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Oak, Prajakta; Pritzke, Tina; Thiel, Isabella; Koschlig, Markus; Mous, Daphne S.; Windhorst, Anita; Jain, Noopur; Eickelberg, Oliver; Förster, Kai; Schulze, Andreas; Goepel, Wolfgang; Reicherzer, Tobias; Ehrhardt, Harald; Rottier, Robbert J.; Ahnert, Peter; Gortner, Ludwig; Desai, Tushar J.; Hilgendorff, Anne (2017): Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease. In: Embo Molecular Medicine, Vol. 9, No. 11: pp. 1504-1520
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Abstract

Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O-2). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-R alpha gene in preterms with nCLD and directly test the effect of PDGF-R alpha haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O-2. In the context of MV-O-2, attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-R alpha-dependent reduction in lung VEGF-A. TGF-beta contributes to the PDGF-R alpha-dependent decrease in myofibroblast function. Remarkably, endotracheal treatment with exogenous PDGF-A rescues both the lung defects in haploinsufficient mice undergoing MV-O-2. 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-2.