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EMBO Mol Med. 2017 Nov;9(11):1504-1520. doi: 10.15252/emmm.201607308.

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

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Comprehensive Pneumology Center, University Hospital of the University of Munich and Helmholtz Zentrum Muenchen, Munich, Germany.
Department of Pediatric Surgery, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
Institute for Medical Informatics, Justus-Liebig-University, Giessen, Germany.
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Department of Neonatology, Perinatal Center Grosshadern, Ludwig-Maximilians University, Munich, Germany.
Department of General Pediatrics, University Clinic of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
Department of General Pediatrics and Neonatology, Justus-Liebig-University and Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany.
Institute for Medical Informatics, Statistics, and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.
Department of Pediatrics and Neonatology, Medical University Vienna, Vienna, Austria.
Department of Internal Medicine, Pulmonary and Critical Care, Stanford University School of Medicine, Stanford, CA, USA
Comprehensive Pneumology Center, University Hospital of the University of Munich and Helmholtz Zentrum Muenchen, Munich, Germany
Center for Comprehensive Developmental Care, Dr. von Haunersches Children's Hospital University Hospital Ludwig-Maximilians University, Munich, Germany.


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.


PDGF‐Rα; VEGF‐A; bronchopulmonary dysplasia; neonatal chronic lung disease; transforming growth factor‐β

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