Takahashi Hiromizu, Friedmacher Florian, Fujiwara Naho, Hofmann Alejandro, Kutasy Balazs, Gosemann Jan-Hendrik, Puri Prem
National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
Pediatr Surg Int. 2013 Nov;29(11):1199-203. doi: 10.1007/s00383-013-3387-4.
Pulmonary hypoplasia (PH) associated with congenital diaphragmatic hernia (CDH) represents one of the major challenges in neonatal intensive care. However, the molecular pathogenesis of PH is still poorly understood. In developing fetal lungs, fibroblast growth factor 18 (FGF-18) plays a crucial role in distal airway maturation. FGF-18 knockouts show smaller lung sizes with reduced alveolar spaces and thicker interstitial mesenchymal compartments, highlighting its important function for fetal lung growth and differentiation. We hypothesized that pulmonary FGF-18 gene expression is downregulated during late gestation in nitrofen-induced hypoplastic lungs.
Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Fetuses were harvested on D18 and D21, and lungs were divided into three groups: controls, hypoplastic lungs without CDH [CDH(-)], and hypoplastic lungs with CDH [CDH(+)] (n = 24 at each time-point). Pulmonary FGF-18 gene expression levels were analyzed by qRT-PCR. Immunohistochemistry was performed to investigate FGF-18 protein expression/distribution.
Relative mRNA levels of pulmonary FGF-18 gene expression were significantly decreased in CDH(-) and CDH(+) on D18 and D21 compared to controls (p < 0.05 and p < 0.01, respectively). Immunoreactivity of FGF-18 was markedly diminished in mesenchymal cells surrounding the airway epithelium on D18 and D21 compared to controls.
Downregulation of FGF-18 gene expression in nitrofen-induced hypoplastic lungs suggests that decreased FGF-18 expression during the canalicular-saccular stages may interfere with saccular-alveolar differentiation and distal airway maturation resulting in PH.
与先天性膈疝（CDH）相关的肺发育不全（PH）是新生儿重症监护中的主要挑战之一。然而，PH的分子发病机制仍知之甚少。在发育中的胎儿肺中，成纤维细胞生长因子18（FGF - 18）在远端气道成熟中起关键作用。FGF - 18基因敲除显示肺体积较小，肺泡间隙减小，间质间充质隔增厚，突出了其对胎儿肺生长和分化的重要功能。我们假设在孕晚期硝基芬诱导的发育不全肺中，肺FGF - 18基因表达下调。
孕鼠在妊娠第9天（D9）暴露于橄榄油或硝基芬。在D18和D21收获胎儿，肺被分为三组：对照组、无CDH的发育不全肺[CDH（-）]和有CDH的发育不全肺[CDH（+）]（每个时间点n = 24）。通过qRT - PCR分析肺FGF - 18基因表达水平。进行免疫组织化学以研究FGF - 18蛋白表达/分布。
与对照组相比，D18和D21时CDH（-）和CDH（+）中肺FGF - 18基因表达的相对mRNA水平显著降低（分别为p < 0.05和p < 0.01）。与对照组相比，D18和D21时气道上皮周围间充质细胞中FGF - 18的免疫反应性明显减弱。
硝基芬诱导的发育不全肺中FGF - 18基因表达下调表明，在小管 - 囊状阶段FGF - 18表达降低可能会干扰囊状 - 肺泡分化和远端气道成熟，从而导致PH。
