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Kyle Hu, Samantha Wang, Erick Lu, Patrick Salveson, Yuan Gao, Karsten Gronert; Dietary DHA Abrogate Intrinsic Sex-Specific Differences in Lacrimal Gland Lipid Mediator Circuits during Dry Eye. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4344.
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We previously demonstrated sex-specific differences in corneal inflammatory reparative responses, which are mediated by estrogen modulation of protective lipid mediators derived from dietary polyunsaturated fatty acids (PUFA). Sex-steroids have long been implicated in Dry Eye (DE) due to the prevalence of disease incidence in women. Sjogren’s Syndrome causes DE by dysregulating immune responses in the lacrimal gland. A post hoc clinical study found a correlation between dietary ω-3 PUFA in women and decreased incidence of DE symptoms. ω-3 DHA is of interest to immune regulation as it’s metabolized into potent lipid mediators. We investigated whether lipid mediator pathways are present and functional in the lacrimal gland, if they exhibit sex-specific differences, and if a DHA-rich diet can confer protective actions against DE development
DE was induced using a model of desiccating stress and scopolamine. Mice were placed on a DHA-rich or DHA-deficient diet for 4 weeks before DE induction. Schirmer’s test was used to assess tear levels. PMN levels were quantified using myeloperoxidase assay, lipid mediator formation by LC/MS/MS-based lipidomics, and gene expression via QPCR. Leukocyte populations were assessed by IHC
Lacrimal glands highly express inflammatory lipid circuits (COX, 15-LOX), which are regulated by desiccating stress. Female mice exhibited an amplified inflammatory response compared to males, evidenced by a marked early infiltration of PMNs, increased pro-inflammatory PGE2, and decreased pro-resolving LXA4. Mice that received the DHA-rich diet had higher tear production (0.9mm) compared to their DHA-poor diet counterparts (0.3mm), suggesting greater protection against desiccating stress. DHA-rich mice contained greater levels of DHA and EPA, and lower levels of ω-6 PUFA AA. Levels of PGE2 were downregulated 2.4-fold and pro-resolving lipid mediators were upregulated in mice on the enriched DHA diet
These results provide the first evidence that lipid autacoid circuits are expressed and functional in vivo in lacrimal glands. There is a sex-specific difference in the inflammatory response to desiccating stress. Dietary DHA in females shifts levels of lipid mediators to resemble males and may confer protection against disease progression by downregulating the immune regulatory COX/PGE2 pathway, a primary target of corticosteroids and NSAIDs
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