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Age-Related Conjunctival P2Y2 Receptor Alterations in the Cu, Zn-Superoxide Dismutase-1 (Sod1)–Knockout Dry Eye Model Mice

Dogru, Murat M.D., Ph.D.; Shinzawa, Megumi M.D.; Kojima, Takashi M.D., Ph.D.; Shimizu, Takahiko M.D., Ph.D.; Tsubota, Kazuo M.D., Ph.D.

doi: 10.1097/ICL.0000000000000581

Purpose: To investigate the effects of aging on the conjunctival P2Y2 receptors, tear functions, and corneal epithelial status from 10 to 50 weeks in the Sod1−/− in comparison with the wild-type mice.

Methods: Eight eyes of 4 Sod1−/− male mice and 8 eyes of 4 C57BL6 strain wild-type male mice were examined at 10 and 50 weeks in this study. Tear film breakup time (BUT) and corneal epithelial damage by fluorescein staining were evaluated. Phenol red–impregnated cotton threads were performed without topical anesthesia to measure aqueous tear quantity. Anterior segment photography was also performed at 10 and 50 weeks. Conjunctival specimens underwent immunohistochemistry stainings with anti P2Y2 antibodies. P2Y2 receptor mRNA expression in the bulbar conjunctiva was investigated by using quantitative real-time polymerase chain reaction.

Results: The mean tear quantity and BUT scores significantly declined, and the mean fluorescein staining scores significantly increased in both strains of mice from 10 to 50 weeks. % mRNA expression for P2Y2 receptors significantly increased in both mice strains from 10 to 50 weeks.

Conclusion: The tear stability, quantity, and ocular surface health decline with aging as evidenced by the decrease in tear BUT, tear quantity, and the increase in ocular surface staining. Conjunctival P2Y2 receptor mRNA was upregulated from 10 to 50 weeks, which we believe is a compensation for the decline of tear functions with aging.

Department of Ophthalmology (M.D., M.S., T.K., and K.T.), Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; and Department of Advanced Aging Medicine (T.S.), Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan.

Address correspondence to Murat Dogru, M.D., Ph.D., Department of Ophthalmology, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo 160-8582, Japan; e-mail:

The authors have no funding or conflicts of interest to disclose.

The authors have no proprietary interest in any of the products mentioned in this article. This work was supported by a research grant from Santen Pharmaceuticals.

Presented at the Tear Film Ocular Surface Society Meeting, September 18–22, 2013, Taormina, Italy.

The work was conducted under a Santen Pharmaceuticals grant for the conduct of the animal study and for the purchase of antibodies and solutions. Neither Santen was involved with the scientific content of the research project nor the authors were paid employees or received any kind of fees from Santen Pharmaceuticals.

Accepted November 12, 2018

© 2019 Contact Lens Association of Ophthalmologists, Inc.