Modulation of Oxidative Stress and Inflammation in the Aged Lacrimal Gland

Abstract

Inflammation and oxidative stress accompany aging. This study investigated the interplay between oxidative stress and inflammation in the lacrimal gland. C57BL/6 mice were used at 2 to 3, 12, and 24 months of age. Nuclear factor erythroid derived-2-related factor 2 (Nrf2)-/- and corresponding wild-type mice were used at 2 to 3 and 12 to 13 months of age. A separate group of 15.5 to 17 monthsof age C57BL/6 mice received a diet containing an Nrf2 inducer (Oltipraz) for 8 weeks. Aged C57BL/6 lacrimal glands showed significantly greater lymphocytic infiltration, higher levels of MHC II, IFN-γ, IL-1β, TNF-α, and cathepsin S (Ctss) mRNA transcripts, and greater nitrotyrosine and 4-hydroxynonenal protein. Young Nrf2-/- mice showed an increase in IL-1β, IFN-γ, MHC II, and Ctss mRNA transcripts compared with young wild-type mice and greater age-related changes at 12 to 13 months of age. Oltipraz diet significantly decreased nitrotyrosine and 4-hydroxynonenal and decreased the expression of IL-1β and TNF-α mRNA transcripts, while decreasing the frequency of CD45+CD4+ cells in lacrimal glands and significantly increasing conjunctival goblet cell density compared with a standard diet. The findings provide novel insight into the development of chronic, low-grade inflammation and oxidative stress in age-related dry eye. New therapies targeting oxidative stress pathways will be valuable in treating age-related dry eye.