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A New Mouse Model of Dry Eye Disease: Oxidative Stress Affects Functional Decline in the Lacrimal Gland

Uchino, Yuichi MD; Kawakita, Tetsuya MD; Ishii, Takamasa PhD; Ishii, Naoaki PhD; Tsubota, Kazuo MD

doi: 10.1097/ICO.0b013e31826a5de1

Purpose: Oxidative damage and inflammation are proposed to be involved in the age-related functional decline of lacrimal glands. The molecular mechanism(s) of how oxidative stress affects the secretory function of lacrimal glands was investigated because this is currently unclear.

Methods: We used a novel mev-1 conditional transgenic mouse model (Tet-mev-1) with a modified tetracycline system. The mev-1 gene encodes the cytochrome b560 large subunit of succinate–ubiquinone oxidoreductase in complex II of mitochondria.

Results: Expression of the mev-1 gene induced excessive oxidative stress associated with ocular surface epithelial damage and a decrease in aqueous secretory function. Tear volume in Tet-mev-1 mice was lower than in wild-type mice, and histopathological analyses showed the hallmarks of lacrimal gland inflammation by intense mononuclear leukocytic infiltration and fibrosis in the lacrimal gland of Tet-mev-1 mice.

Conclusions: This new model provides evidence that mitochondria-induced oxidative damage in the lacrimal gland induces lacrimal dysfunction, resulting in dry eye disease. Our findings strongly suggest that oxidative stress can be a causative factor in the development of dry eye disease.

*Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan

Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa, Japan.

Reprints: Yuichi Uchino, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan (e-mail:

Supported by a Grant-in-Aid for Young Scientists (B) (22791692) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

The authors have no conflicts of interest to disclose.

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