Association of Hyperoxia During Cardiopulmonary Bypass and Postoperative Delirium in the Pediatric Cardiac ICU.

OBJECTIVE: ICU delirium commonly complicates critical illness associated with factors such as cardiopulmonary bypass (CPB) time and the requirement of mechanical ventilation (MV). Recent reports associate hyperoxia with poorer outcomes in critically ill children. This study sought to determine whether hyperoxia on CPB in pediatric patients was associated with a higher prevalence of postoperative delirium. DESIGN: Secondary analysis of data obtained from a prospective cohort study. SETTING: Twenty-two-bed pediatric cardiac ICU in a tertiary children's hospital. PATIENTS: All patients (18 yr old or older) admitted post-CPB, with documented delirium assessment scores using the Preschool/Pediatric Confusion Assessment Method for the ICU and who were enrolled in the Precision Medicine in Pediatric Cardiology Cohort from February 2021 to November 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 148 patients, who underwent cardiac surgery, 35 had delirium within the first 72 hours (24%). There was no association between hyperoxia on CPB and postoperative delirium for all definitions of hyperoxia, including hyperoxic area under the curve above 5 predetermined Pao2 levels: 150 mm Hg (odds ratio [95% CI]: 1.176 [0.605-2.286], p = 0.633); 175 mm Hg (OR 1.177 [95% CI, 0.668-2.075], p = 0.572); 200 mm Hg (OR 1.235 [95% CI, 0.752-2.026], p = 0.405); 250 mm Hg (OR 1.204 [95% CI, 0.859-1.688], p = 0.281), 300 mm Hg (OR 1.178 [95% CI, 0.918-1.511], p = 0.199). In an additional exploratory analysis, comparing patients with delirium within 72 hours versus those without, only the z score for weight differed (mean [sd]: 0.09 [1.41] vs. -0.48 [1.82], p < 0.05). When comparing patients who developed delirium at any point during their ICU stay (n = 45, 30%), MV days, severity of illness (Pediatric Index of Mortality 3 Score) score, CPB time, and z score for weight were associated with delirium (p < 0.05). CONCLUSIONS: Postoperative delirium (72 hr from CPB) occurred in 24% of pediatric patients. Hyperoxia, defined in multiple ways, was not associated with delirium. On exploratory analysis, nutritional status (z score for weight) may be a significant factor in delirium risk. Further delineation of risk factors for postoperative delirium versus ICU delirium warrants additional study.

Epithelial Membrane Protein 2 (EMP2) Blockade Attenuates Pathological Neovascularization in Murine Oxygen-Induced Retinopathy.

Purpose: Retinopathy of prematurity (ROP) results from postnatal hyperoxia exposure in premature infants and is characterized by aberrant neovascularization of retinal blood vessels. Epithelial membrane protein-2 (EMP2) regulates hypoxia-inducible factor (HIF)-induced vascular endothelial growth factor (VEGF) production in the ARPE-19 cell line and genetic knock-out of Emp2 in a murine oxygen-induced retinopathy (OIR) model attenuates neovascularization. We hypothesize that EMP2 blockade via intravitreal injection protects against neovascularization. Methods: Ex vivo choroid sprouting assay was performed, comparing media and human IgG controls versus anti-EMP2 antibody (Ab) treatment. In vivo, eyes from wild-type (WT) mice exposed to hyperoxia from postnatal (P) days 7 to 12 were treated with P12 intravitreal injections of control IgG or anti-EMP2 Abs. Neovascularization was assessed at P17 by flat mount imaging. Local and systemic effects of anti-EMP2 Ab treatment were assessed. Results: Choroid sprouts treated with 30 µg/mL of anti-EMP2 Ab demonstrated a 48% reduction in vessel growth compared to control IgG-treated sprouts. Compared to IgG-treated controls, WT OIR mice treated with 4 µg/g of intravitreal anti-EMP2 Ab demonstrated a 42% reduction in neovascularization. They demonstrated down-regulation of retinal gene expression in pathways related to vasculature development and up-regulation in genes related to fatty acid oxidation and tricarboxylic acid cycle respiratory electron transport, compared to controls. Anti-EMP2 Ab-treated OIR mice did not exhibit gross retinal histologic abnormalities, vision transduction abnormalities, or weight loss. Conclusions: Our results suggest that EMP2 blockade could be a local and specific treatment modality for retinal neovascularization in oxygen-induced retinopathies, without systemic adverse effects.

High oxygen exposure's impact on newborn mice: Temporal changes observed via micro-computed tomography.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) impacts life expectancy and long-term quality of life. Currently, BPD mouse models exposed to high oxygen are frequently used, but to reevaluate their relevance to human BPD, we attempted an assessment using micro-computed tomography (µCT). METHODS: Newborn wildtype male mice underwent either 21% or 95% oxygen exposure for 4 days, followed until 8 wk. Weekly µCT scans and lung histological evaluations were performed independently. RESULTS: Neonatal hyperoxia for 4 days hindered lung development, causing alveolar expansion and simplification. Histologically, during the first postnatal week, the exposed group showed a longer mean linear intercept, enlarged alveolar area, and a decrease in alveolar number, diminishing by week 4. Weekly µCT scans supported these findings, revealing initially lower lung density in newborn mice, increasing with age. However, the high-oxygen group displayed higher lung density initially. This difference diminished over time, with no significant contrast to controls at 3 wk. Although no significant difference in total lung volume was observed at week 1, the high-oxygen group exhibited a decrease by week 2, persisting until 8 wk. CONCLUSION: This study highlights µCT-detected changes in mice exposed to high oxygen. BPD mouse models might follow a different recovery trajectory than humans, suggesting the need for further optimization.

Mechanisms of enhanced cardiorespiratory performance under hyperoxia differ with exposure duration in yellowtail kingfish.

Hyperoxia has been shown to expand the aerobic capacity of some fishes, although there have been very few studies examining the underlying mechanisms and how they vary across different exposure durations. Here, we investigated the cardiorespiratory function of yellowtail kingfish (Seriola lalandi) acutely (~20 h) and chronically (3-5 weeks) acclimated to hyperoxia (~200% air saturation). Our results show that the aerobic performance of kingfish is limited in normoxia and increases with environmental hyperoxia. The aerobic scope was elevated in both hyperoxia treatments driven by a ~33% increase in maximum O2 uptake (MO2max), although the mechanisms differed across treatments. Fish acutely transferred to hyperoxia primarily elevated tissue O2 extraction, while increased stroke volume-mediated maximum cardiac output was the main driving factor in chronically acclimated fish. Still, an improved O2 delivery to the heart in chronic hyperoxia was not the only explanatory factor as such. Here, maximum cardiac output only increased in chronic hyperoxia compared with normoxia when plastic ventricular growth occurred, as increased stroke volume was partly enabled by an ~8%-12% larger relative ventricular mass. Our findings suggest that hyperoxia may be used long term to boost cardiorespiratory function potentially rendering fish more resilient to metabolically challenging events and stages in their life cycle.

Effects of exercise training with intermittent hyperoxic intervention on endurance performance and muscle metabolic properties in male mice.

This study aimed to investigate how intermittent hyperoxic exposure (three cycles of 21% O2 [10 min] and 30% O2 [15 min]) affects exercise performance in mice. Three hours after the acute exposure, there was an observed increase in mRNA levels of phosphofructokinase (Bayes factor [BF] ≥ 10), mitochondrial transcription factor-A (BF ≥10), PPAR-α (BF ≥3), and PPAR-γ (BF ≥3) in the red gastrocnemius muscle (Gr). Four weeks of exercise training under intermittent (INT), but not continuous (HYP), hyperoxia significantly (BF ≥30) increased maximal exercise capacity compared to normoxic exercise-trained (ET) group. INT group exhibited significantly higher activity levels of 3-hydroxyacyl-CoA-dehydrogenase (HAD) in Gr (BF = 7.9) compared to ET group. Pyruvate dehydrogenase complex activity levels were significantly higher in INT group compared to ET group in white gastrocnemius, diaphragm, and left ventricle (BF ≥3). NT-PGC1α protein levels in Gr (BF = 7.7) and HAD activity levels in Gr (BF = 6.9) and soleus muscles (BF = 3.3) showed a significant positive correlation with maximal work values. These findings suggest that exercise training under intermittent hyperoxia is a beneficial strategy for enhancing endurance performance by improving fatty acid and pyruvic acid utilization.

BMAL1 sex-specific effects in the neonatal mouse airway exposed to moderate hyperoxia.

Supplemental O2 (hyperoxia) is a critical intervention for premature infants (<34 weeks) but consequently is associated with development of bronchial airway hyperreactivity (AHR) and asthma. Clinical practice shifted toward the use of moderate hyperoxia (<60% O2), but risk for subsequent airway disease remains. In mouse models of moderate hyperoxia, neonatal mice have increased AHR with effects on airway smooth muscle (ASM), a cell type involved in airway tone, bronchodilation, and remodeling. Understanding mechanisms by which moderate O2 during the perinatal period initiates sustained airway changes is critical to drive therapeutic advancements toward treating airway diseases. We propose that cellular clock factor BMAL1 is functionally important in developing mouse airways. In adult mice, cellular clocks target pathways highly relevant to asthma pathophysiology and Bmal1 deletion increases inflammatory response, worsens lung function, and impacts survival outcomes. Our understanding of BMAL1 in the developing lung is limited, but our previous findings show functional relevance of clocks in human fetal ASM exposed to O2. Here, we characterize Bmal1 in our established mouse neonatal hyperoxia model. Our data show that Bmal1 KO deleteriously impacts the developing lung in the context of O2 and these data highlight the importance of neonatal sex in understanding airway disease.

Transplantation of alveolar macrophages improves the efficacy of endothelial progenitor cell therapy in mouse model of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a severe complication of preterm births, which develops due to exposure to supplemental oxygen and mechanical ventilation. Published studies demonstrated that the number of endothelial progenitor cells (EPC) is decreased in mouse and human BPD lungs and that adoptive transfer of EPC is an effective approach in reversing the hyperoxia-induced lung damage in mouse model of BPD. Recent advancements in macrophage biology identified the specific subtypes of circulating and resident macrophages mediating the developmental and regenerative functions in the lungs. Several studies reported the successful application of macrophage therapy in accelerating the regenerative capacity of damaged tissues and enhancing the therapeutic efficacy of other transplantable progenitor cells. In the present study, we explored the efficacy of combined cell therapy with EPC and resident alveolar macrophages (rAM) in hyperoxia-induced BPD mouse model. rAM and EPC were purified from neonatal mouse lungs and were used for adoptive transfer to the recipient neonatal mice exposed to hyperoxia. Adoptive transfer of rAM alone did not result in engraftment of donor rAM into the lung tissue but increased the mRNA level and protein concentration of proangiogenic CXCL12 chemokine in recipient mouse lungs. Depletion of rAM by chlodronate-liposomes decreased the retention of donor EPC after their transplantation into hyperoxia-injured lungs. Adoptive transfer of rAM in combination with EPC enhanced the therapeutic efficacy of EPC as evidenced by increased retention of EPC, increased capillary density, improved arterial oxygenation, and alveolarization in hyperoxia-injured lungs. Dual therapy with EPC and rAM has promise in human BPD.NEW & NOTEWORTHY Recent studies demonstrated that transplantation of lung-resident endothelial progenitor cells (EPC) is an effective therapy in mouse model of bronchopulmonary dysplasia (BPD). However, key factors regulating the efficacy of EPC are unknown. Herein, we demonstrate that transplantation of tissue-resident alveolar macrophages (rAM) increases CXCL12 expression in neonatal mouse lungs. rAM are required for retention of donor EPC in hyperoxia-injured lungs. Co-transplantation of rAM and EPC improves the efficacy of EPC therapy in mouse BPD model.

PC (16:0/14:0) ameliorates hyperoxia-induced bronchopulmonary dysplasia by upregulating claudin-1 and promoting alveolar type II cell repair.

Bronchopulmonary dysplasia (BPD) remains a significant challenge in neonatal care, the pathogenesis of which potentially involves altered lipid metabolism. Given the critical role of lipids in lung development and the injury response, we hypothesized that specific lipid species could serve as therapeutic agents in BPD. This study aimed to investigate the role of the lipid Phosphatidylcholine (PC) (16:0/14:0) in modulating BPD pathology and to elucidate its underlying mechanisms of action. Our approach integrated in vitro and in vivo methodologies to assess the effects of PC (16:0/14:0) on the histopathology, cellular proliferation, apoptosis, and molecular markers in lung tissue. In a hyperoxia-induced BPD rat model, we observed a reduction in alveolar number and an enlargement in alveolar size, which were ameliorated by PC (16:0/14:0) treatment. Correspondingly, in BPD cell models, PC (16:0/14:0) intervention led to increased cell viability, enhanced proliferation, reduced apoptosis, and elevated surfactant protein C (SPC) expression. RNA sequencing revealed significant gene expression differences between BPD and PC (16:0/14:0) treated groups, with a particular focus on Cldn1 (encoding claudin 1), which was significantly enriched in our analysis. Our findings suggest that PC (16:0/14:0) might protect against hyperoxia-induced alveolar type II cell damage by upregulating CLDN1 expression, potentially serving as a novel therapeutic target for BPD. This study not only advances our understanding of the role of lipids in BPD pathogenesis, but also highlights the significance of PC (16:0/14:0) in the prevention and treatment of BPD, offering new avenues for future research and therapeutic development.

[Research progress of the role of non-coding RNA in hyperoxia-induced acute lung injury].

Hyperoxia-induced acute lung injury (HALI) is an important complication of clinical oxygen therapy, which is mainly characterized by acute respiratory distress syndrome (ARDS) in adults and broncho-pulmonary dysplasia (BPD) in infants. HALI seriously affects the prognosis and quality of life of patients, so it has received more and more attention. However, the pathogenesis of HALI is complex and unclear, and there is no clear treatment method at present. Non-coding RNA (ncRNA) is an important type of functional RNA transcriptome. Due to the lack of effective open reading frame, ncRNA does not have the function of coding proteins. However, ncRNA can still regulate gene expression at multiple levels and affect the occurrence and development of many diseases. In recent years, a large number of in vitro and in vivo studies have shown that ncRNA is involved in the pathogenesis of HALI and is of great significance. This article reviews the expression and significance of ncRNA in HALI, in order to provide new diagnosis and treatment ideas for the prevention and treatment of HALI.

Protective Effects of Resveratrol Against Airway Hyperreactivity, Oxidative Stress, and Lung Inflammation in a Rat Pup Model of Bronchopulmonary Dysplasia.

Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2>95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 mikroM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor - Nomega-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p<0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p<0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-alpha and IL-1beta in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia, Hyperoxia, Airway hyperreactivity, Resveratrol, Pro-inflammatory cytokines.

Acute Hyperoxia Improves Spinal Cord Oxygenation and Circulatory Function Following Cervical Spinal Cord Injury in Rats.

Spinal cord injury is associated with spinal vascular disruptions that result in spinal ischemia and tissue hypoxia. This study evaluated the therapeutic efficacy of normobaric hyperoxia on spinal cord oxygenation and circulatory function at the acute stage of cervical spinal cord injury. Adult male Sprague Dawley rats underwent dorsal cervical laminectomy or cervical spinal cord contusion. At 1-2 days after spinal surgery, spinal cord oxygenation was monitored in anesthetized and spontaneously breathing rats through optical recording of oxygen sensor foils placed on the cervical spinal cord and pulse oximetry. The arterial blood pressure, heart rate, blood gases, and peripheral oxyhemoglobin saturation were also measured under hyperoxic (50% O2) and normoxic (21% O2) conditions. The results showed that contused animals had significantly lower spinal cord oxygenation levels than uninjured animals during normoxia. Peripheral oxyhemoglobin saturation, arterial oxygen partial pressure, and mean arterial blood pressure are significantly reduced following cervical spinal cord contusion. Notably, spinal oxygenation of contused rats could be improved to a level comparable to uninjured animals under hyperoxia. Furthermore, acute hyperoxia elevated blood pressure, arterial oxygen partial pressure, and peripheral oxyhemoglobin saturation. These results suggest that normobaric hyperoxia can significantly improve spinal cord oxygenation and circulatory function in the acute phase after cervical spinal cord injury. We propose that adjuvant normobaric hyperoxia combined with other hemodynamic optimization strategies may prevent secondary damage after spinal cord injury and improve functional recovery.

Calcitonin gene­related peptide alleviates hyperoxia­induced human alveolar cell injury via the CGRPR/TRPV1/Ca2+ axis.

Although exogenous calcitonin gene­related peptide (CGRP) protects against hyperoxia­induced lung injury (HILI), the underlying mechanisms remain unclear. The present study attempted to elucidate the molecular mechanism by which CGRP protects against hyperoxia­induced alveolar cell injury. Human alveolar A549 cells were treated with 95% hyperoxia to establish a hyperoxic cell injury model. ELISA was performed to detect the CGRP secretion. Immunofluorescence, quantitative (q)PCR, and western blotting were used to detect the expression and localization of CGRP receptor (CGRPR) and transient receptor potential vanilloid 1 (TRPV1). Cell counting kit­8 and flow cytometry were used to examine the proliferation and apoptosis of treated cells. Digital calcium imaging and patch clamp were used to analyze the changes in intracellular Ca2+ signaling and membrane currents induced by CGRP in A549 cells. The mRNA and protein expression levels of Cyclin D1, proliferating cell nuclear antigen (PCNA), Bcl­2 and Bax were detected by qPCR and western blotting. The expression levels of CGRPR and TRPV1 in A549 cells were significantly downregulated by hyperoxic treatment, but there was no significant difference in CGRP release between cells cultured under normal air and hyperoxic conditions. CGRP promoted cell proliferation and inhibited apoptosis in hyperoxia, but selective inhibitors of CGRPR and TRPV1 channels could effectively attenuate these effects; TRPV1 knockdown also attenuated this effect. CGRP induced Ca2+ entry via the TRPV1 channels and enhanced the membrane non­selective currents through TRPV1 channels. The CGRP­induced increase in intracellular Ca2+ was reduced by inhibiting the phospholipase C (PLC)/protein kinase C (PKC) pathway. Moreover, PLC and PKC inhibitors attenuated the effects of CGRP in promoting cell proliferation and inhibiting apoptosis. In conclusion, exogenous CGRP acted by inversely regulating the function of TRPV1 channels in alveolar cells. Importantly, CGRP protected alveolar cells from hyperoxia­induced injury via the CGRPR/TRPV1/Ca2+ axis, which may be a potential target for the prevention and treatment of the HILI.

Normobaric Hyperoxia Combined With Endovascular Treatment Based on Temporal Gradient: A Dose-Escalation Study.

BACKGROUND: Normobaric hyperoxia (NBO) has neuroprotective effects in acute ischemic stroke. Thus, we aimed to identify the optimal NBO treatment duration combined with endovascular treatment. METHODS: This is a single-center, randomized controlled, open-label, blinded-end point dose-escalation clinical trial. Patients with acute ischemic stroke who had an indication for endovascular treatment at Tianjin Huanhu Hospital were randomly assigned to 4 groups (1:1 ratio) based on NBO therapy duration: (1) control group (1 L/min oxygen for 4 hours); (2) NBO-2h group (10 L/min for 2 hours); (3) NBO-4h group (10 L/min for 4 hours); and (4) NBO-6h group (10 L/min for 6 hours). The primary outcome was cerebral infarction volume at 72 hours after randomization using an intention-to-treat analysis model. The primary safety outcome was the 90-day mortality rate. RESULTS: Between June 2022 and September 2023, 100 patients were randomly assigned to the following groups: control group (n=25), NBO-2h group (n=25), NBO-4h group (n=25), and NBO-6h group (n=25). The 72-hour cerebral infarct volumes were 39.4±34.3 mL, 30.6±30.1 mL, 19.7±15.4 mL, and 22.6±22.4 mL, respectively (P=0.013). The NBO-4h and NBO-6h groups both showed statistically significant differences (adjusted P values: 0.011 and 0.027, respectively) compared with the control group. Compared with the control group, both the NBO-4h and NBO-6h groups showed significant differences (P<0.05) in the National Institutes of Health Stroke Scale scores at 24 hours, 72 hours, and 7 days, as well as in the change of the National Institutes of Health Stroke Scale scores from baseline to 24 hours. Additionally, there were no significant differences among the 4 groups in terms of 90-day mortality rate, symptomatic intracranial hemorrhage, early neurological deterioration, or severe adverse events. CONCLUSIONS: The effectiveness of NBO therapy was associated with oxygen administration duration. Among patients with acute ischemic stroke who underwent endovascular treatment, NBO therapy for 4 and 6 hours was found to be more effective. Larger-scale multicenter studies are needed to validate these findings. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05404373.

Normoxic Management during Cardiopulmonary Bypass Does Not Reduce Cerebral Mitochondrial Dysfunction in Neonatal Swine.

Optimal oxygen management during pediatric cardiopulmonary bypass (CPB) is unknown. We previously demonstrated an increase in cortical mitochondrial reactive oxygen species and decreased mitochondrial function after CPB using hyperoxic oxygen management. This study investigates whether controlled oxygenation (normoxia) during CPB reduces cortical mitochondrial dysfunction and oxidative injury. Ten neonatal swine underwent three hours of continuous CPB at 34 °C (flow > 100 mL/kg/min) via cervical cannulation targeting a partial pressure of arterial oxygen (PaO2) goal < 150 mmHg (normoxia, n = 5) or >300 mmHg (hyperoxia, n = 5). The animals underwent continuous hemodynamic monitoring and serial arterial blood sampling. Cortical microdialysate was serially sampled to quantify the glycerol concentration (represents neuronal injury) and lactate-to-pyruvate ratio (represents bioenergetic dysfunction). The cortical tissue was analyzed via high-resolution respirometry to quantify mitochondrial oxygen consumption and reactive oxygen species generation, and cortical oxidized protein carbonyl concentrations were quantified to assess for oxidative damage. Serum PaO2 was higher in hyperoxia animals throughout CPB (p < 0.001). There were no differences in cortical glycerol concentration between groups (p > 0.2). The cortical lactate-to-pyruvate ratio was modestly elevated in hyperoxia animals (p < 0.03) but the values were not clinically significant (<30). There were no differences in cortical mitochondrial respiration (p = 0.48), protein carbonyls (p = 0.74), or reactive oxygen species generation (p = 0.93) between groups. Controlled oxygenation during CPB does not significantly affect cortical mitochondrial function or oxidative injury in the acute setting. Further evaluation of the short and long-term effects of oxygen level titration during pediatric CPB on cortical tissue and other at-risk brain regions are needed, especially in the presence of cyanosis.

The effect of hyperoxia on muscle sympathetic nerve activity: a systematic review and meta-analysis.

PURPOSE: We conducted a meta-analysis to determine the effect of hyperoxia on muscle sympathetic nerve activity in healthy individuals and those with cardio-metabolic diseases. METHODS: A comprehensive search of electronic databases was performed until August 2022. All study designs (except reviews) were included: population (humans; apparently healthy or with at least one chronic disease); exposures (muscle sympathetic nerve activity during hyperoxia or hyperbaria); comparators (hyperoxia or hyperbaria vs. normoxia); and outcomes (muscle sympathetic nerve activity, heart rate, blood pressure, minute ventilation). Forty-nine studies were ultimately included in the meta-analysis. RESULTS: In healthy individuals, hyperoxia had no effect on sympathetic burst frequency (mean difference [MD] - 1.07 bursts/min; 95% confidence interval [CI] - 2.17, 0.04bursts/min; P = 0.06), burst incidence (MD 0.27 bursts/100 heartbeats [hb]; 95% CI - 2.10, 2.64 bursts/100 hb; P = 0.82), burst amplitude (P = 0.85), or total activity (P = 0.31). In those with chronic diseases, hyperoxia decreased burst frequency (MD - 5.57 bursts/min; 95% CI - 7.48, - 3.67 bursts/min; P < 0.001) and burst incidence (MD - 4.44 bursts/100 hb; 95% CI - 7.94, - 0.94 bursts/100 hb; P = 0.01), but had no effect on burst amplitude (P = 0.36) or total activity (P = 0.90). Our meta-regression analyses identified an inverse relationship between normoxic burst frequency and change in burst frequency with hyperoxia. In both groups, hyperoxia decreased heart rate but had no effect on any measure of blood pressure. CONCLUSION: Hyperoxia does not change sympathetic activity in healthy humans. Conversely, in those with chronic diseases, hyperoxia decreases sympathetic activity. Regardless of disease status, resting sympathetic burst frequency predicts the degree of change in burst frequency, with larger decreases for those with higher resting activity.

Aryl hydrocarbon receptor (AhR) is regulated by hyperoxia in premature infants.

OBJECTIVE: To investigate whether aryl hydrocarbon receptor (AhR) is involved in hyperoxia-mediated oxidative stress by observing the relationship between AhR and reactive oxygen species (ROS) in peripheral blood mononuclear cells (PBMCs) after oxygen exposure in premature infants. METHODS: After 48 h of oxygen inhalation at different concentrations, discarded peripheral blood was collected to separate PBMCs and plasma. ROS were labeled with MitoSOXTM Red and detected by fluorescence microscopy in PBMCs. The level of MDA in plasma was detected by thiobarbituric acid colorimetry, the level of MCP-1 in plasma was detected by enzyme-linked immunosorbent assay (ELISA), the localization of AhR was detected by immunofluorescence, and the level of AhR expression in PBMCs was detected by Western blotting. RESULTS: As the volume fraction of inspired oxygen increased, compared with those in the air control group, the levels of ROS, MDA in plasma, and MCP-1 in plasma increased gradually in the low concentration oxygen group, medium concentration oxygen group and high concentration oxygen group. The cytoplasm-nuclear translocation rate of AhR gradually increased, and the expression level of AhR gradually decreased. The levels of ROS in PBMCs, MDA in the plasma and MCP-1 in the plasma of premature infants were positively correlated with the cytoplasm-nuclear translocation rate of AhR but negatively correlated with the level of AhR expression. CONCLUSION: Aryl hydrocarbon receptor (AhR) is regulated by hyperoxia in premature infants.

Effects of acute hyperoxia on autonomic function and coronary tone in patients with peripheral artery disease.

Numerous studies have shown that oxidative stress plays an important role in peripheral artery disease (PAD). Prior reports suggested autonomic dysfunction in PAD. We hypothesized that responses of the autonomic nervous system and coronary tone would be impaired in patients with PAD during exposure to acute hyperoxia, an oxidative stressor. In 20 patients with PAD and 16 healthy, sex- and age-matched controls, beat-by-beat heart rate (HR, from ECG) and blood pressure (BP, with Finometer) were recorded for 10 min during room air breathing and 5 min of hyperoxia. Cardiovagal baroreflex sensitivity and HR variability (HRV) were evaluated as measures of autonomic function. Transthoracic coronary echocardiography was used to assess peak coronary blood flow velocity (CBV) in the left anterior descending coronary artery. Cardiovagal baroreflex sensitivity at rest was lower in PAD than in healthy controls. Hyperoxia raised BP solely in the patients with PAD, with no change observed in healthy controls. Hyperoxia induced an increase in cardiac parasympathetic activity assessed by the high-frequency component of HRV in healthy controls but not in PAD. Indices of parasympathetic activity were lower in PAD than in healthy controls throughout the trial as well as during hyperoxia. Hyperoxia induced coronary vasoconstriction in both groups, while the coronary perfusion time fraction was lower in PAD than in healthy controls. These results suggest that the response in parasympathetic activity to hyperoxia (i.e., oxidative stress) is blunted and the coronary perfusion time is shorter in patients with PAD.NEW & NOTEWORTHY Patients with peripheral artery disease (PAD) showed consistently lower parasympathetic activity and blunted cardiovagal baroreflex sensitivity compared with healthy individuals. Notably, hyperoxia, which normally boosts parasympathetic activity in healthy individuals, failed to induce this response in patients with PAD. These data suggest altered autonomic responses during hyperoxia in PAD.

Erratum - LncRNA gadd7 promotes mitochondrial membrane potential decrease and apoptosis of alveolar type II epithelial cells by positively regulating MFN1 in an in vitro model of hyperoxia-induced acute lung injury.

This corrects the article published in European Journal of Histochemistry 2023;67:3535. doi: 10.4081/ejh.2023.3535.

Quercetin alleviates hyperoxia-induced bronchopulmonary dysplasia by inhibiting ferroptosis through the MAPK/PTGS2 pathway: Insights from network pharmacology, molecular docking, and experimental evaluations.

Quercetin, a bioactive natural compound renowned for its potent anti-inflammatory, antioxidant, and antiviral properties, has exhibited therapeutic potential in various diseases. Given that bronchopulmonary dysplasia (BPD) development is closely linked to inflammation and oxidative stress, and quercetin, a robust antioxidant known to activate NRF2 and influence the ferroptosis pathway, offers promise for a wide range of age groups. Nonetheless, the specific role of quercetin in BPD remains largely unexplored. This study aims to uncover the target role of quercetin in BPD through a combination of network pharmacology, molecular docking, computer analyses, and experimental evaluations.

Association between arterial oxygen and mortality across critically ill patients with hematologic malignancies: results from an international collaborative network.

PURPOSE: Patients with hematological malignancies are at high risk for life-threatening complications. To date, little attention has been paid to the impact of hyperoxemia and excess oxygen use on mortality. The aim of this study was to investigate the association between partial pressure of arterial oxygen (PaO2) and 28-day mortality in critically ill patients with hematologic malignancies. METHODS: Data from three international cohorts (Europe, Canada, Oceania) of patients who received respiratory support (noninvasive ventilation, high-flow nasal cannula, invasive mechanical ventilation) were obtained. We used mixed-effect Cox models to investigate the association between day one PaO2 or excess oxygen use (inspired fraction of oxygen ≥ 0.6 with PaO2 > 100 mmHg) on day-28 mortality. RESULTS: 11,249 patients were included. On day one, 5716 patients (50.8%) had normoxemia (60 ≤ PaO2 ≤ 100 mmHg), 1454 (12.9%) hypoxemia (PaO2 < 60 mmHg), and 4079 patients (36.3%) hyperoxemia (PaO2 > 100 mmHg). Excess oxygen was used in 2201 patients (20%). Crude day-28 mortality rate was 40.6%. There was a significant association between PaO2 and day-28 mortality with a U-shaped relationship (p < 0.001). Higher PaO2 levels (> 100 mmHg) were associated with day-28 mortality with a dose-effect relationship. Subgroup analyses showed an association between hyperoxemia and mortality in patients admitted with neurological disorders; however, the opposite relationship was seen across those admitted with sepsis and neutropenia. Excess oxygen use was also associated with subsequent day-28 mortality (adjusted hazard ratio (aHR) [95% confidence interval (CI)]: 1.11[1.04-1.19]). This result persisted after propensity score analysis (matched HR associated with excess oxygen:1.31 [1.20-1.1.44]). CONCLUSION: In critically-ill patients with hematological malignancies, exposure to hyperoxemia and excess oxygen use were associated with increased mortality, with variable magnitude across subgroups. This might be a modifiable factor to improve mortality.