Document Detail


Prolonged mechanical ventilation with air induces apoptosis and causes failure of alveolar septation and angiogenesis in lungs of newborn mice.
MedLine Citation:
PMID:  19854954     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Defective lung septation and angiogenesis, quintessential features of neonatal chronic lung disease (CLD), typically result from lengthy exposure of developing lungs to mechanical ventilation (MV) and hyperoxia. Previous studies showed fewer alveoli and microvessels, with reduced VEGF and increased transforming growth factor-beta (TGFbeta) signaling, and excess, scattered elastin in lungs of premature infants and lambs with CLD vs. normal controls. MV of newborn mice with 40% O(2) for 24 h yielded similar lung structural abnormalities linked to impaired VEGF signaling, dysregulated elastin production, and increased apoptosis. These studies could not determine the relative importance of cyclic stretch vs. hyperoxia in causing these lung growth abnormalities. We therefore studied the impact of MV for 24 h with air on alveolar septation (quantitative lung histology), angiogenesis [CD31 quantitative-immunohistochemistry (IHC), immunoblots], apoptosis [TdT-mediated dUTP nick end labeling (TUNEL), active caspase-3 assays], VEGF signaling [VEGF-A, VEGF receptor 1 (VEGF-R1), VEGF-R2 immunoblots], TGFbeta activation [phosphorylated Smad2 (pSmad2) quantitative-IHC], and elastin production (tropoelastin immunoblots, quantitative image analysis of Hart's stained sections) in lungs of 6-day-old mice. Compared with unventilated controls, MV caused a 3-fold increase in alveolar area, approximately 50% reduction in alveolar number and endothelial surface area, >5-fold increase in apoptosis, >50% decrease in lung VEGF-R2 protein, 4-fold increase of pSmad2 protein, and >50% increase in lung elastin, which was distributed throughout alveolar walls rather than at septal tips. This study is the first to show that prolonged MV of developing lungs, without associated hyperoxia, can inhibit alveolar septation and angiogenesis and increase apoptosis and lung elastin, findings that could reflect stretch-induced changes in VEGF and TGFbeta signaling, as reported in CLD.
Authors:
Lucia M Mokres; Kakoli Parai; Anne Hilgendorff; Robert Ertsey; Cristina M Alvira; Marlene Rabinovitch; Richard D Bland
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-10-23
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  298     ISSN:  1522-1504     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2009-12-18     Completed Date:  2010-01-06     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L23-35     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Air*
Animals
Animals, Newborn
Apoptosis*
Cell Count
Cell Proliferation
Elastin / metabolism
Endothelial Cells / metabolism,  pathology
Immunoblotting
Lung / blood supply*,  metabolism,  pathology*
Mice
Models, Biological
Neovascularization, Pathologic / pathology*
Phosphoproteins / metabolism
Pulmonary Alveoli / metabolism,  pathology*
Respiration, Artificial*
Smad2 Protein / metabolism
Surface Properties
Time Factors
Transforming Growth Factor beta / metabolism
Vascular Endothelial Growth Factor A / metabolism
Vascular Endothelial Growth Factor Receptor-1 / metabolism
Vascular Endothelial Growth Factor Receptor-2 / metabolism
Grant Support
ID/Acronym/Agency:
HL-086216/HL/NHLBI NIH HHS; HL-086631/HL/NHLBI NIH HHS; R01 HL086631/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Phosphoproteins; 0/Smad2 Protein; 0/Smad2 protein, mouse; 0/Transforming Growth Factor beta; 0/Vascular Endothelial Growth Factor A; 9007-58-3/Elastin; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-1; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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