Oshika E, Liu S, Singh G, Michalopoulos G K, Shinozuka H, Katyal S L
Department of Pathology, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Pediatr Res. 1998 Mar;43(3):315-24. doi: 10.1203/00006450-199803000-00002.
We have reported that dexamethasone (DEX) treatment of early embryonic rat lungs in culture induced features of both distorted and accelerated maturation. In this report, we investigated the effects of retinoids on normal and DEX-induced lung development in vitro. Lung maturation was assessed by examining the morphology and the expression of genes related to epithelial differentiation (surfactant proteins, SP-A, SP-B and SP-C and Clara cell protein, CC10) and growth [keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF)]. We cultured d 14 and 15 fetal rat lungs in the presence of DEX (1-1000 nM) and/or all-trans-retinoic acid (RA) (10(-7)-10(-5) M) for 4 d. RA at 10(-6) and 10(-5) M inhibited branching and dilated the distal tubules, and at 10(-5) M caused dilatation of the proximal tubules destined to form the trachea and the main bronchi. The adverse effects of DEX, such as distorted branching, tubular dilatation, and suppression of both lung growth and epithelial cell proliferation, were all prevented by RA. In addition, RA inhibited several features of DEX-induced accelerated maturation, such as: 1) the increased levels of SP-A, SP-B, and CC10 mRNAs; 2) the attenuation of mesenchymal tissue; and 3) the mature distribution of cells expressing SP-C mRNA. In contrast, RA potentiated the increase of KGF and decrease of HGF transcripts induced by DEX. In conclusion, the study shows antagonism by RA of DEX-induced effects on lung morphology and gene expression. We postulate that normal lung development requires a balanced action of endogenous retinoids and glucocorticoids.
我们曾报道，在体外培养中用地塞米松（DEX）处理早期胚胎大鼠肺可诱导出肺成熟异常和加速的特征。在本报告中，我们研究了视黄酸对体外正常和DEX诱导的肺发育的影响。通过检查与上皮分化相关基因（表面活性蛋白，SP-A、SP-B和SP-C以及克拉拉细胞蛋白，CC10）的形态和表达以及生长相关基因[角质形成细胞生长因子（KGF）和肝细胞生长因子（HGF）]来评估肺成熟情况。我们在存在DEX（1 - 1000 nM）和/或全反式视黄酸（RA）（10^(-7) - 10^(-5) M）的情况下培养第14和15天的胎鼠肺4天。10^(-6)和10^(-5) M的RA抑制分支并使远端小管扩张，10^(-5) M的RA导致注定形成气管和主支气管的近端小管扩张。DEX的不良影响，如分支异常、小管扩张以及肺生长和上皮细胞增殖的抑制，均被RA阻止。此外，RA抑制了DEX诱导的加速成熟的几个特征，例如：1）SP-A、SP-B和CC10 mRNA水平的升高；2）间充质组织的减少；3）表达SP-C mRNA的细胞的成熟分布。相反，RA增强了DEX诱导的KGF转录物增加和HGF转录物减少。总之，该研究表明RA对DEX诱导的肺形态和基因表达的影响具有拮抗作用。我们推测正常肺发育需要内源性视黄酸和糖皮质激素的平衡作用。
