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

Bland, Richard D.; Mokres, Lucia M.; Ertsey, Robert; Jacobson, Benjamin; Jiang, Siqi; Rabinovitch, Marlene; Xu, Liwen; Shinwell, Eric S.; Zhang, Feijie; Beasley, Malcolm

doi:10.1152/ajplung.00217.2007

Cited by 69 publications

(59 citation statements)

References 48 publications

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“…Consistent with the presence of, at least transient, VEGF decrease in BPD infants, endotoxin exposure in lambs [52] or mechanical ventilation with supplemental oxygen in mice [53] reduced pulmonary VEGF and VEGFR2 expression. Reciprocally, exogenous VEGF improved alveolarization in hyperoxia-exposed newborn rats [54].…”

Section: Impaired Microvascular Development and Maintenancesupporting

confidence: 55%

“…), and better understanding these represents a challenge to optimize the therapeutic use of retinoids. [107,108] Mechanical injury + ± [1,4] Infections ± - [1] Directly associated genetic disorders -+ [3] Risk-associated gene polymorphisms + + [2] Histological features Airspace enlargement + + [1][2][3][4] Elastic fiber destruction/ disrupted assembly + + [37][38][39][40][41] Extracellular matrix remodeling + + [1][2][3][4] Diminished microvasular bed ± + [52][53][54] Dysmorphic capillary vessels + -…”

Section: Relative Inefficiency Of Retinoidsmentioning

confidence: 99%

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Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

Bourbon

Boucherat

Boczkowski

et al. 2009

Trends in Molecular Medicine

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Section: Impaired Microvascular Development and Maintenancesupporting

confidence: 55%

Section: Relative Inefficiency Of Retinoidsmentioning

confidence: 99%

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

Bourbon

Boucherat

Boczkowski

et al. 2009

Trends in Molecular Medicine

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“…The lungs were fixed intratracheally with 4% buffered paraformaldehyde overnight at 20 cmH2O, as described previously (4). On the day following initial fixation, the lungs were excised and their volumes were measured by fluid displacement (29), after which they were embedded in paraffin for isotropic uniform random sectioning, as previously described (25).…”

Section: Postmortem Processing Of Lungs For Quantitative Histologymentioning

confidence: 99%

Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice

Hilgendorff

Parai

Ertsey

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice ( Eln+/−) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type ( Eln+/+) and Eln+/− littermates at baseline and after MV with air for 8–24 h. Lungs of unventilated Eln+/− mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln+/+ pups. Eln+/− lungs contained fewer capillaries than Eln+/+ lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln+/+ neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln+/− mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln+/− than in Eln+/+ pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln+/− compared with Eln+/+ mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln+/+ and Eln+/− mice. Paucity of lung capillaries in Eln+/− newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln+/− mice.

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“…Excessive elastase activity has been considered as a mediator of pathological elastin degradation, which might underlie the paucity of elastin and bizarre elastin fiber patterns seen in affected lungs (21)(22)(23)36). Additionally, the altered expression of proteins required for proper elastin fiber assembly has also been suggested to uncouple elastin synthesis and the assembly of elastin fibers (7)(8)(9). Several recent studies have revealed that the expression and activity of several ECM maturation systems, including collagen and elastin cross-linking enzymes of the lysyl oxidase (33), lysyl hydroxylase (65), and transglutaminase (64) families, are deregulated in both animal models of BPD and in tissues from BPD patients.…”

mentioning

confidence: 99%

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

Mižíková

Ruiz‐Camp

Steenbock

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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RE. Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia. Am J Physiol Lung Cell Mol Physiol 308: L1145-L1158, 2015. First published April 3, 2015 doi:10.1152/ajplung.00039.2015.-Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O 2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor ␤-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, ␤-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia. lung development; elastin; collagen; lysyl oxidase; alveolarization POSTNATAL LUNG DEVELOPMENT in mice is characterized by a period of intensive growth and remodeling of the lung parenchyma, which rapidly (over a period of days) generates a large number of small alveoli and thus maximizes the alveolar surface area over which gas exchange can take place. Secondary septation, the generation of new septa from preexisting septa, which then divide the air spaces, peaks in mice between 4 and 7 days after birth and is largely complete 21 days after birth. In humans, secondary septation is already well underway during late stages of pregnancy, and thus occurs in utero, and continues several years into postnatal life. Disturbances to the formation of secondary septa, such as the arrested secondary septation associated with bronchopulmonary dysplasia (BPD) in humans, leads to malformed lung...

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

Cited by 69 publications

References 48 publications

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

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