Bronchopulmonary dysplasia (BPD) is a chronic lung disease that develops in premature infants with respiratory insufficiency as a sequela of prolonged ventilatory assistance with supplemental oxygen. Proteolytic destruction of lung connective tissue is thought to be a significant etiologic factor in the impaired alveolar septal development that is characteristic of this disease. Lung secretions obtained from infants ventilated for 6 or more days with concentrations of oxygen in excess of 60% contain inactivated alpha-1-proteinase inhibitor, active elastase and proteolytic degradation products of elastin. In addition, parenchymal elastic fibers observed in BPD lungs at autopsy are tortuous and fragmented, suggestive of proteolytic destruction. Studies conducted on neonatal rats exposed to 100% oxygen during the period of major alveolarization of the lung indicate that lung parenchymal message levels for tropoelastin, the soluble precursor of elastin, are decreased during the exposure but rebound post-exposure, remaining elevated well beyond the normal period of elastin synthesis and alveolarization in the rat. These observations suggest that, in addition to proteolytic destruction of elastic fibers, lung elastin synthesis may be altered in the neonate with respiratory distress. We will continue to examine the hypothesis that the alteration of lung elastic fiber content associated with hyperoxic exposure is a significant etiologic factor in impaired lung development in infants with BPD. The effects of hyperoxia on tropoelastin message expression in rat lung parenchyma will be evaluated to follow changes in tropoelastin mRNA as a function of the developmental period during which the exposure occurs. Studies will then be directed at determining whether rates of nuclear transcription of the gene and/or post-transcriptional modification of tropoelastin mRNA are responsible for the observed changes in tropoelastin mRNA resulting from the hyperoxic exposure. In addition, postmortem lung samples from human infants will be evaluated for tropoelastin mRNA by in situ hybridization to define the developmental period during which tropoelastin gene expression occurs as well as the changes in message expression associated with acute or chronic lung disease. Finally, we will use an in vitro system to evaluate the effects of mechanical strain and/or hyperoxia on neonatal rat lung fibroblasts in order to better understand the separate and combined effects of hyperoxia and barotrauma on tropoelastin synthesis in the immature lung. We anticipate that the results of the proposed studies will enhance our understanding of the adverse effects of prolonged mechanical ventilation with supplemental oxygen on the developing lung.
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