Lung tissue ischemia and cellular hypoxia due to interruption of blood flow and ventilation such as during lung transplantation, atelectasis, or thromboembolism, result in acute lung injury during reoxygenation which is indistinguishable from acute respiratory distress syndrome. Both mitochondrial manganese-containing superoxide dismutase (MnSOD) and cytosolic, copper zinc containing superoxide dismutase (CuZnSOD) are critical intracellular antioxidants. MnSOD is concentrated in alveolar epithelial Type II cells and protects the lung from oxidant injury by induction in response to oxidant stress. MnSOD protein is relatively abundant in Type II cells and a decrease in MnSOD, by itself, increases sensitivity of alveolar cells to oxidant stress, including that produced by hyperoxia and TNF-alpha. The hypothesis that will be tested by this application is that hypoxia decreases SOD expression in alveolar Type II cells and that decreased alveolar Type II cell SOD activity is a predisposing factor for oxidant injury during reoxygenation and other types of oxidant stress.
The specific aims to be addressed are: 1) define the biological importance of the hypoxia-induced decreases in alveolar Type II cell SOD expression; 2) identify the mechanisms by which hypoxia reduces SOD expression in alveolar Type II cells; and 3) determine whether repletion of MnSOD by gene transfer reverses the increased sensitivity to oxidant stress. These studies will be done by using a combination of isolated Type II cells from rabbits and in vivo experiments on transgenic mice to investigate the impact of the reduction in SOD expression on the cellular responses to oxidant stress in the lung. Heterozygous MnSOD knockout mice will be used to define the importance of specific decreases in MnSOD expression. Since the effects of hypoxia on alveolar Type II cell SOD expression has not been fully investigated, this study will fill gaps in our knowledge of alveolar Type II cell biology and the effects of hypoxia on antioxidant defenses. The potential exists for generating specific new information regarding the biological importance of hypoxia-induced SOD depletion from alveolar Type II cells and the mechanisms by which hypoxia decreases SOD in Type II cells and the potential therapeutic efficacy of restoring SOD activity to pre-hypoxia levels for restoring resistance to oxidant stress.
