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K. Gronert, N. Maheshwari, N. Khan, I.R. Hassan, M. Dunn, M. Laniado Schwartzman; A Novel Role for Endogenous Anti–Inflammatory Lipid Mediators in Promoting Epithelial Wound Healing and Host Defense in the Cornea . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2641.
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Purpose: 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 A4 (LXA4) and docosahexaenoic acid– derived neuroprotectin D1 (NPD1) are lipid autacoids formed by 12/15–lipoxygenase (LOX) pathways that exhibit anti–inflammatory and neuroprotective properties. We set out to determine if these lipid mediators are formed in the cornea as part of an endogenous program to limit the sequelae of corneal injury. Methods: Corneal injury was induced in Balb/c mice by epithelial removal up to the corneal limbal border using an Algerbrush or by thermal cauterization. Wound size and degree of injury were determined by slit lamp biomicroscopy and documented for quantitation and analysis by a CCD camera. Neutrophil content of corneas was quantitated by measuring myeloperoxidase activity. mRNA expression of 12/15–lipoxygenases (Alox15) and LXA4 receptor was determined by RT–PCR analysis. Eicosanoid, NPD1 and chemokines were quantitated by specific ELISA and/or RP–HPLC and GC/MS analysis. To investigate the impact of LXA, NPD1 and eicosanoids on the inflammatory/reparative response mice were treated topically by eye drop 3 times daily for 24–96 hrs. Results: Corneas generate endogenous LXA4 and NPD1. 15–LOX and LXA4 receptor expression as well as LXA4 formation were abrogated by epithelial removal and restored during wound healing. Amplification of these pathways by topical treatment with LXA4 or NPD1 increased the rate of re–epithelialization (65–90%, n=6–10, p<0.03) and attenuated the sequelae of thermal injury. In contrast, the pro–inflammatory eicosanoids, LTB4 and 12R–HETrE, had no impact on corneal re–epithelialization. Epithelial removal induced a temporally defined influx of neutrophils into the stroma that was significantly increased with LXA4 and NPD1 treatment, whereas formation of key pro–inflammatory chemokines in response to the corneal injury was abrogated by these endogenous lipid mediators. Conclusions: Collectively, these results are the first identification of an anti–inflammatory lipid pathway in the cornea. Furthermore they identify a novel action for the 12/15–LOX products, LXA4 and NPD1, in wound healing that is distinct from their well established anti–inflammatory properties.
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