The role of dietary zinc and copper-zinc superoxide dismutase gene expression in response to oxidative stress in the lung and brain

The balance between the antioxidant defenses and the rate of production of reactive oxygen species (ROS), or oxidative stress, is believed to be a critical factor that determines the extent of tissue injury in a number of diseases. The antioxidant defenses, which consist of a network of enzymes, proteins and low molecular weight scavengers, function to protect cellular components against the damaging effects of ROS. This dissertation work focuses on the functional role of two components of the antioxidant defense system: the trace element zinc, and the antioxidant enzyme copper-zinc superoxide dismutase (CuZnSOD). This work was initiated based on accumulating evidence indicating that ROS mediated tissue injury may be a common pathogenic mechanism in several diseases associated with premature birth, including bronchopulmonary dysplasia and cerebral palsy, and that low antioxidant status may be a critical determinant of disease progression. We have hypothesized that low zinc nutritional status and reduced CuZnSOD activity increases the potential for ROS mediated tissue damage in lung and brain tissue. Further, we proposed that exposure to oxygen therapy, a common treatment strategy applied to premature infants, would markedly increase oxidative tissue damage in these tissues. To test this hypothesis we used an animal model to examine the effects of dietary zinc deficiency, reduced CuZnSOD expression and exposure to hyperoxia on oxidative tissue damage in lung and brain tissue. In addition, we examined the stress response of antioxidant metalloproteins that may play a critical role in maintaining homeostasis under oxidative stress, and have also performed a global analysis of gene expression in the brain of zinc deficient animals using cDNA microarray technology.; Results from the first set of experiments demonstrated that exposure to hyperoxia increased oxidative tissue damage in the lung and also induced the expression of ceruloplasmin and metallothionein, suggesting that these metalloproteins may function as antioxidants in addition to their role in trace metal homeostasis. Subsequent work in brain tissue demonstrated that reduced expression of CuZnSOD increased oxidative tissue damage following exposure to hyperoxia, thus demonstrating the deleterious consequences of a compromised antioxidant defense system. And finally, the microarray analysis demonstrated that in the brain there are a number of genes from different cellular pathways whose expression is changed in response to zinc deficiency.