ROLE OF GLUCOCORTICOIDS IN PULMONARY MATURATION

该项目使用糖皮质激素缺乏的小鼠模型来 探讨糖皮质激素在胎儿肺发育中的作用。 通过靶向灭活促肾上腺皮质激素释放所产生的小鼠 激素基因异常导致肺发育异常导致新生儿 死于呼吸衰竭。这种模式的一个主要优点是 肺发育不良在产前是完全可逆的 糖皮质激素治疗。我们在表面活性物质中发现了异常 生物合成与胎儿肺发育不良有关，但相信 这些都不足以解释肺部病变的大小 异常，并怀疑糖皮质激素有其他重要的 胎儿肺发育中的功能与组织重塑有关。 我们将使用该模型来定义 正常肺成熟所需的糖皮质激素治疗； 确定糖皮质激素是否通过以下途径介导肺重塑 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，并确定 这些靶点在发育级联中影响下游细胞类型。 涉及细胞-细胞相互作用或旁分泌释放 并确定促肾上腺皮质激素是否释放 在胎儿肺中高水平表达的激素具有刺激作用 胎儿的脑垂体轴，从而促进肺的成熟。 由于糖皮质激素现在广泛用于产前治疗， 肺透明膜病，并越来越多地用于产后 支气管肺发育不良的治疗及对其的进一步认识 促进正常肺成熟的行动将有助于 了解肺发育异常的病理机制 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.