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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 -
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 -
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 -
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 -
American Journal of Physiology. Lung... Feb 2020Airway microbial dysbiosis is associated with subsequent bronchopulmonary dysplasia (BPD) development in very preterm infants. However, the relationship of airway...
Airway microbial dysbiosis is associated with subsequent bronchopulmonary dysplasia (BPD) development in very preterm infants. However, the relationship of airway microbiome in normal pulmonary development has not been defined. To better understand the role of the airway microbiome, we compared normal and abnormal alveolar and pulmonary vascular development in mice with or without a microbiome. We hypothesized that the lungs of germ-free (GF) mice would have an exaggerated phenotypic response to hyperoxia compared with non-germ-free (NGF) mice. With the use of a novel gnotobiotic hyperoxia chamber, GF and NGF mice were exposed to either normoxia or hyperoxia. Alveolar morphometry, pulmonary mechanics, echocardiograms, inflammatory markers, and measures of pulmonary hypertension were studied. GF and NGF mice in normoxia showed no difference, whereas GF mice in hyperoxia showed protected lung structure and mechanics and decreased markers of inflammation compared with NGF mice. We speculate that an increase in abundance of pathogenic bacteria in NGF mice may play a role in BPD pathogenesis by regulating the proinflammatory signaling and neutrophilic inflammation in lungs. Manipulation of the airway microbiome may be a potential therapeutic intervention in BPD and other lung diseases.
Topics: Animals; Animals, Newborn; Biomechanical Phenomena; Blood Pressure; Disease Models, Animal; Germ-Free Life; Heart Ventricles; Hyperoxia; Inflammation; Mice; Mice, Inbred C57BL; Microvessels; Pulmonary Alveoli; Systole
PubMed: 31644312
DOI: 10.1152/ajplung.00316.2019 -
American Journal of Physiology.... Jul 2018Molecular oxygen (O) is a vital element in human survival and plays a major role in a diverse range of biological and physiological processes. Although normobaric... (Review)
Review
Molecular oxygen (O) is a vital element in human survival and plays a major role in a diverse range of biological and physiological processes. Although normobaric hyperoxia can increase arterial oxygen content ([Formula: see text]), it also causes vasoconstriction and hence reduces O delivery in various vascular beds, including the heart, skeletal muscle, and brain. Thus, a seemingly paradoxical situation exists in which the administration of oxygen may place tissues at increased risk of hypoxic stress. Nevertheless, with various degrees of effectiveness, and not without consequences, supplemental oxygen is used clinically in an attempt to correct tissue hypoxia (e.g., brain ischemia, traumatic brain injury, carbon monoxide poisoning, etc.) and chronic hypoxemia (e.g., severe COPD, etc.) and to help with wound healing, necrosis, or reperfusion injuries (e.g., compromised grafts). Hyperoxia has also been used liberally by athletes in a belief that it offers performance-enhancing benefits; such benefits also extend to hypoxemic patients both at rest and during rehabilitation. This review aims to provide a comprehensive overview of the effects of hyperoxia in humans from the "bench to bedside." The first section will focus on the basic physiological principles of partial pressure of arterial O, [Formula: see text], and barometric pressure and how these changes lead to variation in regional O delivery. This review provides an overview of the evidence for and against the use of hyperoxia as an aid to enhance physical performance. The final section addresses pathophysiological concepts, clinical studies, and implications for therapy. The potential of O toxicity and future research directions are also considered.
Topics: Administration, Inhalation; Animals; Athletic Performance; Biomarkers; Exercise Tolerance; Hemodynamics; Humans; Hyperoxia; Lung; Oxygen; Partial Pressure; Pulmonary Ventilation; Regional Blood Flow; Risk Assessment; Vasoconstriction
PubMed: 29488785
DOI: 10.1152/ajpregu.00165.2017 -
Seminars in Nephrology May 2022Although oxygen supplementation is beneficial to support life in the clinic, excessive oxygen therapy also has been linked to damage to organs such as the lung or the... (Review)
Review
Although oxygen supplementation is beneficial to support life in the clinic, excessive oxygen therapy also has been linked to damage to organs such as the lung or the eye. However, there is a lack of understanding of whether high oxygen therapy directly affects the kidney, leading to acute kidney injury, and what molecular mechanisms may be involved in this process. In this review, we revise our current understanding of the mechanisms by which hyperoxia leads to organ damage and highlight possible areas of investigation for the scientific community interested in novel mechanisms of kidney disease. Overall, we found a significant need for both animal and clinical studies evaluating the role of hyperoxia in inducing kidney damage. Thus, we urge the research community to further investigate oxygen therapy and its impact on kidney health with the goal of optimizing oxygen therapy guidelines and improving patient care.
Topics: Animals; Humans; Oxygen; Hyperoxia; Oxidative Stress; Kidney; Acute Kidney Injury
PubMed: 36404211
DOI: 10.1016/j.semnephrol.2022.10.008 -
Minerva Anestesiologica Jan 2020Oxygen administration is particularly relevant in patients undergoing surgery under general anesthesia and in those who suffer from acute or critical illness.... (Review)
Review
Oxygen administration is particularly relevant in patients undergoing surgery under general anesthesia and in those who suffer from acute or critical illness. Nevertheless, excess O2, or hyperoxia, is also known to be harmful. Toxicity arises from the enhanced formation of reactive oxygen species (ROS) that, exceeding the antioxidant defense, may generate oxidative stress. Oxidative stress markers are used to quantify ROS toxicity in clinical and non-clinical settings and represent a promising tool to assess the optimal FiO2 in anesthesia and critical care setting. Despite controversial, the guidelines for the regulation of FiO2 in such settings suggest the adoption of high perioperative oxygen levels. However, hyperoxia has also been shown to be an independent mortality risk factor in critically ill patients. In this literature review, we discuss the biochemical mechanisms behind oxidative stress and the available biomarkers for assessing the pro-oxidant vs antioxidant status. Then, we summarize recent knowledge on the hyperoxia-related consequences in the most common anesthesia and critical care settings, such as traumatic brain injury or cardiac arrest. To this purpose, we searched the PubMed database according to the following combination of key words: ("hyperoxia" OR "FiO2" OR "oxygen therapy") AND ("oxidative stress" OR "ROS" OR "RNS" OR "lipid peroxidation") AND ("anesthesia" OR "surgery" OR "intensive care"). We focused in the results from the past 20 years. Available evidence points toward a conservative monitoring and use of oxygen, unless there is solid proof of its efficacy.
Topics: Anesthesia; Critical Care; Humans; Hyperoxia; Oxidative Stress; Oxygen Inhalation Therapy; Reactive Oxygen Species
PubMed: 31680497
DOI: 10.23736/S0375-9393.19.13906-5 -
Respiratory Research Aug 2022Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants that may cause long-term lung dysfunction. Accumulating evidence supports the vascular...
BACKGROUND
Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants that may cause long-term lung dysfunction. Accumulating evidence supports the vascular hypothesis of BPD, in which lung endothelial cell dysfunction drives this disease. We recently reported that endothelial carnitine palmitoyltransferase 1a (Cpt1a) is reduced by hyperoxia, and that endothelial cell-specific Cpt1a knockout mice are more susceptible to developing hyperoxia-induced injury than wild type mice. Whether Cpt1a upregulation attenuates hyperoxia-induced endothelial cell dysfunction and lung injury remains unknown. We hypothesized that upregulation of Cpt1a by baicalin or L-carnitine ameliorates hyperoxia-induced endothelial cell dysfunction and persistent lung injury.
METHODS
Lung endothelial cells or newborn mice (< 12 h old) were treated with baicalin or L-carnitine after hyperoxia (50% and 95% O) followed by air recovery.
RESULTS
We found that incubation with L-carnitine (40 and 80 mg/L) and baicalin (22.5 and 45 mg/L) reduced hyperoxia-induced apoptosis, impaired cell migration and angiogenesis in cultured lung endothelial cells. This was associated with increased Cpt1a gene expression. In mice, neonatal hyperoxia caused persistent alveolar and vascular simplification in a concentration-dependent manner. Treatment with L-carnitine (150 and 300 mg/kg) and baicalin (50 and 100 mg/kg) attenuated neonatal hyperoxia-induced alveolar and vascular simplification in adult mice. These effects were diminished in endothelial cell-specific Cpt1a knockout mice.
CONCLUSIONS
Upregulating Cpt1a by baicalin or L-carnitine ameliorates hyperoxia-induced lung endothelial cell dysfunction, and persistent alveolar and vascular simplification. These findings provide potential therapeutic avenues for using L-carnitine and baicalin as Cpt1a upregulators to prevent persistent lung injury in premature infants with BPD.
Topics: Animals; Mice; Animals, Newborn; Bronchopulmonary Dysplasia; Carnitine; Carnitine O-Palmitoyltransferase; Endothelial Cells; Hyperoxia; Lung Injury; Mice, Knockout; Vascular Diseases
PubMed: 35964084
DOI: 10.1186/s12931-022-02135-1