There is a gender difference in human fetal lung development with delayed lung maturation and increased incidence and severity of RDS and bronchopulmonary dysplasia in male infants. In animal studies, androgens delay fetal lung maturation while estrogens have stimulatory effects. Epidermal growth factor (EGF) stimulates aspects of fetal lung maturation and appears to be involved in early branching morphogenesis. In this application it is hypothesized that the effects of sex steroids on human fetal lung development occur by modulation of pulmonary EGF receptors. Experiments will be carried out in explant culture of human fetal lung and in a human lung cell line.
In aim 1 the effects of culture, dihydrotestosterone and estradiol on EGF receptor protein and binding capacity as well as surfactant components and lung morphology will be characterized by gender.
Aim 2 will examine mechanisms for the observed effects of sex hormones on EGF receptor, measuring content, transcription rate and stability of mRNA and exploring regulation of the EGF receptor promoter in transfection studies.
Aim 3 will examine effects of inhibiting EGF receptor on parameters of type II cell differentiation. Experimental approaches include blocking antibodies to EGF and its receptor, antisense oligonucleotides directed against EGF receptor and inhibition of tyrosine kinase activity. These studies will characterize the effects of androgens and estrogens in cultured human fetal lung and provide further information on the role of EGF in lung development.
