Role of PDGF-A/PDFG-Receptor alpha signaling in normal and abnormal lung development

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Mechanical ventilation with O2-rich gas (MV) is a life-saving remedy for respiratory failure but also promotes lung injury, which in neonates translates to defective alveolar septation, angiogenesis and elastin deposition resulting in lung growth arrest as seen in neonatal chronic lung disease (CLD). Adverse effects of MV on developing lungs have been ascribed to impaired signaling of various growth factors, including PDGF. A critical role of PDGF signaling in lung development emerged from the discovery that lungs of mice deficient in PDGF-A or its receptor (PDGF-Rα) showed impaired lung growth, leading to neonatal death or shortened survival. The failure in alveolar septation, leading to an emphysematous-like lung phenotype was attributed to lack of migration of alveolar smooth muscle progenitor cells (myofibroblasts, MFBs). Later studies showed that lambs with CLD had reduced lung expression of PDGF-A and PDGF-Rα. PDGF-A protein also was reduced in lungs of newborn mice with alveolar hypoplasia after 24h of MV. We recently found that 7d-old mice bearing a single allele of PDGF-Rα had larger and fewer alveoli and disordered lung elastin compared to WT controls. Lung pathology resembled CLD. Our goal now is to define the role of impaired PDGF signaling in the growth failure and impaired ECM remodeling seen in developing lungs exposed to MV. We will study how PDGF-Rα heterozygosity affects proliferation, migration and elastin synthesis of cultured lung MFBs, which express PDGF-Rα. We will see how PDGF-A treatment during cyclic stretch ± hyperoxia affects PDGF-Rα signaling in lung MFBs. In vivo studies will test how PDGF-Rα haploinsufficiency is involved in MV-induced lung growth arrest and aberrant elastin deposition in newborn mice and if PDGF-A treatment can prevent or attenuate adverse effects of MV. This work will yield new insights on how PDGF signaling regulates alveolar septation and matrix remodeling of the newborn lung, which will help formulate new strategies to promote lung growth during MV.