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Articles in PresS, published online ahead of print May 3, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00250.2000
Submitted on July 27, 2000
Accepted on April 30, 2002
1 The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
2 Department of Pediatrics, Emory University, Atlanta, GA, USA
3 The Moran Eye Center, University of Utah, Salt Lake City, UT, USA
* To whom correspondence should be addressed. E-mail: mjbrady{at}lung.bumc.bu.edu.
Gamma-glutamyl transferase (GGT) is critical to glutathione homeostasis by providing substrates for glutathione synthesis. We hypothesized loss of GGT would cause oxidant stress in the lung. We compared the lungs of GGTenu1 mice, a genetic model of GGT deficiency with normal mice in normoxia to study this. We found GGT promoter 3 (P3) alone expressed in normal lung but GGT P3 plus P1, an oxidant-inducible GGT promoter, in GGTenu1 lung. Glutathione content was barely decreased in GGTenu1 lung homogenate and elevated ~2-fold in epithelial lining fluid, but the fraction of GSSG was increased 3-fold and 4-fold, respectively. Glutathione content in GGTenu1alveolar macrophages was decreased ~6-fold and the GSSG fraction increased 7-fold. Immunohistochemical studies showed glutathione deficiency together with an intense signal for 3-nitrotyrosine in non-ciliated bronchiolar epithelial (Clara) cells and expression of heme oxygenase-1 in the vasculature only in GGTenu1 lung. When GGTenu1 mice were exposed to hyperoxia, survival was decreased by 25% from control due to accelerated formation of vascular pulmonary edema, widespread oxidant stress in the epithelium, diffuse depletion of glutathione and severe bronchiolar cellular injury. These data indicate a critical role for GGT in lung glutathione homeostasis and antioxidant defense in normoxia and hyperoxia.
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