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Keywords = alveolar simplification

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23 pages, 10910 KB  
Article
The Impact of Antenatal and Postnatal Factors on the Development of the Pulmonary Microvasculature in Preterm Infants
by Raluca Chirculescu, Ruxandra Viorica Stănculescu, Paul Cristian Bălănescu and Gheorghe Peltecu
Children 2025, 12(5), 650; https://doi.org/10.3390/children12050650 - 18 May 2025
Viewed by 633
Abstract
This research aimed to assess the influence of prenatal and postnatal factors on the remodeling of the pulmonary microvasculature. Methods: The investigation analyzed 67 cases of preterm infants, whose lifespans ranged from 1 day to 149 days. After selecting the cases from [...] Read more.
This research aimed to assess the influence of prenatal and postnatal factors on the remodeling of the pulmonary microvasculature. Methods: The investigation analyzed 67 cases of preterm infants, whose lifespans ranged from 1 day to 149 days. After selecting the cases from the autopsy database, two lung tissue microarrays were created. Histological slides were stained using the hematoxylin and eosin technique to precisely capture the microscopic details. For the assessment of pulmonary microvascularization and the media layer of the vascular walls, an immunohistochemical analysis was performed utilizing CD34 and SMA markers. Results: Following the assessment of the quantity of capillaries positive for CD34, a negative correlation was identified between the average capillary count per alveolus and the duration of oxygen therapy. Preterm infants who developed pulmonary fibrosis exhibited an average reduction of 5.43 capillaries in comparison to other newborns. Preterm neonates born to mothers with preeclampsia exhibited an average reduction of 2.82 capillaries compared to those born to mothers unaffected by this pregnancy complication. A positive correlation was evident between increased thickness of the arteriolar media, lifespan, and the duration of oxygen therapy, as well as in those preterm infants who developed pulmonary fibrosis. Conclusions: Antenatal risk factors did not exert a significant impact on pulmonary vascular remodeling, whereas postnatal influences, particularly oxygen therapy, demonstrated a detrimental effect on the density of capillary structures within the alveolocapillary membrane. Premature neonates with increased thickness of the arteriolar media had a greater susceptibility to pulmonary hypertension. Full article
(This article belongs to the Special Issue Recent Advances in Maternal and Fetal Health (2nd Edition))
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15 pages, 2443 KB  
Article
Summed Tissue Resistance of Periodontal Ligaments and Alveolar Bone in Orthodontic Distal Retraction of Maxillary Canines: Mathematical Simulation of Clinical Data and Interpretation of Results
by Olimpia Bunta, Vlad Muresan, Dana Festila and Mihaela Baciut
Dent. J. 2025, 13(2), 55; https://doi.org/10.3390/dj13020055 - 27 Jan 2025
Viewed by 1404
Abstract
Background: The mechanical properties of either alveolar bone or periodontal ligaments under orthodontic loading, as well as orthodontic tooth movement, have been studied in recent years using computational approaches. In previous studies, we developed a theoretical mathematical approach that uses a weighting [...] Read more.
Background: The mechanical properties of either alveolar bone or periodontal ligaments under orthodontic loading, as well as orthodontic tooth movement, have been studied in recent years using computational approaches. In previous studies, we developed a theoretical mathematical approach that uses a weighting coefficient of the summed resistance of periodontal structures, namely the bone and periodontal ligaments, in relation to apex movement, the center of rotation, orthodontic force loading, and time in order to quantify the biological response to orthodontic biomechanics. Methods: We analyzed the distal retraction of three maxillary canines and integrated the clinical data obtained in the previously developed mathematical programs. Results: The values of the (σ) weighting coefficient of the tissue resistance were interpreted in the context of the clinical data obtained: the smaller the value of (σ), the higher the actual tissue resistance, with a greater difference between the crown and root movement; also, the higher the value of (σ), the lower the actual tissue resistance, with a small difference between the crown and apex movement. Conclusions: The clinical interpretation of the results allows us to set a premise for the refinement of the mathematical programs so that we can use them in assessing the orthodontic biomechanics of larger patient groups over longer periods of time and create premises of treatment protocol simplification and adjustment. Full article
(This article belongs to the Special Issue Orthodontics and New Technologies: 2nd Edition)
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11 pages, 3619 KB  
Communication
Myeloid Nrf2 Protects against Neonatal Oxidant-Stress-Induced Lung Inflammation and Alveolar Simplification in Mice
by Chandra Mohan Tamatam, Lalith Kumar Venkareddy, Aparna Ankireddy, Narsa Machireddy and Sekhar P. Reddy
Antioxidants 2024, 13(6), 698; https://doi.org/10.3390/antiox13060698 - 7 Jun 2024
Cited by 1 | Viewed by 1565
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic condition affecting preterm infants, characterized by lung alveolar simplification/hypoalveolarization and vascular remodeling. The nuclear factor erythroid 2 like 2 (Nfe2l2, or Nrf2) plays a critical role in the cytoprotective response to neonatal hyperoxia, and its global deficiency [...] Read more.
Bronchopulmonary dysplasia (BPD) is a chronic condition affecting preterm infants, characterized by lung alveolar simplification/hypoalveolarization and vascular remodeling. The nuclear factor erythroid 2 like 2 (Nfe2l2, or Nrf2) plays a critical role in the cytoprotective response to neonatal hyperoxia, and its global deficiency exacerbates hypoalveolarization in mice. The abnormal recruitment and activation of myeloid cells are associated with the pathogenesis of BPD. Therefore, we employed a genetic approach to investigate the role of myeloid Nrf2 in regulating hyperoxia-induced hypoalveolarization. Pups, both wild-type (Nrf2f/f) and those with a myeloid Nrf2 deletion (abbreviated as Nrf2∆/∆mye), were exposed to hyperoxia for 72 h at postnatal day 1 (Pnd1), and then sacrificed at either Pnd4 or Pnd18 following a two-week recovery period. We analyzed the hypoalveolarization, inflammation, and gene expression related to cytoprotective and inflammatory responses in the lungs of these pups. The hypoalveolarization induced by hyperoxia was significantly greater in Nrf2∆/∆mye pups compared to their Nrf2f/f counterparts (35.88% vs. 21.01%, respectively) and was accompanied by increased levels of inflammatory cells and IL-1β activation in the lungs. Antioxidant gene expression in response to neonatal hyperoxia was lower in Nrf2∆/∆mye pups compared to their Nrf2f/f counterparts. Furthermore, Nrf2-deficient macrophages exposed to hyperoxia exhibited markedly decreased cytoprotective gene expression and increased IL-1β levels compared to Nrf2-sufficient cells. Our findings demonstrate the crucial role of myeloid Nrf2 in mitigating hyperoxia-induced lung hypoalveolarization and inflammatory responses in neonatal mice. Full article
(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)
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19 pages, 1875 KB  
Article
Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia
by Giorgio Aquila, Yannick Regin, Xabier Murgia, Fabrizio Salomone, Costanza Casiraghi, Chiara Catozzi, Enrica Scalera, Matteo Storti, Francesca Stretti, Giancarlo Aquino, Giorgia Cavatorta, Roberta Volta, Carmelina Di Pasquale, Caterina Amato, Fabio Bignami, Davide Amidani, Barbara Pioselli, Elisa Sgarbi, Paolo Ronchi, Giuseppe Mazzola, Ignacio Valenzuela and Jaan Toelenadd Show full author list remove Hide full author list
Pharmaceutics 2022, 14(7), 1507; https://doi.org/10.3390/pharmaceutics14071507 - 20 Jul 2022
Cited by 3 | Viewed by 4033
Abstract
Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated [...] Read more.
Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated the PPARγ selectivity, epithelial permeability, and lung tissue binding of three types of TZDs in vitro (rosiglitazone (RGZ), pioglitazone, and DRF-2546), followed by an in vivo study in preterm rabbits exposed to hyperoxia (95% oxygen) to investigate the pharmacokinetics and the pulmonary outcomes of daily RGZ administration. In addition, blood lipids and a comparative lung proteomics analysis were also performed on Day 7. All TZDs showed high epithelial permeability through Caco-2 monolayers and high plasma and lung tissue binding; however, RGZ showed the highest affinity for PPARγ. The pharmacokinetic profiling of RGZ (1 mg/kg) revealed an equivalent biodistribution after either intratracheal or intraperitoneal administration, with detectable levels in lungs and plasma after 24 h. However, daily RGZ doses of 1 mg/kg did not improve lung function in preterm rabbits exposed to hyperoxia, and daily 10 mg/kg doses were even associated with a significant lung function worsening, which could be partially explained by the upregulation of lung inflammation and lipid metabolism pathways revealed by the proteomic analysis. Notably, daily postnatal RGZ produced an aberrant modulation of serum lipids, particularly in rabbit pups treated with the 10 mg/kg dose. In conclusion, daily postnatal RGZ did not improve lung function and caused dyslipidemia in preterm rabbits exposed to hyperoxia. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)
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15 pages, 3518 KB  
Article
Extracellular Signal-Regulated Kinase 1 Alone Is Dispensable for Hyperoxia-Mediated Alveolar and Pulmonary Vascular Simplification in Neonatal Mice
by Renuka T. Menon, Shyam Thapa, Amrit Kumar Shrestha, Roberto Barrios and Binoy Shivanna
Antioxidants 2022, 11(6), 1130; https://doi.org/10.3390/antiox11061130 - 8 Jun 2022
Cited by 6 | Viewed by 2541
Abstract
Bronchopulmonary dysplasia (BPD) is a morbid lung disease distinguished by lung alveolar and vascular simplification. Hyperoxia, an important BPD causative factor, increases extracellular signal-regulated kinases (ERK)-1/2 expression, whereas decreased lung endothelial cell ERK2 expression reduces angiogenesis and potentiates hyperoxia-mediated BPD in mice. However, [...] Read more.
Bronchopulmonary dysplasia (BPD) is a morbid lung disease distinguished by lung alveolar and vascular simplification. Hyperoxia, an important BPD causative factor, increases extracellular signal-regulated kinases (ERK)-1/2 expression, whereas decreased lung endothelial cell ERK2 expression reduces angiogenesis and potentiates hyperoxia-mediated BPD in mice. However, ERK1′s role in experimental BPD is unclear. Thus, we hypothesized that hyperoxia-induced experimental BPD would be more severe in global ERK1-knockout (ERK1-/-) mice than their wild-type (ERK1+/+ mice) littermates. We determined the extent of lung development, ERK1/2 expression, inflammation, and oxidative stress in ERK1-/- and ERK1+/+ mice exposed to normoxia (FiO2 21%) or hyperoxia (FiO2 70%). We also quantified the extent of angiogenesis and hydrogen peroxide (H2O2) production in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs) with normal and decreased ERK1 signaling. Compared with ERK1+/+ mice, ERK1-/- mice displayed increased pulmonary ERK2 activation upon hyperoxia exposure. However, the extent of hyperoxia-induced inflammation, oxidative stress, and interrupted lung development was similar in ERK1-/- and ERK1+/+ mice. ERK1 knockdown in HPMECs increased ERK2 activation at baseline, but did not affect in vitro angiogenesis and hyperoxia-induced H2O2 production. Thus, we conclude ERK1 is dispensable for hyperoxia-induced experimental BPD due to compensatory ERK2 activation. Full article
(This article belongs to the Topic Oxidative Stress and Inflammation)
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15 pages, 3085 KB  
Article
Endothelial Adenosine Monophosphate-Activated Protein Kinase-Alpha1 Deficiency Potentiates Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension
by Ahmed Elsaie, Renuka T. Menon, Amrit K. Shrestha, Sharada H. Gowda, Nidhy P. Varghese, Roberto J. Barrios, Cynthia L. Blanco, Girija G. Konduri and Binoy Shivanna
Antioxidants 2021, 10(12), 1913; https://doi.org/10.3390/antiox10121913 - 29 Nov 2021
Cited by 10 | Viewed by 2926
Abstract
Bronchopulmonary dysplasia and pulmonary hypertension, or BPD-PH, are serious chronic lung disorders of prematurity, without curative therapies. Hyperoxia, a known causative factor of BPD-PH, activates adenosine monophosphate-activated protein kinase (AMPK) α1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung [...] Read more.
Bronchopulmonary dysplasia and pulmonary hypertension, or BPD-PH, are serious chronic lung disorders of prematurity, without curative therapies. Hyperoxia, a known causative factor of BPD-PH, activates adenosine monophosphate-activated protein kinase (AMPK) α1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung injury is unclear. Thus, we hypothesized that (1) endothelial AMPKα1 is necessary to protect neonatal mice against hyperoxia-induced BPD-PH, and (2) AMPKα1 knockdown decreases angiogenesis in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs). We performed lung morphometric and echocardiographic studies on postnatal day (P) 28 on endothelial AMPKα1-sufficient and -deficient mice exposed to 21% O2 (normoxia) or 70% O2 (hyperoxia) from P1–P14. We also performed tubule formation assays on control- or AMPKα1-siRNA transfected HPMECs, exposed to 21% O2 or 70% O2 for 48 h. Hyperoxia-mediated alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and PH were significantly amplified in endothelial AMPKα1-deficient mice. AMPKα1 siRNA knocked down AMPKα1 expression in HPMECs, and decreased their ability to form tubules in normoxia and hyperoxia. Furthermore, AMPKα1 knockdown decreased proliferating cell nuclear antigen expression in hyperoxic conditions. Our results indicate that AMPKα1 is required to reduce hyperoxia-induced BPD-PH burden in neonatal mice, and promotes angiogenesis in HPMECs to limit lung injury. Full article
(This article belongs to the Special Issue Oxidative Stress in Newborns and Children)
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32 pages, 1281 KB  
Review
Alveologenesis: What Governs Secondary Septa Formation
by Alexandra L. Rippa, Elena V. Alpeeva, Andrey V. Vasiliev and Ekaterina A. Vorotelyak
Int. J. Mol. Sci. 2021, 22(22), 12107; https://doi.org/10.3390/ijms222212107 - 9 Nov 2021
Cited by 24 | Viewed by 8741
Abstract
The simplification of alveoli leads to various lung pathologies such as bronchopulmonary dysplasia and emphysema. Deep insight into the process of emergence of the secondary septa during development and regeneration after pneumonectomy, and into the contribution of the drivers of alveologenesis and neo-alveolarization [...] Read more.
The simplification of alveoli leads to various lung pathologies such as bronchopulmonary dysplasia and emphysema. Deep insight into the process of emergence of the secondary septa during development and regeneration after pneumonectomy, and into the contribution of the drivers of alveologenesis and neo-alveolarization is required in an efficient search for therapeutic approaches. In this review, we describe the formation of the gas exchange units of the lung as a multifactorial process, which includes changes in the actomyosin cytoskeleton of alveocytes and myofibroblasts, elastogenesis, retinoic acid signaling, and the contribution of alveolar mesenchymal cells in secondary septation. Knowledge of the mechanistic context of alveologenesis remains incomplete. The characterization of the mechanisms that govern the emergence and depletion of αSMA will allow for an understanding of how the niche of fibroblasts is changing. Taking into account the intense studies that have been performed on the pool of lung mesenchymal cells, we present data on the typing of interstitial fibroblasts and their role in the formation and maintenance of alveoli. On the whole, when identifying cell subpopulations in lung mesenchyme, one has to consider the developmental context, the changing cellular functions, and the lability of gene signatures. Full article
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20 pages, 5747 KB  
Article
Chitin-Derived AVR-48 Prevents Experimental Bronchopulmonary Dysplasia (BPD) and BPD-Associated Pulmonary Hypertension in Newborn Mice
by Pragnya Das, Suchismita Acharya, Varsha M. Prahaladan, Ogan K. Kumova, Shadi Malaeb, Sumita Behera, Beamon Agarwal, Dale J. Christensen, Alison J. Carey and Vineet Bhandari
Int. J. Mol. Sci. 2021, 22(16), 8547; https://doi.org/10.3390/ijms22168547 - 9 Aug 2021
Cited by 10 | Viewed by 3907
Abstract
Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and a key contributor to the large health care burden associated with prematurity, longer hospital stays, higher hospital costs, and frequent re-hospitalizations of affected patients through the first year of life and increased [...] Read more.
Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and a key contributor to the large health care burden associated with prematurity, longer hospital stays, higher hospital costs, and frequent re-hospitalizations of affected patients through the first year of life and increased resource utilization throughout childhood. This disease is associated with abnormal pulmonary function that may lead to BPD-associated pulmonary hypertension (PH), a major contributor to neonatal mortality and morbidity. In the absence of any definitive treatment options, this life-threatening disease is associated with high resource utilization during and after neonatal intensive care unit (NICU) stay. The goal of this study was to test the safety and efficacy of a small molecule derivative of chitin, AVR-48, as prophylactic therapy for preventing experimental BPD in a mouse model. Two doses of AVR-48 were delivered either intranasally (0.11 mg/kg), intraperitoneally (10 mg/kg), or intravenously (IV) (10 mg/kg) to newborn mouse pups on postnatal day (P)2 and P4. The outcomes were assessed by measuring total inflammatory cells in the broncho-alveolar lavage fluid (BALF), chord length, septal thickness, and radial alveolar counts of the alveoli, Fulton’s Index (for PH), cell proliferation and cell death by immunostaining, and markers of inflammation by Western blotting and ELISA. The bioavailability and safety of the drug were assessed by pharmacokinetic and toxicity studies in both neonatal mice and rat pups (P3-P5). Following AVR-48 treatment, alveolar simplification was improved, as evident from chord length, septal thickness, and radial alveolar counts; total inflammatory cells were decreased in the BALF; Fulton’s Index was decreased and lung inflammation and cell death were decreased, while angiogenesis and cell proliferation were increased. AVR-48 was found to be safe and the no-observed-adverse-effect level (NOAEL) in rat pups was determined to be 100 mg/kg when delivered via IV dosing with a 20-fold safety margin. With no reported toxicity and with a shorter half-life, AVR-48 is able to reverse the worsening cardiopulmonary phenotype of experimental BPD and BPD-PH, compared to controls, thus positioning it as a future drug candidate. Full article
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13 pages, 3914 KB  
Article
Neonatal Extracellular Superoxide Dismutase Knockout Mice Increase Total Superoxide Dismutase Activity and VEGF Expression after Chronic Hyperoxia
by Maxwell Mathias, Joann Taylor, Elizabeth Mendralla and Marta Perez
Antioxidants 2021, 10(8), 1236; https://doi.org/10.3390/antiox10081236 - 1 Aug 2021
Cited by 5 | Viewed by 3578
Abstract
Bronchopulmonary dysplasia (BPD) is a common lung disease affecting premature infants that develops after exposure to supplemental oxygen and reactive oxygen intermediates. Extracellular superoxide dismutase (SOD3) is an enzyme that processes superoxide radicals and has been shown to facilitate vascular endothelial growth factor [...] Read more.
Bronchopulmonary dysplasia (BPD) is a common lung disease affecting premature infants that develops after exposure to supplemental oxygen and reactive oxygen intermediates. Extracellular superoxide dismutase (SOD3) is an enzyme that processes superoxide radicals and has been shown to facilitate vascular endothelial growth factor (VEGF) and nitric oxide (NO) signaling in vascular endothelium. We utilized a mouse model of neonatal hyperoxic lung injury and SOD3 knockout (KO) mice to evaluate its function during chronic hyperoxia exposure. Wild-type age-matched neonatal C57Bl/6 (WT) and SOD3−/− (KO) mice were placed in normoxia (21% FiO2, RA) or chronic hyperoxia (75% FiO2, O2) within 24 h of birth for 14 days continuously and then euthanized. Lungs were harvested for histologic evaluation, as well as comparison of antioxidant enzyme expression, SOD activity, VEGF expression, and portions of the NO signaling pathway. Surprisingly, KO-O2 mice survived without additional alveolar simplification, microvascular remodeling, or nuclear oxidation when compared to WT-O2 mice. KO-O2 mice had increased total SOD activity and increased VEGF expression when compared to WT-O2 mice. No genotype differences were noted in intracellular antioxidant enzyme expression or the NO signaling pathway. These results demonstrate that SOD3 KO mice can survive prolonged hyperoxia without exacerbation of alveolar or vascular phenotype. Full article
(This article belongs to the Special Issue Antioxidants and Lung Diseases)
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17 pages, 1925 KB  
Article
Left Ventricle Phenotyping Utilizing Tissue Doppler Imaging in Premature Infants with Varying Severity of Bronchopulmonary Dysplasia
by Eunice Torres, Philip T. Levy, Afif El-Khuffash, Hongjie Gu, Aaron Hamvas and Gautam K. Singh
J. Clin. Med. 2021, 10(10), 2211; https://doi.org/10.3390/jcm10102211 - 20 May 2021
Cited by 7 | Viewed by 2988
Abstract
Bronchopulmonary dysplasia (BPD) is characterized by alveolar-capillary simplification and is associated with pulmonary hypertension (PH) in preterm infants. The contribution of left ventricle (LV) disease towards this severe BPD-PH phenotype is not well established. We aimed to describe the longitudinal trajectory of the [...] Read more.
Bronchopulmonary dysplasia (BPD) is characterized by alveolar-capillary simplification and is associated with pulmonary hypertension (PH) in preterm infants. The contribution of left ventricle (LV) disease towards this severe BPD-PH phenotype is not well established. We aimed to describe the longitudinal trajectory of the LV function as measured by tissue Doppler imaging (TDI) and its association with BPD-PH. We retrospectively assessed prospectively acquired clinical and echocardiographic data from 77 preterm infants born between 2011 and 2013. We characterized the LV function by measuring systolic and diastolic myocardial velocities (s’, e’, a’), isovolumetric relaxation time (IVRT), and myocardial performance index with TDI at three time periods from 32 and 36 weeks, postmenstrual age through one year of age. We also measured post systolic motion (PSM), a marker of myocardial dysfunction that results from asynchronous movement of the ventricular walls, and not previously described in preterm infants. Patients were stratified into groups according to BPD severity and the presence of PH and compared over time. Conventional TDI measures of the LV function were similar between groups, but the septal PSM was significantly prolonged over the first year of age in patients with BPD-PH. PSM provides a novel objective way to assess the hemodynamic impact of lung and pulmonary vascular disease severity on LV function in preterm infants with BPD and PH. Full article
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18 pages, 3214 KB  
Article
Hyperoxic Exposure Caused Lung Lipid Compositional Changes in Neonatal Mice
by Abigail L. Peterson, Jennifer F. Carr, Xiangming Ji, Phyllis A. Dennery and Hongwei Yao
Metabolites 2020, 10(9), 340; https://doi.org/10.3390/metabo10090340 - 21 Aug 2020
Cited by 17 | Viewed by 3163
Abstract
Treatments with supplemental oxygen in premature infants can impair lung development, leading to bronchopulmonary dysplasia (BPD). Although a stage-specific alteration of lung lipidome occurs during postnatal lung development, whether neonatal hyperoxia, a known mediator of BPD in rodent models, changes lipid profiles in [...] Read more.
Treatments with supplemental oxygen in premature infants can impair lung development, leading to bronchopulmonary dysplasia (BPD). Although a stage-specific alteration of lung lipidome occurs during postnatal lung development, whether neonatal hyperoxia, a known mediator of BPD in rodent models, changes lipid profiles in mouse lungs is still to be elucidated. To answer this question, newborn mice were exposed to hyperoxia for 3 days and allowed to recover in normoxia until postnatal day (pnd) 7 and pnd14, time-points spanning the peak stage of alveologenesis. A total of 2263 lung lipid species were detected by liquid chromatography–mass spectrometry, covering 5 lipid categories and 18 lipid subclasses. The most commonly identified lipid species were glycerophospholipids, followed by sphingolipids and glycerolipids. In normoxic conditions, certain glycerophospholipid and glycerolipid species augmented at pnd14 compared to pnd7. At pnd7, hyperoxia generally increased glycerophospholipid, sphingolipid, and glycerolipid species. Hyperoxia increased NADPH, acetyl CoA, and citrate acid but reduced carnitine and acyl carnitine. Hyperoxia increased oxidized glutathione but reduced catalase. These changes were not apparent at pnd14. Hyperoxia reduced docosahexaenoic acid and arachidonic acid at pnd14 but not at pnd7. Altogether, the lung lipidome changes throughout alveolarization. Neonatal hyperoxia alters the lung lipidome, which may contribute to alveolar simplification and dysregulated vascular development. Full article
(This article belongs to the Special Issue Fatty Acid Metabolism)
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21 pages, 6582 KB  
Article
Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia
by Cho-Ming Chao, Gianni Carraro, Zvonimir A. Rako, Johannes Kolck, Jamschid Sedighi, Volker Zimmermann, Alena Moiseenko, Jochen Wilhelm, Brittany M. Young, Lei Chong, Jin Wu, Adriana Contreras, Parviz Minoo, Guillermo Barreto, David Warburton and Saverio Bellusci
Cells 2020, 9(4), 859; https://doi.org/10.3390/cells9040859 - 2 Apr 2020
Cited by 10 | Viewed by 4018
Abstract
Background: Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA (miR) are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several miR [...] Read more.
Background: Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA (miR) are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several miR in BPD, a causal role remains to be established. Results: Our results showed that the expression level of miR-154 increases during lung development and decreases postnatally. Further, hyperoxia treatment maintains high levels of miR-154 in alveolar type 2 cells (AT2). We hypothesized that the decrease in miR-154 expression in AT2 cells is required for normal alveologenesis. To test this hypothesis, we generated a novel transgenic mouse allowing doxycycline-based miR-154 overexpression. Maintenance of miR-154 expression in the postnatal distal lung epithelium under normoxia conditions is sufficient to reproduce the hypoalveologenesis phenotype triggered by hyperoxia. Using a pull-down assay, we identified Caveolin1 as a key downstream target of miR-154. Caveolin1 protein is downregulated in response to overexpression of miR-154. This is associated with increased phosphorylation of Smad3 and Tgf-ß signaling. We found that AT2 cells overexpressing miR-154 display decreased expression of AT2 markers and increased expression of AT1 markers. Conclusion: Our results suggest that down-regulation of miR-154 in postnatal lung may function as an important physiological switch that permits the induction of the correct alveolar developmental program, while conversely, failure to down-regulate miR-154 suppresses alveolarization, leading to the common clinically observed phenotype of alveolar simplification. Full article
(This article belongs to the Special Issue FGF Signaling in Lung Development, Homeostasis and Disease)
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16 pages, 4936 KB  
Article
Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia
by Laurie G. Sherlock, Ashley Trumpie, Laura Hernandez-Lagunas, Sarah McKenna, Susan Fisher, Russell Bowler, Clyde J. Wright, Cassidy Delaney and Eva Nozik-Grayck
Antioxidants 2018, 7(3), 42; https://doi.org/10.3390/antiox7030042 - 14 Mar 2018
Cited by 17 | Viewed by 6173
Abstract
Background: A naturally occurring single nucleotide polymorphism (SNP), (R213G), in extracellular superoxide dismutase (SOD3), decreases SOD3 matrix binding affinity. Humans and mature mice expressing the R213G SNP exhibit increased cardiovascular disease but decreased lung disease. The impact of this [...] Read more.
Background: A naturally occurring single nucleotide polymorphism (SNP), (R213G), in extracellular superoxide dismutase (SOD3), decreases SOD3 matrix binding affinity. Humans and mature mice expressing the R213G SNP exhibit increased cardiovascular disease but decreased lung disease. The impact of this SNP on the neonatal lung at baseline or with injury is unknown. Methods: Wild type and homozygous R213G mice were injected with intraperitoneal bleomycin or phosphate buffered saline (PBS) three times weekly for three weeks and tissue harvested at 22 days of life. Vascular and alveolar development were evaluated by morphometric analysis and immunostaining of lung sections. Pulmonary hypertension (PH) was assessed by right ventricular hypertrophy (RVH). Lung protein expression for superoxide dismutase (SOD) isoforms, catalase, vascular endothelial growth factor receptor 2 (VEGFR2), endothelial nitric oxide synthase (eNOS) and guanosine triphosphate cyclohydrolase-1 (GTPCH-1) was evaluated by western blot. SOD activity and SOD3 expression were measured in serum. Results: In R213G mice, SOD3 lung protein expression decreased, serum SOD3 protein expression and SOD serum activity increased compared to wild type (WT) mice. Under control conditions, R213G mice developed pulmonary vascular remodeling (decreased vessel density and increased medial wall thickness) and PH; alveolar development was similar between strains. After bleomycin injury, in contrast to WT, R213G mice were protected from impaired alveolar development and their vascular abnormalities and PH did not worsen. Bleomycin decreased VEGFR2 and GTPCH-1 only in WT mice. Conclusion: R213G neonatal mice demonstrate impaired vascular development and PH at baseline without alveolar simplification, yet are protected from bleomycin induced lung injury and worsening of pulmonary vascular remodeling and PH. These results show that vessel bound SOD3 is essential in normal pulmonary vascular development, and increased serum SOD3 expression and SOD activity prevent lung injury in experimental bronchopulmonary dysplasia (BPD) and PH. Full article
(This article belongs to the Special Issue Superoxide Dismutase (SOD) Enzymes, Mimetics and Oxygen Radicals)
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24 pages, 9459 KB  
Review
Diagnostic Approach to Pulmonary Hypertension in Premature Neonates
by Vasantha H.S. Kumar
Children 2017, 4(9), 75; https://doi.org/10.3390/children4090075 - 24 Aug 2017
Cited by 19 | Viewed by 14028
Abstract
Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease in premature infants following respiratory distress at birth. With increasing survival of extremely low birth weight infants, alveolar simplification is the defining lung characteristic of infants with BPD, and along with pulmonary hypertension, [...] Read more.
Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease in premature infants following respiratory distress at birth. With increasing survival of extremely low birth weight infants, alveolar simplification is the defining lung characteristic of infants with BPD, and along with pulmonary hypertension, increasingly contributes to both respiratory morbidity and mortality in these infants. Growth restricted infants, infants born to mothers with oligohydramnios or following prolonged preterm rupture of membranes are at particular risk for early onset pulmonary hypertension. Altered vascular and alveolar growth particularly in canalicular and early saccular stages of lung development following mechanical ventilation and oxygen therapy, results in developmental lung arrest leading to BPD with pulmonary hypertension (PH). Early recognition of PH in infants with risk factors is important for optimal management of these infants. Screening tools for early diagnosis of PH are evolving; however, echocardiography is the mainstay for non-invasive diagnosis of PH in infants. Cardiac computed tomography (CT) and magnetic resonance are being used as imaging modalities, however their role in improving outcomes in these patients is uncertain. Follow-up of infants at risk for PH will help not only in early diagnosis, but also in appropriate management of these infants. Aggressive management of lung disease, avoidance of hypoxemic episodes, and optimal nutrition determine the progression of PH, as epigenetic factors may have significant effects, particularly in growth-restricted infants. Infants with diagnosis of PH are managed with pulmonary vasodilators and those resistant to therapy need to be worked up for the presence of cardio-vascular anomalies. The management of infants and toddlers with PH, especially following premature birth is an emerging field. Nonetheless, combination therapies in a multi-disciplinary setting improves outcomes for these infants. Full article
(This article belongs to the Special Issue New Trend in Pediatric Cardiology: Pulmonary Hypertension)
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