Proper functioning of the lung at birth depends on development and maturation of many interacting pulmonary cell types in utero. Among these, major cell types are the alveolar pneumocytes or AT2 cells which are the major site of synthesis and secretion of surfactant. Surfactant is essential for maintaining the structural integrity of the alveolus and is composed of a complex of phospholipids and three major proteins; SP-A, SP-B and SP-C. Interruptions in development of the fetus in utero by premature birth is accompanied by many clinical complications including hyaline membrane disease and bronchopulmonary dysplasia. By examining alterations in the expression of SP-A, SP-B, and SP-C genes in a primate model of premature birth and survival, we have demonstrated that a specific aberration in the expression of SP-A, but not SP-B or SP-C, occurs in prematurely delivered fetuses. Due to this aberration, premature infants also lack the ability to respond to hyperoxia by increasing the production of SP-A, which is a part of the normal response to hyperoxia of the AT2 cells in the lung of adults and neonates of various species. Based on these observations, we have hypothesized that immature AT2 cells in premature fetuses lack factors (transcriptional or otherwise) that are necessary for optimal expression of the SP-A (but not SP-B and SP-C) and perhaps other physiologically important genes whose expression may be required for extrauterine adaptation. To test this hypothesis, we propose to clone and characterize cDNAs whose expression correlates with maturation of AT2 cells during in utero development.
Our aims are to find genes whose activity is necessary for development and maturation of AT2 cells in utero.
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