期刊
RESPIRATORY RESEARCH
卷 14, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1465-9921-14-68
关键词
Alveolar development; Emphysema; Pulmonary fibrosis; Cell cycle-regulation; Secondary septation; Platelet-derived Growth factor Receptor-alpha
资金
- Department of Veterans Affairs Research Service
Background: Secondary pulmonary alveolar septal formation requires platelet derived growth factor (PDGF-A) and platelet derived growth factor receptor-alpha (PDGFR alpha), and their regulation influences alveolar septal areal density and thickness. Insufficient PDGFR alpha expression in lung fibroblasts (LF) results in failed septation. Methods: Mice in which the endogenous PDGFR alpha-gene regulates expression of the green fluorescent protein were used to temporally and spatially track PDGFR alpha-signaling. Transition from the G(1)/Go to the S-phase of the cell cycle was compared in PDGFR alpha-expressing and non-expressing LF using flow cytometry. Laser scanning confocal microscopy was used to quantify p27(kip1) and forkhead box other 3a (FoxO3a) in the nuclei of alveolar cells from mice bearing the PDGFR alpha-GFP knock-in, and p27(kip1) in mice with a conditional deletion of PDGFR alpha-gene function. The effects of PDGF-A on the phosphorylation and the intracellular location of FoxO3a were examined using Western immuoblotting and immunocytochemistry. Results: In neonatal mouse lungs, entry of the PDGFR alpha-expressing LF subpopulation into the S-phase of the cell cycle diminished sooner than in their non-expressing LF counterparts. This preferential diminution was influenced by PDGFR alpha-mediated signaling, which phosphorylates and promotes cytoplasmic localization of FoxO3a. Comparative observations of LF at different ages during secondary septation and in mice that lack PDGFR alpha in alveolar LF demonstrated that nuclear localization of the G(1) cyclin-dependent kinase inhibitor p27(kip1) correlated with reduced LF entry into S-phase. Conclusions: Nuclear localization of FoxO3a, an important regulator of p27(kip1) gene-expression, correlates with diminished proliferation of the PDGFR alpha-expressing LF subpopulation. These mechanisms for diminishing the effects of PDGFR alpha-mediated signaling likely regulate secondary septal formation and their derangement may contribute to imbalanced fibroblast cell kinetics in parenchymal lung diseases.
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