Increased sensitivity of homozygous Sod2 mutant mice to oxygen toxicity

Free Radic Biol Med. 2002 Jan 15;32(2):175-86. doi: 10.1016/s0891-5849(01)00776-6.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcysteine / pharmacology*
  • Animals
  • Apoptosis*
  • Body Weight / drug effects
  • Cell Division / drug effects
  • Glutamate-Cysteine Ligase / drug effects
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / metabolism
  • Glutathione Peroxidase / drug effects
  • Glutathione Peroxidase / metabolism
  • Glutathione Reductase / drug effects
  • Glutathione Reductase / metabolism
  • Hyperoxia / metabolism
  • Lung / drug effects*
  • Lung / enzymology
  • Lung / pathology
  • Mice
  • Mice, Knockout / metabolism
  • Organ Size / drug effects
  • Oxygen / toxicity*
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Sulfhydryl Compounds / blood
  • Superoxide Dismutase / deficiency
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*

Substances

  • RNA, Messenger
  • Sulfhydryl Compounds
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Glutathione Reductase
  • Glutamate-Cysteine Ligase
  • Glutathione
  • Oxygen
  • Acetylcysteine