The overall objectives of this proposal are to study the influence of hyperoxia on proliferation and differentiation of the alveolar epithelium during neonatal lung growth, to determine the importance of timing of hyperoxia on these changes, and to study the changes in gene expression of alveolar epithelial cells that are associated with such alterations. The experimental model will be newborn rats exposed to air or 861/, oxygen.
The specific aims are: 1) to determine changes in the number and subcellular morphology of alveolar type II and type I cells in the lungs of neonatal rats exposed to 85% oxygen or air during the first or second week of life; 2) to determine changes in the proliferation rate of alveolar type II cells in the lungs of neonatal rats exposed to 85% oxygen or air during the 1st or 2nd week of life; 3) to determine the changes in the rate of differentiation of alveolar type II cells to type I cells at different points during exposure of neonatal rats to 85% oxygen or air during the 1st or 2nd week of life; 4) to use in situ hybridization to determine the changes in expression of proto-oncogenes, growth factor receptor genes, and basement membrane genes in alveolar type II cells in the lung tissue of neonatal rats exposed to 85% oxygen or air during the 1st or 2nd week of life; and 5) to study changes in gene expression (steady-state in mRNA levels and nuclear run-off transcriptions) in alveolar type II cells isolated at different time points from the lungs of neonatal rats exposed to 85% oxygen or air during the 1st or 2nd week of life. We expect the results of these experiments to provide insight into the biology of epithelial repair in the lung parenchyma and into the pathogenesis of bronchopulmonary dysplasia in newborn infants.
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