title: Age-related dysfunction of the lacrimal gland and oxidative stress: evidence from the Cu,Zn-superoxide dismutase-1 (Sod1) knockout mice.
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.
authors.affiliation: Department of Ocular Surface and Visual Optics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.forename: Tais H
authors.initials: TH
authors.lastname: Wakamatsu
authors.forename: Murat
authors.initials: M
authors.lastname: Dogru
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Ayako
authors.initials: A
authors.lastname: Igarashi
authors.forename: Osama M A
authors.initials: OM
authors.lastname: Ibrahim
authors.forename: Takaaki
authors.initials: T
authors.lastname: Inaba
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
authors.forename: Setsuko
authors.initials: S
authors.lastname: Noda
authors.forename: Hiroto
authors.initials: H
authors.lastname: Obata
authors.forename: Shigeru
authors.initials: S
authors.lastname: Nakamura
authors.forename: Alda
authors.initials: A
authors.lastname: Wakamatsu
authors.forename: Takuji
authors.initials: T
authors.lastname: Shirasawa
authors.forename: Jun
authors.initials: J
authors.lastname: Shimazaki
authors.forename: Kazuno
authors.initials: K
authors.lastname: Negishi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000375:Aging / Q000473:pathology / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000473:pathology / Q000503:physiopathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005355:Fibrosis; D007765:Lacrimal Apparatus / Q000473:pathology / Q000503:physiopathology* / Q000648:ultrastructure; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000648:ultrastructure; D018384:Oxidative Stress / Q000502:physiology*; D013482:Superoxide Dismutase / Q000172:deficiency / Q000502:physiology*; D013666:Tears / Q000378:metabolism
chemical_list: D016207:Cytokines; D000080242:8-Hydroxy-2'-Deoxyguanosine; D013482:Superoxide Dismutase; D003849:Deoxyguanosine