title: Reactive oxygen intermediates during programmed cell death induced in the thymus of the Ts(1716)65Dn mouse, a murine model for human Down's syndrome.
abstract: Down's syndrome (DS) is one of the most frequent genetic disorders in humans. It has been suggested that overexpression of copper-zinc superoxide dismutase (SOD-1) in DS may be involved in some of the abnormalities observed, mainly neurodegenerative and immunopathological processes. One of the consequences is early thymic involution. Recently, Ts(1716)65Dn mice (Ts65Dn mice), made segmentally trisomic for a chromosome 16 segment, fulfill the criteria for a DS model. To study the possible role of SOD-1 overexpression in thymocyte biology, we analyzed the role of reactive oxygen intermediates during in vivo and in vitro programmed cell death (PCD) induced in the thymus of Ts65Dn mice. Our main findings can be summarized as follows. Ts65Dn thymuses exhibit greater PCD activity than controls, as ascertained by a combination of morphological, histochemical, and ultrastructural procedures. Ts65Dn thymocytes were highly susceptible to PCD induced by both LPS (in vivo) and dexamethasone, a synthetic glucocorticoid agonist (both in vivo and in vitro). Thymus abnormalities were probably caused by SOD-1 hyperexpression in Ts65Dn cells, in that reactive oxygen intermediate generation (specifically H2O2 production) is enhanced in thymocytes and clearly correlates with apoptosis. Similarly, oxidative injury correlated with the formation of lipid peroxidation by-products and antioxidants which partly inhibit PCD in thymocytes.
authors.affiliation: Servicio de Inmunología, Hospital Universitario "Marqués de Valdecilla," Instituto Nacional de la Salud, Santander, Spain.
authors.forename: J E
authors.initials: JE
authors.lastname: Paz-Miguel
authors.forename: R
authors.initials: R
authors.lastname: Flores
authors.forename: P
authors.initials: P
authors.lastname: Sánchez-Velasco
authors.forename: G
authors.initials: G
authors.lastname: Ocejo-Vinyals
authors.forename: J
authors.initials: J
authors.lastname: Escribano de Diego
authors.forename: J
authors.initials: J
authors.lastname: López de Rego
authors.forename: F
authors.initials: F
authors.lastname: Leyva-Cobián
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D003907:Dexamethasone / Q000008:administration & dosage; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors
chemical_list: D000975:Antioxidants; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D003907:Dexamethasone; D013482:Superoxide Dismutase