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Downregulation of insulin-like growth factor binding protein 3 and 5 in nitrofen-induced pulmonary hypoplasia
Elke Ruttenstock1, Takashi Doi, Jens Dingemann
1The Children's Research Centre, Our Lady's Children's Hospital, University College Dublin, Dublin 12, Ireland.
Purpose:
The high mortality in congenital diaphragmatic hernia (CDH) is mainly attributed to pulmonary hypoplasia. Recent studies suggest that retinoid signaling pathway (RSP) is inhibited in the nitrofen-induced hypoplastic lung. The insulin-like growth factor (IGF) system plays a crucial role in fetal lung development by interaction of IGFBP-3 and IGFBP-5 with RSP. We hypothesized that pulmonary IGFBP-3 and IGFBP-5 gene expression levels are downregulated in the nitrofen-induced pulmonary hypoplasia.
Methods:
Pregnant rats were exposed to either olive oil or 100 mg nitrofen on day 9.5 (D9.5) of gestation. Fetal lungs were harvested on D18 and D21 and divided into control and nitrofen groups. IGFBP-3 and IGFBP-5 pulmonary gene and protein expression were determined using real-time RT-PCR and immunohistochemistry.
Results:
Relative levels of IGFBP-3 mRNA were significantly decreased in the nitrofen group (8.00 +/- 14.44) in D21 compared to controls (14.81 +/- 16.11; p < 0.05). Expression levels of IGFBP-5 mRNA were also significantly decreased in nitrofen group (10.66 +/- 4.83) on D18 compared to controls (17.92 +/- 4.77). Immunohistochemistry showed decreased IGFBP-3 expression on D21 and decreased IGFBP-5 immunoreactivity on D18 in hypoplastic lungs compared to controls.
Conclusion:
Downregulation of IGFBP-3 and IGFBP-5 gene expression may cause pulmonary hypoplasia in the nitrofen-induced CDH model by interfering with retinoid signaling pathway.
Insights
Congenital diaphragmatic hernia (CDH) lung hypoplasia is linked to reduced IGFBP-3 and IGFBP-5 gene expression. This downregulation may disrupt retinoid signaling pathways, impacting fetal lung development in CDH models.
Area of Science:
- Developmental Biology
- Genetics
- Pulmonary Medicine
Background:
- Congenital diaphragmatic hernia (CDH) is a severe condition characterized by high mortality, primarily due to pulmonary hypoplasia.
- The retinoid signaling pathway (RSP) is implicated in lung development, with evidence suggesting its inhibition in nitrofen-induced CDH models.
- The insulin-like growth factor (IGF) system, particularly IGFBP-3 and IGFBP-5, interacts with RSP and is crucial for fetal lung growth.
Purpose of the Study:
- To investigate the hypothesis that pulmonary IGFBP-3 and IGFBP-5 gene expression levels are downregulated in a nitrofen-induced model of pulmonary hypoplasia.
- To explore the potential role of IGFBP-3 and IGFBP-5 in the pathogenesis of CDH-related lung development abnormalities.
Main Methods:
- Pregnant rats were administered nitrofen or olive oil on day 9.5 of gestation.
- Fetal lungs were harvested at days 18 and 21 for analysis.
- Pulmonary gene and protein expression of IGFBP-3 and IGFBP-5 were quantified using real-time RT-PCR and immunohistochemistry.
Main Results:
- Significantly decreased IGFBP-3 mRNA levels were observed in nitrofen-exposed fetal lungs on day 21 compared to controls.
- Significantly decreased IGFBP-5 mRNA levels were found in nitrofen-exposed fetal lungs on day 18 compared to controls.
- Immunohistochemistry confirmed reduced IGFBP-3 expression on day 21 and reduced IGFBP-5 immunoreactivity on day 18 in hypoplastic lungs.
Conclusions:
- Downregulation of IGFBP-3 and IGFBP-5 gene expression is a key feature of the nitrofen-induced CDH model.
- This downregulation may contribute to pulmonary hypoplasia by interfering with the retinoid signaling pathway.
- IGFBP-3 and IGFBP-5 represent potential therapeutic targets for managing CDH-related lung development issues.
