S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
Alteration of TGF-β-ALK-Smad signaling in hyperoxia-induced bronchopulmonary dysplasia model of newborn rats
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과 소아과학 전공, 2013. 8. 김한석.
- Background: Bronchopulmonary dysplasia (BPD) is a main chronic lung disease that commonly occurs in preterm infants. BPD is characterized by impaired alveolarization and vascularization of the developing lung. The transforming growth factor-β (TGF-β) signaling pathway is known to play an important role during lung vascular development.
Objective: To investigate whether the regulation of TGF-β-ALK-Smad signaling pathway influences the disruption of pulmonary vascular development in newborn rats using a hyperoxia-induced BPD model.
Methods: Neonatal rats were continuously exposed to 21% or 85% O2 for 7 days and subsequently kept in normoxic conditions for another 14 days. Lung tissues were harvested at each time point and were evaluated for the expression of TGF-β1, ALK1, ALK5, phosphorylated Smad1/5, phosphorylated Smad2/3, VEGF and endoglin by both biochemical and immunohistological analyses.
Results: Double-fluorescence immunohistochemical staining indicated that these molecules were mainly expressed in pulmonary endothelial cells. The expression of TGF-β1 and ALK5 mRNA and protein were significantly increased in the D5 hyperoxia group, while the expression of ALK1 mRNA and protein was significantly decreased. The level of phosphorylated Smad1/5 was significantly decreased in the D7 hyperoxia group, whereas the expression of phosphorylated Smad2/3 was increased. In addition, the expression of vascular endothelial growth factor (VEGF) mRNA was increased at D1, with a subsequent decrease in the D7 hyperoxia group. There was no significant difference in endoglin expression over the entire experimental period.
Conclusion: Our results indicate that exposure to hyperoxia altered the balance between the TGF-β-ALK1-Smad1/5 and TGF-β-ALK5-Smad2/3 signaling pathways in pulmonary endothelial cells, which may ultimately lead to the development of BPD.