Wang Jun, Liu Hao, Gao Linlin, Liu Xiaomei
Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Obstetrics and Gynecology, Benxi Central Hospital of China Medical University, Benxi, China.
Front Pediatr. 2018 Apr 20;6:109. doi: 10.3389/fped.2018.00109. eCollection 2018.
Patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) often experience persistent respiratory tract disease. In experimental models, doxorubicin-induced developmental lung abnormalities may result from downregulation of branching morphogenesis factor fibroblast growth factor (Fgf10). This study investigated the temporospatial expression of Fgf10 pathway components and lung epithelial factors in an doxorubicin-induced EA-TEF model by quantitative polymerase chain reaction, immunohistochemistry, and immunoblotting. Epigenetic regulation of gene expression by histone deacetylation was also investigated. Bone morphogenetic protein (Bmp) 4 and Cathepsin H (Ctsh), downstream targets of , were significantly downregulated in the EA-TEF model during the saccular stage, consistent with Fgf10 expression. The developmental expression pattern of P2x7 receptor (ATI-cell marker), , and in lung epithelial cells was not affected. (ATII-cell Marker) and (Clara cell marker) were significantly downregulated at the canalicular stage. Meanwhile, histone deacetylase (Hdac) 1 was upregulated and subsequently decreased acetylation of histone H3 Lys56 in the EA-TEF model, which returned to a normal level at the saccular stage. In conclusion, disturbed molecular signaling involving Fgf10/Ctsh was associated with impaired airway branching and epithelial cell development in lung morphogenesis, as evidenced by downregulated Sftpc and Scgb1a1 protein expression. The influence of Hdac1 activity on gene and protein expression in lung epithelial cells deserves further study.
食管闭锁（EA）和气管食管瘘（TEF）患者常患有持续性呼吸道疾病。在实验模型中，阿霉素诱导的肺发育异常可能是由于分支形态发生因子成纤维细胞生长因子（Fgf10）的下调所致。本研究通过定量聚合酶链反应、免疫组织化学和免疫印迹法，研究了阿霉素诱导的EA - TEF模型中Fgf10信号通路成分和肺上皮因子的时空表达。还研究了组蛋白去乙酰化对基因表达的表观遗传调控。在囊泡期，Fgf10的下游靶点骨形态发生蛋白（Bmp）4和组织蛋白酶H（Ctsh）在EA - TEF模型中显著下调，与Fgf10表达一致。肺上皮细胞中P2x7受体（ATI细胞标志物）、 和 的发育表达模式未受影响。表面活性蛋白C（Sftpc，ATII细胞标志物）和分泌性粒蛋白1a1（Scgb1a1，克拉拉细胞标志物）在细支气管期显著下调。同时，在EA - TEF模型中组蛋白去乙酰化酶（Hdac）1上调，随后组蛋白H3赖氨酸56的乙酰化水平降低，在囊泡期恢复到正常水平。总之，涉及Fgf10/Ctsh的分子信号紊乱与肺形态发生过程中气道分支和上皮细胞发育受损有关，Sftpc和Scgb1a1蛋白表达下调证明了这一点。Hdac1活性对肺上皮细胞基因和蛋白表达的影响值得进一步研究。
