Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice

2007 ◽  
Vol 293 (5) ◽  
pp. L1099-L1110 ◽  
Author(s):  
Richard D. Bland ◽  
Lucia M. Mokres ◽  
Robert Ertsey ◽  
Berit E. Jacobson ◽  
Shu Jiang ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Development ◽  
Structural Changes ◽  
Structural Defects ◽  
Normal Lung ◽  
Myeloperoxidase Activity ◽  
Newborn Mice ◽  
Tenascin C ◽  
Expression Of Genes ◽  
Old Mice

Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. Am J Physiol Lung Cell Mol Physiol 293: , 2007. First published August 17, 2007; — Mechanical ventilation (MV) with O2-rich gas offers life-saving treatment for extremely premature infants with respiratory failure but often leads to neonatal chronic lung disease (CLD), characterized by defective formation of alveoli and blood vessels in the developing lung. We discovered that MV of 2- to 4-day-old mice with 40% O2 for 8 h, compared with unventilated control pups, reduced lung expression of genes that regulate lung septation and angiogenesis (VEGF-A and its receptor, VEGF-R2; PDGF-A; and tenascin-C). MV with air for 8 h yielded similar results for PDGF-A and tenascin-C but did not alter lung mRNA expression of VEGF or VEGF-R2. MV of 4- to 6-day-old mice with 40% O2 for 24 h reduced lung protein abundance of VEGF-A, VEGF-R2, PDGF-A, and tenascin-C and resulted in lung structural abnormalities consistent with evolving CLD. After MV with 40% O2 for 24 h, lung volume was similar to unventilated controls, whereas distal air space size, assessed morphometrically, was greater in lungs of ventilated pups, indicative of impaired septation. Immunostaining for vimentin, which is expressed in myofibroblasts, was reduced in distal lung after 24 h of MV with 40% O2. These molecular, cellular, and structural changes occurred without detectable lung inflammation as evaluated by histology and assays for proinflammatory cytokines, myeloperoxidase activity, and water content in lung. Thus lengthy MV of newborn mice with O2-rich gas reduces lung expression of genes and proteins that are critical for normal lung growth and development. These changes yielded lung structural defects similar to those observed in evolving CLD.

Mechanical ventilation uncouples synthesis and assembly of elastin and increases apoptosis in lungs of newborn mice.

2008 ◽  
Vol 294 (1) ◽  
pp. L3-L14 ◽  
Author(s):  
Richard D. Bland ◽  
Robert Ertsey ◽  
Lucia M. Mokres ◽  
Liwen Xu ◽  
Berit E. Jacobson ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lysyl Oxidase ◽  
Prolonged Mechanical Ventilation ◽  
Elastic Fiber ◽  
Elastase Activity ◽  
Fiber Density ◽  
Newborn Mice ◽  
Fiber Assembly ◽  
Expression Of Genes ◽  
Fibrillin 1

Prolonged mechanical ventilation (MV) with O2-rich gas inhibits lung growth and causes excess, disordered accumulation of lung elastin in preterm infants, often resulting in chronic lung disease (CLD). Using newborn mice, in which alveolarization occurs postnatally, we designed studies to determine how MV with either 40% O2or air might lead to dysregulated elastin production and impaired lung septation. MV of newborn mice for 8 h with either 40% O2or air increased lung mRNA for tropoelastin and lysyl oxidase, relative to unventilated controls, without increasing lung expression of genes that regulate elastic fiber assembly (lysyl oxidase-like-1, fibrillin-1, fibrillin-2, fibulin-5, emilin-1). Serine elastase activity in lung increased fourfold after MV with 40% O2, but not with air. We then extended MV with 40% O2to 24 h and found that lung content of tropoelastin protein doubled, whereas lung content of elastin assembly proteins did not change (lysyl oxidases, fibrillins) or decreased (fibulin-5, emilin-1). Quantitative image analysis of lung sections showed that elastic fiber density increased by 50% after MV for 24 h, with elastin distributed throughout the walls of air spaces, rather than at septal tips, as in control lungs. Dysregulation of elastin was associated with a threefold increase in lung cell apoptosis (TUNEL and caspase-3 assays), which might account for the increased air space size previously reported in this model. Our findings of increased elastin synthesis, coupled with increased elastase activity and reduced lung abundance of proteins that regulate elastic fiber assembly, could explain altered lung elastin deposition, increased apoptosis, and defective septation, as observed in CLD.

scholarly journals Absence of TNF-α enhances inflammatory response in the newborn lung undergoing mechanical ventilation

2016 ◽  
Vol 310 (10) ◽  
pp. L909-L918 ◽  
Author(s):  
Harald Ehrhardt ◽  
Tina Pritzke ◽  
Prajakta Oak ◽  
Melina Kossert ◽  
Luisa Biebach ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Preterm Infants ◽  
Structural Changes ◽  
Transforming Growth Factor ◽  
Treatment Strategies ◽  
Mechanical Stretch ◽  
Newborn Mice ◽  
Tnf Α

Bronchopulmonary dysplasia (BPD), characterized by impaired alveolarization and vascularization in association with lung inflammation and apoptosis, often occurs after mechanical ventilation with oxygen-rich gas (MV-O2). As heightened expression of the proinflammatory cytokine TNF-α has been described in infants with BPD, we hypothesized that absence of TNF-α would reduce pulmonary inflammation, and attenuate structural changes in newborn mice undergoing MV-O2. Neonatal TNF-α null (TNF-α−/−) and wild type (TNF-α+/+) mice received MV-O2 for 8 h; controls spontaneously breathed 40% O2. Histologic, mRNA, and protein analysis in vivo were complemented by in vitro studies subjecting primary pulmonary myofibroblasts to mechanical stretch. Finally, TNF-α level in tracheal aspirates from preterm infants were determined by ELISA. Although MV-O2 induced larger and fewer alveoli in both, TNF-α−/− and TNF-α+/+ mice, it caused enhanced lung apoptosis (TUNEL, caspase-3/-6/-8), infiltration of macrophages and neutrophils, and proinflammatory mediator expression (IL-1β, CXCL-1, MCP-1) in TNF-α−/− mice. These differences were associated with increased pulmonary transforming growth factor-β (TGF-β) signaling, decreased TGF-β inhibitor SMAD-7 expression, and reduced pulmonary NF-κB activity in ventilated TNF-α−/− mice. Preterm infants who went on to develop BPD showed significantly lower TNF-α levels at birth. Our results suggest a critical balance between TNF-α and TGF-β signaling in the developing lung, and underscore the critical importance of these key pathways in the pathogenesis of BPD. Future treatment strategies need to weigh the potential benefits of inhibiting pathologic cytokine expression against the potential of altering key developmental pathways.

scholarly journals Neonatal hyperoxia leads to persistent alterations in NK responses to influenza A virus infection

2015 ◽  
Vol 308 (1) ◽  
pp. L76-L85 ◽  
Author(s):  
Emma C. Reilly ◽  
Kyle C. Martin ◽  
Guang-bi Jin ◽  
Min Yee ◽  
Michael A. O'Reilly ◽  
...  
Keyword(s):  
Nk Cells ◽  
Influenza A Virus ◽  
Lung Development ◽  
Influenza A ◽  
Nk Cell ◽  
Normal Lung ◽  
Low Birth Weight Infants ◽  
Newborn Mice ◽  
Peripheral Tissues ◽  
Neonatal Hyperoxia

Respiratory distress in preterm or low birth weight infants is often treated with supplemental oxygen. However, this therapy can disrupt normal lung development and architecture and alter responses to respiratory insults. Similarly, exposure of newborn mice to 100% oxygen during saccular lung development leads to permanent alveolar simplification, and upon challenge with influenza A virus, mice exhibit reduced host resistance. Natural killer (NK) cells are key players in antiviral immunity, and emerging evidence suggest they also help to maintain homeostasis in peripheral tissues, including the lung, by promoting epithelial cell regeneration via IL-22. We tested the hypothesis that adult mice exposed to hyperoxia as neonates have modified NK cell responses to infection. We report here that mice exposed to neonatal hyperoxia had fewer IL-22+ NK cells in their lungs after influenza virus challenge and a parallel increase in IFN-γ+ NK cells. Using reciprocal bone marrow chimeric mice, we show that exposure of either hematopoietic or nonhematopoietic cells was sufficient to increase the severity of infection and to diminish the frequency of IL-22+ NK cells in the infected lung. Overall, our findings suggest that neonatal hyperoxia leads to long-term changes in the reparative vs. cytotoxic nature of NK cells and that this is due in part to intrinsic changes in hematopoietic cells. These differences may contribute to how oxygen alters the host response to respiratory viral infections.

scholarly journals Unique Aspects of the Developing Lung Circulation: Structural Development and Regulation of Vasomotor Tone

2016 ◽  
Vol 6 (4) ◽  
pp. 407-425 ◽  
Author(s):  
Yuangsheng Gao ◽  
David N. Cornfield ◽  
Kurt R. Stenmark ◽  
Bernard Thébaud ◽  
Steven H. Abman ◽  
...  
Keyword(s):  
Lung Development ◽  
Lung Diseases ◽  
Vascular Tone ◽  
Current Knowledge ◽  
Normal Lung ◽  
Pulmonary Vasculature ◽  
Structural Development ◽  
Vasomotor Tone ◽  
Disease States ◽  
Vasculogenesis And Angiogenesis

This review summarizes our current knowledge on lung vasculogenesis and angiogenesis during normal lung development and the regulation of fetal and postnatal pulmonary vascular tone. In comparison to that of the adult, the pulmonary circulation of the fetus and newborn displays many unique characteristics. Moreover, altered development of pulmonary vasculature plays a more prominent role in compromised pulmonary vasoreactivity than in the adult. Clinically, a better understanding of the developmental changes in pulmonary vasculature and vasomotor tone and the mechanisms that are disrupted in disease states can lead to the development of new therapies for lung diseases characterized by impaired alveolar structure and pulmonary hypertension.

scholarly journals Molecular regulation of lung maturation in near-term fetal sheep by maternal daily vitamin C treatment in late gestation

2021 ◽  
Author(s):  
Erin V. McGillick ◽  
Sandra Orgeig ◽  
Beth J. Allison ◽  
Kirsty L. Brain ◽  
Youguo Niu ◽  
...  
Keyword(s):  
Vitamin C ◽  
Lung Development ◽  
Fetal Lung ◽  
Late Gestation ◽  
Lung Maturation ◽  
Maternal Vitamin ◽  
Healthy Pregnancy ◽  
Daily Vitamin ◽  
Expression Of Genes ◽  
Fetal Lung Maturation

Abstract Background In the fetus, the appropriate balance of prooxidants and antioxidants is essential to negate the detrimental effects of oxidative stress on lung maturation. Antioxidants improve respiratory function in postnatal life and adulthood. However, the outcomes and biological mechanisms of antioxidant action in the fetal lung are unknown. Methods We investigated the effect of maternal daily vitamin C treatment (200 mg/kg, intravenously) for a month in late gestation (105–138 days gestation, term ~145 days) on molecular regulation of fetal lung maturation in sheep. Expression of genes and proteins regulating lung development was quantified in fetal lung tissue. The number of surfactant-producing cells was determined by immunohistochemistry. Results Maternal vitamin C treatment increased fetal lung gene expression of the antioxidant enzyme SOD-1, hypoxia signaling genes (HIF-2α, HIF-3α, ADM, and EGLN-3), genes regulating sodium movement (SCNN1-A, SCNN1-B, ATP1-A1, and ATP1-B1), surfactant maturation (SFTP-B and ABCA3), and airway remodeling (ELN). There was no effect of maternal vitamin C treatment on the expression of protein markers evaluated or on the number of surfactant protein-producing cells in fetal lung tissue. Conclusions Maternal vitamin C treatment in the last third of pregnancy in sheep acts at the molecular level to increase the expression of genes that are important for fetal lung maturation in a healthy pregnancy. Impact Maternal daily vitamin C treatment for a month in late gestation in sheep increases the expression of gene-regulating pathways that are essential for normal fetal lung development. Following late gestation vitamin C exposure in a healthy pregnancy, an increase in lung gene but not protein expression may act as a mechanism to aid in the preparation for exposure to the air-breathing environment after birth. In the future, the availability/development of compounds with greater antioxidant properties than vitamin C or more specific targets at the site of oxidative stress in vivo may translate clinically to improve respiratory outcomes in complicated pregnancies at birth.

scholarly journals In vitro models of fetal lung development to enhance research into congenital lung diseases

2021 ◽  
Author(s):  
Soichi Shibuya ◽  
Jessica Allen-Hyttinen ◽  
Paolo De Coppi ◽  
Federica Michielin
Keyword(s):  
Lung Development ◽  
Lung Diseases ◽  
Ex Vivo ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
In Vitro Models ◽  
Normal Lung ◽  
Novel Therapeutic Strategies ◽  
Pseudoglandular Stage

Abstract Purpose This paper aims to build upon previous work to definitively establish in vitro models of murine pseudoglandular stage lung development. These can be easily translated to human fetal lung samples to allow the investigation of lung development in physiologic and pathologic conditions. Methods Lungs were harvested from mouse embryos at E12.5 and cultured in three different settings, i.e., whole lung culture, mesenchyme-free epithelium culture, and organoid culture. For the whole lung culture, extracted lungs were embedded in Matrigel and incubated on permeable filters. Separately, distal epithelial tips were isolated by firstly removing mesothelial and mesenchymal cells, and then severing the tips from the airway tubes. These were then cultured either in branch-promoting or self-renewing conditions. Results Cultured whole lungs underwent branching morphogenesis similarly to native lungs. Real-time qPCR analysis demonstrated expression of key genes essential for lung bud formation. The culture condition for epithelial tips was optimized by testing different concentrations of FGF10 and CHIR99021 and evaluating branching formation. The epithelial rudiments in self-renewing conditions formed spherical 3D structures with homogeneous Sox9 expression. Conclusion We report efficient protocols for ex vivo culture systems of pseudoglandular stage mouse embryonic lungs. These models can be applied to human samples and could be useful to paediatric surgeons to investigate normal lung development, understand the pathogenesis of congenital lung diseases, and explore novel therapeutic strategies.

scholarly journals Brain injury after 50 h of lung-protective mechanical ventilation in a preclinical model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thiago G. Bassi ◽  
Elizabeth C. Rohrs ◽  
Karl C. Fernandez ◽  
Marlena Ornowska ◽  
Michelle Nicholas ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Brain Injury ◽  
Neuronal Damage ◽  
Normal Lung ◽  
Preclinical Model ◽  
Negative Consequences ◽  
Mechanically Ventilated ◽  
Protective Mechanical Ventilation ◽  
Hippocampal Apoptosis ◽  
Lung Protective Mechanical Ventilation

AbstractMechanical ventilation is the cornerstone of the Intensive Care Unit. However, it has been associated with many negative consequences. Recently, ventilator-induced brain injury has been reported in rodents under injurious ventilation settings. Our group wanted to explore the extent of brain injury after 50 h of mechanical ventilation, sedation and physical immobility, quantifying hippocampal apoptosis and inflammation, in a normal-lung porcine study. After 50 h of lung-protective mechanical ventilation, sedation and immobility, greater levels of hippocampal apoptosis and neuroinflammation were clearly observed in the mechanically ventilated group, in comparison to a never-ventilated group. Markers in the serum for astrocyte damage and neuronal damage were also higher in the mechanically ventilated group. Therefore, our study demonstrated that considerable hippocampal insult can be observed after 50 h of lung-protective mechanical ventilation, sedation and physical immobility.

Suppression of cell proliferation and programmed cell death by dexamethasone during postnatal lung development

2002 ◽  
Vol 282 (3) ◽  
pp. L477-L483 ◽  
Author(s):  
Cédric Luyet ◽  
Peter H. Burri ◽  
Johannes C. Schittny
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Lung Development ◽  
Structural Changes ◽  
Tissue Transglutaminase ◽  
Lung Parenchyma ◽  
Lung Maturation ◽  
Morphological Criteria ◽  
Postnatal Lung Development

Prematurely born babies are often treated with glucocorticoids. We studied the consequences of an early postnatal and short dexamethasone treatment (0.1–0.01 μg/g, days 1–4) on lung development in rats, focusing on its influence on peaks of cell proliferation around day 4 and of programmed cell death at days 19–21. By morphological criteria, we observed a dexamethasone-induced premature maturation of the septa ( day 4), followed by a transient septal immatureness and delayed alveolarization leading to complete rescue of the structural changes. The numbers of proliferating (anti-Ki67) and dying cells (TdT-mediated dUTP nick end labeling) were determined and compared with controls. In dexamethasone-treated animals, both the peak of cell proliferation and the peak of programmed cell death were reduced to baseline, whereas the expression of tissue transglutaminase (transglutaminase-C), another marker for postnatal lung maturation, was not significantly altered. We hypothesize that a short neonatal course of dexamethasone leads to severe but transient structural changes of the lung parenchyma and influences the balance between cell proliferation and cell death even in later stages of lung maturation.

Low-dose aspirin prevents age-related endothelial dysfunction in a mouse model of physiological aging

2008 ◽  
Vol 294 (4) ◽  
pp. H1562-H1570 ◽  
Author(s):  
Hélène Bulckaen ◽  
Gaétan Prévost ◽  
Eric Boulanger ◽  
Géraldine Robitaille ◽  
Valérie Roquet ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Protective Effect ◽  
Structural Changes ◽  
Low Dose ◽  
Age Groups ◽  
Dose Aspirin ◽  
Age Related ◽  
Low Dose Aspirin ◽  
Old Mice

The age-related impairment of endothelium-dependent vasodilatation contributes to increased cardiovascular risk in the elderly. For primary and secondary prevention, aspirin can reduce the incidence of cardiovascular events in this patient population. The present work evaluated the effect of low-dose aspirin on age-related endothelial dysfunction in C57B/J6 aging mice and investigated its protective antioxidative effect. Age-related endothelial dysfunction was assessed by the response to acetylcholine of phenylephrine-induced precontracted aortic segments isolated from 12-, 36-, 60-, and 84-wk-old mice. The effect of low-dose aspirin was examined in mice presenting a decrease in endothelial-dependent relaxation (EDR). The effects of age and aspirin treatment on structural changes were determined in mouse aortic sections. The effect of aspirin on the oxidative stress markers malondialdehyde and 8-hydroxy-2′-deoxyguanosine (8-OhdG) was also quantified. Compared with that of 12-wk-old mice, the EDR was significantly reduced in 60- and 84-wk-old mice ( P < 0.05); 68-wk-old mice treated with aspirin displayed a higher EDR compared with control mice of the same age (83.9 ± 4 vs. 66.3 ± 5%; P < 0.05). Aspirin treatment decreased 8-OHdG levels ( P < 0.05), but no significant effect on intima/media thickness ratio was observed. The protective effect of aspirin was not observed when treatment was initiated in older mice (96 wk of age). It was found that low-dose aspirin is able to prevent age-related endothelial dysfunction in aging mice. However, the absence of this effect in the older age groups demonstrates that treatment should be initiated early on. The underlying mechanism may involve the protective effect of aspirin against oxidative stress.

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