Klings, Elizabeth S., Lowry, Matthew H., Li, Guihua, Jean, Jyh-Chang, Fernandez, Bernadette O., Garcia-Saura, Maria F., Feelisch, Martin and Joyce-Brady, Martin. (2009) Hyperoxia-induced lung injury in gamma-glutamyl transferase deficiency is associated with alterations in nitrosative and nitrative stress. American Journal of Pathology, Vol.175 (No.6). pp. 2309-2318. ISSN 0002-9440

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Abstract

γ-Glutamyl transferase (GGT) regulates glutathione metabolism and cysteine supply. GGT inactivation in GGTenu1 mice limits cysteine availability causing cellular glutathione deficiency. In lung, the resultant oxidant burden is associated with increased nitric oxide (NO) production, yet GGTenu1 mice still exhibit higher mortality in hyperoxia. We hypothesized that NO metabolism is altered under severe oxidant stress and contributes to lung cellular injury and death. We compared lung injury, NO synthase (NOS) expression, nitrate/nitrite production, nitroso product formation, peroxynitrite accumulation, and cell death in wild-type and GGTenu1 mice in normoxia and hyperoxia. The role of NOS activity in cell death was determined by NOS inhibition. Exposure of wild-type mice to hyperoxia caused increased lung injury, altered NO metabolism, and induction of cell death compared with normoxia, which was attenuated by NOS inhibition. Each of these lung injury indices were magnified in hyperoxia-exposed GGTenu1 mice except nitrosation, which showed a diminished decrease compared with wild-type mice. NOS inhibition attenuated cell death only slightly, likely due to further exacerbation of oxidant stress. Taken together, these data suggest that apoptosis in hyperoxia is partially NO-dependent and reiterate the importance of cellular glutathione in lung antioxidant defense. Therefore, reduced denitrosylation of proteins, possibly resulting in impaired cellular repair, and excessive apoptotic cell death likely contribute to increased lung injury and mortality of GGTenu1 mice in hyperoxia.

Item Type:	Journal Article
Subjects:	R Medicine > R Medicine (General)
Divisions:	Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Journal or Publication Title:	American Journal of Pathology
Publisher:	American Society for Investigative Pathology Inc.
ISSN:	0002-9440
Date:	December 2009
Volume:	Vol.175
Number:	No.6
Page Range:	pp. 2309-2318
Identification Number:	10.2353/ajpath.2009.081017
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
URI:	http://wrap.warwick.ac.uk/id/eprint/45864

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