Division of Newborn Medicine, Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center and Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA ; Division of Neonatology, Department of Pediatrics, Tufts Medical Center, Boston, MA 02111, USA.
Biomed Res Int. 2013;2013:320249. doi: 10.1155/2013/320249. Epub 2013 Sep 3.
Androgens enhance airway branching but delay alveolar maturation contributing to increased respiratory morbidity in prematurely born male infants. Hoxb5 protein positively regulates airway branching in developing lung. In other organs, androgen regulation intersects with Hox proteins and TGF β -SMAD signaling, but these interactions have not been studied in the lung. We hypothesized that androgen alteration of airway branching early in lung development requires Hoxb5 expression and that these androgen-Hoxb5 interactions occur partially through regional changes in TGF β signaling. To evaluate acute effects of androgen and TGF β on Hoxb5, E11 whole fetal mouse lungs were cultured with dihydrotestosterone (DHT) with/without Hoxb5 siRNA or TGF β inhibitory antibody. Chronic in utero DHT exposure was accomplished by exposing pregnant mice to DHT (subcutaneous pellet) from E11 to E18. DHT's ability to enhance airway branching and alter phosphorylated SMAD2 cellular localization was partially dependent on Hoxb5. Hoxb5 inhibition also changed the cellular distribution of SMAD7 protein. Chronic in utero DHT increased Hoxb5 and altered SMAD7 mesenchymal localization. TGF β inhibition enhanced airway branching, and Hoxb5 protein cellular localization was more diffuse. We conclude that DHT controls lung airway development partially through modulation of Hoxb5 protein expression and that this level of regulation involves interactions with TGF β signaling.
雄激素促进气道分支，但延迟肺泡成熟，导致早产儿男性婴儿呼吸发病率增加。Hoxb5 蛋白正向调节发育肺中的气道分支。在其他器官中，雄激素调节与 Hox 蛋白和 TGFβ-SMAD 信号通路交叉，但这些相互作用在肺中尚未研究。我们假设雄激素对肺发育早期气道分支的改变需要 Hoxb5 表达，并且这些雄激素-Hoxb5 相互作用部分通过 TGFβ 信号的区域变化发生。为了评估雄激素和 TGFβ 对 Hoxb5 的急性影响，用二氢睾酮（DHT）和/或 Hoxb5 siRNA 或 TGFβ 抑制性抗体培养 E11 全胎鼠肺。通过从 E11 到 E18 向怀孕小鼠皮下植入 DHT 丸来实现慢性宫内 DHT 暴露。DHT 增强气道分支和改变磷酸化 SMAD2 细胞定位的能力部分依赖于 Hoxb5。Hoxb5 抑制也改变了 SMAD7 蛋白的细胞分布。慢性宫内 DHT 增加了 Hoxb5 并改变了 SMAD7 间充质定位。TGFβ 抑制增强了气道分支，Hoxb5 蛋白细胞定位更加弥散。我们得出结论，DHT 通过调节 Hoxb5 蛋白表达来控制肺气道发育，这种调节水平涉及与 TGFβ 信号通路的相互作用。
