γ-Glutamyl transferase deficiency results in lung oxidant stress in normoxia
γ-Glutamyl transferase deficiency results in lung oxidant stress in normoxia
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DOI：
10.1152/ajplung.00250.2000
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发表时间：
2002-10-01
影响因子：
4.9
通讯作者：
Joyce-Brady, M
中科院分区：
文献类型：
--
作者：
Jean, JC;Liu, Y;Joyce-Brady, M
γ-谷氨酰转移酶（GGT）通过提供谷胱甘肽合成的底物而对谷胱甘肽体内平衡至关重要。我们假设GGT的缺失会导致肺中的氧化应激。我们比较了GGT（enu 1）小鼠的肺，GGT缺乏症的遗传模型，与正常小鼠在常氧研究这一假设。我们发现GGT启动子3（P3）在正常肺中单独表达，但GGT P3加P1（一种氧化诱导型GGT启动子）在GGT（enu 1）肺中表达。谷氨酰转肽酶（enu 1）肺匀浆中的谷胱甘肽含量几乎没有下降，上皮细胞衬里液中的谷胱甘肽含量升高了近两倍，但氧化型谷胱甘肽的含量分别增加了三倍和四倍。谷氨酰转肽酶（enu 1）肺泡巨噬细胞中的谷胱甘肽含量减少了近六倍，氧化型谷胱甘肽部分增加了七倍。免疫组化研究显示谷胱甘肽缺乏症与3-硝基酪氨酸在无纤毛细支气管上皮细胞（克拉拉）和血红素氧合酶-1的表达在血管中的强烈信号仅在GGT（enu 1）肺。当GGT（enu 1）小鼠暴露于高氧，生存率下降了25%，因为血管性肺水肿，上皮细胞中广泛的氧化应激，弥漫性谷胱甘肽耗竭，和严重的细支气管细胞损伤的加速形成的控制。这些数据表明，在正常氧和高氧下，GGT在肺谷胱甘肽稳态和抗氧化防御中起关键作用。
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.