Gamma-glutamyl transferase deficiency results in lung oxidant stress in normoxia.

نویسندگان

  • Jyh Chang Jean
  • Yue Liu
  • Lou Ann Brown
  • Robert E Marc
  • Elizabeth Klings
  • Martin Joyce-Brady
چکیده

gamma-Glutamyl transferase (GGT) is critical to glutathione homeostasis by providing substrates for glutathione synthesis. We hypothesized that loss of GGT would cause oxidant stress in the lung. We compared the lungs of GGT(enu1) mice, a genetic model of GGT deficiency, with normal mice in normoxia to study this hypothesis. We found GGT promoter 3 (P3) alone expressed in normal lung but GGT P3 plus P1, an oxidant-inducible GGT promoter, in GGT(enu1) lung. Glutathione content was barely decreased in GGT(enu1) lung homogenate and elevated nearly twofold in epithelial lining fluid, but the fraction of oxidized glutathione was increased three- and fourfold, respectively. Glutathione content in GGT(enu1) alveolar macrophages was decreased nearly sixfold, and the oxidized glutathione fraction was increased sevenfold. Immunohistochemical studies showed glutathione deficiency together with an intense signal for 3-nitrotyrosine in nonciliated bronchiolar epithelial (Clara) cells and expression of heme oxygenase-1 in the vasculature only in GGT(enu1) lung. When GGT(enu1) mice were exposed to hyperoxia, survival was decreased by 25% from control because of 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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منابع مشابه

-Glutamyl transferase deficiency results in lung oxidant stress in normoxia

Jean, Jyh Chang, Yue Liu, Lou Ann Brown, Robert E. Marc, Elizabeth Klings, and Martin Joyce-Brady. -Glutamyl transferase deficiency results in lung oxidant stress in normoxia. Am J Physiol Lung Cell Mol Physiol 283: L766–L776, 2002. First published May 3, 2002; 10.1152/ ajplung.00250.2000.— -Glutamyl transferase (GGT) is critical to glutathione homeostasis by providing substrates for glutathion...

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An extensive literature now supports a fundamental role for glutathione in the antioxidant protection of the lung and its gas exchange surface [1]. However, the physiological significance of lung glutathione turnover by the extracellular catabolic enzyme gamma-glutamyl transferase (GGT) has remained controversial. The function of GGT in the lung has been a major research focus in my laboratory....

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gamma-Glutamyl transferase (GGT) deficiency in the GGTenu1 mouse results from a single point mutation that leads to a stop codon in the first coding exon of GGT mRNA.

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عنوان ژورنال:
  • American journal of physiology. Lung cellular and molecular physiology

دوره 283 4  شماره 

صفحات  -

تاریخ انتشار 2002