Science and Research

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

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
Publication details
DOI: 10.15252/emmm.201607308
Journal: EMBO molecular medicine
Pages: 1504-1520 
Number: 11
Work Type: Original
Location: CPC-M, UGMLC
Disease Area: DPLD
Partner / Member: HMGU, JLU
Access-Number: 28923828
See publication on PubMed

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