SURFACTANT PROTEIN A GENE AND ITS REGULATION

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Bronchopulmonary dysplasia (BPD) develops as a complication of acute lung injury associated with neonatal respiratory distress syndrome (RDS) and its therapy. Although the prevalent use of exogenous surfactant for treatment of premature infants has greatly reduced the severity of RDS and the mortality rate of infants with birthweights of <1,000 grams, surfactant therapy has only a modest effect to reduce the incidence of BPD. Further reductions in the incidence of BPD and associated lung injury require development of antenatal and/or postnatal therapeutic regimens to enhance lung maturation and augment effects of exogenous surfactant therapy. Natural lung surfactant preparations Contain surfactant proteins, SP-B and SP-C, but lack SP-A, a major surfactant protein that is developmentally regulated in association with surfactant phospholipids. SP-A appears to facilite the reduction of alveolar surface tension, to mediate surfactant reuptake by type II cells, to block the surfactant inactivating effects of serum proteins and enhance immune function within the alveolus. The prematurely born, ventilated baboon provides an excellent model for study of the etiology of BPD and its treatment. In consideration of the potential importance of SP-A in surfactant function, its absence from clinically approved exogenous surfactants containing SP-B and SP-C, which are relatively ineffective in preventing BPD, it is proposed to characterize the baboon SP-A gene(s), its mRNA transcripts and regulation during fetal and early postnatal development. In preliminary studies, we found that SP-A gene expression in baboon fetal lung in culture is regulated by cAMP, glucocorticoids and oxygen in a manner that is similar, if not identical, to the human. Cyclic AMP causes a marked induction of SP-A mRNA levels, whereas, Dex causes a dose-dependent inhibition of SP-A mRNA accumulation. We also have obtained evidence that baboon SP-A is encoded by a single copy gene. Genomic clones have been isolated that contain the baboon SP-A gene and >6 kb of 5'-flanking region. In the proposed studies, developmental changes in expression of the SP-A gene and its transcripts, and in the effects of cAMP, glucocorticoids and oxygen on SP-A gene expression in baboon fetal lung in culture will be investigated. Agents found to enhance lung maturation and SP-A gene expression will be administered postnatally to prematurely delivered baboons in combination with exogenous surfactant; efficacy of these treatments to reduce severity of RDS and BPD will be compared to effects of exogenous surfactant alone. Studies also will be implemented to define the cis-acting elements involved in the developmental and multifactorial regulation of SP-A gene expression in baboon fetal lung and to study developmental changes in the binding of lung nuclear proteins to these regions. It is our view that understanding of basic mechanisms involved in regulation of SP-A gene expression will lead to the development of therapies to accelerate pulmonary surfactant production in prematurely born infants and, prevent the deleterious effects of mechanical ventilation and oxygen resulting in BPD.