Age-related dysfunction of the lacrimal gland and oxidative stress: Evidence from the Cu,Zn-superoxide dismutase-1 (Sod1) knockout mice

Takashi Kojima, Tais H. Wakamatsu, Murat Dogru, Yoko Ogawa, Ayako Igarashi, Osama M.A. Ibrahim, Takaaki Inaba, Takahiko Shimizu, Setsuko Noda, Hiroto Obata, Shigeru Nakamura, Alda Wakamatsu, Takuji Shirasawa, Jun Shimazaki, Kazuno Negishi, Kazuo Tsubota

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Abstract

An imbalance between free radical generation and radical scavenging antioxidant systems results in oxidative stress, which has been associated with cell injury observed in many age-related diseases. The superoxide dismutase (SOD) family is a major antioxidant system, and deficiency of Cu,Zn-superoxide dismutase-1 (Sod1) in mice leads to many different phenotypes that resemble accelerated aging. In this study we examined the morphologic features and the secretory functions of the lacrimal glands in Sod1 -/- mice. Lacrimal glands showed atrophy of acinar units; fibrosis; infiltration with CD4 + T cells, monocytes, and neutrophils; increased staining with both 4-hydroxy-2-nonenal and 8-hydroxy-2′-deoxyguanosine; increases in apoptotic cells; and the presence of the epithelial-mesenchymal transition in senescent Sod1 -/- mice. Electron microscopy findings revealed evidence of epithelial-mesenchymal transition, presence of swollen and degenerated mitochondria, and the presence of apoptotic cell death in the lacrimal glands of senescent Sod1 -/- mice. These alterations were also associated with the accumulation of secretory vesicles in acinar epithelial cells, decreased production of both stimulated and nonstimulated tears, and a decline in total protein secretion from the lacrimal glands. Our results suggest that Sod1 -/- mice may be a good model system in which to study the mechanism of reactive oxygen species-mediated lacrimal gland alterations.

Original languageEnglish
Pages (from-to)1879-1896
Number of pages18
JournalAmerican Journal of Pathology
Volume180
Issue number5
DOIs
Publication statusPublished - 2012 May 1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Kojima, T., Wakamatsu, T. H., Dogru, M., Ogawa, Y., Igarashi, A., Ibrahim, O. M. A., Inaba, T., Shimizu, T., Noda, S., Obata, H., Nakamura, S., Wakamatsu, A., Shirasawa, T., Shimazaki, J., Negishi, K., & Tsubota, K. (2012). Age-related dysfunction of the lacrimal gland and oxidative stress: Evidence from the Cu,Zn-superoxide dismutase-1 (Sod1) knockout mice. American Journal of Pathology, 180(5), 1879-1896. https://doi.org/10.1016/j.ajpath.2012.01.019