Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease. Issue 11 (18th September 2017)

• Record Type: Journal Article
• Authors: Oak, Prajakta; Pritzke, Tina; Thiel, Isabella; Koschlig, Markus; Mous, Daphne S; Windhorst, Anita; Jain, Noopur; Eickelberg, Oliver; Foerster, Kai; Schulze, Andreas; Goepel, Wolfgang; Reicherzer, Tobias; Ehrhardt, Harald; Rottier, Robbert J; Ahnert, Peter; Gortner, Ludwig; Desai, Tushar J; Hilgendorff, Anne
• Is Part Of: EMBO molecular medicine. Volume 9:Issue 11(2017)
• Page Start: 1504
• Page End: 1520
• Publication Date: 2017-09-18
• Subjects: bronchopulmonary dysplasia -- neonatal chronic lung disease -- PDGF‐Rα -- transforming growth factor‐β -- VEGF‐A; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201607308
• Languages: English
• ISSNs: 1757-4676

Abstract

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 . Synopsis: A genetic approach in a neonatal mouse ventilation model shows that PDGFRA haploinsufficiency is sufficient to produce neonatal chronic lung disease (nCLD)‐like pathology, and that therapeutic ligand provision can rescue these defects. Mechanical ventilation with oxygen‐rich gas (MV‐O2 ) results in attenuated signaling via PDGFRA in myofibroblasts in part due to an effect of TGF‐β, resulting in impaired secondary septation and reduced expression of VEGF‐A with increased endothelial cell apoptosis, cardinal features of nCLD. PDGFRA‐haploinsufficiency in mice confers enhanced susceptibility to development of nCLD with MV‐O2, which can be rescued by endotracheal provision of exogenous PDGF. Human preterm infants with nCLD show significant enrichment for SNPs in the PDGFRA gene associated with reduced protein level expression of PDGFRA and impaired lung myofibroblast activity. Abstract : A genetic approach in a neonatal mouse ventilation model shows that PDGFRA haploinsufficiency is sufficient to produce neonatal chronic lung disease (nCLD)‐like pathology, and that therapeutic ligand provision can rescue these defects.