Oxygen-induced pulmonary injury in gamma-glutamyl transpeptidase-deficient mice.
We used mice with a targeted disruption in g-glutamyl transpeptidase (GGT-deficient mice) to study the role of glutathione (GSH) in protection against oxygen-induced lung injury. These mice had reduced levels of lung GSH and restricted ability to synthesize GSH because of low levels of cysteine. When GGT-deficient mice were exposed to 80% oxygen, they developed diffuse pulmonary injury and died within eight days. Ten of 12 wild-type mice were alive after 18 days. Administration of N-acetylcysteine (NAC) to GGT-deficient mice corrected GSH values and prevented the development of severe pulmonary injury and death. Oxygen exposure induced an increase in lung GSH levels in both wild-type and GGT-deficient mice, but induced levels in the mutant mice were <50% of those in wild-type mice. Cysteine levels were approximately 50-fold lower than GSH levels the lungs of both wild-type and GGT-deficient mice. Levels of lung RNA coding for the heavy subunit of g-glutamyl cysteine synthetase rose three- to fourfold after oxygen exposure in both wild-type and GGT-deficient mice. In contrast, oxygen exposure failed to provoke increases in glutathione synthetase, glutathione peroxidase, glutaredoxin, or thioredoxin.
Barrios
R
R
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Shi
Z Z
ZZ
Kala
S V
SV
Wiseman
A L
AL
Welty
S E
SE
Kala
G
G
Bahler
A A
AA
Ou
C N
CN
Lieberman
M W
MW
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D003545:Cysteine / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000502:physiology*; D018496:Hyperoxia / Q000209:etiology / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D055370:Lung Injury; D051379:Mice; D012313:RNA / Q000235:genetics; D005723:gamma-Glutamyltransferase / Q000172:deficiency*
D012313:RNA; D005723:gamma-Glutamyltransferase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine