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-Ralpha gene in preterms with nCLD and directly test the effect of PDGF-Ralpha 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-Ralpha-dependent reduction in lung VEGF-A. TGF-beta contributes to the PDGF-Ralpha-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.
- Oak, P.
- Pritzke, T.
- Thiel, I.
- Koschlig, M.
- Mous, D. S.
- Windhorst, A.
- Jain, N.
- Eickelberg, O.
- Foerster, K.
- Schulze, A.
- Goepel, W.
- Reicherzer, T.
- Ehrhardt, H.
- Rottier, R. J.
- Ahnert, P.
- Gortner, L.
- Desai, T. J.
- Hilgendorff, A.
Keywords
- Animals
- Animals, Newborn
- Cells, Cultured
- Chronic Disease
- Fibroblasts/cytology/metabolism
- Haploinsufficiency
- Human Umbilical Vein Endothelial Cells
- Humans
- Infant, Newborn
- Lung/metabolism
- Lung Diseases/metabolism/*pathology/prevention & control
- Mice
- Mice, Inbred C57BL
- Oxygen/metabolism
- Platelet-Derived Growth Factor/*metabolism/pharmacology/therapeutic use
- Receptor, Platelet-Derived Growth Factor alpha/antagonists &
- inhibitors/genetics/metabolism
- Respiration, Artificial
- Signal Transduction/drug effects
- Vascular Endothelial Growth Factor A/metabolism
- *PDGF-Ralpha
- *vegf-a
- *bronchopulmonary dysplasia
- *neonatal chronic lung disease
- *transforming growth factor-beta