Insulin receptor is downregulated in the nitrofen-induced hypoplastic lung
Insulin receptor is downregulated in the nitrofen-induced hypoplastic lung
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DOI：
10.1016/j.jpedsurg.2010.02.018
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发表时间：
2010-05-01
影响因子：
2.4
通讯作者：
Puri, Prem
中科院分区：
文献类型：
--
作者：
Ruttenstock, Elke;Doi, Takashi;Puri, Prem
目的：先天性膈疝（CDH）肺发育不全的发病机制仍知之甚少。在胎儿肺部发育过程中，胰岛素受体 (IR) 通过介导细胞对葡萄糖的摄取发挥着重要作用，而葡萄糖是表面活性剂磷脂生物合成的主要底物。在胎鼠肺中，IR 基因在 II 型肺细胞上表达。最近的研究表明，妊娠晚期肺IR的下调通过抑制表面活性剂合成而导致肺发育不全。我们假设在除草醚诱导的 CDH 模型中，IR 的肺部基因表达在肺部发育后期下调。方法：定时怀孕 Sprague-Dawley 大鼠在妊娠第 9 天（D9）暴露于橄榄油或除草醚。第 15 天、第 18 天和第 21 天进行了剖腹产。胎儿肺被分为 3 组：对照组、不含 CDH 的除草醚组 (CDH[-]) 和含 CDH 的除草醚组 (CDH[+])（每个时间点分别为 n = 8）。 IR 的相对信使 RNA (mRNA) 水平通过使用实时逆转录聚合酶链式反应测定。采用免疫组织化学方法评估IR蛋白表达。结果：与对照组相比，CDH(-)和CDH(+)组D21上IR mRNA的相对表达水平显着降低（分别为3.99+/-1.50和5.14+/-0.99）（7.45+/-3.95；P<0.05）。免疫组织化学显示，与对照肺相比，发育不良肺D21近端肺泡上皮中IR表达降低。结论：肺发育后期发育不良肺中IR基因和蛋白表达的下调可能会干扰正常的表面活性剂合成，导致除草醚诱导的CDH模型中肺发育不全。 (C) 2010 Elsevier Inc. 保留所有权利。
Purpose: The pathogenesis of pulmonary hypoplasia in congenital diaphragmatic hernia (CDH) is still poorly understood. During fetal lung development, the insulin receptor (IR) plays an important role by mediating the cellular uptake of glucose, which is a major substrate for the biosynthesis of surfactant phospholipids. In fetal rat lung, IR gene expression has been revealed on type II pneumocytes. Recent studies have demonstrated that downregulation of pulmonary IR in late gestation causes pulmonary hypoplasia by inhibition of surfactant synthesis. We hypothesized that pulmonary gene expression of IR is downregulated during the late stages of lung development in the nitrofen-induced CDH model.Methods: Timed pregnant Sprague-Dawley rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Cesarean deliveries were performed on D15, D18, and D21. Fetal lungs were divided into 3 groups: control, nitrofen without CDH (CDH[-]), and nitrofen with CDH (CDH[+]) (n = 8 at each time-point, respectively). Relative messenger RNA (mRNA) levels of IR were determined by using real time reverse transcription polymerase chain reaction. Immunohistochemistry was performed to evaluate protein expression of IR.Results: Relative expression levels of IR mRNA on D21 were significantly decreased in CDH(-) and CDH(+) group (3.99 +/- 1.50 and 5.14 +/- 0.99, respectively) compared to control (7.45 +/- 3.95; P < .05). Immunohistochemistry showed decreased IR expression in the proximal alveolar epithelium on D21 in hypoplastic lungs compared to control lungs.Conclusion: Downregulation of IR gene and protein expression in hypoplastic lung during late stages of lung development may interfere with normal surfactant synthesis, causing pulmonary hypoplasia in the nitrofen-induced CDH model. (C) 2010 Elsevier Inc. All rights reserved.