Fibroblasts expressing PDGF-receptor-alpha diminish during alveolar septal thinning in mice

Stephen E McGowan; Diann M McCoy

doi:10.1203/PDR.0b013e31821cfb5a

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Fibroblasts expressing PDGF-receptor-alpha diminish during alveolar septal thinning in mice

Journal article

Open access

Peer reviewed

Fibroblasts expressing PDGF-receptor-alpha diminish during alveolar septal thinning in mice

Stephen E McGowan and Diann M McCoy

Pediatric research, Vol.70(1), pp.44-49

07/2011

DOI: 10.1203/PDR.0b013e31821cfb5a

PMID: 21659960

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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.

Phosphorylation

Cell Proliferation

Age Factors

Transcriptional Activation

Actins - metabolism

Myofibroblasts - enzymology

NF-kappa B - metabolism

Green Fluorescent Proteins - genetics

Pulmonary Alveoli - enzymology

Flow Cytometry

Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors

Aging

Proto-Oncogene Proteins c-akt - metabolism

Genes, Reporter

Animals, Newborn

Myofibroblasts - pathology

Promoter Regions, Genetic

Pulmonary Alveoli - growth & development

Pulmonary Alveoli - pathology

Receptor, Platelet-Derived Growth Factor alpha - metabolism

Signal Transduction

Cells, Cultured

Mice, Transgenic

Pyrimidines - pharmacology

Imatinib Mesylate

Piperazines - pharmacology

Platelet-Derived Growth Factor - metabolism

Animals

Analysis of Variance

Receptor, Platelet-Derived Growth Factor alpha - genetics

Proto-Oncogene Proteins c-abl - metabolism

Mice

Protein Kinase Inhibitors - pharmacology

Benzamides

Apoptosis

Details

Title: Subtitle: Fibroblasts expressing PDGF-receptor-alpha diminish during alveolar septal thinning in mice
Creators: Stephen E McGowan - Department of Veterans Affairs Research Service, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. stephen-mcgowan@uiowa.edu
Diann M McCoy
Resource Type: Journal article
Publication Details: Pediatric research, Vol.70(1), pp.44-49
Publisher: United States
DOI: 10.1203/PDR.0b013e31821cfb5a
PMID: 21659960
ISSN: 1530-0447
eISSN: 1530-0447
Grant note: I01 BX000508 / BLRD VA
Language: English
Date published: 07/2011
Academic Unit: International Programs; Internal Medicine
Record Identifier: 9983984524002771

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