Richard Bland
Publication Details
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Prolonged Mechanical Ventilation with Air Induces Apoptosis and Causes Failure of Alveolar Septation and Angiogenesis in Lungs of Newborn Mice.
Am J Physiol Lung Cell Mol Physiol. 2009Defective 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 micro-vessels, with reduced VEGF and increased TGFbeta signaling, and excess, scattered elastin in lungs of premature infants and lambs with CLD vs normal controls. MV of newborn mice with 40% O2 for 24h 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 24h with air on alveolar septation (quantitative lung histology), angiogenesis (CD-31 quantitative-IHC, immunoblots), apoptosis (TUNEL, active caspase-3 assays), VEGF signaling (VEGF-A, VEGF-R1, VEGF-R2 immunoblots), TGFbeta activation (pSmad-2 quantitative-IHC) and elastin production (tropoelastin immunoblots; quantitative image analysis of Hart's-stained sections) in lungs of 6d-old mice. Compared to unventilated controls, MV caused a 3-fold increase in alveolar area, ~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 pSmad-2 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, increase apoptosis and lung elastin, findings that could reflect stretch-induced changes in VEGF and TGFbeta signaling, as reported in CLD. Key words: Bronchopulmonary Dysplasia (BPD), Neonatal Chronic Lung Disease (CLD), Lung growth and development, Alveolar and pulmonary capillary formation, VEGF and VEGF-R2; TGF; mechanical stretch; elastin.
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