Transgenic and knockout models for studying the role of lung antioxidant enzymes in defense against hyperoxia
Transgenic and knockout models for studying the role of lung antioxidant enzymes in defense against hyperoxia
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DOI：
10.1164/rccm.2206017
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发表时间：
2002-12-15
影响因子：
24.7
通讯作者：
Ho, YS
中科院分区：
文献类型：
--
作者：
Ho, YS
尽管许多早期研究都表明抗氧化酶在预防高氧暴露引起的肺损伤中发挥作用，但尚未对该假设进行直接检验。我们打算使用转基因小鼠来解决这个问题，在这些小鼠中，一种抗氧化酶的表达被增强或减弱。我们推断，如果抗氧化酶在保护肺细胞免受氧化剂介导的损伤中起作用，则其基因表达水平将与对高氧的耐受程度相关。通过将基于人β-肌动蛋白启动子的MnSOD转基因整合到小鼠基因组中，在B6 C3系小鼠的肺泡I型和11型细胞、成纤维细胞和毛细血管内皮细胞中过表达功能性人锰超氧化物歧化酶（MnSOD）。然而，MnSOD过表达未能延长生存的转基因小鼠暴露于大于99%的氧气与野生型小鼠相比。此外，铜锌超氧化物歧化酶或细胞谷胱甘肽过氧化物酶缺乏的小鼠表现出显着的敏感性，许多模型的氧化组织损伤，但不高氧过敏。这些数据表明，这三种抗氧化酶在防止氧化剂介导的肺损伤高氧暴露的作用是可以忽略不计的，和其他细胞的抗氧化酶和系统可能主要用于肺防御高氧。
Although a role for antioxidant enzymes in preventing lung injury from hyperoxic exposure has been implicated in a number of early studies, a direct test for the hypothesis was not available. We intended to address this question using genetically modified mice in which the expression of a single antioxidant enzyme was either enhanced or diminished. We reasoned that if an antioxidant enzyme functions in protecting lung cells against oxidant-mediated injury, the level of its gene expression would correlate with the degree of tolerance to hyperoxia. Overexpression of functional human manganese superoxide dismutase (MnSOD) in lung alveolar type I and type 11 cells, fibroblasts, and capillary endothelial cells in strain B6C3 mice was achieved by incorporating a human beta-actin promoter-based MnSOD transgene into the mouse genome. However, MnSOD overexpression failed to prolong the survival of transgenic mice on exposure to greater than 99% oxygen compared with wildtype mice. In addition, mice deficient in copper-zinc superoxide dismutase or cellular glutathione peroxidase exhibited a marked sensitivity to numerous models of oxidant tissue injury but were not hypersensitive to hyperoxia. These data suggest that the role of these three antioxidant enzymes in preventing oxidant-mediated lung injury from hyperoxic exposure is negligible, and other cellular antioxidant enzymes and systems may be primarily used by the lungs in defense against hyperoxia.