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

作者：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^*

来源：EMBO Molecular Medicine, 2017, 9(11): 1504-1520.

DOI：10.15252/emmm.201607308

• bronchopulmonary dysplasia
• neonatal chronic lung disease
• PDGF-R alpha
• transforming growth factor- beta
• VEGF-A

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.

• 出版日期2017-11
• 单位河北医科大学