title: Pulmonary FGF-18 gene expression is downregulated during the canalicular-saccular stages in nitrofen-induced hypoplastic lungs.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
authors: Hiromizu
authors: H
authors: Takahashi
authors: Florian
authors: F
authors: Friedmacher
authors: Naho
authors: N
authors: Fujiwara
authors: Alejandro
authors: A
authors: Hofmann
authors: Balazs
authors: B
authors: Kutasy
authors: Jan-Hendrik
authors: JH
authors: Gosemann
authors: Prem
authors: P
authors: Puri
mesh_terms: D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D008168:Lung / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D008171:Lung Diseases / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D038081:Organogenesis; D010647:Phenyl Ethers / Q000633:toxicity; D011247:Pregnancy; D011270:Pregnancy, Animal; D012313:RNA / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D010647:Phenyl Ethers; C113569:fibroblast growth factor 18; D005346:Fibroblast Growth Factors; D012313:RNA; C007350:nitrofen
references: Nature. 2008 Jun 5;453(7196):745-50
references: 18463632
references: Pediatr Surg Int. 2008 Jul;24(7):755-61
references: 18401587
references: J Pediatr Surg. 2009 Apr;44(4):720-8
references: 19361631
references: Am J Surg. 2005 Aug;190(2):324-32
references: 16023454
references: Genes Dev. 2002 Apr 1;16(7):870-9
references: 11937494
references: Am J Respir Crit Care Med. 2007 May 15;175(10):1066-77
references: 17303798
references: Dev Dyn. 2003 Apr;226(4):663-74
references: 12666204
references: Pediatr Surg Int. 2012 Feb;28(2):195-9
references: 21994076
references: Respir Res. 2003;4:5
references: 12818006
references: Pediatr Surg Int. 2013 Jan;29(1):19-24
references: 23143077
references: Histol Histopathol. 2007 Jan;22(1):97-105
references: 17128416
references: J Cereb Blood Flow Metab. 2004 Jan;24(1):114-23
references: 14688623
references: Dev Biol. 2007 Feb 1;302(1):80-91
references: 17014841
references: Mech Dev. 2000 Mar 15;92(1):55-81
references: 10704888
references: Am J Physiol Lung Cell Mol Physiol. 2005 Jan;288(1):L43-51
references: 15447937
references: Mech Dev. 1999 Aug;86(1-2):125-36
references: 10446271
references: Semin Pediatr Surg. 2010 Aug;19(3):180-5
references: 20610190
references: Annu Rev Physiol. 2000;62:875-915
references: 10845115
references: Physiol Genomics. 2011 Nov 7;43(21):1226-40
references: 21878612
references: J Pediatr Surg. 2003 Jul;38(7):1021-4
references: 12861530
references: Dev Cell. 2010 Jan 19;18(1):8-23
references: 20152174
references: Am J Respir Crit Care Med. 2002 Oct 1;166(7):911-5
references: 12359645
references: Pediatr Res. 1992 May;31(5):435-40
references: 1318538
references: J Biol Chem. 1998 Jul 17;273(29):18161-4
references: 9660775
references: Development. 2006 May;133(9):1611-24
references: 16613830
references: J Biol Chem. 2002 Jun 21;277(25):22743-9
references: 11927601
references: Mol Cell Biol. 1998 Oct;18(10):6063-74
references: 9742123
references: Exp Lung Res. 1994 Nov-Dec;20(6):491-515
references: 7882903
references: J Biol Chem. 1996 Jun 21;271(25):15292-7
references: 8663044
references: Annu Rev Physiol. 2004;66:625-45
references: 14977416
references: Biochem Biophys Res Commun. 2004 Sep 24;322(3):887-92
references: 15336546