ROLE OF GLUCOCORTICOIDS IN PULMONARY MATURATION

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This project employs a mouse model of glucocorticoid deficiency to investigate the role of glucocorticoids in fetal pulmonary development. Mice created by targeted inactivation of the corticotropin -releasing hormone gene have abnormal pulmonary development leading to neonatal death from respiratory failure. A major virtue of this model is that the pulmonary dysplasia is completely reversible following prenatal glucocorticoid therapy. We have found abnormalities in surfactant biosynthesis associated with the fetal pulmonary dysplasia, but believe that these are not sufficient to explain the magnitude of the pulmonary abnormalties, and suspect that glucocorticoid has other important functions in fetal pulmonary development related to tissue remodeling. We will use this model to define the level and time course of glucocorticoid administration necessary for normal pulmonary maturation; determine whether glucocorticoid mediates pulmonary remodeling by decreasing the number of specific cell populations in lung; attempt to identify the cell targets of glucocorticoid action and ascertain whether these targets influence downstream cell types in a developmental cascade involving either cell-cell interaction or paracrine release of a diffusable factor; and determine whether corticotropin releasing hormone, expressed in high levels in fetal lung, functions to stimulate the fetal pituitary adrenal axis, and thereby promote lung maturation. Since glucocorticoids are now widely used in the prenatal treatment to hyaline membrane disease, and are increasingly used in the postnatal treatment of bronchopulmonary dysplasia, further knowledge of their action in promoting normal pulmonary maturation will be useful in understanding the pathology of abnormal pulmonary development and in designing more rationale treatment regimens.