title: Increased sensitivity of homozygous Sod2 mutant mice to oxygen toxicity.
abstract: Induction or overexpression of pulmonary manganese superoxide dismutase (MnSOD) has been shown to protect against oxygen (O2) toxicity. Genetic inactivation of MnSOD (Sod2) results in multiple organ failure and early neonatal death. However, lungs or O2-tolerance of Sod2 knockout mice have not been investigated. We evaluated survival, lung histopathology, and other pulmonary antioxidants (glutathione cycle) of homozygous (-/-) and heterozygous (+/-) Sod2 mutant mice compared with wild-type controls (Sod2+/+) following 48 h exposure to either room air or to O2. The ability of antioxidant N-acetylcysteine to compensate for the loss of MnSOD was explored. Mortality of Sod2-/- mice increased from 0% in room air to 18 and 83% in 50 and 80% O2, respectively. N-acetylcysteine did not alter mortality of Sod2-/- mice. Histopathological analysis revealed abnormalities in saccules of Sod2-/- mice exposed either to room air or to 50% O2 suggestive of delayed postnatal lung development. In 50% O2, activities of glutamate-cysteine ligase (GCL) (previously known as gamma-glutamylcysteine synthetase, gamma-GCS) and glutathione peroxidase increased in Sod2-/- (35 and 70%, respectively) and Sod2+/- (12 and 70%, respectively) mice, but glutathione levels remained unaltered. We conclude that MnSOD is required for normal O2 tolerance and that in the absence of MnSOD there is a compensatory increase in pulmonary glutathione-dependent antioxidant defense in hyperoxia.
authors.affiliation: Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland. tiina.asikainen@hus.fi
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Asikainen
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Huang
authors.forename: Eero
authors.initials: E
authors.lastname: Taskinen
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
authors.forename: Elaine
authors.initials: E
authors.lastname: Carlson
authors.forename: Risto
authors.initials: R
authors.lastname: Lapatto
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: Kari O
authors.initials: KO
authors.lastname: Raivio
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000187:drug effects / Q000378:metabolism; D005980:Glutathione Reductase / Q000187:drug effects / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010100:Oxygen / Q000633:toxicity*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000097:blood; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D000111:Acetylcysteine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D010100:Oxygen; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2