Jaskoll T, Choy H A, Melnick M
Laboratory for Developmental Genetics, University of Southern California, Los Angeles 90089-0641, USA.
Pediatr Res. 1996 May;39(5):749-59. doi: 10.1203/00006450-199605000-00002.
Lung morphogenesis has been shown to be regulated by glucocorticoids (CORT). Because CORT has been primarily thought to affect fetal lung development, previous studies have focused on the role of CORT receptor (GR)-mediated regulation of fetal lung development. Although endogenous CORT increases during embryonic and fetal stages and exogenous CORT treatment in vivo and in vitro clearly accelerates embryonic lung development, little is known about the morphoregulatory role of the embryonic CORT-GR signal transduction pathway during lung development. In this study, we characterize the embryonic mouse CORT-GR pathway and demonstrate: stage-specific in situ patterns of GR immunolocalization; similarity in GR relative mobility with progressive (E13 --> E17) development; that embryonic GR can be activated to bind a GR response element (GRE); significantly increasing levels of functional GR with increasing lung maturation; and the presence of heat shock protein (hsp) 70 and hsp90 from early (E13) to late (E17) developmental stages. These results support the purported importance of the embryonic CORT-GR signal transduction pathway in progressive lung differentiation. To demonstrate that the embryonic CORT-GR directed pathway plays a role in lung development, early embryonic (E12) lungs were exposed to CORT in utero and surfactant-associated protein A (SP-A) expression was analyzed; CORT treatment up-regulates SP-A mRNA expression and spatiotemporal protein distribution. Finally, to determine whether CORT-GR-directed pulmonary morphogenesis in vivo involves the modulation of growth factors, we studied the effect of CORT on TGF-beta gene expression. Northern analysis of TGF-beta 1, TGF-beta 2, and TGF-beta 3 transcript levels in vivo indicates that CORT regulates the rate of lung morpho- and histodifferentiation by down-regulating TGF-beta 3 gene expression.
肺形态发生已被证明受糖皮质激素（CORT）调节。由于CORT主要被认为会影响胎儿肺发育，此前的研究主要聚焦于CORT受体（GR）介导的对胎儿肺发育的调节作用。尽管在胚胎期和胎儿期内源性CORT会增加，且体内外给予外源性CORT处理均能明显加速胚胎肺发育，但关于胚胎期CORT - GR信号转导通路在肺发育过程中的形态调节作用却知之甚少。在本研究中，我们对胚胎期小鼠的CORT - GR通路进行了表征并证明：GR免疫定位的阶段特异性原位模式；随着发育进程（E13至E17）GR相对迁移率的相似性；胚胎期GR可被激活以结合GR反应元件（GRE）；随着肺成熟度增加功能性GR水平显著升高；以及从发育早期（E13）到晚期（E17）均存在热休克蛋白（hsp）70和hsp90。这些结果支持了胚胎期CORT - GR信号转导通路在肺渐进性分化中所宣称的重要性。为证明胚胎期CORT - GR导向的通路在肺发育中起作用，对早期胚胎（E12）肺进行子宫内CORT暴露并分析表面活性物质相关蛋白A（SP - A）的表达；CORT处理上调了SP - A mRNA表达及蛋白的时空分布。最后，为确定体内CORT - GR导向的肺形态发生是否涉及生长因子的调节，我们研究了CORT对TGF -β基因表达的影响。体内TGF -β1、TGF -β2和TGF -β3转录水平的Northern分析表明，CORT通过下调TGF -β3基因表达来调节肺形态和组织分化的速率。
