Open AccessAttenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease
Author(s) -
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
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201607308
Subject(s) - lung disease , lung , medicine , platelet derived growth factor receptor , cancer research , biology , immunology , receptor , growth factor
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 SNP s 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 2 . In the context of MV ‐O 2 , 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 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 .