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The Journal of Clinical Investigation Nov 2022Preterm birth is the leading cause of death in children under 5 years of age. Premature infants who receive life-saving oxygen therapy often develop bronchopulmonary...
Preterm birth is the leading cause of death in children under 5 years of age. Premature infants who receive life-saving oxygen therapy often develop bronchopulmonary dysplasia (BPD), a chronic lung disease. Infants with BPD are at a high risk of abnormal neurodevelopment, including motor and cognitive difficulties. While neural progenitor cells (NPCs) are crucial for proper brain development, it is unclear whether they play a role in BPD-associated neurodevelopmental deficits. Here, we show that hyperoxia-induced experimental BPD in newborn mice led to lifelong impairments in cerebrovascular structure and function as well as impairments in NPC self-renewal and neurogenesis. A neurosphere assay utilizing nonhuman primate preterm baboon NPCs confirmed impairment in NPC function. Moreover, gene expression profiling revealed that genes involved in cell proliferation, angiogenesis, vascular autoregulation, neuronal formation, and neurotransmission were dysregulated following neonatal hyperoxia. These impairments were associated with motor and cognitive decline in aging hyperoxia-exposed mice, reminiscent of deficits observed in patients with BPD. Together, our findings establish a relationship between BPD and abnormal neurodevelopmental outcomes and identify molecular and cellular players of neonatal brain injury that persist throughout adulthood that may be targeted for early intervention to aid this vulnerable patient population.
Topics: Infant, Newborn; Female; Mice; Humans; Animals; Hyperoxia; Animals, Newborn; Premature Birth; Bronchopulmonary Dysplasia; Neurogenesis; Cognitive Dysfunction; Cognition; Lung
PubMed: 36136598
DOI: 10.1172/JCI146095 -
Respiratory Physiology & Neurobiology Jan 2013Preterm infants often experience hyperoxia while receiving supplemental oxygen. Prolonged exposure to hyperoxia during development is associated with pathologies such as... (Review)
Review
Preterm infants often experience hyperoxia while receiving supplemental oxygen. Prolonged exposure to hyperoxia during development is associated with pathologies such as bronchopulmonary dysplasia and retinopathy of prematurity. Over the last 25 years, however, experiments with animal models have revealed that moderate exposures to hyperoxia (e.g., 30-60% O(2) for days to weeks) can also have profound effects on the developing respiratory control system that may lead to hypoventilation and diminished responses to acute hypoxia. This plasticity, which is generally inducible only during critical periods of development, has a complex time course that includes both transient and permanent respiratory deficits. Although the molecular mechanisms of hyperoxia-induced plasticity are only beginning to be elucidated, it is clear that many of the respiratory effects are linked to abnormal morphological and functional development of the carotid body, the principal site of arterial O(2) chemoreception for respiratory control. Specifically, developmental hyperoxia reduces carotid body size, decreases the number of chemoafferent neurons, and (at least transiently) diminishes the O(2) sensitivity of individual carotid body glomus cells. Recent evidence suggests that hyperoxia may also directly or indirectly impact development of the central neural control of breathing. Collectively, these findings emphasize the vulnerability of the developing respiratory control system to environmental perturbations.
Topics: Animals; Carotid Body; Humans; Hyperoxia
PubMed: 22640932
DOI: 10.1016/j.resp.2012.05.019 -
Physiological Reports May 2021Supplemental oxygen and mechanical ventilation commonly used in premature infants may lead to chronic lung disease of prematurity, which is characterized by arrested...
Supplemental oxygen and mechanical ventilation commonly used in premature infants may lead to chronic lung disease of prematurity, which is characterized by arrested alveolar development and dysmorphic vascular development. Hyperoxia is also known to dysregulate p53, senescence, and metabolism. However, whether these changes in p53, senescence, and metabolism are intertwined in response to hyperoxia is still unknown. Given that the lung epithelium is the first cell to encounter ambient oxygen during a hyperoxic exposure, we used mouse lung epithelial cells (MLE-12), surfactant protein expressing type II cells, to explore whether hyperoxic exposure alters senescence and glycolysis. We measured glycolytic rate using a Seahorse Bioanalyzer assay and senescence using a senescence-associated β galactosidase activity assay with X-gal and C FDG as substrates. We found that hyperoxic exposure caused senescence and increased glycolysis as well as reduced proliferation. This was associated with increased double stranded DNA damage, p53 phosphorylation and nuclear localization. Furthermore, hyperoxia-induced senescence was p53-dependent, but not pRB-dependent, as shown in p53KO and pRBKO cell lines. Despite the inhibitory effects of p53 on glycolysis, we observed that glycolysis was upregulated in hyperoxia-exposed MLE-12 cells. This was attributable to a subpopulation of highly glycolytic senescent cells detected by C FDG sorting. Nevertheless, inhibition of glycolysis did not prevent hyperoxia-induced senescence. Therapeutic strategies modulating p53 and glycolysis may be useful to mitigate the detrimental consequences of hyperoxia in the neonatal lung.
Topics: Animals; Cell Line; Cell Proliferation; Cells, Cultured; Cellular Senescence; DNA Damage; Glycolysis; Hyperoxia; Lung; Mice; Respiratory Mucosa; Tumor Suppressor Protein p53
PubMed: 34042288
DOI: 10.14814/phy2.14839 -
Cell Reports Jul 2023Although increasing evidence suggests potential iatrogenic injury from supplemental oxygen therapy, significant exposure to hyperoxia in critically ill patients is...
Although increasing evidence suggests potential iatrogenic injury from supplemental oxygen therapy, significant exposure to hyperoxia in critically ill patients is inevitable. This study shows that hyperoxia causes lung injury in a time- and dose-dependent manner. In addition, prolonged inspiration of oxygen at concentrations higher than 80% is found to cause redox imbalance and impair alveolar microvascular structure. Knockout of C-X-C motif chemokine receptor 1 (Cxcr1) inhibits the release of reactive oxygen species (ROS) from neutrophils and synergistically enhances the ability of endothelial cells to eliminate ROS. We also combine transcriptome, proteome, and metabolome analysis and find that CXCR1 knockdown promotes glutamine metabolism and leads to reduced glutathione by upregulating the expression of malic enzyme 1. This preclinical evidence suggests that a conservative oxygen strategy should be recommended and indicates that targeting CXCR1 has the potential to restore redox homeostasis by reducing oxygen toxicity when inspiratory hyperoxia treatment is necessary.
Topics: Humans; Endothelial Cells; Glutamine; Hyperoxia; Lung; Lung Injury; Oxygen; Reactive Oxygen Species; Animals; Mice; Receptors, Interleukin-8A
PubMed: 37405911
DOI: 10.1016/j.celrep.2023.112745 -
Stem Cells (Dayton, Ohio) May 2022Late lung development is a period of alveolar and microvascular formation, which is pivotal in ensuring sufficient and effective gas exchange. Defects in late lung...
Late lung development is a period of alveolar and microvascular formation, which is pivotal in ensuring sufficient and effective gas exchange. Defects in late lung development manifest in premature infants as a chronic lung disease named bronchopulmonary dysplasia (BPD). Numerous studies demonstrated the therapeutic properties of exogenous bone marrow and umbilical cord-derived mesenchymal stromal cells (MSCs) in experimental BPD. However, very little is known regarding the regenerative capacity of resident lung MSCs (L-MSCs) during normal development and in BPD. In this study we aimed to characterize the L-MSC population in homeostasis and upon injury. We used single-cell RNA sequencing (scRNA-seq) to profile in situ Ly6a+ L-MSCs in the lungs of normal and O2-exposed neonatal mice (a well-established model to mimic BPD) at 3 developmental timepoints (postnatal days 3, 7, and 14). Hyperoxia exposure increased the number and altered the expression profile of L-MSCs, particularly by increasing the expression of multiple pro-inflammatory, pro-fibrotic, and anti-angiogenic genes. In order to identify potential changes induced in the L-MSCs transcriptome by storage and culture, we profiled 15 000 Ly6a+ L-MSCs after in vitro culture. We observed great differences in expression profiles of in situ and cultured L-MSCs, particularly those derived from healthy lungs. Additionally, we have identified the location of Ly6a+/Col14a1+ L-MSCs in the developing lung and propose Serpinf1 as a novel, culture-stable marker of L-MSCs. Finally, cell communication analysis suggests inflammatory signals from immune and endothelial cells as main drivers of hyperoxia-induced changes in L-MSCs transcriptome.
Topics: Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Endothelial Cells; Humans; Hyperoxia; Infant, Newborn; Lung; Mesenchymal Stem Cells; Mice; Sequence Analysis, RNA
PubMed: 35445270
DOI: 10.1093/stmcls/sxab023 -
American Journal of Respiratory Cell... May 2017Prematurity complicates 12% of births, and young adults with a history of prematurity are at risk to develop right ventricular (RV) hypertrophy and impairment. The...
Prematurity complicates 12% of births, and young adults with a history of prematurity are at risk to develop right ventricular (RV) hypertrophy and impairment. The long-term risk for pulmonary vascular disease, as well as mechanisms of RV dysfunction and ventricular-vascular uncoupling after prematurity, remain poorly defined. Using an established model of prematurity-related lung disease, pups from timed-pregnant Sprague Dawley rats were randomized to normoxia or hyperoxia (fraction of inspired oxygen, 0.85) exposure for the first 14 days of life. After aging to 1 year in standard conditions, rats underwent hemodynamic assessment followed by tissue harvest for biochemical and histological evaluation. Aged hyperoxia-exposed rats developed significantly greater RV hypertrophy, associated with a 40% increase in RV systolic pressures. Although cardiac index was similar, hyperoxia-exposed rats demonstrated a reduced RV ejection fraction and significant RV-pulmonary vascular uncoupling. Hyperoxia-exposed RV cardiomyocytes demonstrated evidence of mitochondrial dysregulation and mitochondrial DNA damage, suggesting potential mitochondrial dysfunction as a cause of RV dysfunction. Aged rats exposed to postnatal hyperoxia recapitulate many features of young adults born prematurely, including increased RV hypertrophy and decreased RV ejection fraction. Our data suggest that postnatal hyperoxia exposure results in mitochondrial dysregulation that persists into adulthood with eventual RV dysfunction. Further evaluation of long-term mitochondrial function is warranted in both animal models of premature lung disease and in human adults who were born preterm.
Topics: Aging; Animals; Animals, Newborn; Autophagy; Body Weight; DNA Damage; DNA, Mitochondrial; Female; Fibrosis; Gene Expression Profiling; Hemodynamics; Hyperoxia; Hypertrophy, Right Ventricular; Male; Myocardium; Myocytes, Cardiac; Organ Size; Organelle Biogenesis; Rats, Sprague-Dawley; Ventricular Function, Right
PubMed: 28129517
DOI: 10.1165/rcmb.2016-0256OC -
Respiratory Medicine Oct 2016The management of acute hypoxemic respiratory failure frequently includes the use of supraphysiological fractions of inspired oxygen (FiO), which can be beneficial in... (Review)
Review
The management of acute hypoxemic respiratory failure frequently includes the use of supraphysiological fractions of inspired oxygen (FiO), which can be beneficial in the short-term but not without risks in the long-term, causing acute lung injury (ALI). Over the last few years, much attention has been devoted to the intracellular signaling transduction pathways that lead to hyperoxia-induced cell damage, particularly MAP kinase cascades. Identification of involved signaling molecules and understanding of the regulation of the main signal transduction pathways might provide the basis for improving the outcome of patients under high FiO exposure through more effective therapeutic interventions. This review, which includes studies published from 1987 to 2015, presents an overview on recent progresses in the hyperoxia ALI field with special emphasis on potential therapeutic targets and clinical approaches based on the molecular mechanisms underlying hyperoxia-induced inflammation. Further studies are needed to gain deeper insight into controversial molecular mechanisms underlying hyperoxia-induced cell death, which may play a critical role in future pharmacological interventions, as well as into hyperoxia-induced cell damage, that could monitor and therefore prevent hyperoxia ALI.
Topics: Acute Lung Injury; Cell Death; Dual Oxidases; Humans; Hyperbaric Oxygenation; Hyperoxia; Inflammation; Lung; MAP Kinase Signaling System; NADPH Oxidases; Oxidative Stress; Reactive Oxygen Species; Respiration, Artificial; Signal Transduction
PubMed: 27692143
DOI: 10.1016/j.rmed.2016.08.010 -
BMJ Open Respiratory Research Dec 2023Supraphysiological oxygen administration causes unfavourable clinical outcomes in various diseases. This study aimed to determine whether hyperoxia would be associated... (Observational Study)
Observational Study
BACKGROUND
Supraphysiological oxygen administration causes unfavourable clinical outcomes in various diseases. This study aimed to determine whether hyperoxia would be associated with increased mortality in patients with severe infection.
METHODS
A post-hoc analysis of a nationwide multicentre prospective observational study on sepsis (SPICE Study) was conducted, including adult patients admitted to the intensive care unit with available arterial partial pressure of oxygen (PaO) at the treatment initiation for severe infection. Hyperoxia was defined as a PaO level of ≥300 mm Hg and in-hospital mortality was compared between patients with and without hyperoxia.
RESULTS
Of the 563 patients eligible for the study, 49 had hyperoxia at treatment initiation for severe infection. The in-hospital all-cause mortality rates of patients with and without hyperoxia were 14 (29.2%) and 90 (17.6%), respectively. Inverse probability weighting analyses with propensity scores revealed the association between hyperoxia and increased in-hospital mortality rate (28.8% vs 18.8%; adjusted OR 1.75 (1.03 to 2.97); p=0.038), adjusting for patient demographics, comorbidities, site of infection, severity of infection, haemodynamic and respiratory status, laboratory data and location of patient at infection development. Acute lung injury developed more frequently in patients with hyperoxia on the following days after infection treatment, whereas sepsis-related mortality was comparable regardless of hyperoxia exposure.
CONCLUSION
Hyperoxia with PaO ≥300 mm Hg at treatment initiation of severe infection was associated with an increased in-hospital mortality rate in patients requiring intensive care. The amount of oxygen to administer to patients with severe infection should be carefully determined.
TRIAL REGISTRATION NUMBER
University Hospital Medical Information Network Clinical Trial Registry (UMIN000027452).
Topics: Adult; Humans; Hyperoxia; Retrospective Studies; Oxygen; Acute Lung Injury; Sepsis
PubMed: 38097355
DOI: 10.1136/bmjresp-2023-001968 -
Medical Sciences (Basel, Switzerland) Nov 2023Acute hypoxic respiratory failure (AHRF) is a prominent feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) critical illness. The severity of gas... (Review)
Review
Acute hypoxic respiratory failure (AHRF) is a prominent feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) critical illness. The severity of gas exchange impairment correlates with worse prognosis, and AHRF requiring mechanical ventilation is associated with substantial mortality. Persistent impaired gas exchange leading to hypoxemia often warrants the prolonged administration of a high fraction of inspired oxygen (FiO). In SARS-CoV-2 AHRF, systemic vasculopathy with lung microthrombosis and microangiopathy further exacerbates poor gas exchange due to alveolar inflammation and oedema. Capillary congestion with microthrombosis is a common autopsy finding in the lungs of patients who die with coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome. The need for a high FiO to normalise arterial hypoxemia and tissue hypoxia can result in alveolar hyperoxia. This in turn can lead to local alveolar oxidative stress with associated inflammation, alveolar epithelial cell apoptosis, surfactant dysfunction, pulmonary vascular abnormalities, resorption atelectasis, and impairment of innate immunity predisposing to secondary bacterial infections. While oxygen is a life-saving treatment, alveolar hyperoxia may exacerbate pre-existing lung injury. In this review, we provide a summary of oxygen toxicity mechanisms, evaluating the consequences of alveolar hyperoxia in COVID-19 and propose established and potential exploratory treatment pathways to minimise alveolar hyperoxia.
Topics: Humans; SARS-CoV-2; COVID-19; Critical Illness; Hyperoxia; Lung Injury; Oxygen; Hypoxia; Respiratory Distress Syndrome; Inflammation
PubMed: 37987325
DOI: 10.3390/medsci11040070 -
Journal of Neuroinflammation Sep 2023Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have...
BACKGROUND
Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain's inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found pharmacological inhibition of caspase-1, which blocks GSDMD activation, attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury.
METHODS
Newborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O) from postnatal days 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1) and CD68, markers of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes.
RESULTS
Hyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O exposure did not increase AIF1 + , CD68 + , or TUNEL + cell numbers or decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air-exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, hypoxia-induced factor 1 pathway, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO.
CONCLUSIONS
GSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.
Topics: Animals; Humans; Infant, Newborn; Mice; Animals, Newborn; Brain Injuries; Gene Knockout Techniques; Hippocampus; Hyperoxia; Infant, Premature; Mice, Knockout; Phosphate-Binding Proteins; Pore Forming Cytotoxic Proteins
PubMed: 37679766
DOI: 10.1186/s12974-023-02878-8