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BMP4 and LGL1 are Down Regulated in an Ovine Model of Congenital Diaphragmatic Hernia
Heather M A Emmerton-Coughlin1, K Kathryn Martin1, Jacky S S Chiu2
1Division of General Surgery, London Health Sciences Centre, The University of Western Ontario , London, ON , Canada.
Background/Purpose:
The molecular pathophysiology of lung hypoplasia in congenital diaphragmatic hernia (CDH) remains poorly understood. The Wnt signaling pathway and downstream targets, such as bone morphogenetic proteins (BMP) 4 and other factors such as late gestation lung protein 1 (LGL1), are essential to normal lung development. Nitrofen-induced hypoplastic CDH rodent lungs demonstrate down regulation of the Wnt pathway including BMP4 and reduced LGL1 expression. The aim of the current study was to examine the molecular pathophysiology associated with a surgically induced CDH in an ovine model.
Methods:
Left thoracotomy was performed at 80 days in 14 fetal sheep; CDH was created in seven experimental animals. Lungs were harvested at 136 days (term = 145 days). Lung weight (LW) and mean terminal bronchiole density (MTBD) were measured to determine the degree of pulmonary hypoplasia. Quantitative real time PCR was undertaken to analyze Wnt2, Wnt7b, BMP4, and LGL1 mRNA expression.
Results:
Total LW was decreased while MTBD was increased in the CDH group (p < 0.05), confirming pulmonary hypoplasia. BMP4 and LGL1 mRNA was significantly reduced in CDH lungs (p < 0.05). Wnt2 mRNA was decreased, although not significantly (p < 0.06).
Conclusion:
For the first time, down regulation of BMP4 and LGL1 are reported in an ovine CDH model. In contrast to other animal models, these changes are persistent to near term. These findings suggest that mechanical compression from herniated viscera may play a more important role in causing pulmonary hypoplasia in CDH, rather than a primary defect in lung organogenesis.
Insights
Congenital diaphragmatic hernia (CDH) in fetal sheep shows reduced bone morphogenetic protein 4 (BMP4) and late gestation lung protein 1 (LGL1) expression. Mechanical compression may cause lung hypoplasia more than primary organogenesis defects.
Area of Science:
- Developmental biology
- Genetics
- Pathophysiology
Background:
- Congenital diaphragmatic hernia (CDH) causes lung hypoplasia, but its molecular basis is unclear.
- Wnt signaling pathway, bone morphogenetic protein 4 (BMP4), and late gestation lung protein 1 (LGL1) are crucial for lung development.
- Previous studies in rodent models showed Wnt pathway downregulation and reduced BMP4 and LGL1 in CDH.
Purpose of the Study:
- To investigate the molecular pathophysiology of lung hypoplasia in a surgically induced ovine model of CDH.
- To analyze the expression of Wnt signaling pathway components (Wnt2, Wnt7b), BMP4, and LGL1 in CDH lungs.
Main Methods:
- Surgical induction of CDH in 14 fetal sheep at 80 days gestation.
- Lung tissue harvested at 136 days gestation for analysis.
- Quantitative real-time PCR used to measure mRNA expression of Wnt2, Wnt7b, BMP4, and LGL1.
Main Results:
- CDH lungs exhibited significantly reduced lung weight and increased mean terminal bronchiole density, confirming pulmonary hypoplasia.
- Significant downregulation of BMP4 and LGL1 mRNA was observed in CDH lungs (p < 0.05).
- A non-significant decrease in Wnt2 mRNA was noted in CDH lungs (p < 0.06).
Conclusions:
- This study reports, for the first time, the downregulation of BMP4 and LGL1 in an ovine CDH model.
- These molecular changes persist until near term in the ovine model.
- Findings suggest mechanical compression from herniated viscera may be a significant factor in CDH-induced lung hypoplasia, rather than solely a primary defect in lung organogenesis.
