Key laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China.
Cardio-Pulmonary Institute and Institute for Lung Health, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
Cells. 2020 Apr 2;9(4):859. doi: 10.3390/cells9040859.
Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA ( are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several in BPD, a causal role remains to be established.
Our results showed that the expression level of increases during lung development and decreases postnatally. Further, hyperoxia treatment maintains high levels of in alveolar type 2 cells (AT2). We hypothesized that the decrease in expression in AT2 cells is required for normal alveologenesis. To test this hypothesis, we generated a novel transgenic mouse allowing doxycycline-based overexpression. Maintenance of expression in the postnatal distal lung epithelium under normoxia conditions is sufficient to reproduce the hypoalveologenesis phenotype triggered by hyperoxia. Using a pull-down assay, we identified as a key downstream target of . Caveolin1 protein is downregulated in response to overexpression of . This is associated with increased phosphorylation of Smad3 and Tgf-ß signaling. We found that AT2 cells overexpressing display decreased expression of AT2 markers and increased expression of AT1 markers.
Our results suggest that down-regulation of in postnatal lung may function as an important physiological switch that permits the induction of the correct alveolar developmental program, while conversely, failure to down-regulate suppresses alveolarization, leading to the common clinically observed phenotype of alveolar simplification.
支气管肺发育不良（BPD）是一种早产儿肺部疾病，其特征为肺泡简化。已知 microRNA（miRNA）参与肺部的许多生物学和病理过程。尽管已经描述了几种 miRNA 在 BPD 中的表达改变，但因果关系仍有待确定。
我们的结果表明，在肺发育过程中，miR-204 的表达水平增加，出生后则降低。此外，高氧处理可维持肺泡 II 型细胞（AT2）中 miR-204 的高水平。我们假设 AT2 细胞中 miR-204 表达的降低是正常肺泡发生所必需的。为了验证这一假设，我们生成了一种新型转基因小鼠，使其能够基于强力霉素进行 miR-204 过表达。在正常氧条件下维持 miR-204 在出生后远端肺上皮中的表达足以再现高氧引发的低肺泡发生表型。通过下拉测定，我们鉴定出 caveolin1 蛋白是 miR-204 的关键下游靶标。caveolin1 蛋白的表达在过表达 miR-204 时下调。这与 Smad3 和 TGF-β信号的磷酸化增加有关。我们发现，过表达 miR-204 的 AT2 细胞显示 AT2 标志物的表达降低，而 AT1 标志物的表达增加。
我们的结果表明，miR-204 在出生后肺部的下调可能作为一种重要的生理开关，允许诱导正确的肺泡发育程序，而相反，miR-204 下调的失败则抑制肺泡化，导致临床上常见的肺泡简化表型。
