ANDROGEN INHIBITION OF FETAL LUNG MATURATION

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The main objective of this project is to better define the mechanisms controlling maturation of the fetal lung. This will be accomplished by continuing the study of the mechanisms of the sex difference in the timing of fetal lung development, addressing four specific aims. Specific Aim No. 1 is to further characterize the mechanism regulating the production of fibroblast pneumonocyte factor (FPF) by fetal lung fibroblasts. The mouse model of testicular feminization (Tfm mouse) will be used. Will study the mechanism of the sex difference in the expression of FPF in male, female, and androgen-insensitive male fetuses, by determining whether hormones or exogenous growth factors such as epidermal growth factor (EGF), platlet-derived growth factor (PDGF) or somatomedin C stimulate the production of FPF. Specific Aim No. 2 is to study the factors produced by the fetal lung to regulate its growth and differentiation. The presence of different factors at different developmental stages which sequentially regulate growth and differentiation is a likely explanation of how sex differences in surfactant synthesis arise. FPF conditioned media from the Tfm mouse will be studied to identify whether the lack of FPF activity in males coincides with growth-promoting activity. Sex-specific organ culture of fetal rabbit lung will be used in further experiments to prepare conditioned media from early and late stages in fetal lung maturation. This conditioned media will be tested for growth-promoting and differentiation activity in males and females. Specific Aim No. 3 is to study the mechanisms which regulate the expression of endogenous growth factors in the lung. The hormonal mediation of the effects of endogenous or exogenous growth factors (EGF, PDGF, somatomedin-C) will be studied. Specific Aim No. 4 is to begin to characterize the growth and differentiation factors made by the fetal lung as identified in Specific Aim No. 2. Conditioned media will be fractionated by HPLC and gel columns to isolate the active fractions. Studies will be initiated to isolate the specific proteins involved and to begin to characterize them. The information gained from these studies will be useful for devising strategies to prevent hyaline membrane disease in premature infants. Such strategies must be firmly based on a knowledge of the events in fetal lung development which need to be enhanced in male and in females. In addition these studies will provide valuable insights into the general understanding of the biological clock which regulates the timing of developmental events.