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I.R. Hassan, N. Maheshwari, N. Khan, M. Dunn, K. Gronert; A Novel Role for the 15–Lipoxygenase (Alox15) in Promoting Re–Epithelialization of the Mouse Cornea . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2150.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: 12/15–lipoxygenases (LOX) are key enzymes in the formation of the eicosanoid lipoxin A4 (LXA4). We have recently demonstrated that LXA4 and another 12/15–LOX product, DHA–derived neuroprotectin D1, are formed in mouse corneas and that these anti–inflammatory lipids have an epithelial bioaction that limits the sequelae of corneal injury. Mice express at least 4 distinct 12/15 lipoxygenases. We set out to identify the LOX that initiates LXA4 formation in mouse corneas and to define its endogenous role in maintaining corneal function. Methods: Corneal injury was induced in 15–LOX deficient mice and in age and gender matched congenic C57BL/6J mice by epithelial removal up to the corneal limbal border using an Algerbrush. Wound size and degree of injury were determined by slit lamp biomicroscopy and documented for quantitation and analysis by a CCD camera. RNA expression of 12/15–lipoxygenases (Alox12, Alox15, Alox15b, Aloxe3) and 5–LOX were determined by RT–PCR analysis. Endogenous LXA4 levels were quantitated by a specific ELISA and RP–HPLC analysis. Results: The mouse cornea predominantly expressed the leukocyte–type 12/15–LOX (Alox15) and expression was restricted to the epithelium. In addition, 5–LOX mRNA was also expressed at low levels in healthy corneas and dramatically increased with corneal injury. Targeted deletion of Alox15 in the 15–LOX deficient mice demonstrated a significant 65± 5% (p=0.0009, ANOVA, n=4) and 38± 4% (p=0.04, ANOVA, n=4) decrease in re–epithelialization 24 and 48 hrs, respectively, after epithelial removal. This defect in re–epithelialization was associated with impaired endogenous formation of LXA4 (43% decrease, n=3). Conclusions: Our findings identify a previously unknown phenotype of delayed wound healing in 15–LOX–/– mice and provide direct in vivo evidence for a novel role of the 15–LOX (Alox15) and its products in epithelial wound healing. Taken together, these findings identify a constitutive lipid pathway in corneal epithelial cells that attenuates inflammation and promotes re–epithelialization.
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