Glucocorticoid pathways in fetal lung development

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(Applicant's Abstract) Premature infants are at risk for developing acute and chronic pulmonary disease, a significant cause of mortality, prolonged hospitalization, and long-term morbidity. The beneficial effect of prenatal glucocorticoid (GC) treatment on premature lungs is well documented. Despite the decreased incidence and severity of hyaline membrane disease in recent years with the widespread use of prenatal GC and postnatal surfactant therapies, the incidence of chronic lung disease (CLD, defined as oxygen dependence after 36 weeks gestational age) has not had a corresponding decline. This suggests that in infants with CLD, developmental or acquired lung defects are not ameliorated by either GC treatment in the immediate prenatal period or surfactant treatment in the postnatal period. This suggestion is supported by findings in mice with GC deficiency due to targeted deletion of the corticotropin-releasing hormone (Crh) gene. Untreated mice die in the immediate postnatal period, with major defects in lung development (normal branching, but mesenchymal and epithelial hypercellularity, abnormal Clara cell differentiation, and decreased alveolarization), but only minor deficiencies in surfactant expression. Moreover, successful GC rescue of Crh-/- fetuses requires that the steroid be given before embryonic day 13.5, several days prior to any previously described effects of GC in fetal lung. This suggests that GC has major effects on pulmonary development that occur very early in lung organogenesis. This time frame is likely too early to affect surfactant synthesis, but may well involve modulation of one or several paracrine growth factor systems which have recently been described to have important roles in lung development, including members of the sonic hedgehog, fibroblast growth factor, transforming growth factor, and platelet derived growth factor families. The investigators propose to identify those factors which govern late (post- branching) lung development that are GC-responsive, and their pathways of interaction with GC, using organ explant cultures from Crh-/- fetal mice and treatment with GC and/or members of the above growth factor families. Candidate genes, cDNAs on Affymetrix murine oligonucleotide chips, as well as cDNAs identified via differential display techniques, will be examined (Specific Aim 1) Novel candidate genes will be characterized by mRNA and protein localization and developmental regulation in the normal and Crh-/- fetal lung, and by targeted gene deletion in vivo (Specific Aim 2). Finally, an essential role for the fetal lung in the stimulation of the fetal GC secretion leading to normal lung development will be sought (Specific Aim 3).