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Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease.
- Source :
-
EMBO molecular medicine [EMBO Mol Med] 2017 Nov; Vol. 9 (11), pp. 1504-1520. - Publication Year :
- 2017
-
Abstract
- Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O <subscript>2</subscript> ). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Rα gene in preterms with nCLD and directly test the effect of PDGF-Rα haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O <subscript>2</subscript> In the context of MV-O <subscript>2</subscript> , attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-Rα-dependent reduction in lung VEGF-A. TGF-β contributes to the PDGF-Rα-dependent decrease in myofibroblast function. Remarkably, endotracheal treatment with exogenous PDGF-A rescues both the lung defects in haploinsufficient mice undergoing MV-O <subscript>2</subscript> Overall, our results establish attenuated PDGF signaling as an important driver of nCLD pathology with provision of PDGF-A as a protective strategy for newborns undergoing MV-O <subscript>2</subscript> .<br /> (© 2017 Helmholtz Zentrum München Published under the terms of the CC BY 4.0 license.)
- Subjects :
- Animals
Animals, Newborn
Cells, Cultured
Chronic Disease
Fibroblasts cytology
Fibroblasts metabolism
Haploinsufficiency
Human Umbilical Vein Endothelial Cells
Humans
Infant, Newborn
Lung metabolism
Lung Diseases metabolism
Lung Diseases prevention & control
Mice
Mice, Inbred C57BL
Oxygen metabolism
Platelet-Derived Growth Factor pharmacology
Platelet-Derived Growth Factor therapeutic use
Receptor, Platelet-Derived Growth Factor alpha antagonists & inhibitors
Receptor, Platelet-Derived Growth Factor alpha genetics
Receptor, Platelet-Derived Growth Factor alpha metabolism
Respiration, Artificial
Signal Transduction drug effects
Vascular Endothelial Growth Factor A metabolism
Lung Diseases pathology
Platelet-Derived Growth Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1757-4684
- Volume :
- 9
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- EMBO molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 28923828
- Full Text :
- https://doi.org/10.15252/emmm.201607308