Arrested Alveolar Development in Bronchopulmonary Dysplasia

Mitochondria are involved in energy metabolism and redox reactions in the cell. Emerging data indicate that mitochondria play an essential role in physiological and pathological processes of neonatal lung development. Mitochondrial damage due to exposure to high concentrations of oxygen is an indeed important factor for simplification of lung structure and development of bronchopulmonary dysplasia (BPD), as reported in humans and rodent models. Here, we comprehensively review research that have determined the effects of oxygen environment on alveolar development and morphology, summarize changes in mitochondria under high oxygen concentrations, and discuss several mitochondrial mechanisms that may affect cell plasticity and their effects on BPD. Thus, the pathophysiological effects of mitochondria may provide insights into targeted mitochondrial and BPD therapy.

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Pulmonary vascular and alveolar development in preterm lambs chronically colonized with Ureaplasma parvum

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00369.2009 ◽

2010 ◽

Vol 299 (2) ◽

pp. L232-L241 ◽

Cited By ~ 24

Author(s):

Graeme R. Polglase ◽

Richard G. B. Dalton ◽

Ilias Nitsos ◽

Christine L. Knox ◽

J. Jane Pillow ◽

...

Keyword(s):

Bronchopulmonary Dysplasia ◽

Chronic Exposure ◽

Vascular Development ◽

Pulmonary Resistance ◽

Ureaplasma Parvum ◽

Alveolar Development ◽

Sustained Effects ◽

Air Space ◽

High Doses ◽

Timing Of Exposure

Ureaplasma species, the most commonly isolated microorganisms in women with chorioamnionitis, are associated with preterm delivery. Chorioamnionitis increases the risk and severity of bronchopulmonary dysplasia and persistent pulmonary hypertension in newborns. It is not known whether the timing of exposure to inflammation in utero is an important contributor to the pathogenesis of bronchopulmonary dysplasia. We hypothesized that chronic inflammation would alter the pulmonary air space and vascular development after 70 days of exposure to infection. Pregnant ewes were given intra-amniotic injection of Ureaplasma parvum serovars 3 or 6 at low (2 × 104cfu) or high doses (2 × 107cfu) or media (controls) at 55 days gestational age. Fetuses were delivered at 125 days (term = 150 days). U. parvum was grown from the lungs of all exposed fetuses, and neutrophils and monocytes were increased in the air spaces. Lung mRNA expression of IL-1β and IL-8, but not IL-6, was modestly increased in U. parvum -exposed fetuses. U. parvum exposure increased surfactant and improved lung gas volumes. The changes in lung inflammation and maturation were independent of serovar or dose. Exposure to U. parvum did not change multiple indices of air space or vascular development. Parenchymal elastin and collagen content were similar between groups. Expression of several endothelial proteins and pulmonary resistance arteriolar media thickness were also not different between groups. We conclude that chronic exposure to U. parvum does not cause sustained effects on air space or vascular development in premature lambs.

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Anti-neutrophil chemokine preserves alveolar development in hyperoxia-exposed newborn rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.281.2.l336 ◽

2001 ◽

Vol 281 (2) ◽

pp. L336-L344 ◽

Cited By ~ 67

Author(s):

Richard L. Auten ◽

S. Nicholas Mason ◽

David T. Tanaka ◽

Karen Welty-Wolf ◽

Mary H. Whorton

Keyword(s):

Lung Injury ◽

Bronchopulmonary Dysplasia ◽

Antigen Expression ◽

Lung Compliance ◽

Nuclear Antigen ◽

Brdu Incorporation ◽

Newborn Rats ◽

Alveolar Volume ◽

Alveolar Development ◽

Air Control

Inflammation may contribute to lung injury and impaired alveolar development in bronchopulmonary dysplasia. We treated hyperoxia-exposed newborn rats with antibodies to the neutrophil chemokine cytokine-induced neutrophil chemoattractant-1 (CINC-1) during 95% O2exposure to reduce adverse effects of hyperoxia-induced inflammation on lung development. Rats were exposed at birth to air, 95% O2, or 95% O2+ anti-CINC-1 (injected on days 3 and 4). Bromodeoxyuridine (BrdU) was injected 6 h before death. Anti-CINC-1 treatment improved weight gain but not survival at day 8. Anti-CINC-1 reduced bronchoalveolar lavage neutrophils at day 8 to levels equal to air controls. Total detectable lung CINC-1 was reduced to air control levels. Lung compliance was improved by anti-CINC-1, achieving air control levels in the 10-μg anti-CINC-1 group. Anti-CINC-1 preserved proliferating cell nuclear antigen expression in airway epithelium despite 95% O2exposure. BrdU incorporation was depressed by hyperoxia but preserved by anti-CINC-1 to levels similar to air control. Alveolar volume and surface density were decreased by hyperoxia but preserved by anti-CINC-1 to levels equal to air control. Blockade of neutrophil influx in newborns may avert early lung injury and avoid alveolar developmental arrest that contributes to bronchopulmonary dysplasia.

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Overexpression of Spock2 in mice leads to altered lung alveolar development and worsens lesions induced by hyperoxia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00191.2019 ◽

2020 ◽

Vol 319 (1) ◽

pp. L71-L81 ◽

Cited By ~ 1

Author(s):

Alice Hadchouel ◽

Marie-Laure Franco-Montoya ◽

Sophie Guerin ◽

Marcio Do Cruzeiro ◽

Mickaël Lhuillier ◽

...

Keyword(s):

Bronchopulmonary Dysplasia ◽

Lung Development ◽

Transgenic Mouse Model ◽

Matrix Metalloproteinase 2 ◽

Preterm Neonates ◽

Alveolar Cells ◽

Very Preterm ◽

Rat Pups ◽

Alveolar Development

SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 ( SPOCK2) was previously associated with genetic susceptibility to bronchopulmonary dysplasia in a French population of very preterm neonates. Its expression increases during lung development and is increased after exposure of rat pups to hyperoxia compared with controls bred in room air. To further investigate the role of SPOCK2 during lung development, we designed two mouse models, one that uses a specific anti-Spock2 antibody and one that reproduces the hyperoxia-induced Spock2 expression with a transgenic mouse model resulting in a conditional and lung-targeted overexpression of Spock2. When mice were bred under hyperoxic conditions, treatment with anti-Spock2 antibodies significantly improved alveolarization. Lung overexpression of Spock2 altered alveolar development in pups bred in room air and worsened hyperoxia-induced lesions. Neither treatment with anti-Spock2 antibody nor overexpression of Spock2 was associated with abnormal activation of matrix metalloproteinase-2. These two models did not alter the expression of known players in alveolar development. This study brings strong arguments for the deleterious role of SPOCK2 on lung alveolar development especially after lung injury, suggesting its role in bronchopulmonary dysplasia susceptibility. These effects are not mediated by a deregulation in metalloproteases activity and in expression of factors essential to normal alveolarization. The balance between types 1 and 2 epithelial alveolar cells may be involved.

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