GENETOXIC RESPONSE TO OXIDATIVE DAMAGE

氧化应激，由细胞暴露于“活性氧”引起 活性氧（ROS）是急性和慢性细胞损伤的主要原因， 被认为在衰老过程中起着重要作用。 的主要原因 细胞内的氧化应激包括电离辐射、 外来化学物质、炎症和正常代谢。 细胞内 ROS的靶包括蛋白质、脂质和DNA。 虽然在细菌中 许多涉及三种不同调节子的基因已被证明是诱导的， 由于氧化损伤，对氧化损伤的分子反应知之甚少。 高等真核生物中的氧化应激 这里的研究集中在 急性遗传反应氧化损伤的表征， 哺乳动物的细胞和组织，希望能识别出基因， 在细胞对氧化应激的反应中起重要作用。 三种不同的体外氧化应激模型系统已经被 采用的方法包括：1）高氧（95%氧气）处理培养的肺 成纤维细胞，2）黄嘌呤-黄嘌呤氧化酶处理大鼠近端 肾小管上皮细胞，和3）肾毒性半胱氨酸的影响 结合物，S-（1，2-二氯乙烯基）-L-半胱氨酸（DCVD）对猪肾的作用 上皮细胞 cCAAT/增强子结合（C/EBP）相关基因gadd 153 和假定的转录调节因子，被证明是由每一个 治疗，这表明它代表了一种普遍的反应， 氧化损伤 在体外培养的其他研究中， 成纤维细胞以及检查大鼠肺组织的体内研究 暴露于100%的氧气中，我们已经证明了另外两个C/EBP相关基因， C/EBP β和C/EBP也响应于高氧而被诱导。 我们已经开始研究比较老年大鼠和年轻大鼠的敏感性 高氧的破坏作用 我们观察到老年大鼠（24 月龄）对高氧诱导的肺损伤的敏感性低于 是年轻的（6个月大）大鼠。 呼吸道感染导致的死亡率 处于100%氧气环境中的幼鼠平均 老年大鼠暴露66小时与88小时相比。 我们 目前正在研究这种与年龄相关的生存差异是否 与任何年龄相关的遗传反应差异相关， 高氧。

Oxidative stress, resulting from the exposure of cells to "reactive oxygen species" (ROS) is a major cause of both acute and chronic cell injury and is postulated to play an important role in aging. Major causes of oxidative stress in the cell include ionizing radiation, detoxification of foreign chemicals, inflammation, and normal metabolism. Intracellular targets of ROS include proteins, lipids and DNA. Although in bacteria many genes involving three distinct regulons have been shown to be induced by oxidative damage, little is known about the molecular response to oxidative stress in higher eukaryotes. Studies here have focused on characterization of the acute genetic response to oxidant damage in mammalian cells and tissues with hopes of identifying genes which play an important role in the cellular response to oxidative stress. Three different in vitro model systems of oxidative stress have been employed including 1) hyperoxia (95% oxygen) treatment of cultured lung fibroblasts, 2) xanthine-xanthine oxidase treatment of rat proximal tubular epithelial cells, and 3) the effects of the nephrotoxic cysteine conjugate, S-(1,2-dichlorovinyl)-L-cysteine (DCVD) on porcine renal epithelial cells. gadd153, a CCAAT/enhancer-binding (C/EBP)-related gene and putative transcriptional regulator, was shown to be induced by each of the treatments, suggesting that it represents a generalized response to oxidant injury. In additional studies with the in vitro cultured fibroblasts as well as in vivo studies examining lung tissue from rats exposed to 100% oxygen we have shown that two other C/EBP-related genes, C/EBPbeta and C/EBP, are also induced in response to hyperoxia. We have begun studies to compare the sensitivity of aged versus young rats to the damaging effects of hyperoxia. We have observed that old rats (24 months of age) are less susceptible to hyperoxia-induced lung injury than are young (6 months of age) rats. Mortality resulting from respiratory distress in young rats placed in 100% oxygen occurred at an average exposure of 66 hours compared to 88 hours exposure in old rats. We are currently examining whether this age-related difference in survival is correlated with any age-related difference in the genetic response to hyperoxia.