Neonatal hyperoxia depletes pulmonary vein cardiomyocytes in adult mice via mitochondrial oxidation

Supplemental oxygen given to preterm infants has been associated with permanently altering postnatal lung development. Now that these individuals are reaching adulthood, there is growing concern that early life oxygen exposure may also promote cardiovascular disease through poorly understood mechanisms. We previously reported that adult mice exposed to 100% oxygen between postnatal days 0 and 4 develop pulmonary hypertension, defined pathologically by capillary rarefaction, dilation of arterioles and veins, cardiac failure, and a reduced lifespan. Here, Affymetrix Gene Arrays are used to identify early transcriptional changes that take place in the lung before pulmonary capillary rarefaction. We discovered neonatal hyperoxia reduced expression of cardiac muscle genes, including those involved in contraction, calcium signaling, mitochondrial respiration, and vasodilation. Quantitative RT-PCR, immunohistochemistry, and genetic lineage mapping using Myh6CreER; Rosa26RmT/mG mice revealed this reflected loss of pulmonary vein cardiomyocytes. The greatest loss of cadiomyocytes was seen within the lung followed by a graded loss beginning at the hilum and extending into the left atrium. Loss of these cells was seen by 2 wk of age in mice exposed to ≥80% oxygen and was attributed, in part, to reduced proliferation. Administering mitoTEMPO, a scavenger of mitochondrial superoxide during neonatal hyperoxia prevented loss of these cells. Since pulmonary vein cardiomyocytes help pump oxygen-rich blood out of the lung, their early loss following neonatal hyperoxia may contribute to cardiovascular disease seen in these mice, and perhaps in people who were born preterm.

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Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice

10.1101/2020.07.22.215962 ◽

2020 ◽

Cited By ~ 1

Author(s):

Min Yee ◽

E. David Cohen ◽

Jeannie Haak ◽

Andrew M. Dylag ◽

Michael A. O’Reilly

Keyword(s):

Lung Disease ◽

Influenza A ◽

The Elderly ◽

Virus Infections ◽

Alveolar Epithelial ◽

Mitochondrial Superoxide ◽

Adult Mice ◽

Club Cells ◽

Age Dependent ◽

Neonatal Hyperoxia

ABSTRACTThe severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen at birth increases their risk of being hospitalized when infected with RSV and other respiratory viruses. Our prior studies in mice showed how high levels of oxygen (hyperoxia) between postnatal days 0-4 increases the severity of influenza A virus infections by reducing the number of alveolar epithelial type 2 (AT2) cells. Because AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), we expected their expression would decline as AT2 cells were depleted by hyperoxia. Instead, we made the surprising discovery that expression of Ace2 and Tmprss2 mRNA increases as mice age and is accelerated by exposing mice to neonatal hyperoxia. ACE2 is primarily expressed at birth by airway Club cells and becomes detectable in AT2 cells by one year of life. Neonatal hyperoxia increases ACE2 expression in Club cells and makes it detectable in 2-month-old AT2 cells. This early and increased expression of SARS-CoV-2 receptors was not seen in adult mice who had been administered the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia. Our finding that early life insults such as hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in the respiratory epithelium helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.

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Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice

Scientific Reports ◽

10.1038/s41598-020-79595-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Min Yee ◽

E. David Cohen ◽

Jeannie Haak ◽

Andrew M. Dylag ◽

Michael A. O’Reilly

Keyword(s):

Lung Disease ◽

Influenza A ◽

Viral Infections ◽

The Elderly ◽

Virus Infections ◽

Mitochondrial Superoxide ◽

Adult Mice ◽

Club Cells ◽

Age Dependent ◽

Neonatal Hyperoxia

AbstractThe severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen (hyperoxia) at birth increases the severity of respiratory viral infections. Hyperoxia at birth increases the severity of influenza A virus infections in adult mice by reducing the number of alveolar epithelial type 2 (AT2) cells. Since AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), their expression should decline as AT2 cells are depleted by hyperoxia. Instead, ACE2 was detected in airway Club cells and endothelial cells at birth, and then AT2 cells at one year of age. Neonatal hyperoxia stimulated expression of ACE2 in Club cells and in AT2 cells by 2 months of age. It also stimulated expression of TMPRSS2 in the lung. Increased expression of SARS-CoV-2 receptors was blocked by mitoTEMPO, a mitochondrial superoxide scavenger that reduced oxidative stress and DNA damage seen in oxygen-exposed mice. Our finding that hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in mice helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.

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Oxygen-dependent changes in lung development do not affect epithelial infection with influenza A virus

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00203.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. L940-L949 ◽

Cited By ~ 4

Author(s):

William Domm ◽

Min Yee ◽

Ravi S. Misra ◽

Robert Gelein ◽

Aitor Nogales ◽

...

Keyword(s):

Hong Kong ◽

Influenza A Virus ◽

Lung Development ◽

Influenza A ◽

Supplemental Oxygen ◽

Modest Increase ◽

Alveolar Epithelial ◽

Adult Mice ◽

Persistent Inflammation ◽

Neonatal Hyperoxia

Infants born prematurely often require supplemental oxygen, which contributes to aberrant lung development and increased pulmonary morbidity following a respiratory viral infection. We have been using a mouse model to understand how early-life hyperoxia affects the adult lung response to influenza A virus (IAV) infection. Prior studies showed how neonatal hyperoxia (100% oxygen) increased sensitivity of adult mice to infection with IAV [IAV (A/Hong Kong/X31) H3N2] as defined by persistent inflammation, pulmonary fibrosis, and mortality. Since neonatal hyperoxia alters lung structure, we used a novel fluorescence-expressing reporter strain of H1N1 IAV [A/Puerto Rico/8/34 mCherry (PR8-mCherry)] to evaluate whether it also altered early infection of the respiratory epithelium. Like Hong Kong/X31, neonatal hyperoxia increased morbidity and mortality of adult mice infected with PR8-mCherry. Whole lung imaging and histology suggested a modest increase in mCherry expression in adult mice exposed to neonatal hyperoxia compared with room air-exposed animals. However, this did not reflect an increase in airway or alveolar epithelial infection when mCherry-positive cells were identified and quantified by flow cytometry. Instead, a modest increase in the number of CD45-positive macrophages expressing mCherry was detected. While neonatal hyperoxia does not alter early epithelial infection with IAV, it may increase the activity of macrophages toward infected cells, thereby enhancing early epithelial injury.

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HIRA stabilizes skeletal muscle lineage identity

Nature Communications ◽

10.1038/s41467-021-23775-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Joana Esteves de Lima ◽

Reem Bou Akar ◽

Léo Machado ◽

Yuefeng Li ◽

Bernadette Drayton-Libotte ◽

...

Keyword(s):

Skeletal Muscle ◽

Cell Lineage ◽

Promoter Regions ◽

Cell Fates ◽

Regulatory Regions ◽

Muscle Stem Cells ◽

Adult Mice ◽

H3k4me3 Mark ◽

Muscle Genes ◽

Muscle Gene

AbstractThe epigenetic mechanisms coordinating the maintenance of adult cellular lineages and the inhibition of alternative cell fates remain poorly understood. Here we show that targeted ablation of the histone chaperone HIRA in myogenic cells leads to extensive transcriptional modifications, consistent with a role in maintaining skeletal muscle cellular identity. We demonstrate that conditional ablation of HIRA in muscle stem cells of adult mice compromises their capacity to regenerate and self-renew, leading to tissue repair failure. Chromatin analysis of Hira-deficient cells show a significant reduction of histone variant H3.3 deposition and H3K27ac modification at regulatory regions of muscle genes. Additionally, we find that genes from alternative lineages are ectopically expressed in Hira-mutant cells via MLL1/MLL2-mediated increase of H3K4me3 mark at silent promoter regions. Therefore, we conclude that HIRA sustains the chromatin landscape governing muscle cell lineage identity via incorporation of H3.3 at muscle gene regulatory regions, while preventing the expression of alternative lineage genes.

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Abstract 427: A Patient-Specific 3D Bioprinted Platform for in vitro Disease Modeling and Treatment Planning in Pulmonary Vein Stenosis

Circulation Research ◽

10.1161/res.127.suppl_1.427 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Vahid Serpooshan ◽

Martin L Tomov ◽

Akaash Kumar ◽

Bowen Jing ◽

Sai Raviteja Bhamidipati ◽

...

Keyword(s):

Cardiovascular Disease ◽

Pulmonary Vein ◽

Disease Modeling ◽

Unmet Need ◽

Cfd Modeling ◽

Pulmonary Vein Stenosis ◽

Patient Specific ◽

Clinical Interventions ◽

Vein Stenosis

Pulmonary vein stenosis (PVS) is an acute pediatric cardiovascular disease that is always lethal if not treated early. While current clinical interventions (stenting and angioplasties) have shown promising results in treating PVS, they require multiple re-interventions that can lead to re-stenosis and diminished long-term efficacy. Thus, there is an unmet need to develop functional in vitro models of PVS that can serve as a platform to study clinical interventions. Patient-inspired 3D bioprinted tissue models provide a unique model to recapitulate and analyze the complex tissue microenvironment impacted by PVS. Here, we developed perfusable in vitro models of healthy and stenotic pulmonary vein by 3D reconstruction and bioprinting inspired by patient CT data ( Figure 1 ). Models were seeded with human endothelial (ECs) and smooth muscle cells (SMCs) to form a bilayer structure and perfused using a bioreactor to study cell response to stenotic geometry, and to the stent-based treatment. Flow hemodynamics through printed veins were quantified via Computational Fluid Dynamics (CFD) modeling, 4D MRI and 3D Ultrasound Particle Imaging Velocimetry (echo PIV). Cell growth and endothelialization were analyzed. Our work demonstrates the feasibility of bioprinting various cardiovascular cells, to create perfusable, patient-specific vascular constructs that mimic complex in vivo geometries. Deeper understanding of EC-SMC crosstalk mechanisms in in vitro biomimetic models that incorporate tissue-like geometrical, chemical, and biomechanical ques could offer substantial insights for prevention and treatment of PVS, as well as other cardiovascular disease.

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The case of the missing pulmonary vein: A focused update on anomalous pulmonary venous connection in congenital cardiovascular disease

Echocardiography ◽

10.1111/echo.14490 ◽

2019 ◽

Vol 36 (10) ◽

pp. 1930-1935

Author(s):

Frank Han ◽

Sara Kiparizoska ◽

William Campbell ◽

Camille Richards ◽

Brian Kogon ◽

...

Keyword(s):

Cardiovascular Disease ◽

Pulmonary Vein ◽

Anomalous Pulmonary Venous Connection

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Neonatal exposure to mild hyperoxia causes persistent increases in oxidative stress and immune cells in the lungs of mice without altering lung structure

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00359.2014 ◽

2015 ◽

Vol 309 (5) ◽

pp. L488-L496 ◽

Cited By ~ 14

Author(s):

Sheena Bouch ◽

Megan O'Reilly ◽

Richard Harding ◽

Foula Sozo

Keyword(s):

Oxidative Stress ◽

Immune Cells ◽

Respiratory Illness ◽

Lavage Fluid ◽

Supplemental Oxygen ◽

Heme Oxygenase 1 ◽

Lung Structure ◽

Increased Risk ◽

Neonatal Hyperoxia ◽

Tissue Fraction

Preterm infants often require supplemental oxygen due to lung immaturity, but hyperoxia can contribute to an increased risk of respiratory illness later in life. Our aim was to compare the effects of mild and moderate levels of neonatal hyperoxia on markers of pulmonary oxidative stress and inflammation and on lung architecture; both immediate and persistent effects were assessed. Neonatal mice (C57BL6/J) were raised in either room air (21% O2), mild (40% O2), or moderate (65% O2) hyperoxia from birth until postnatal day 7 (P7d). The mice were killed at either P7d (immediate effects) or lived in air until adulthood (P56d, persistent effects). We enumerated macrophages in lung tissue at P7d and immune cells in bronchoalveolar lavage fluid (BALF) at P56d. At P7d and P56d, we assessed pulmonary oxidative stress [ heme oxygenase-1 ( HO-1) and nitrotyrosine staining] and lung architecture. The data were interrogated for sex differences. At P7d, HO-1 gene expression was greater in the 65% O2 group than in the 21% O2 group. At P56d, the area of nitrotyrosine staining and number of immune cells were greater in the 40% O2 and 65% O2 groups relative to the 21% O2 group. Exposure to 65% O2, but not 40% O2, led to larger alveoli and lower tissue fraction in the short term and to persistently fewer bronchiolar-alveolar attachments. Exposure to 40% O2 or 65% O2 causes persistent increases in pulmonary oxidative stress and immune cells, suggesting chronic inflammation within the adult lung. Unlike 65% O2, 40% O2 does not affect lung architecture.

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