Impact of hyperoxia on the gut during critical illnesses.

Molecular oxygen is typically delivered to patients via oxygen inhalation or extracorporeal membrane oxygenation (ECMO), potentially resulting in systemic hyperoxia from liberal oxygen inhalation or localized hyperoxia in the lower body from peripheral venoarterial (VA) ECMO. Consequently, this exposes the gastrointestinal tract to excessive oxygen levels. Hyperoxia can trigger organ damage due to the overproduction of reactive oxygen species and is associated with increased mortality. The gut and gut microbiome play pivotal roles in critical illnesses and even small variations in oxygen levels can have a dramatic influence on the physiology and ecology of gut microbes. Here, we reviewed the emerging preclinical evidence which highlights how excessive inhaled oxygen can provoke diffuse villous damage, barrier dysfunction in the gut, and gut dysbiosis. The hallmark of this dysbiosis includes the expansion of oxygen-tolerant pathogens (e.g., Enterobacteriaceae) and the depletion of beneficial oxygen-intolerant microbes (e.g., Muribaculaceae). Furthermore, we discussed potential impact of oxygen on the gut in various underlying critical illnesses involving inspiratory oxygen and peripheral VA-ECMO. Currently, the available findings in this area are somewhat controversial, and a consensus has not yet to be reached. It appears that targeting near-physiological oxygenation levels may offer a means to avoid hyperoxia-induced gut injury and hypoxia-induced mesenteric ischemia. However, the optimal oxygenation target may vary depending on special clinical conditions, including acute hypoxia in adults and neonates, as well as particular patients undergoing gastrointestinal surgery or VA-ECMO support. Last, we outlined the current challenges and the need for future studies in this area. Insights into this vital ongoing research can assist clinicians in optimizing oxygenation for critically ill patients.

Outcomes of pregnancy in mice with pulmonary hypertension induced by Hypoxia/SU5416.

BACKGROUND: Pulmonary hypertension (PH) seriously affects the health of patients. We have found in clinical studies that PH has adverse effects on both maternal and offspring. OBJECTIVE: To establish a animal model of PH induced by hypoxia/SU5416 and observe the effects of PH on pregnant mice and their fetuses. METHODS: Twenty-four C57 mice aged 7-9 weeks were selected and divided into 4 groups with 6 mice in each group. ① Female mice with normal oxygen; ② Female mice with hypoxia/SU5416; ③ Pregnant mice with normal oxygen; ④ Pregnant mice with hypoxia/SU5416. After 19 days, weight, right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) were compared in each group. Lung tissue and right ventricular blood were collected. The number and weight of fetal mice were also compared between the two pregnant groups. RESULTS: There was no significant difference in RVSP and RVHI between female and pregnant mice under the same condition. Compared with normal oxygen condition, two groups of mice in hypoxia/SU5416 had poor development, RVSP and RVHI were significantly increased, the number of fetal mice was small, hypoplasia, degeneration and even abortion. CONCLUSION: The model of mice PH was successfully established. PH affects the development and health of female and pregnant mice, and seriously affects the fetuses.

Higher versus lower fractions of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit.

BACKGROUND: This is an updated review concerning 'Higher versus lower fractions of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit'. Supplementary oxygen is provided to most patients in intensive care units (ICUs) to prevent global and organ hypoxia (inadequate oxygen levels). Oxygen has been administered liberally, resulting in high proportions of patients with hyperoxemia (exposure of tissues to abnormally high concentrations of oxygen). This has been associated with increased mortality and morbidity in some settings, but not in others. Thus far, only limited data have been available to inform clinical practice guidelines, and the optimum oxygenation target for ICU patients is uncertain. Because of the publication of new trial evidence, we have updated this review. OBJECTIVES: To update the assessment of benefits and harms of higher versus lower fractions of inspired oxygen (FiO2) or targets of arterial oxygenation for adults admitted to the ICU. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, BIOSIS Previews, and LILACS. We searched for ongoing or unpublished trials in clinical trial registers and scanned the reference lists and citations of included trials. Literature searches for this updated review were conducted in November 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared higher versus lower FiO2 or targets of arterial oxygenation (partial pressure of oxygen (PaO2), peripheral or arterial oxygen saturation (SpO2 or SaO2)) for adults admitted to the ICU. We included trials irrespective of publication type, publication status, and language. We excluded trials randomising participants to hypoxaemia (FiO2 below 0.21, SaO2/SpO2 below 80%, or PaO2 below 6 kPa) or to hyperbaric oxygen, and cross-over trials and quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Four review authors independently, and in pairs, screened the references identified in the literature searches and extracted the data. Our primary outcomes were all-cause mortality, the proportion of participants with one or more serious adverse events (SAEs), and quality of life. We analysed all outcomes at maximum follow-up. Only three trials reported the proportion of participants with one or more SAEs as a composite outcome. However, most trials reported on events categorised as SAEs according to the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) criteria. We, therefore, conducted two analyses of the effect of higher versus lower oxygenation strategies using 1) the single SAE with the highest reported proportion in each trial, and 2) the cumulated proportion of participants with an SAE in each trial. Two trials reported on quality of life. Secondary outcomes were lung injury, myocardial infarction, stroke, and sepsis. No trial reported on lung injury as a composite outcome, but four trials reported on the occurrence of acute respiratory distress syndrome (ARDS) and five on pneumonia. We, therefore, conducted two analyses of the effect of higher versus lower oxygenation strategies using 1) the single lung injury event with the highest reported proportion in each trial, and 2) the cumulated proportion of participants with ARDS or pneumonia in each trial. We assessed the risk of systematic errors by evaluating the risk of bias in the included trials using the Risk of Bias 2 tool. We used the GRADEpro tool to assess the overall certainty of the evidence. We also evaluated the risk of publication bias for outcomes reported by 10b or more trials. MAIN RESULTS: We included 19 RCTs (10,385 participants), of which 17 reported relevant outcomes for this review (10,248 participants). For all-cause mortality, 10 trials were judged to be at overall low risk of bias, and six at overall high risk of bias. For the reported SAEs, 10 trials were judged to be at overall low risk of bias, and seven at overall high risk of bias. Two trials reported on quality of life, of which one was judged to be at overall low risk of bias and one at high risk of bias for this outcome. Meta-analysis of all trials, regardless of risk of bias, indicated no significant difference from higher or lower oxygenation strategies at maximum follow-up with regard to mortality (risk ratio (RR) 1.01, 95% confidence interval (C)I 0.96 to 1.06; I2 = 14%; 16 trials; 9408 participants; very low-certainty evidence); occurrence of SAEs: the highest proportion of any specific SAE in each trial RR 1.01 (95% CI 0.96 to 1.06; I2 = 36%; 9466 participants; 17 trials; very low-certainty evidence), or quality of life (mean difference (MD) 0.5 points in participants assigned to higher oxygenation strategies (95% CI -2.75 to 1.75; I2 = 34%, 1649 participants; 2 trials; very low-certainty evidence)). Meta-analysis of the cumulated number of SAEs suggested benefit of a lower oxygenation strategy (RR 1.04 (95% CI 1.02 to 1.07; I2 = 74%; 9489 participants; 17 trials; very low certainty evidence)). However, trial sequential analyses, with correction for sparse data and repetitive testing, could reject a relative risk increase or reduction of 10% for mortality and the highest proportion of SAEs, and 20% for both the cumulated number of SAEs and quality of life. Given the very low-certainty of evidence, it is necessary to interpret these findings with caution. Meta-analysis of all trials indicated no statistically significant evidence of a difference between higher or lower oxygenation strategies on the occurrence of lung injuries at maximum follow-up (the highest reported proportion of lung injury RR 1.08, 95% CI 0.85 to 1.38; I2 = 0%; 2048 participants; 8 trials; very low-certainty evidence). Meta-analysis of all trials indicated harm from higher oxygenation strategies as compared with lower on the occurrence of sepsis at maximum follow-up (RR 1.85, 95% CI 1.17 to 2.93; I2 = 0%; 752 participants; 3 trials; very low-certainty evidence). Meta-analysis indicated no differences regarding the occurrences of myocardial infarction or stroke. AUTHORS' CONCLUSIONS: In adult ICU patients, it is still not possible to draw clear conclusions about the effects of higher versus lower oxygenation strategies on all-cause mortality, SAEs, quality of life, lung injuries, myocardial infarction, stroke, and sepsis at maximum follow-up. This is due to low or very low-certainty evidence.

Secretogranin III stringently regulates pathological but not physiological angiogenesis in oxygen-induced retinopathy.

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized Scg3 binding exclusively to disease-related disorganized retinal neovessels and neovascular tufts, whereas VEGF bound to both disorganized and well-organized neovessels. Homozygous deletion of the Scg3 gene showed undetectable effects on physiological retinal neovascularization but markedly reduced the severity of OIR-induced pathological angiogenesis. Furthermore, anti-Scg3 humanized antibody Fab (hFab) inhibited pathological angiogenesis with similar efficacy to anti-VEGF aflibercept. Aflibercept dose-dependently blocked physiological angiogenesis in neonatal retinas, whereas anti-Scg3 hFab was without adverse effects at any dose and supported a therapeutic window at least 10X wider than that of aflibercept. Therefore, Scg3 stringently regulates pathological but not physiological angiogenesis, and anti-Scg3 hFab satisfies essential criteria for development as a safe and effective disease-targeted anti-angiogenic therapy for ROP.

Novel Function of Nogo-A as Negative Regulator of Endothelial Progenitor Cell Angiogenic Activity: Impact in Oxygen-Induced Retinopathy.

Endothelial Progenitor Cells (EPCs) can actively participate in revascularization in oxygen-induced retinopathy (OIR). Yet the mechanisms responsible for their dysfunction is unclear. Nogo-A, whose function is traditionally related to the inhibition of neurite function in the central nervous system, has recently been documented to display anti-angiogenic pro-repellent properties. Based on the significant impact of EPCs in retinal vascularization, we surmised that Nogo-A affects EPC function, and proceeded to investigate the role of Nogo-A on EPC function in OIR. The expression of Nogo-A and its specific receptor NgR1 was significantly increased in isolated EPCs exposed to hyperoxia, as well as in EPCs isolated from rats subjected to OIR compared with respective controls (EPCs exposed to normoxia). EPCs exposed to hyperoxia displayed reduced migratory and tubulogenic activity, associated with the suppressed expression of prominent EPC-recruitment factors SDF-1/CXCR4. The inhibition of Nogo-A (using a Nogo-66 neutralizing antagonist peptide) or siRNA-NGR1 in hyperoxia-exposed EPCs restored SDF-1/CXCR4 expression and, in turn, rescued the curtailed neovascular functions of EPCs in hyperoxia. The in vivo intraperitoneal injection of engineered EPCs (Nogo-A-inhibited or NgR1-suppressed) in OIR rats at P5 (prior to exposure to hyperoxia) prevented retinal and choroidal vaso-obliteration upon localization adjacent to vasculature; coherently, the inhibition of Nogo-A/NgR1 in EPCs enhanced the expression of key angiogenic factors VEGF, SDF-1, PDGF, and EPO in retina; CXCR4 knock-down abrogated suppressed NgR1 pro-angiogenic effects. The findings revealed that hyperoxia-induced EPC malfunction is mediated to a significant extent by Nogo-A/NgR1 signaling via CXCR4 suppression; the inhibition of Nogo-A in EPCs restores specific angiogenic growth factors in retina and the ensuing vascularization of the retina in an OIR model.

Early Depletion of Neutrophils Reduces Retinal Inflammation and Neovascularization in Mice with Oxygen-Induced Retinopathy.

Retinal inflammation is a central feature of ocular neovascular diseases such as diabetic retinopathy and retinopathy of prematurity, but the contribution of neutrophils to this process is not fully understood. We studied oxygen-induced retinopathy (OIR) which develops in two phases, featuring hyperoxia-induced retinal vaso-obliteration in phase I, followed by retinal neovascularization in phase II. As neutrophils are acute responders to tissue damage, we evaluated whether neutrophil depletion with an anti-Ly6G mAb administered in phase I OIR influenced retinal inflammation and vascular injury. Neutrophils were measured in blood and spleen via flow cytometry, and myeloperoxidase, an indicator of neutrophil activity, was evaluated in the retina using Western blotting. Retinal vasculopathy was assessed by quantitating vaso-obliteration, neovascularization, vascular leakage, and VEGF levels. The inflammatory factors, TNF, MCP-1, and ICAM-1 were measured in retina. In the OIR controls, neutrophils were increased in the blood and spleen in phase I but not phase II OIR. In OIR, the anti-Ly6G mAb reduced neutrophils in the blood and spleen, and myeloperoxidase, inflammation, and vasculopathy in the retina. Our findings revealed that the early rise in neutrophils in OIR primes the retina for an inflammatory and angiogenic response that promotes severe damage to the retinal vasculature.

MicroRNA-124-3p Attenuated Retinal Neovascularization in Oxygen-Induced Retinopathy Mice by Inhibiting the Dysfunction of Retinal Neuroglial Cells through STAT3 Pathway.

MicroRNA (miRNA) is a non-coding RNA that can regulate the expression of many target genes, and it is widely involved in various important physiological activities. MiR-124-3p was found to associate with the normal development of retinal vessels in our previous study, but the mechanism of its anti-angiogenic effect on pathological retinal neovascularization still needed to be explored. Therefore, this study aimed to investigate the effect and mechanism of miR-124-3p on retinal neovascularization in mice with oxygen-induced retinopathy (OIR). Here, we found that intravitreal injection of miR-124-3p agomir attenuated pathological retinal neovascularization in OIR mice. Moreover, miR-124-3p preserved the astrocytic template, inhibited reactive gliosis, and reduced the inflammatory response as well as necroptosis. Furthermore, miR-124-3p inhibited the signal transducer and activator of transcription 3 (STAT3) pathway and decreased the expression of hypoxia-inducible factor-1α and vascular endothelial growth factor. Taken together, our results revealed that miR-124-3p inhibited retinal neovascularization and neuroglial dysfunction by targeting STAT3 in OIR mice.

Hyperbaric oxygen combined with hydrogen-rich saline protects against acute lung injury.

Background: This study sought to investigate therapeutic effects of hydrogen-rich saline (HRS) combined with hyperbaric oxygen (HBO2) in an experimental rat model of acute lung injury (ALI). Method: Forty male Sprague-Dawley rats were randomly divided into sham, LPS, LPS + HBO2, LPS + HRS, and LPS + HBO2 + HRS groups. After an intratracheal injection of LPS-induced ALI, the rats were given a single-agent HBO2 or HRS or HBO2 + HRS treatment. The treatments were continued for three days in this experimental rat model of ALI. At the end of experiment, the lung pathological, inflammatory factors, and cell apoptosis in the pulmonary tissue were detected by Tunel method and cell apoptosis rate was calculated accordingly. Results: In the groups treated with HBO2 + HRS, pulmonary pathological data, wet-dry weight ratio, and inflammatory factors of pulmonary tissues and alveolar lavage fluid were significantly superior to those of the sham group (p≺0.05). Cell apoptosis detection revealed that no single agent treatment of HRS or HBO2, or combination treatment, could alleviate all cell apoptosis. HRS combined with HBO2 treatment was superior to single treatment (p≺0.05). Conclusion: HRS or HBO2 single treatment could decrease inflammatory cytokines release in lung tissue, reduce the accumulation of oxidative products and alleviate apoptosis of pulmonary cells, then lead to positive therapeutic effects on ALI induced by LPS. Furthermore, HBO2 combined with HRS treatment presented a synergy effect on cell apoptosis decrease and a decline in inflammatory cytokine release and related inflammatory product generation, compared with a single treatment.

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OBJECTIVES: To study the protective effect of melatonin (Mel) against oxygen-induced retinopathy (OIR) in neonatal mice and the role of the HMGB1/NF-κB/NLRP3 axis. METHODS: Neonatal C57BL/6J mice, aged 7 days, were randomly divided into a control group, a model group (OIR group), and a Mel treatment group (OIR+Mel group), with 9 mice in each group. The hyperoxia induction method was used to establish a model of OIR. Hematoxylin and eosin staining and retinal flat-mount preparation were used to observe retinal structure and neovascularization. Immunofluorescent staining was used to measure the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis and lymphocyte antigen 6G. Colorimetry was used to measure the activity of myeloperoxidase. RESULTS: The OIR group had destruction of retinal structure with a large perfusion-free area and neovascularization, while the OIR+Mel group had improvement in destruction of retinal structure with reductions in neovascularization and perfusion-free area. Compared with the control group, the OIR group had significant increases in the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis, the expression of lymphocyte antigen 6G, and the activity of myeloperoxidase (P<0.05). Compared with the OIR group, the OIR+Mel group had significant reductions in the above indices (P<0.05). Compared with the control group, the OIR group had significant reductions in the expression of melatonin receptors in the retina (P<0.05). Compared with the OIR group, the OIR+Mel group had significant increases in the expression of melatonin receptors (P<0.05). CONCLUSIONS: Mel can alleviate OIR-induced retinal damage in neonatal mice by inhibiting the HMGB1/NF-κB/NLRP3 axis and may exert an effect through the melatonin receptor pathway.

Adenosine A2A receptor antagonism protects against hyperoxia-induced retinal vascular loss via cellular proliferation.

Retinopathy of prematurity (ROP) remains one of the major causes of blindness in children worldwide. While current ROP treatments are mostly disruptive to reduce proliferative neovascularization by targeting the hypoxic phase, protection against early hyperoxia-induced retinal vascular loss represents an effective therapeutic window, but no such therapeutic strategy is available. Built upon our recent demonstration that the protection against oxygen-induced retinopathy by adenosine A2A receptor (A2A R) antagonists is most effective when administered at the hyperoxia (not hypoxic) phase, we here uncovered the cellular mechanism underlying the A2A R-mediated protection against early hyperoxia-induced retinal vascular loss by reversing the inhibition of cellular proliferation via possibly multiple signaling pathways. Specifically, we revealed two distinct stages of the hyperoxia phase with greater cellular proliferation and apoptosis activities and upregulation of adenosine signaling at postnatal 9 day (P9) but reduced cellular activities and adenosine-A2A R signaling at P12. Importantly, the A2A R-mediated protection at P9 was associated with the reversal of hyperoxia-induced inhibition of progenitor cells at the peripheral retina at P9 and of retinal endothelial proliferation at P9 and P12. The critical role of cellular proliferation in the hyperoxia-induced retinal vascular loss was validated by the increased avascular areas by siRNA knockdown of the multiple signaling molecules involved in modulation of cellular proliferation, including activin receptor-like kinase 1, DNA-binding protein inhibitor 1, and vascular endothelial growth factor-A.

Involvement of TFAP2A in the activation of GSDMD gene promoter in hyperoxia-induced ALI.

Oxygen therapy is a common treatment in neonatal intensive care units, but long-term continuous hyperoxia ventilation may induce acute lung injury (ALI). Gasdermin D (GSDMD)-mediated pyroptosis participates in various diseases including ALI, but the role of GSDMD in hyperoxia-induced ALI is yet understood. Here, we showed a significant increase in GSDMD after exposure to high oxygen. To elucidate the molecular mechanisms involved in GSDMD regulation, we identified the core promoter of GSDMD, -98 ~ -12 bp relative to the transcriptional start site (TSS). The results of mutational analysis, overexpression or siRNA interference, EMSA and ChIP demonstrated that E2F4 and TFAP2A positively regulate the transcriptional activity of the GSDMD by binding to its promoter. However, only TFAP2A showed a regulatory effect on the expression of GSDMD. Moreover, TFAP2A was increased in the lung tissues of rats exposed to hyperoxia and showed a strong linear correlation with GSDMD. Our results indicated that TFAP2A positively regulates the GSDMD expression via binding to the promoter region of GSDMD.

A transcriptome-based signature of pathological angiogenesis predicts breast cancer patient survival.

The specific genes and molecules that drive physiological angiogenesis differ from those involved in pathological angiogenesis, suggesting distinct mechanisms for these seemingly related processes. Unveiling genes and pathways preferentially associated with pathologic angiogenesis is key to understanding its mechanisms, thereby facilitating development of novel approaches to managing angiogenesis-dependent diseases. To better understand these different processes, we elucidated the transcriptome of the mouse retina in the well-accepted oxygen-induced retinopathy (OIR) model of pathological angiogenesis. We identified 153 genes changed between normal and OIR retinas, which represent a molecular signature relevant to other angiogenesis-dependent processes such as cancer. These genes robustly predict the survival of breast cancer patients, which was validated in an independent 1,000-patient test cohort (40% difference in 15-year survival; p = 2.56 x 10-21). These results suggest that the OIR model reveals key genes involved in pathological angiogenesis, and these may find important applications in stratifying tumors for treatment intensification or for angiogenesis-targeted therapies.

Effect of Helmet Noninvasive Ventilation vs Usual Respiratory Support on Mortality Among Patients With Acute Hypoxemic Respiratory Failure Due to COVID-19: The HELMET-COVID Randomized Clinical Trial.

Importance: Helmet noninvasive ventilation has been used in patients with COVID-19 with the premise that helmet interface is more effective than mask interface in delivering prolonged treatments with high positive airway pressure, but data about its effectiveness are limited. Objective: To evaluate whether helmet noninvasive ventilation compared with usual respiratory support reduces mortality in patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. Design, Setting, and Participants: This was a multicenter, pragmatic, randomized clinical trial that was conducted in 8 sites in Saudi Arabia and Kuwait between February 8, 2021, and November 16, 2021. Adult patients with acute hypoxemic respiratory failure (n = 320) due to suspected or confirmed COVID-19 were included. The final follow-up date for the primary outcome was December 14, 2021. Interventions: Patients were randomized to receive helmet noninvasive ventilation (n = 159) or usual respiratory support (n = 161), which included mask noninvasive ventilation, high-flow nasal oxygen, and standard oxygen. Main Outcomes and Measures: The primary outcome was 28-day all-cause mortality. There were 12 prespecified secondary outcomes, including endotracheal intubation, barotrauma, skin pressure injury, and serious adverse events. Results: Among 322 patients who were randomized, 320 were included in the primary analysis, all of whom completed the trial. Median age was 58 years, and 187 were men (58.4%). Within 28 days, 43 of 159 patients (27.0%) died in the helmet noninvasive ventilation group compared with 42 of 161 (26.1%) in the usual respiratory support group (risk difference, 1.0% [95% CI, -8.7% to 10.6%]; relative risk, 1.04 [95% CI, 0.72-1.49]; P = .85). Within 28 days, 75 of 159 patients (47.2%) required endotracheal intubation in the helmet noninvasive ventilation group compared with 81 of 161 (50.3%) in the usual respiratory support group (risk difference, -3.1% [95% CI, -14.1% to 7.8%]; relative risk, 0.94 [95% CI, 0.75-1.17]). There were no significant differences between the 2 groups in any of the prespecified secondary end points. Barotrauma occurred in 30 of 159 patients (18.9%) in the helmet noninvasive ventilation group and 25 of 161 (15.5%) in the usual respiratory support group. Skin pressure injury occurred in 5 of 159 patients (3.1%) in the helmet noninvasive ventilation group and 10 of 161 (6.2%) in the usual respiratory support group. There were 2 serious adverse events in the helmet noninvasive ventilation group and 1 in the usual respiratory support group. Conclusions and Relevance: Results of this study suggest that helmet noninvasive ventilation did not significantly reduce 28-day mortality compared with usual respiratory support among patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. However, interpretation of the findings is limited by imprecision in the effect estimate, which does not exclude potentially clinically important benefit or harm. Trial Registration: ClinicalTrials.gov Identifier: NCT04477668.

Ellagic acid protects type II collagen induced arthritis in rat via diminution of IKB phosphorylation and suppression IKB-NF-kB complex activation: in vivo and in silico study.

OBJECTIVE: The present study was designed to explore the potential anti-inflammatory and anti-arthritic effects of ellagic acid (EA) in collagen-induced arthritis (CIA). METHODS: CIA rats were treated with MTX (0.25 mg/kg body wt.) and EA (50 mg/kg b.wt.) for a period of 20 days. The effects of treatment in the rats were assessed biochemically by analyzing inflammatory mediators (NF-kB, iNOS, TNF-α, IL-1ß, IL-6 and IL-10) and oxidative stress related parameters (MPO, NO, LPO, catalase, SOD, GSH). In addition, we also assessed the expression of some inflammatory mediators TNF-α, CD8 + though immunohistochemistry in the joint tissue. RESULTS: In the present study, we found expression and synthesis of transcription factor NF-kB was prominent in CIA rats. In addition, main pro-inflammatory cytokines such as TNF-α, IL-1ß, IL-6, and the anti-inflammatory IL-10, was also stand out. Further, reactive oxygen/nitrogen species was also elevated in CIA rats. Treatment with EA ameliorates all the above mentioned inflammatory and oxidative stress related parameters to near normal. Further, we also confirmed the expression of TNF-α, CD8+ T cells through immunohistochemistry was mitigates in joint tissue of EA treated rats. We find EA significantly inhibited the developmental phase of arthritis. CONCLUSION: These results suggest that EA act as potent anti-arthritic and anti-inflammatory agent that could be used as a tool for the development of new drug for the treatment of arthritis.

International Multicenter Registry for Hyperbaric Oxygen Therapy: Results through June 2021.

Introduction: The International Multicenter Registry for Hyperbaric Oxygen Therapy (International Report Registered Identifier DERR1-10.2196/18857) was established in 2011 to capture outcomes and complications data for both Undersea and Hyperbaric Medical Society (UHMS) approved and selected unapproved hyperbaric oxygen (HBO2) therapy indications. Methods: A Research Electronic Data Capture (REDCap) template was designed and distributed to all participating centers for prospective data collection. Centers contributed de-identified demographic, treatment, complications, and outcome data. This report provides summary data on sites and enrollment, as well as pre- and post-treatment data on quality of life (EQ-5D-5L questionnaire), head and neck radiationoutcomes, non-healing wounds (Strauss score), and idiopathic sudden sensorineural hearing loss. Data were analyzed mainly using the Wilcoxon signed-rank test. Results: Twenty-two centers contributed data for 2,880 patients. The most common UHMS-approved indication was delayed radiation injury, followed by enhancement of wound healing, and carbon monoxide poisoning. One hundred and twenty-five patients were treated for non-UHMS approved indications. Quality of life, head and neck radiation symptoms, Strauss wound scores, and hearing were significantly improved after HBO2. Complication rates were low and comparable to previous reports. The registry also offered the ability to analyze factors that affect outcomes, such as smoking and severity of hearing loss. Discussion: The registry accrues prospective data on defined outcomes from multiple centers and allows for analysis of factors affecting outcomes. This registry does not have a control group, which is a limitation. Nevertheless, the registry provides a unique, comprehensive dataset on HBO2 outcomes from multiple centers internationally.

Involvement of spinal cannabinoid receptor type 2 in the analgesia effect of hyperbaric oxygen treatment on paclitaxel-induced neuropathic pain.

BACKGROUND: Chemotherapy-induced neuropathic pain (CINP) is intractable, and spinal cannabinoid receptors (CBRs) are potential therapeutic targets for CINP. Previous studies demonstrated that hyperbaric oxygen (HBO2) may contribute in alleviating specific peripheral neuropathic pain. However, neither CINP nor CBR have been clarified. We hypothesized that HBO2 is capable of alleviating CINP, and the effect could be explained by the activation of spinal CBRs. METHODS: A series of paclitaxel-induced CINP models were established on male Sprague-Dawley rats. Then HBO2 treatment was administered for seven consecutive days at 2.5 atmospheres absolute. Two groups were treated with AM251 (an antagonist of CBR type-1, CBR1) or AM630 (an antagonist of CBR type-2, CBR2) respectively 30 minutes before each HBO2 treatment. The mechanical withdrawal threshold was assessed before, during and at two weeks after HBO2 treatment. Lumbar spinal cords were collected for Western blot analysis of CBR1, CBR2, GFAP and CD11b, and ELISA analysis of proinflammatory cytokines IL-1ß and TNF-α. RESULTS: A mechanical allodynia was successfully exhibited and the spinal GFAP, CD11b, IL-1ß and TNF-α significantly increased after the modeling, and these effects could be further reversed by HBO2 treatment, which could be blocked by AM630, other than AM251. CONCLUSION: HBO2 treatment can alleviate paclitaxel-induced neuropathic pain, and be mediated by CBR2. Spinal glial cells and proinflammatory cytokines are involved in this process.

Oxygen-induced hypercapnia: physiological mechanisms and clinical implications.

Oxygen is probably the most commonly prescribed drug in the emergency setting and is a life-saving modality as well. However, like any other drug, oxygen therapy may also lead to various adverse effects. Patients with chronic obstructive pulmonary disease (COPD) may develop hypercapnia during supplemental oxygen therapy, particularly if uncontrolled. The risk of hypercapnia is not restricted to COPD only; it has also been reported in patients with morbid obesity, asthma, cystic fibrosis, chest wall skeletal deformities, bronchiectasis, chest wall deformities, or neuromuscular disorders. However, the risk of hypercapnia should not be a deterrent to oxygen therapy in hypoxemic patients with chronic lung diseases, as hypoxemia may lead to life-threatening cardiovascular complications. Various mechanisms leading to the development of oxygen-induced hypercapnia are the abolition of 'hypoxic drive', loss of hypoxic vasoconstriction and absorption atelectasis leading to an increase in dead-space ventilation and Haldane effect. The international guideline recommends a target oxygen saturation of 88% to 92% in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and other chronic lung diseases at risk of hypercapnia.  Oxygen should be administered only when oxygen saturation is below 88%. We searched PubMed, EMBASE, and the CINAHL from inception to June 2022. We used the following search terms: "Hypercapnia", "Oxygen therapy in COPD", "Oxygen-associated hypercapnia", "oxygen therapy", and "Hypoxic drive". All types of study are selected. This review will focus on the physiological mechanisms of oxygen-induced hypercapnia and its clinical implications.

An imbalance in autophagy contributes to retinal damage in a rat model of oxygen-induced retinopathy.

In retinopathy of prematurity (ROP), the abnormal retinal neovascularization is often accompanied by retinal neuronal dysfunction. Here, a rat model of oxygen-induced retinopathy (OIR), which mimics the ROP disease, was used to investigate changes in the expression of key mediators of autophagy and markers of cell death in the rat retina. In addition, rats were treated from birth to postnatal day 14 and 18 with 3-methyladenine (3-MA), an inhibitor of autophagy. Immunoblot and immunofluorescence analysis demonstrated that autophagic mechanisms are dysregulated in the retina of OIR rats and indicated a possible correlation between autophagy and necroptosis, but not apoptosis. We found that 3-MA acts predominantly by reducing autophagic and necroptotic markers in the OIR retinas, having no effects on apoptotic markers. However, 3-MA does not ameliorate retinal function, which results compromised in this model. Taken together, these results revealed the crucial role of autophagy in retinal cells of OIR rats. Thus, inhibiting autophagy may be viewed as a putative strategy to counteract ROP.

Prolonged oxygen exposure causes the mobilization and functional damage of stem or progenitor cells and exacerbates cardiac ischemia or reperfusion injury in healthy mice.

Oxygen is often administered to patients and occasionally to healthy individuals as well; however, the cellular toxicity of oxygen, especially following prolonged exposure, is widely known. To evaluate the potential effect of oxygen exposure on circulating stem/progenitor cells and cardiac ischemia/reperfusion (I/R) injury, we exposed healthy adult mice to 100% oxygen for 20 or 60 min. We then examined the c-kit-positive stem/progenitor cells and colony-forming cells and measured the cytokine/chemokine levels in peripheral blood. We also induced cardiac I/R injury in mice at 3 h after 60 min of oxygen exposure and examined the recruitment of inflammatory cells and the fibrotic area in the heart. The proportion of c-kit-positive stem/progenitor cells significantly increased in peripheral blood at 3 and 24 h after oxygen exposure for either 20 or 60 min (p < .01 vs. control). However, the abundance of colony-forming cells in peripheral blood conversely decreased at 3 and 24 h after oxygen exposure for only 60 min (p < .05 vs. control). Oxygen exposure for either 20 or 60 min resulted in significantly decreased plasma vascular endothelial growth factor levels at 3 h, whereas oxygen exposure for only 60 min reduced plasma insulin-like growth factor 1 levels at 24 h (p < .05 vs. control). Protein array indicated the increase in the levels of some cytokines/chemokines, such as CXCL6 (GCP-2) at 24 h after 60 min of oxygen exposure. Moreover, oxygen exposure for 60 min enhanced the recruitment of Ly6g- and CD11c-positive inflammatory cells at 3 days (p < .05 vs. control) and increased the fibrotic area at 14 days in the heart after I/R injury (p < .05 vs. control). Prolonged oxygen exposure induced the mobilization and functional impairment of stem/progenitor cells and likely enhanced inflammatory responses to exacerbate cardiac I/R injury in healthy mice.

Hyperoxia and modulation of pulmonary vascular and immune responses in COVID-19.

Oxygen is the most commonly used therapy in hospitalized patients with COVID-19. In those patients who develop worsening pneumonia and acute respiratory distress syndrome (ARDS), high concentrations of oxygen may need to be administered for prolonged time periods, often together with mechanical ventilation. Hyperoxia, although lifesaving and essential for maintaining adequate oxygenation in the short term, may have adverse long-term consequences upon lung parenchymal structure and function. How hyperoxia per se impacts lung disease in COVID-19 has remained largely unexplored. Numbers of experimental studies have previously established that hyperoxia is associated with deleterious outcomes inclusive of perturbations in immunologic responses, abnormal metabolic function, and alterations in hemodynamics and alveolar barrier function. Such changes may ultimately progress into clinically evident lung injury and adverse remodeling and result in parenchymal fibrosis when exposure is prolonged. Given that significant exposure to hyperoxia in patients with severe COVID-19 may be unavoidable to preserve life, these sequelae of hyperoxia, superimposed on the cytopathic effects of SARS-CoV-2 virus, may well impact pathogenesis of COVID-19-induced ARDS.