Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease.

Abstract

Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O2). 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-O2 In the context of MV-O2, 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-O2 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-O2.

• Authors: Prajakta Oak, Tina Pritzke, Isabella Thiel, Markus Koschlig, Daphne S Mous, Anita Windhorst, Noopur Jain, Oliver Eickelberg, Kai Foerster, Andreas Schulze, Wolfgang Goepel, Tobias Reicherzer, Harald Ehrhardt, Robbert J Rottier, Peter Ahnert, Ludwig Gortner, Tushar J Desai, Anne Hilgendorff
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 9 Issue 11 Pg. 1504-1520 (11 2017) ISSN: 1757-4684 [Electronic] England
• PMID: 28923828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 Helmholtz Zentrum München Published under the terms of the CC BY 4.0 license.

Chemical References

• Platelet-Derived Growth Factor
• Vascular Endothelial Growth Factor A
• platelet-derived growth factor A
• Receptor, Platelet-Derived Growth Factor alpha
• Oxygen

Topics

• Animals
• Animals, Newborn
• Cells, Cultured
• Chronic Disease
• Fibroblasts (cytology, metabolism)
• Haploinsufficiency
• Human Umbilical Vein Endothelial Cells
• Humans
• Infant, Newborn
• Lung (metabolism)
• Lung Diseases (metabolism, pathology, prevention & control)
• Mice
• Mice, Inbred C57BL
• Oxygen (metabolism)
• Platelet-Derived Growth Factor (metabolism, pharmacology, therapeutic use)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, genetics, metabolism)
• Respiration, Artificial
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor A (metabolism)