Adrenomedullin Deficiency Potentiates Lipopolysaccharide-Induced Experimental Bronchopulmonary Dysplasia in Neonatal Mice

Abstract Background The main features of bronchopulmonary dysplasia (BPD) are alveolar simplification, pulmonary growth arrest, and abnormal lung function. Multiple studies have highlighted microRNA-29 (miR-29) as a potential biomarker for lung diseases and cancers. Upregulation of miR-29a has been known to downregulate GRB2-associated-binding protein 1 (GAB1), which is often highly expressed in the lung. The current study was designed to investigate the potential role of miR-29a in hyperoxia-induced BPD by targeting GAB1 in a neonatal mouse model. Methods The expression of miR-29a and GAB1 in lung tissues of neonatal mice with hyperoxia-induced BPD and mouse alveolar epithelial cells (MLE-12) was determined using RT-qPCR and western blot analysis. Subsequently, the relationship between miR-29a and GAB1 was verified using in silico analysis. In order to assess the effects of miR-29a or GAB1 on BPD, the pathological characteristics of alveoli, as well as proliferation and apoptosis of cells were measured through gain- and loss-of-function studies. Results Upregulation of miR-29a and downregulation of GAB1 were evident in both lung tissues and MLE-12 cells following BPD modeling. GAB1 was a direct target gene of miR-29a. Inhibition of miR-29a and overexpression of GAB1 were shown to alleviate lung injury, promote cell proliferation and inhibit apoptosis but reduce chord length in lung tissues of neonatal mice following hyperoxia-induced BPD modeling. Conclusion Altogether, down-regulation of miR-29a can potentially elevate GAB1 expression, reducing cell apoptosis and stimulating proliferation, ultimately retarding the development of BPD in mice. This study highlights the potential of a promising new target for preventing BPD.

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Reduced platelet-derived growth factor receptor expression is a primary feature of human bronchopulmonary dysplasia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00342.2013 ◽

2014 ◽

Vol 307 (3) ◽

pp. L231-L239 ◽

Cited By ~ 52

Author(s):

Antonia P. Popova ◽

J. Kelley Bentley ◽

Tracy X. Cui ◽

Michelle N. Richardson ◽

Marisa J. Linn ◽

...

Keyword(s):

Growth Factor ◽

Bronchopulmonary Dysplasia ◽

Animal Studies ◽

Growth Factor Receptor ◽

Receptor Expression ◽

Platelet Derived Growth Factor ◽

Boyden Chamber ◽

Human Lung Tissue ◽

Neonatal Mice ◽

Neonatal Lung

Animal studies have shown that platelet-derived growth factor (PDGF) signaling is required for normal alveolarization. Changes in PDGF receptor (PDGFR) expression in infants with bronchopulmonary dysplasia (BPD), a disease of hypoalveolarization, have not been examined. We hypothesized that PDGFR expression is reduced in neonatal lung mesenchymal stromal cells (MSCs) from infants who develop BPD. MSCs from tracheal aspirates of premature infants requiring mechanical ventilation in the first week of life were studied. MSC migration was assessed in a Boyden chamber. Human lung tissue was obtained from the University of Rochester Neonatal Lung Biorepository. Neonatal mice were exposed to air or 75% oxygen for 14 days. PDGFR expression was quantified by qPCR, immunoblotting, and stereology. MSCs were isolated from 25 neonates (mean gestational age 27.7 wk); 13 developed BPD and 12 did not. MSCs from infants who develop BPD showed lower PDGFR-α and PDGFR-β mRNA and protein expression and decreased migration to PDGF isoforms. Lungs from infants dying with BPD show thickened alveolar walls and paucity of PDGFR-α-positive cells in the dysmorphic alveolar septa. Similarly, lungs from hyperoxia-exposed neonatal mice showed lower expression of PDGFR-α and PDGFR-β, with significant reductions in the volume of PDGFR-α-positive alveolar tips. In conclusion, MSCs from infants who develop BPD hold stable alterations in PDGFR gene expression that favor hypoalveolarization. These data demonstrate that defective PDGFR signaling is a primary feature of human BPD.

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Integrated microRNA-mRNA analyses of distinct expression profiles in hyperoxia-induced bronchopulmonary dysplasia in neonatal mice.

10.22541/au.159986358.86063731 ◽

2020 ◽

Author(s):

zhiqiang wang ◽

sheng zhang ◽

lina zhu ◽

jun duan ◽

bo huang ◽

...

Keyword(s):

Bronchopulmonary Dysplasia ◽

Expression Profiles ◽

Neonatal Mice

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A Preconception Paternal Fish Oil Diet Prevents Toxicant-Driven New Bronchopulmonary Dysplasia in Neonatal Mice

Toxics ◽

10.3390/toxics10010007 ◽

2021 ◽

Vol 10 (1) ◽

pp. 7

Author(s):

Jelonia T. Rumph ◽

Kayla J. Rayford ◽

Victoria R. Stephens ◽

Sharareh Ameli ◽

Pius N. Nde ◽

...

Keyword(s):

Risk Factors ◽

Birth Weight ◽

Low Birth Weight ◽

Fish Oil ◽

Bronchopulmonary Dysplasia ◽

Toxicant Exposure ◽

Placental Dysfunction ◽

Neonatal Mice ◽

History Of ◽

Fish Oil Diet

New bronchopulmonary dysplasia is a developmental lung disease associated with placental dysfunction and impaired alveolarization. Risk factors for new BPD include prematurity, delayed postnatal growth, the dysregulation of epithelial-to-mesenchymal transition (EMT), and parental exposure to toxicants. Our group previously reported that a history of paternal toxicant exposure increased the risk of prematurity and low birth weight in offspring. A history of paternal toxicant exposure also increased the offspring’s risk of new BPD and disease severity was increased in offspring who additionally received a supplemental formula diet, which has also been linked to poor lung development. Risk factors associated with new BPD are well-defined, but it is unclear whether the disease can be prevented. Herein, we assessed whether a paternal fish oil diet could attenuate the development of new BPD in the offspring of toxicant exposed mice, with and without neonatal formula feeding. We investigated the impact of a paternal fish oil diet preconception because we previously reported that this intervention reduces the risk of TCDD associated placental dysfunction, prematurity, and low birth weight. We found that a paternal fish oil diet significantly reduced the risk of new BPD in neonatal mice with a history of paternal toxicant exposure regardless of neonatal diet. Furthermore, our evidence suggests that the protective effects of a paternal fish oil diet are mediated in part by the modulation of small molecules involved in EMT.

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CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00270.2010 ◽

2011 ◽

Vol 300 (3) ◽

pp. L330-L340 ◽

Cited By ~ 47

Author(s):

Shaoyi Chen ◽

Min Rong ◽

Astrid Platteau ◽

Dorothy Hehre ◽

Heather Smith ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Bronchopulmonary Dysplasia ◽

Vascular Remodeling ◽

Tissue Growth ◽

Clara Cell ◽

Alveolar Type ◽

Lung Pathology ◽

Pulmonary Vascular Remodeling ◽

Neonatal Mice ◽

Gsk 3Β

The pathological hallmarks of bronchopulmonary dysplasia (BPD), one of the most common long-term pulmonary complications associated with preterm birth, include arrested alveolarization, abnormal vascular growth, and variable interstitial fibrosis. Severe BPD is often complicated by pulmonary hypertension characterized by excessive pulmonary vascular remodeling and right ventricular hypertrophy that significantly contributes to the mortality and morbidity of these infants. Connective tissue growth factor (CTGF) is a multifunctional protein that coordinates complex biological processes during tissue development and remodeling. We have previously shown that conditional overexpression of CTGF in airway epithelium under the control of the Clara cell secretory protein promoter results in BPD-like architecture in neonatal mice. In this study, we have generated a doxycycline-inducible double transgenic mouse model with overexpression of CTGF in alveolar type II epithelial (AT II) cells under the control of the surfactant protein C promoter. Overexpression of CTGF in neonatal mice caused dramatic macrophage and neutrophil infiltration in alveolar air spaces and perivascular regions. Overexpression of CTGF also significantly decreased alveolarization and vascular development. Furthermore, overexpression of CTGF induced pulmonary vascular remodeling and pulmonary hypertension. Most importantly, we have also demonstrated that these pathological changes are associated with activation of integrin-linked kinase (ILK)/glucose synthesis kinase-3β (GSK-3β)/β-catenin signaling. These data indicate that overexpression of CTGF in AT II cells results in lung pathology similar to those observed in infants with severe BPD and that ILK/GSK-3β/β-catenin signaling may play an important role in the pathogenesis of severe BPD.

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Global Extracellular Signal-Regulated Kinase (ERK)-1 Deficiency Does Not Potentiate Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension in Neonatal Mice

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a4656 ◽

2020 ◽

Author(s):

B. Shivanna ◽

A. Shrestha ◽

R. Menon

Keyword(s):

Pulmonary Hypertension ◽

Bronchopulmonary Dysplasia ◽

Extracellular Signal Regulated Kinase ◽

Neonatal Mice ◽

Extracellular Signal

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Hyperoxia reduces bone marrow, circulating, and lung endothelial progenitor cells in the developing lung: implications for the pathogenesis of bronchopulmonary dysplasia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00347.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. L1073-L1084 ◽

Cited By ~ 157

Author(s):

Vivek Balasubramaniam ◽

Cela F. Mervis ◽

Anne M. Maxey ◽

Neil E. Markham ◽

Steven H. Abman

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Bronchopulmonary Dysplasia ◽

Receptor Expression ◽

Vascular Density ◽

Endothelial Progenitor ◽

Neonatal Mice ◽

Adult Mice ◽

Lung Structure

Hyperoxia disrupts vascular and alveolar growth of the developing lung and contributes to the development of bronchopulmonary dysplasia (BPD). Endothelial progenitor cells (EPC) have been implicated in repair of the vasculature, but their role in lung vascular development is unknown. Since disruption of vascular growth impairs lung structure, we hypothesized that neonatal hyperoxia impairs EPC mobilization and homing to the lung, contributing to abnormalities in lung structure. Neonatal mice (1-day-old) were exposed to 80% O2at Denver's altitude (= 65% at sea level) or room air for 10 days. Adult mice were also exposed for comparison. Blood, lung, and bone marrow were harvested after hyperoxia. Hyperoxia decreased pulmonary vascular density by 72% in neonatal but not adult mice. In contrast to the adult, hyperoxia simplified distal lung structure neonatal mice. Moderate hyperoxia reduced EPCs (CD45−/Sca-1+/CD133+/VEGFR-2+) in the blood (55%; P < 0.03), bone marrow (48%; P < 0.01), and lungs (66%; P < 0.01) of neonatal mice. EPCs increased in bone marrow (2.5-fold; P < 0.01) and lungs (2-fold; P < 0.03) of hyperoxia-exposed adult mice. VEGF, nitric oxide (NO), and erythropoietin (Epo) contribute to mobilization and homing of EPCs. Lung VEGF, VEGF receptor-2, endothelial NO synthase, and Epo receptor expression were reduced by hyperoxia in neonatal but not adult mice. We conclude that moderate hyperoxia decreases vessel density, impairs lung structure, and reduces EPCs in the circulation, bone marrow, and lung of neonatal mice but increases EPCs in adults. This developmental difference may contribute to the increased susceptibility of the developing lung to hyperoxia and may contribute to impaired lung vascular and alveolar growth in BPD.

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