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Critical Care (London, England) Dec 2021Oxygen (O) toxicity remains a concern, particularly to the lung. This is mainly related to excessive production of reactive oxygen species (ROS). Supplemental O, i.e.... (Review)
Review
Oxygen (O) toxicity remains a concern, particularly to the lung. This is mainly related to excessive production of reactive oxygen species (ROS). Supplemental O, i.e. inspiratory O concentrations (FO) > 0.21 may cause hyperoxaemia (i.e. arterial (a) PO > 100 mmHg) and, subsequently, hyperoxia (increased tissue O concentration), thereby enhancing ROS formation. Here, we review the pathophysiology of O toxicity and the potential harms of supplemental O in various ICU conditions. The current evidence base suggests that PaO > 300 mmHg (40 kPa) should be avoided, but it remains uncertain whether there is an "optimal level" which may vary for given clinical conditions. Since even moderately supra-physiological PaO may be associated with deleterious side effects, it seems advisable at present to titrate O to maintain PaO within the normal range, avoiding both hypoxaemia and excess hyperoxaemia.
Topics: Humans; Hyperoxia; Lung; Oxygen; Reactive Oxygen Species
PubMed: 34924022
DOI: 10.1186/s13054-021-03815-y -
Current Opinion in Anaesthesiology Apr 2018To examine the potential harmful effects of hyperoxia and summarize the results of most recent clinical studies evaluating oxygen therapy in critically ill patients. (Review)
Review
PURPOSE OF REVIEW
To examine the potential harmful effects of hyperoxia and summarize the results of most recent clinical studies evaluating oxygen therapy in critically ill patients.
RECENT FINDINGS
Excessive oxygen supplementation may have detrimental pulmonary and systemic effects because of enhanced oxidative stress and inflammation. Hyperoxia-induced lung injury includes altered surfactant protein composition, reduced mucociliary clearance and histological damage, resulting in atelectasis, reduced lung compliance and increased risk of infections. Hyperoxemia causes vasoconstriction, reduction in coronary blood flow and cardiac output and may alter microvascular perfusion. Observational studies showed a close relationship between hyperoxemia and increased mortality in several subsets of critically ill patients. In absence of hypoxemia, the routine use of oxygen therapy in patients with myocardial infarction, stroke, traumatic brain injury, cardiac arrest and sepsis, showed no benefit but rather it seems to be harmful. In patients admitted to intensive care unit, a conservative oxygen therapy aimed to maintain arterial oxygenation within physiological range has been proved to be well tolerated and may improve outcome.
SUMMARY
Liberal O2 use and unnecessary hyperoxia may be detrimental in critically ill patients. The current evidence supports the use of a conservative strategy in O2 therapy to avoid patient exposure to unnecessary hyperoxemia.
Topics: Clinical Trials as Topic; Conservative Treatment; Critical Illness; Humans; Hyperoxia; Hypoxia; Intensive Care Units; Lung; Lung Injury; Oxidative Stress; Oxygen; Oxygen Inhalation Therapy; Treatment Outcome; Vasoconstriction
PubMed: 29334496
DOI: 10.1097/ACO.0000000000000559 -
American Journal of Respiratory and... Sep 2021Oxygen supplementation is one of the most common interventions in critically ill patients. Despite over a century of data suggesting both beneficial and detrimental... (Review)
Review
Oxygen supplementation is one of the most common interventions in critically ill patients. Despite over a century of data suggesting both beneficial and detrimental effects of supplemental oxygen, optimal arterial oxygenation targets in adult patients remain unclear. Laboratory animal studies have consistently showed that exposure to a high Fi causes respiratory failure and early death. Human autopsy studies from the 1960s purported to provide histologic evidence of pulmonary oxygen toxicity in the form of diffuse alveolar damage. However, concomitant ventilator-induced lung injury and/or other causes of acute lung injury may explain these findings. Although some observational studies in general populations of critically adults showed higher mortality in association with higher oxygen exposures, this finding has not been consistent. For some specific populations, such as those with cardiac arrest, studies have suggested harm from targeting supraphysiologic Pa levels. More recently, randomized clinical trials of arterial oxygenation targets in narrower physiologic ranges were conducted in critically ill adult patients. Although two smaller trials came to opposite conclusions, the two largest of these trials showed no differences in clinical outcomes in study groups that received conservative versus liberal oxygen targets, suggesting that either strategy is reasonable. It is possible that some strategies are of benefit in some subpopulations, and this remains an important ongoing area of research. Because of the ubiquity of oxygen supplementation in critically ill adults, even small treatment effects could have a large impact on a global scale.
Topics: Adult; Animals; Critical Care; Critical Illness; Humans; Hyperoxia; Oxygen; Oxygen Inhalation Therapy; Respiratory Insufficiency
PubMed: 34086536
DOI: 10.1164/rccm.202102-0417CI -
Molecular Cell Mar 2023Oxygen is toxic across all three domains of life. Yet, the underlying molecular mechanisms remain largely unknown. Here, we systematically investigate the major cellular...
Oxygen is toxic across all three domains of life. Yet, the underlying molecular mechanisms remain largely unknown. Here, we systematically investigate the major cellular pathways affected by excess molecular oxygen. We find that hyperoxia destabilizes a specific subset of Fe-S cluster (ISC)-containing proteins, resulting in impaired diphthamide synthesis, purine metabolism, nucleotide excision repair, and electron transport chain (ETC) function. Our findings translate to primary human lung cells and a mouse model of pulmonary oxygen toxicity. We demonstrate that the ETC is the most vulnerable to damage, resulting in decreased mitochondrial oxygen consumption. This leads to further tissue hyperoxia and cyclic damage of the additional ISC-containing pathways. In support of this model, primary ETC dysfunction in the Ndufs4 KO mouse model causes lung tissue hyperoxia and dramatically increases sensitivity to hyperoxia-mediated ISC damage. This work has important implications for hyperoxia pathologies, including bronchopulmonary dysplasia, ischemia-reperfusion injury, aging, and mitochondrial disorders.
Topics: Animals; Humans; Mice; Electron Transport Complex I; Hyperoxia; Lung; Mitochondria; Mitochondrial Diseases; Oxygen
PubMed: 36893757
DOI: 10.1016/j.molcel.2023.02.013 -
The European Respiratory Journal Feb 2022Premature infants exposed to oxygen are at risk for bronchopulmonary dysplasia (BPD), which is characterised by lung growth arrest. Inflammation is important, but the...
RATIONALE
Premature infants exposed to oxygen are at risk for bronchopulmonary dysplasia (BPD), which is characterised by lung growth arrest. Inflammation is important, but the mechanisms remain elusive. Here, we investigated inflammatory pathways and therapeutic targets in severe clinical and experimental BPD.
METHODS AND RESULTS
First, transcriptomic analysis with cellular deconvolution identified a lung-intrinsic M1-like-driven cytokine pattern in newborn mice after hyperoxia. These findings were confirmed by gene expression of macrophage-regulating chemokines (, , ) and markers (, , ). Secondly, hyperoxia-activated interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signalling was measured and related to loss of alveolar epithelial type II cells (ATII) as well as increased mesenchymal marker. null mice exhibited preserved ATII survival, reduced myofibroblasts and improved elastic fibre assembly, thus enabling lung growth and protecting lung function. Pharmacological inhibition of global IL-6 signalling and IL-6 trans-signalling promoted alveolarisation and ATII survival after hyperoxia. Third, hyperoxia triggered M1-like polarisation, possibly Krüppel-like factor 4; hyperoxia-conditioned medium of macrophages and IL-6-impaired ATII proliferation. Finally, clinical data demonstrated elevated macrophage-related plasma cytokines as potential biomarkers that identify infants receiving oxygen at increased risk of developing BPD. Moreover, macrophage-derived and active STAT3 were related to loss of epithelial cells in BPD lungs.
CONCLUSION
We present a novel IL-6-mediated mechanism by which hyperoxia activates macrophages in immature lungs, impairs ATII homeostasis and disrupts elastic fibre formation, thereby inhibiting lung growth. The data provide evidence that IL-6 trans-signalling could offer an innovative pharmacological target to enable lung growth in severe neonatal chronic lung disease.
Topics: Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Disease Models, Animal; Hyperoxia; Interleukin-6; Lung; Macrophages; Mice
PubMed: 34446466
DOI: 10.1183/13993003.02248-2020 -
Biomolecules Jun 2020Effective metabolism is highly dependent on a narrow therapeutic range of oxygen. Accordingly, low levels of oxygen, or hypoxia, are one of the most powerful inducers of... (Review)
Review
Effective metabolism is highly dependent on a narrow therapeutic range of oxygen. Accordingly, low levels of oxygen, or hypoxia, are one of the most powerful inducers of gene expression, metabolic changes, and regenerative processes, including angiogenesis and stimulation of stem cell proliferation, migration, and differentiation. The sensing of decreased oxygen levels (hypoxia) or increased oxygen levels (hyperoxia), occurs through specialized chemoreceptor cells and metabolic changes at the cellular level, which regulate the response. Interestingly, fluctuations in the free oxygen concentration rather than the absolute level of oxygen can be interpreted at the cellular level as a lack of oxygen. Thus, repeated intermittent hyperoxia can induce many of the mediators and cellular mechanisms that are usually induced during hypoxia. This is called the hyperoxic-hypoxic paradox (HHP). This article reviews oxygen physiology, the main cellular processes triggered by hypoxia, and the cascade of events triggered by the HHP.
Topics: Animals; Cell Hypoxia; Humans; Hyperoxia; Oxygen
PubMed: 32630465
DOI: 10.3390/biom10060958 -
Nature Communications Mar 2021During late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as...
During late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development. Here, we use MULTI-seq to generate scRNA-seq profiles of over 66,000 cells from 36 mice during normal or impaired lung development secondary to hyperoxia with validation of some of the findings in lungs from BPD patients. We observe dynamic populations of cells, including several rare cell types and putative progenitors. Hyperoxia exposure, which mimics the BPD phenotype, alters the composition of all cellular compartments, particularly alveolar epithelium, stromal fibroblasts, capillary endothelium and macrophage populations. Pathway analysis and predicted dynamic cellular crosstalk suggest inflammatory signaling as the main driver of hyperoxia-induced changes. Our data provides a single-cell view of cellular changes associated with late lung development in health and disease.
Topics: Animals; Bronchopulmonary Dysplasia; Genotype; Hyperoxia; Lung; Male; Mice; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 33692365
DOI: 10.1038/s41467-021-21865-2 -
Pediatrics and Neonatology Mar 2022Supplemental oxygen is often used to treat newborns with respiratory disorders. Exposure to high concentration of oxygen and long-term oxygen causes inflammation and... (Review)
Review
Supplemental oxygen is often used to treat newborns with respiratory disorders. Exposure to high concentration of oxygen and long-term oxygen causes inflammation and acute lung injury. The acute inflammatory phase is followed by a fibroproliferative repair phase, leading to lung fibrosis. Many infants with lung fibrosis develop significant respiratory morbidities including reactive airways dysfunction and obstructive lung disease during childhood. Despite the absence of effective treatments and the incomplete understanding regarding mechanisms underlying fibrosis, extensive literature regarding lung fibrosis from in vitro and in vivo hyperoxia-exposed models is available. In this review, we discuss molecular mediators and signaling pathways responsible for increased fibroblast proliferation and collagen production, excessive extracellular matrix accumulation, and eventually, lung fibrosis. We discuss each of these mediators separately to facilitate clear understanding as well as significant interactions occurring among these molecular mediators and signaling pathways.
Topics: Humans; Hyperoxia; Infant, Newborn; Inflammation; Lung; Oxygen; Pulmonary Fibrosis
PubMed: 35181258
DOI: 10.1016/j.pedneo.2021.11.008 -
Developmental Neuroscience 2016Despite major advances in obstetrics and neonatal intensive care, preterm infants frequently suffer from neurological impairments in later life. Preterm and also... (Review)
Review
Despite major advances in obstetrics and neonatal intensive care, preterm infants frequently suffer from neurological impairments in later life. Preterm and also full-term neonates are generally susceptible to injury caused by reactive oxygen species due to the immaturity of endogenous radical scavenging systems. It is well known that high oxygen levels experienced during the critical phase of maturation can profoundly influence developmental processes. Supraphysiological oxygen concentrations used for resuscitation or in the care of critically ill infants are known to have deleterious effects on the developing lung and retina, contributing to the pathophysiology of neonatal diseases like bronchopulmonary dysplasia and retinopathy of prematurity. Moreover, experimental work from the last decade suggests that hyperoxia also leads to neuronal and glial cell death, contributing to the injury of white and grey matter observed in preterm infants. During the critical phase of brain maturation, hyperoxia can alter developmental processes, resulting in the disruption of neural plasticity and myelination. However, oxygen therapy can often not be avoided in neonatal intensive care. Therefore, in situations requiring oxygen supplementation, in addition to the development of appropriate monitoring systems, protective and/or regenerative strategies are highly warranted. Here, we summarise the clinical and experimental evidence as well as potential therapeutic strategies, providing an overview of the pathophysiology of oxygen exposure on the developing central nervous system and its impact on neonatal brain injury.
Topics: Animals; Brain; Brain Injuries; Cell Death; Humans; Hyperoxia; Oligodendroglia; Oxygen
PubMed: 28152539
DOI: 10.1159/000454917 -
American Journal of Physiology. Heart... Dec 2021
Topics: Humans; Hyperoxia; Lung
PubMed: 34738834
DOI: 10.1152/ajpheart.00580.2021