title: Fibroblasts expressing PDGF-receptor-alpha diminish during alveolar septal thinning in mice.
abstract: In mice, secondary alveolar septal formation primarily occurs during a brief postnatal period and is accompanied by transient expansion of the interstitial lung fibroblast (LF) population. PDGF-A, which solely signals through PDGF-receptor-alpha (PDGF-Rα), is required for expansion, but the receptor's relevant downstream targets remain incompletely defined. We have evaluated the proliferation, apoptosis, and differential response to the selective protein tyrosine kinase inhibitor, imatinib, by pdgfrα-expressing LF (pdgfrα-LF) and compared them with their nonexpressing LF counterparts. Our objective was to determine whether diminished signaling through PDGF-Rα-mediated pathways regulates the decline in myofibroblasts, which accompanies septal thinning and ensures more efficient alveolar gas exchange. Using quantitative stereology and flow cytometry at postnatal d 12 and 14, we observed that imatinib caused a selective suppression of proliferation and an increase in apoptosis. The number of the alpha smooth muscle actin (αSMA) producing pdgfrα-LF was also reduced. Using cultures of neonatal mouse LF, we showed that imatinib did not suppress PDGF-Rα gene expression but reduced PDGF-A-mediated Akt phosphorylation, potentially explaining the increase in apoptosis. Our findings are relevant to bronchopulmonary dysplasia in which positive pressure ventilation interferes with myofibroblast depletion, septal thinning, and capillary maturation.
authors.affiliation: Department of Veterans Affairs Research Service, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. stephen-mcgowan@uiowa.edu
authors.forename: Stephen E
authors.initials: SE
authors.lastname: McGowan
authors.forename: Diann M
authors.initials: DM
authors.lastname: McCoy
mesh_terms: D000199:Actins / Q000378:metabolism; D000367:Age Factors; D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001549:Benzamides; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D000068877:Imatinib Mesylate; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D000199:Actins; D001549:Benzamides; D016328:NF-kappa B; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C075278:platelet-derived growth factor A; D049452:Green Fluorescent Proteins; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D016315:Proto-Oncogene Proteins c-abl; D051057:Proto-Oncogene Proteins c-akt