PDGFRα signaling is required for alveolar development in the mouse lung

Hyperoxia-induced oxidant stress contributes to the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. Mitochondrial functional differences due to mitochondrial DNA (mtDNA) variations are important modifiers of oxidant stress responses. The objective of this study was to determine whether mtDNA variation independently modifies lung development and mechanical dysfunction in newborn mice exposed to hyperoxia. Newborn C57BL6 wild type (C57n/C57mt, C57WT) and C3H/HeN wild type (C3Hn/C3Hmt, C3HWT) mice and novel Mitochondrial-nuclear eXchange (MNX) strains with nuclear DNA (nDNA) from their parent strain and mtDNA from the other—C57MNX (C57n/C3Hmt) and C3HMNX (C3Hn/C57mt)—were exposed to 21% or 85% O2 from birth to postnatal day 14 (P14). Lung mechanics and histopathology were examined on P15. Neonatal mouse lung fibroblast (NMLF) bioenergetics and mitochondrial superoxide (O2−) generation were measured. Pulmonary resistance and mitochondrial O2− generation were increased while alveolarization, compliance, and NMLF basal and maximal oxygen consumption rate were decreased in hyperoxia-exposed C57WT mice (C57n/C57mt) versus C57MNX mice (C57n/C3Hmt) and in hyperoxia-exposed C3HMNX mice (C3Hn/C57mt) versus C3HWT (C3Hn/C3Hmt) mice. Our study suggests that neonatal C57 mtDNA-carrying strains have increased hyperoxia-induced hypoalveolarization, pulmonary mechanical dysfunction, and mitochondrial bioenergetic and redox dysfunction versus C3H mtDNA strains. Therefore, mtDNA haplogroup variation-induced differences in mitochondrial function could modify neonatal alveolar development and BPD susceptibility.

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Transforming growth factor-β regulates endothelin-1 signaling in the newborn mouse lung during hypoxia exposure

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00258.2011 ◽

2012 ◽

Vol 302 (9) ◽

pp. L857-L865 ◽

Cited By ~ 19

Author(s):

Nelida Olave ◽

Teodora Nicola ◽

Wei Zhang ◽

Arlene Bulger ◽

Masheika James ◽

...

Keyword(s):

Growth Factor ◽

Lung Function ◽

Vascular Remodeling ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Mouse Lung ◽

Newborn Mouse ◽

Newborn Mice ◽

Endothelin 1 ◽

Alveolar Development

We have previously shown that inhibition of transforming growth factor-β (TGF-β) signaling attenuates hypoxia-induced inhibition of alveolar development and abnormal pulmonary vascular remodeling in the newborn mice and that endothelin-A receptor (ETAR) antagonists prevent and reverse the vascular remodeling. The current study tested the hypothesis that inhibition of TGF-β signaling attenuates endothelin-1 (ET-1) expression and thereby reduces effects of hypoxia on the newborn lung. C57BL/6 mice were exposed from birth to 2 wk of age to either air or hypoxia (12% O2) while being given either BQ610 (ETAR antagonist), BQ788 (ETBR antagonist), 1D11 (TGF-β neutralizing antibody), or vehicle. Lung function and development and TGF-β and ET-1 synthesis were assessed. Hypoxia inhibited alveolar development, decreased lung compliance, and increased lung resistance. These effects were associated with increased TGF-β synthesis and signaling and increased ET-1 synthesis. BQ610 (but not BQ788) improved lung function, without altering alveolar development or increased TGF-β signaling in hypoxia-exposed animals. Inhibition of TGF-β signaling reduced ET-1 in vivo, which was confirmed in vitro in mouse pulmonary endothelial, fibroblast, and epithelial cells. ETAR blockade improves function but not development of the hypoxic newborn lung. Reduction of ET-1 via inhibition of TGF-β signaling indicates that TGF-β is upstream of ET-1 during hypoxia-induced signaling in the newborn lung.

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Iloprost attenuates hyperoxia-mediated impairment of lung development in newborn mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00125.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. L535-L544 ◽

Cited By ~ 7

Author(s):

Nelida Olave ◽

Charitharth Vivek Lal ◽

Brian Halloran ◽

Vineet Bhandari ◽

Namasivayam Ambalavanan

Keyword(s):

Left Ventricle ◽

Right Ventricle ◽

Lung Development ◽

Mouse Lung ◽

Synthetic Analog ◽

Newborn Mouse ◽

Newborn Mice ◽

Proinflammatory Mediators ◽

Alveolar Development ◽

Cox 2

Cyclooxygenase-2 (COX-2/PTGS2) mediates hyperoxia-induced impairment of lung development in newborn animals and is increased in the lungs of human infants with bronchopulmonary dysplasia (BPD). COX-2 catalyzes the production of cytoprotective prostaglandins, such as prostacyclin (PGI2), as well as proinflammatory mediators, such as thromboxane A2. Our objective was to determine whether iloprost, a synthetic analog of PGI2, would attenuate hyperoxia effects in the newborn mouse lung. To test this hypothesis, newborn C57BL/6 mice along with their dams were exposed to normoxia (21% O2) or hyperoxia (85% O2) from 4 to 14 days of age in combination with daily intraperitoneal injections of either iloprost 200 µg·kg−1·day−1, nimesulide (selective COX-2 antagonist) 100 mg·kg−1·day−1, or vehicle. Alveolar development was estimated by radial alveolar counts and mean linear intercepts. Lung function was determined on a flexiVent, and multiple cytokines and myeloperoxidase (MPO) were quantitated in lung homogenates. Lung vascular and microvascular morphometry was performed, and right ventricle/left ventricle ratios were determined. We determined that iloprost (but not nimesulide) administration attenuated hyperoxia-induced inhibition of alveolar development and microvascular density in newborn mice. Iloprost and nimesulide both attenuated hyperoxia-induced, increased lung resistance but did not improve lung compliance that was reduced by hyperoxia. Iloprost and nimesulide reduced hyperoxia-induced increases in MPO and some cytokines (IL-1β and TNF-α) but not others (IL-6 and KC/Gro). There were no changes in pulmonary arterial wall thickness or right ventricle/left ventricle ratios. We conclude that iloprost improves lung development and reduces lung inflammation in a newborn mouse model of BPD.

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406: Novel Nuclear Proteins in Mouse Lung Alveolar Development

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2008.11.413 ◽

2009 ◽

Vol 28 (2) ◽

pp. S206-S207

Author(s):

S.K. Murari ◽

J. Dong ◽

S. Sutor ◽

T. Kislinger ◽

D.A. Wigle

Keyword(s):

Nuclear Proteins ◽

Mouse Lung ◽

Alveolar Development

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Loss of Thy-1 inhibits alveolar development in the newborn mouse lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90603.2008 ◽

2009 ◽

Vol 296 (5) ◽

pp. L738-L750 ◽

Cited By ~ 51

Author(s):

Teodora Nicola ◽

James S. Hagood ◽

Masheika L. James ◽

Mark W. MacEwen ◽

Timothy A. Williams ◽

...

Keyword(s):

Lung Development ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Neutralizing Antibody ◽

Lung Compliance ◽

Extracellular Matrix Protein ◽

Endothelial Cell Proliferation ◽

Mouse Lung ◽

Newborn Mouse ◽

Alveolar Development

Transforming growth factor (TGF)-β mediates hypoxia-induced inhibition of alveolar development in the newborn lung. TGF-β is regulated primarily at the level of activation of latent TGF-β. Fibroblasts expressing Thy-1 (CD90) inhibit TGF-β activation. We hypothesized that loss of Thy-1 due to hypoxia may be a mechanism by which hypoxia increases TGF-β activation and that animals deficient in Thy-1 will simulate the effects of hypoxia on lung development. To determine if loss of Thy-1 occurred during hypoxia, non-transgenic (C57BL/6) wild-type (WT) mice exposed to hypoxia were evaluated for Thy-1 mRNA and protein. To determine if Thy-1 deficiency simulated hypoxia, WT and Thy-1 null ( Thy-1 −/−) mice were exposed to air or hypoxia from birth to 2 wk, the critical period of lung development, and lung histology, function, parameters related to TGF-β signaling, and extracellular matrix protein content were measured. To test if the phenotype in Thy-1 −/− mice was due to excessive TGF-β signaling, measurements were also performed in Thy-1 −/− mice administered TGF-β neutralizing antibody (1D11). We observed that hypoxia reduced Thy-1 mRNA and Thy-1 staining in WT mice. Thy-1 −/− mice had impaired alveolarization, increased TGF-β signaling, reduced lung epithelial and endothelial cell proliferation but increased fibroblast proliferation, and increased collagen and elastin. Lung compliance was lower, and tissue but not airway resistance was higher in Thy-1 −/− mice at 2 wk. Thy-1 −/− mice given 1D11 had improved alveolar development and lung function. These data support the hypothesis that hypoxia, by reducing Thy-1, increases TGF-β activation, and thereby inhibits normal alveolar development.

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Profiling target genes of FGF18 in the postnatal mouse lung: possible relevance for alveolar development

Physiological Genomics ◽

10.1152/physiolgenomics.00034.2011 ◽

2011 ◽

Vol 43 (21) ◽

pp. 1226-1240 ◽

Cited By ~ 26

Author(s):

Marie-Laure Franco-Montoya ◽

Olivier Boucherat ◽

Christelle Thibault ◽

Bernadette Chailley-Heu ◽

Roberto Incitti ◽

...

Keyword(s):

Target Genes ◽

Epithelial Mesenchymal Transition ◽

Expression Profiles ◽

Mouse Lung ◽

Mesenchymal Transition ◽

Driving Mechanisms ◽

Alveolar Development ◽

Genome Wide ◽

Extracellular Matrix Components ◽

Enhanced Expression

Better understanding alveolarization mechanisms could help improve prevention and treatment of diseases characterized by reduced alveolar number. Although signaling through fibroblast growth factor (FGF) receptors is essential for alveolarization, involved ligands are unidentified. FGF18, the expression of which peaks coincidentally with alveolar septation, is likely to be involved. Herein, a mouse model with inducible, lung-targeted FGF18 transgene was used to advance the onset of FGF18 expression peak, and genome-wide expression changes were determined by comparison with littermate controls. Quantitative RT-PCR was used to confirm expression changes of selected up- and downregulated genes and to determine their expression profiles in the course of lung postnatal development. This allowed identifying so-far unknown target genes of the factor, among which a number are known to be involved in alveolarization. The major target was adrenomedullin, a promoter of lung angiogenesis and alveolar development, whose transcript was increased 6.9-fold. Other genes involved in angiogenesis presented marked expression increases, including Wnt2 and cullin2. Although it appeared to favor cell migration notably through enhanced expression of Snai1/2, FGF18 also induced various changes consistent with prevention of epithelial-mesenchymal transition. Together with antifibrotic effects driven by induction of E prostanoid receptor 2 and repression of numerous myofibroblast markers, this could prevent alveolar septation-driving mechanisms from becoming excessive and deleterious. Last, FGF18 up- or downregulated genes of extracellular matrix components and epithelial cell markers previously shown to be up- or downregulated during alveolarization. These findings therefore argue for an involvement of FGF18 in the control of various developmental events during the alveolar stage.

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