Inhibiting Lung Elastase Activity Enables Lung Growth in Mechanically Ventilated Newborn Mice

Hilgendorff, Anne; Parai, Kakoli; Ertsey, Robert; Jain, Noopur; Navarro, Edwin F.; Jc, Peterson; Tamošiūnienė, Rasa; Nicolls, Mark R.; Starcher, Barry; Rabinovitch, Marlene; Bland, Richard D.

doi:10.1164/rccm.201012-2010oc

Cited by 71 publications

(79 citation statements)

References 63 publications

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“…We wondered if this might reflect a difference in lung elastase activity that has been linked to MV of newborn mice (10,11). We indeed found that MV increased serine elastase activity in the lungs of Eln ϩ/ϩ mice but not in the Eln…”

Section: Discussionmentioning

confidence: 90%

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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Section: Discussionmentioning

confidence: 90%

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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“…Our results confirm recently published experiments showing that prolonged ventilation with 40% oxygen increased MMP9 and elastase activity, resulting in elastin degradation and emphysematous alveoli, similar to findings in BPD. Treatment with the elastase inhibitor elafin showed promising reduction of these alterations (6,25). Similar to pediatric with acute respiratory distress syndrome (ARDS) patients, in which higher MMP9 and MMP8 activity in tracheal aspirates was correlated with a longer need for MV (26), an increase in MMP8 in bronchoalveolar lavage fluid and lung tissue of rodents was observed after exposure to high-pressure ventilation or prolonged (48 h) high oxygen exposure (27).…”

Section: Discussionmentioning

confidence: 92%

“…Models trying to decipher genes involved in the pathophysiology of BPD are mainly based on MV and oxygen application to young mammals with immature lungs of different species (3). In newborn rodent models, analyses of lung structure and gene and protein expression are performed for practical reasons directly at the end of MV (4)(5)(6). However, later appearing changes of gene expression might also have an impact on lung development and the evolution towards BPD and cannot be discovered by such models.…”

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confidence: 99%

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

et al. 2015

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Background: Preterm infants having immature lungs often require respiratory support, potentially leading to bronchopulmonary dysplasia (BPD). Conventional BPD rodent models based on mechanical ventilation (MV) present outcome measured at the end of the ventilation period. A reversible intubation and ventilation model in newborn rats recently allowed discovering that different sets of genes modified their expression related to time after MV. In a newborn rat model, the expression profile 48 h after MV was analyzed with gene arrays to detect potentially interesting candidates with an impact on BPD development. Methods: Rat pups were injected P4-5 with 2 mg/kg lipopolysaccharide (LPS). One day later, MV with 21 or 60% oxygen was applied during 6 h. Animals were sacrified 48 h after end of ventilation. Affymetrix gene arrays assessed the total gene expression profile in lung tissue. results: In fully treated animals (LPS + MV + 60% O 2 ) vs. controls, 271 genes changed expression significantly. All modified genes could be classified in six pathways: tissue remodeling/ wound repair, immune system and inflammatory response, hematopoiesis, vasodilatation, and oxidative stress. Major alterations were found in the MMP and complement system. conclusion: MMPs and complement factors play a central role in several of the pathways identified and may represent interesting targets for BPD treatment/prevention.

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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).…”

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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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Inhibiting Lung Elastase Activity Enables Lung Growth in Mechanically Ventilated Newborn Mice

Cited by 71 publications

References 63 publications

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

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

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

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

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