title: A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense.
abstract: The surface of the eye actively suppresses inflammation while maintaining a remarkable capacity for epithelial wound repair. Our understanding of mechanisms that balance inflammatory/reparative responses to provide effective host defense while preserving tissue function is limited, in particular, in the cornea. Lipoxin A(4) (LXA(4)) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1) are lipid autacoids formed by 12/15-lipoxygenase (LOX) pathways that exhibit anti-inflammatory and neuroprotective properties. Here, we demonstrate that mouse corneas generate endogenous LXA(4) and NPD1. 12/15-LOX (Alox15) and LXA(4) receptor mRNA expression as well as LXA(4) formation were abrogated by epithelial removal and restored during wound healing. Amplification of these pathways by topical treatment with LXA(4) or NPD1 (1 microg) increased the rate of re-epithelialization (65-90%, n = 6-10, p < 0.03) and attenuated the sequelae of thermal injury. In contrast, the proinflammatory eicosanoids, LTB(4) and 12R-hydroxyeicosatrienoic acid, had no impact on corneal re-epithelialization. Epithelial removal induced a temporally defined influx of neutrophils into the stroma as well as formation of the proinflammatory chemokine KC. Topical treatment with LXA(4) and NPD1 significantly increased PMNs in the cornea while abrogating KC formation by 60%. More importantly, Alox15-deficient mice exhibited a defect in both corneal re-epithelialization and neutrophil recruitment that correlated with a 43% reduction in endogenous LXA(4) formation. Collectively, these results identify a novel action for the mouse 12/15-LOX (Alox15) and its products, LXA(4) and NPD1, in wound healing that is distinct from their well established anti-inflammatory properties.
authors.affiliation: New York Medical College, Department of Pharmacology, Valhalla, New York 10595, USA. karsten_gronert@nymc.edu <karsten_gronert@nymc.edu>
authors.forename: Karsten
authors.initials: K
authors.lastname: Gronert
authors.forename: Neha
authors.initials: N
authors.lastname: Maheshwari
authors.forename: Nabeela
authors.initials: N
authors.lastname: Khan
authors.forename: Iram R
authors.initials: IR
authors.lastname: Hassan
authors.forename: Michael
authors.initials: M
authors.lastname: Dunn
authors.forename: Michal
authors.initials: M
authors.lastname: Laniado Schwartzman
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001092:Arachidonate 12-Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003315:Cornea / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015777:Eicosanoids / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006358:Hot Temperature; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry; D007249:Inflammation; D007962:Leukocytes / Q000378:metabolism; D007975:Leukotriene B4 / Q000494:pharmacology; D050356:Lipid Metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D009504:Neutrophils / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014466:Ultraviolet Rays; D014945:Wound Healing
chemical_list: C475064:12-15-lipoxygenase; D000893:Anti-Inflammatory Agents; D018925:Chemokines; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D012333:RNA, Messenger; C487679:protectin D1; D007975:Leukotriene B4; D004281:Docosahexaenoic Acids; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase