Acute and chronic lung injuries are a major cause of morbidity and mortality in neonates, children and adults. One form of lung injury is through the toxic effects of supplemental oxygen exposure. Adult respiratory distress is a significant problem that affects 100-150,000 patients in the U.S. alone and results in mortality in approximately50% of those affected. Similarly, while great progress has been made in surfactant replacement therapies in children born prematurely, they still suffer from the toxic effects of oxygen exposure and often die of bronchopulmonary dysplasia. Pulmonary oxygen toxicity is due to elevated levels of reactive oxygen species (ROS) which exert their cytotoxic effects through production of DNA strand breaks, peroxidation of lipids and enzymatic alterations of proteins. It has been suggested that cells growth arrest in order to repair cellular damage, or undergo apoptosis (programmed cell death) when the damage is to extensive to be repaired. Our preliminary studies have shown that lungs of adult mice exposed to >95% oxygen have increased expression of the growth inhibitory cytokine transforming growth factor-beta (TGF- beta). Continued exposure resulted in DNA damage and increased expression of genes that promote DNA repair and apoptosis. Additional studies revealed that mice with reduced expression of TGF-beta had increased DNA damage. Based upon these findings, we hypothesize that reduced levels of TGF-beta sensitizes pulmonary epithelial cells to hyperoxia. We will prove this by showing that mice with decreased expression of TGF-beta have increased DNA damage and expression of genes that regulate DNA repair and apoptosis. These studies are significant because understanding how ROS injure and kill pulmonary epithelial cells is critically important for improving clinical therapies that rely on supplemental oxygen.
