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Samantha B. Wang, Kyle M. Hu, Kyle J. Seamon, Yangdi Chen, Karsten Gronert; Estrogen Receptor β Drives Sex-specific Differences In Corneal Epithelial Wound Healing. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1859.
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There is a striking prevalence of Dry Eye Syndrome in women. A hallmark of this immune/inflammatory disease is recurrent epithelial injury. Hence, it is of considerable interest that post hoc analysis of a clinical ulcerative keratitis study demonstrates that corneal wounds in women heal twice as slowly as in men. There is strong evidence pointing to an estrogenic effect on the intrinsic anti-inflammatory 15-LOX/LXA4 circuit in the cornea, which also drives epithelial wound healing. Models of Dry Eye are conducted solely in females due to the female dominated incidence of disease ignoring potential sex-specific differences in the corneal response to stress and disease. We thus set out to define sex-specific differences and estrogen’s role in corneal epithelial responses to stress and injury.
Dry Eye was induced in mice using a standard model of desiccating stress. Corneal epithelial abrasion was used as a model of mechanical injury and corneal epithelial sheets isolated to assess epithelial specific responses. An in vitro scratch injury model with human corneal epithelial cells was used to directly assess the role of ERα, ERβ and LXA4. Formation of lipid autacoids was assessed using LC/MS/MS-based lipidomics and gene expression was quantified by QPCR. Wound healing was measured by image analysis software.
Dry Eye induced greater epithelial wounds in females when directly compared to male mice. This correlated with 40% increase in PGE2 formation, a marker of inflammation, and an 82% reduction in 15-HETE formation, a marker of the protective LXA4 circuit in the cornea. Estrogen inhibited epithelial wound healing (93%), expression of 15-LOX (47%) and endogenous LXA4 formation (64%). LXA4 treatment rescued epithelial cells from the estrogen effect and restored normal wound healing. The ERβ agonist and but the not ERα agonist selectively inhibited wound healing, 15-LOX expression, and LXA4 formation, correlating with specific upregulation of ERβ after corneal injury.
These results provide evidence that estrogen drives sex-specific differences in epithelial responses to corneal injury. Specifically, these epithelial responses are ERβ-driven as this nuclear hormone receptor is upregulated during corneal injury and down-regulates epithelial wound healing and functional expression of the 15LOX/LXA4 circuit. These findings have potentially important implications for the pathogenesis of ocular surface disease in woman.
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