
abstract: 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.
authors.affiliation: Center of Neuroscience Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Haibin
authors.initials: H
authors.lastname: Tian
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Shraddha P
authors.initials: SP
authors.lastname: Shah
authors.forename: Song
authors.initials: S
authors.lastname: Hong
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000378:metabolism; D012898:Autacoids / Q000096:biosynthesis / Q000494:pharmacology*; D002460:Cell Line; D003920:Diabetes Mellitus / Q000473:pathology*; D004281:Docosahexaenoic Acids / Q000096:biosynthesis / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: C475064:12-15-lipoxygenase; C569432:14,21-dihydroxydocosa-4,7,10,12,16,19-hexaenoic acid; D012898:Autacoids; D017382:Reactive Oxygen Species; D016753:Interleukin-10; D004281:Docosahexaenoic Acids; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase