Exposure of immature lung to high oxygen tensions can alter growth of alveolar tissue and pulmonary vasculature in the developing lung (1,2). Hyperoxic exposure in the neonatal period is an important factor in the development of bronchopulmonary dysplasia (BPD) the most common form of chronic lung disease in infants and children. Lung growth of infants with BPD is impaired with failure of normal alveolar multiplication (3) possibly secondary to the early exposure of hyperoxia in the neonatal period. Hyperoxia is known to cause growth arrest in alveolar cells in culture (4). Studies have also shown that hyperoxic exposure delays DNA synthesis in neonatal murine lung (5,6). The underlying molecular mechanisms regulating cellular growth arrest in neonatal lung exposed to hyperoxia have not been extensively evaluated. In this proposal the applicant hypothesizes that growth arrest secondary to hyperoxia in the neonatal lung is associated with the regulation of known and novel genes. Using subtractive hybridization a novel ubiquitin conjugating enzyme 2 (Ubc-2) was isolated and found to be markedly downregulated during hyperoxia. The applicant hypothesizes that growth arrest secondary to hyperoxia in the neonatal lung is associated with the down regulation of ubiquitin conjugating enzymes necessary for the degradation of specific cyclin inhibitors. This novel Ubc-2 enzyme is homologous to RAD6 an enzyme in Saccharomyces cerevisiae involved in DNA repair (7,8) and human Ubc2 an enzyme involved in degradation of the cyclin inhibitor p27 (9). Down regulation of this novel ubiquitin enzyme gene suggests a role for cyclin inhibitors in the regulation of hyperoxic growth arrest in neonatal lung. This gene may also have a role in DNA repair in cells exposed to hyperoxia based on its homology to RAD6. Down regulation of the ubiquitin pathway resulting in increase levels of cyclin inhibitors leading to cellular growth arrest could contribute to the impaired alveolar growth found in infants with BPD. In addition to evaluating the role of this novel ubiquitin enzyme in growth arrest other genes identified by subtractive hybridization which may have a role in cell cycle regulation or mitogeneses will be evaluated.
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|McGrath-Morrow, Sharon A; Stahl, Jennifer (2002) Inhibition of glutamine synthetase in a549 cells during hyperoxia. Am J Respir Cell Mol Biol 27:99-106|
|McGrath-Morrow, S A; Stahl, J (2001) Apoptosis in neonatal murine lung exposed to hyperoxia. Am J Respir Cell Mol Biol 25:150-5|
|McGrath-Morrow, S A; Stahl, J (2001) Growth arrest in A549 cells during hyperoxic stress is associated with decreased cyclin B1 and increased p21(Waf1/Cip1/Sdi1) levels. Biochim Biophys Acta 1538:90-7|
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|McGrath, S A (1998) Induction of p21WAF/CIP1 during hyperoxia. Am J Respir Cell Mol Biol 18:179-87|