Alteration of TGF-β-ALK-Smad signaling in hyperoxia-induced bronchopulmonary dysplasia model of newborn rats.
Bronchopulmonary dysplasia (BPD) is a main chronic lung disease commonly occurs in preterm infants. BPD is characterized by impaired alveolarization and vascularization of the developing lung. Transforming growth factor-β (TGF-β) signaling pathway is known to play an important role during lung vascular development. In the present study, we examined whether the regulation of TGF-β-ALK-Smad signaling pathway influence on the disruption of pulmonary vascular development in newborn rats as hyperoxia-induced BPD model.



Newborn rats were continuously exposed to 21% or 85% O2 for 7 days, and subsequently kept in normoxic condition for another 14 days. Lung tissues harvested at each time point were evaluated for the expression of TGF-β1, ALK1, ALK5, phosphorylated Smad1/5, phosphorylated Smad2/3, VEGF, and endoglin, as accessed by both biochemical and immunohistological analyses.



Double-fluorescence immunohistochemical staining indicated these molecules were mainly expressed in pulmonary endothelial cells. The expression of TGF-β1 and ALK5 mRNA and protein were significantly increased in D5 hyperoxia group, while that of ALK1 mRNA and protein were significantly decreased. The level of phosphorylated Smad1/5 was significantly decreased in D7 hyperoxia group, whereas that of phosphorylated Smad2/3 was oppositely increased. In addition, the expression of vascular endothelial growth factor (VEGF) mRNA was increased at D1 with subsequent decrease in D7 hyperoxia group. There was no significantly difference in endoglin expression in entire experimental period.



These results indicate that exposure to hyperoxia altered the balance between TGF-β-ALK1-Smad1/5 and TGF-β-ALK5-Smad2/3 pathways in pulmonary endothelial cells, which may ultimately lead to the development of BPD.
a Department of Pediatrics , Yanbian University Hospital , Yanji , Jilin Province , China.
Meihua
M
Jin
b Department of Pediatrics , Inha University College of Medicine , Incheon , Korea.
Juyoung
J
Lee
c Department of Pediatrics , Seoul National University College of Medicine , Seoul , Korea.
Kyung-Yup
KY
Lee
a Department of Pediatrics , Yanbian University Hospital , Yanji , Jilin Province , China.
Zhengyong
Z
Jin
d Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Korea.
Jhang Ho
JH
Pak
c Department of Pediatrics , Seoul National University College of Medicine , Seoul , Korea.
Han-Suk
HS
Kim
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism / Q000503:physiopathology*; D018496:Hyperoxia / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply / Q000254:growth & development; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000032:analysis / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism
D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
VEGF; angiogenesis; endoglin; endothelial cell