Inflammation and lung maturation from stretch injury in preterm fetal sheep

Hillman, Noah H.; Polglase, Graeme R.; Pillow, J. Jane; Saito, Masatoshi; Kallapur, Suhas G.; Jobe, Alan H.

doi:10.1152/ajplung.00294.2010

Cited by 81 publications

(85 citation statements)

References 48 publications

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“…Because we used a survival model of MV-induced lung injury, this work demonstrates that in neonatal mice, 8 hours of normoxemic MV with a large Tv result in significantly delayed pulmonary alveolarization, detected at 2 weeks of life. Similar results were obtained using VILI models in neonatal lambs and nonhuman primates (10,17,18). In those studies, however, animals were exposed to additional potential pulmonary stressors, including hyperoxia, parenteral nutrition, prolonged sedation and muscle paralysis, the surgical ligation of patent ductus arteriosus, and the administration of systemic antibiotics.…”

Section: Discussionsupporting

confidence: 65%

“…The initial response of the lungs to ventilationinduced stress has been shown to involve a release of proinflammatory mediators. These mediators are responsible for increased pulmonary vascular permeability, the inactivation of surfactant, and the disruption of normal alveolar development (8)(9)(10). Immature lungs are especially susceptible to VILI because of surfactant deficiency, which results in poor lung compliance.…”

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confidence: 99%

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Mechanical Ventilation Causes Pulmonary Mitochondrial Dysfunction and Delayed Alveolarization in Neonatal Mice

Ratner

Sosunov

Niatsetskaya

et al. 2013

Am J Respir Cell Mol Biol

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Hyperoxia inhibits pulmonary bioenergetics, causing delayed alveolarization in mice. We hypothesized that mechanical ventilation (MV) also causes a failure of bioenergetics to support alveolarization. To test this hypothesis, neonatal mice were ventilated with room air for 8 hours (prolonged) or for 2 hours (brief) with 15 ml/g (aggressive) tidal volume (Tv), or for 8 hours with 8 ml/g (gentle) Tv. After 24 hours or 10 days of recovery, lung mitochondria were examined for adenosine diphosphate (ADP)-phosphorylating respiration, using complex I (C-I)-dependent, complex II (C-II)-dependent, or cytochrome C oxidase (C-IV)-dependent substrates, ATP production rate, and the activity of C-I and C-II. A separate cohort of mice was exposed to 2,4-dinitrophenol (DNP), a known uncoupler of oxidative phosphorylation. At 10 days of recovery, pulmonary alveolarization and the expression of vascular endothelial growth factor (VEGF) were assessed. Sham-operated littermates were used as control mice. At 24 hours after aggressive MV, mitochondrial ATP production rates and the activity of C-I and C-II were significantly decreased compared with control mice. However, at 10 days of recovery, only mice exposed to prolonged-aggressive MV continued to exhibit significantly depressed mitochondrial respiration. This was associated with significantly poorer alveolarization and VEGF expression. In contrast, mice exposed to brief-aggressive or prolonged-gentle MV exhibited restored mitochondrial ADPphosphorylation, normal alveolarization and pulmonary VEGF content. Exposure to DNP fully replicated the phenotype consistent with alveolar developmental arrest. Our data suggest that the failure of bioenergetics to support normal lung development caused by aggressive and prolonged ventilation should be considered a fundamental mechanism for the development of bronchopulmonary dysplasia in premature neonates.Keywords: mechanical ventilation; mitochondrial dysfunction; alveolarization; bioenergetics; mouse model of BPD Bronchopulmonary dysplasia (BPD) is one of the most common complications of prematurity. BPD remains the leading cause of long-term morbidity in infants born prematurely (1-3). The exact mechanisms responsible for the development of BPD remain poorly understood. This limits the introduction of highly demanded effective therapeutic strategies against this devastating disease.In addition to prematurity, multiple risk factors are also associated with the development of BPD, including a prolonged exposure to hyperoxia, the use of mechanical ventilation (MV), sepsis, fluid overload, and the presence of patent ductus arteriosus (4). Importantly, despite the diversity of these risk factors, BPD has received a unique pathological definition, namely, a failure of alveolar development. This implies the existence of a common mechanism responsible for the arrest of alveolar growth and development in premature neonates.In premature infants, it is well-established that the use of MV and exposure to a high concentration of oxygen are associated w...

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

Mechanical Ventilation Causes Pulmonary Mitochondrial Dysfunction and Delayed Alveolarization in Neonatal Mice

Ratner

Sosunov

Niatsetskaya

et al. 2013

Am J Respir Cell Mol Biol

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“…The key proinflammatory cytokines initiated by ventilation are IL-1␤, IL-6, and IL-8. Ventilation also increases early response markers of lung injury (EGR-1, CTGF, and CYR61), which are rapidly (within minutes to hours) increased in response to ventilation (26,61). Placental insufficiency and chronic growth restriction have been previously shown to increase inflammatory markers in the maternal (7) and fetal (9,33) circulations, and previous studies have linked fetal inflammation to worse respiratory outcomes (25,53,64).…”

Section: Effect Of Iugr On Fetal Lung Inflammationmentioning

confidence: 96%

Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs

Allison

Hooper

Coia

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Intrauterine growth restriction (IUGR) and preterm birth are frequent comorbidities and, combined, increase the risk of adverse respiratory outcomes compared with that in appropriately grown (AG) infants. Potential underlying reasons for this increased respiratory morbidity in IUGR infants compared with AG infants include altered fetal lung development, fetal lung inflammation, increased respiratory requirements, and/or increased ventilation-induced lung injury. IUGR was surgically induced in preterm fetal sheep (0.7 gestation) by ligation of a single umbilical artery. Four weeks later, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Ventilator requirements, lung inflammation, early markers of lung injury, and morphological changes in lung parenchymal and vascular structure and surfactant composition were analyzed. IUGR preterm lambs weighed 30% less than AG preterm lambs, with increased brain-to-body weight ratio, indicating brain sparing. IUGR did not induce lung inflammation or injury or alter lung parenchymal and vascular structure compared with AG fetuses. IUGR and AG lambs had similar oxygenation and respiratory requirements after birth and had significant, but similar, increases in proinflammatory cytokine expression, lung injury markers, gene expression, and surfactant phosphatidylcholine species compared with unventilated controls. IUGR does not induce pulmonary structural changes in our model. Furthermore, IUGR and AG preterm lambs have similar ventilator requirements in the immediate postnatal period. This study suggests that increased morbidity and mortality in IUGR infants is not due to altered lung tissue or vascular structure, or to an altered response to early ventilation.

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“…For example, even brief periods of alveolar stretch can induce an inflammatory cascade (227) that can in turn influence alveoli and the pulmonary vasculature. Here, the extent of stretch is likely important (8,40,163,195), and stretch effects may involve a range of pathways including Fas/FasL (93), Rac1 (41), PLA2 (116), GEF-H1 (17), caveolins (222), and Rho kinase (42), with modulating effects of oxygen (78,164), ROS (31), and inflammation per se (72,82).…”

Section: Materials Matrix and Mechanobiologymentioning

confidence: 99%

Coming to terms with tissue engineering and regenerative medicine in the lung

Prakash

Tschumperlin

Stenmark

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Inflammation and lung maturation from stretch injury in preterm fetal sheep

Abstract: Hillman NH, Polglase GR, Pillow JJ, Saito M, Kallapur SG, Jobe AH. Inflammation and lung maturation from stretch injury in preterm fetal sheep.

Cited by 81 publications

References 48 publications

Mechanical Ventilation Causes Pulmonary Mitochondrial Dysfunction and Delayed Alveolarization in Neonatal Mice

Mechanical Ventilation Causes Pulmonary Mitochondrial Dysfunction and Delayed Alveolarization in Neonatal Mice

Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs

Coming to terms with tissue engineering and regenerative medicine in the lung

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