ROLE OF GLUCOCORTICOIDS IN PULMONARY MATURATION

该项目采用糖皮质激素缺乏的小鼠模型， 探讨糖皮质激素在胎儿肺发育中的作用。 通过靶向失活促肾上腺皮质激素释放因子 导致新生儿肺发育异常激素基因 死于呼吸衰竭 这种模式的主要优点是， 肺发育不良是完全可逆的， 糖皮质激素治疗 我们发现表面活性剂 与胎儿肺发育不良相关的生物合成，但相信 这些都不足以解释肺动脉高压的严重程度 异常，并怀疑糖皮质激素有其他重要的 与组织重塑有关的胎儿肺发育功能。 我们将使用这个模型来定义 正常肺成熟所需的糖皮质激素给药; 确定糖皮质激素是否介导肺重塑， 减少肺中特定细胞群的数量;试图 确定糖皮质激素作用的细胞靶点， 这些靶点在发育级联中影响下游细胞类型 涉及细胞间相互作用或旁分泌释放 扩散因子;并确定是否促肾上腺皮质激素释放 在胎儿肺中高水平表达的激素， 胎儿垂体肾上腺轴，从而促进肺成熟。 由于糖皮质激素现在广泛用于产前治疗， 透明膜病，并越来越多地用于产后 支气管肺发育不良的治疗，进一步了解他们的 促进正常肺成熟的作用将有助于 了解肺发育异常的病理学， 设计更合理的治疗方案。

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.