Insulinlike growth factor receptor type 1 and type 2 are downregulated in the nitrofen-induced hypoplastic lung.
OBJECTIVE
In congenital diaphragmatic hernia (CDH), high mortality rates are attributed to severe pulmonary hypoplasia. The insulinlike growth factor receptor type 1 (IGF-1R) and type 2 (IGF-2R) play a critical role in the alveologenesis during lung development. The IGF-1R null mutation mice die after birth because of respiratory failure. The IGF-2R knockout mice showed retarded lungs with poorly formed alveoli. We hypothesized that IGF-1R and IGF-2R gene expression levels are downregulated in the nitrofen-induced CDH model.


METHODS
Pregnant rats were exposed to either olive oil or 100 mg of nitrofen on day 9.5 (D9.5) of gestation. Fetuses were harvested on D18 and D21 and divided into control and nitrofen groups. Relative messenger RNA (mRNA) levels of IGF-1R and IGF-2R were determined using real time reverse transcription polymerase chain reaction. Immunohistochemistry was performed to determine protein expression.


RESULTS
Relative levels of IGF-1R mRNA were significantly decreased in the nitrofen group (2.91 +/- 0.81) on D21 compared to controls (5.29 +/- 2.59) (P < .05). Expression levels of IGF-2R mRNA on D21 were also significantly decreased in nitrofen group (1.76 +/- 0.49) compared to controls (3.59 +/- 2.45) (P < .05). Immunohistochemistry performed on D21 showed decreased IGF-1R and also IGF-2R expression in nitrofen group.


CONCLUSIONS
Downregulation of IGF-1R and IGF-2R gene expression may interfere with normal alveologenesis causing pulmonary hypoplasia in the nitrofen-induced CDH model.
Ruttenstock
Elke
E
The Children's Research Center, Our Lady's Children's Hospital, Dublin 12, Ireland; University College Dublin, Dublin 4, Ireland.
Doi
Takashi
T
Dingemann
Jens
J
Puri
Prem
P
D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D008168:Lung / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D008171:Lung Diseases / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D010647:Phenyl Ethers / Q000633:toxicity; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics*; D017527:Receptor, IGF Type 2 / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D010647:Phenyl Ethers; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D017526:Receptor, IGF Type 1; C007350:nitrofen