GENETOXIC RESPONSE TO OXIDATIVE DAMAGE

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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.