Hyperoxia Treatment Research Articles

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.

Recent progress in neonatal hyperoxic lung injury.

With the progress in neonatal intensive care, there has been an increase in the survival rates of premature infants. However, this has also led to an increased incidence of neonatal hyperoxia lung injury and bronchopulmonary dysplasia (BPD), whose pathogenesis is believed to be influenced by various prenatal and postnatal factors, although the exact mechanisms remain unclear. Recent studies suggest that multiple mechanisms might be involved in neonatal hyperoxic lung injury and BPD, with sex also possibly playing an important role, and numerous drugs have been proposed and shown promise for improving the treatment outcomes of hyperoxic lung injury. Therefore, this paper aims to analyze and summarize sex differences in neonatal hyperoxic lung injury, potential pathogenesis and treatment progress to provide new ideas for basic and clinical research in this field.

Calcitonin gene‑related peptide alleviates hyperoxia‑induced human alveolar cell injury via the CGRPR/TRPV1/Ca2+ axis.

Although exogenous calcitonin gene‑related peptide (CGRP) protects against hyperoxia‑induced lung injury (HILI), the underlying mechanisms remain unclear. The present study attempted to elucidate the molecular mechanism by which CGRP protects against hyperoxia‑induced 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 kit‑8 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), Bcl‑2 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 non‑selective currents through TRPV1 channels. The CGRP‑induced 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 hyperoxia‑induced injury via the CGRPR/TRPV1/Ca2+ axis, which may be a potential target for the prevention and treatment of the HILI.

Normobaric Hyperoxia Treatment after Mid-cervical Contusion Injury in Rats

Severe hypoxia at or near the site of spinal cord injury (SCI) contributes to necrosis and secondary tissue damage. Prior studies of O2 therapy after SCI have primarily used pressurized hyperoxic exposure ( i.e., hyperbaric oxygen). We tested the hypothesis that daily exposure to 100% O2, delivered at atmospheric pressure ( i.e., normobaric hyperoxia) could accelerate the recovery of inspiratory tidal volume after cervical SCI. Three groups of adult male Sprague Dawley rats received a 150 kdyn impact right lateral C4 cervical SCI. In group 1, normobaric hyperoxia (100% O2 at 1 atmosphere pressure, 2 hours) was initiated within 20 min of SCI and continued daily for 7 days. In group 2, the same normobaric hyperoxia paradigm was initiated on day 8 post-injury and continued until day 14. A third group received a sham treatment, consisting of exposure to normobaric normoxia (21% O2, 1 ATA) daily for 14 days. Whole-body plethysmography was used to examine breathing patterns before-, 1-, and 2-weeks post-SCI. All three groups lost and then gained body mass at similar rates over days 1-14 post-SCI. Mortality rates during the first week after SCI were 23% (5/22) in rats not exposed to hyperoxia, and 10% (1/10) in the daily hyperoxia group. Tidal volume (VT) and breathing rate were compared using 2-way repeated measures ANOVA. The breathing rate (br/min) was similar between groups at 1-week post-injury. We observed a trend (p=0.182) for reduced breathing rate at the 2-week time point in the week-1 hyperoxia group (69±18) compared to the week-2 hyperoxia group (89±21) and the normoxia group (83±17). Inspiratory VT (mL/breath) was elevated in the week-1 hyperoxia group (0.59±0.08) as compared to the week-2 hyperoxia (0.44±0.05) and normoxia groups (0.44±0.06) at 1-week post-SCI (p=0.002). When VT was normalized to body weight (mL/breath/kg) the same effect of O2 exposure was observed (p=0.001). The effect was transient, however, and at day 14 post-SCI VT was similar across the three experimental groups (p>0.50). We conclude that normobaric hyperoxia treatment during the first week after cervical SCI alters the pattern of breathing, and may have benefit to recovery. R01HL153140-04. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Oxygen Therapy After Spinal Cord Injury Reduces Spinal Microglial Inflammatory Signalling

Spinal cord injury (SCI) interrupts blood flow, causing O2 partial pressure near the site of injury to decrease to very low levels. Spinal hypoxia contributes to tissue necrosis and neuroinflammation, leading to secondary injury. The majority of prior O2 therapy studies after SCI use hyperbaric O2 (HBO), and considerable evidence suggests HBO decreases spinal inflammation and neurodegeneration. HBO consists of 100% O2 (hyperoxia), which is easy to implement, at elevated pressure (hyperbaria), which is challenging to implement. Using an adult rat model of cervical SCI (C2 hemilesion), we compared the impact of daily HBO vs. normobaric hyperoxia therapy on the pro-inflammatory profile of spinal microglia isolated via immunomagnetic cell separation. Rats (n=3 per group) were given C2 hemilesion, followed by 14 days of normobaric hyperoxia (100% O2, 1 hour/day) or HBO (100% O2, 3 ATA, 1 hour/day). The C2-C6 spinal cord was harvested for immunomagnetic microglial isolation using CD11b antibodies. We screened pro-inflammatory gene expression with a PCR array (Rat Toll-Like Receptor Signaling Pathway, Qiagen). Both types of O2 therapy impacted suppressed microglial pro-inflammatory gene expression. In particular, subunit expression of the canonical transcription factor orchestrating microglial inflammatory responses, NFkB2, was significantly reduced. Downregulation of NFkB after HBO has been previously reported, but this is the first evidence for downregulation of NFkB after normobaric O2, and the first evidence for a microglia-specific response. Other pro-inflammatory genes with reduced expression after O2 therapy include: Clec4e, IL1β and CD14. Clec4e is as a transmembrane pattern recognition receptor and “necrotic cell sensor”. Thus, Clec4e downregulation after O2 therapy suggests a shift towards reduced necrosis after SCI. These initial results indicate that both HBO and normobaric hyperoxia treatments reduce the spinal microglia pro-inflammatory responses to cervical SCI, possibly leading to increased cell survival. HL153140 (DDF), HL147554 (GSM), HL149800 (DDF), McKnight Brain Institute (DDF, GSM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Influence of age and sex on physical, cardiac electrical and functional alterations in progressive hyperoxia treatment: A time course study in a murine model

Oxygen supplementation is a widely used treatment for ICU patients. However, it can lead to hyperoxia, which in turn can result in oxidative stress, cardiac remodeling, and even mortality. This paper expands upon previous research conducted by our lab to establish time-dependent cardiac changes under hyperoxia. In this study, both young and aged mice (male and female) underwent 72 h of hyperoxia exposure and were monitored at 24-hour intervals for cardiac electrophysiological and functional parameters using ECG and electrocardiogram data. Our analysis showed that young male mice experienced significant weight loss as well as significant lung edema by 48 h. Although young male mice were highly susceptible to physical changes, they were resistant to early cardiac functional and electrophysiological changes compared to the other groups. Both young and aged female and aged males developed functional impairments by 24 h of hyperoxia exposure. Furthermore, sex and age differences were noted in the onset of electrophysiological changes. While some groups could resist early cardiac remodeling, our data suggests that 72 h of hyperoxia exposure is sufficient to induce significant cardiac remodeling across all age and sex groups. Our data establishes that time-dependent cardiac changes due to oxygen supplementation can have devastating consequences even with short exposure periods. These findings can aid in developing clinical practices for individuals admitted to the ICU by elucidating the impact of aging, sex, and length of stay under mechanical ventilation to limit hyperoxia-induced cardiac remodeling.

AMPK/MTOR/TP53 Signaling Pathway Regulation by Calcitonin Gene-Related Peptide Reduces Oxygen-Induced Lung Damage in Neonatal Rats through Autophagy Promotion.

Our previous studies indicated that calcitonin gene-related peptide (CGRP) alleviates hyperoxia-induced lung injury and suggested the possible involvement of autophagy in this process. Herein, we aimed to further explore the potential involvement of tumor protein p53 (TP53) and autophagy in the mode of action of CGRP against hyperoxia-induced lung injury in vitro and in vivo. The study conducted tests on type II alveolar epithelial cells (AECII) and rats that were subjected to hyperoxia treatment or combined treatment of hyperoxia with CGRP, CGRP inhibitor, rapamycin (an autophagy agonist), 3-methyladenine (3-MA, an autophagy inhibitor), TP53 silencing/inhibitor (pifithrin-α), or expression vector/activator (PRIMA-1 (2,2-bis(hydroxymethyl)-3-quinuclidinone)) and their corresponding controls. We found that oxidative stress, apoptosis, and autophagy were all increased by hyperoxia treatment in vitro. However, treating AECII cells with CGRP reversed hyperoxia-induced oxidative stress and apoptosis but further promoted autophagy. In addition, the combined treatment with rapamycin or TP53 silencing with CGRP promoted the effect of CGRP, while contrary results were obtained with combined therapy with 3-MA or TP53 overexpression. In vivo, the number of hyperoxia-induced autophagosomes was promoted in the lung tissue of neonatal rats. Furthermore, hyperoxia increased the expression levels of AMP-activated protein kinase (AMPK) alpha 1 (also known as protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1)) but inhibited TP53 and mechanistic target of rapamycin (MTOR); these expression trends were regulated by CGRP treatment. In conclusion, we showed that CGRP can attenuate hyperoxia-induced lung injury in neonatal rats by enhancing autophagy and regulating the TP53/AMPK/MTOR crosstalk axis.

Targeting CXCR1 alleviates hyperoxia-induced lung injury through promoting glutamine metabolism

Although increasing evidence suggests potential iatrogenic injury from supplemental oxygen therapy, significant exposure to hyperoxia in critically ill patients is inevitable. This study shows that hyperoxia causes lung injury in a time- and dose-dependent manner. In addition, prolonged inspiration of oxygen at concentrations higher than 80% is found to cause redox imbalance and impair alveolar microvascular structure. Knockout of C-X-C motif chemokine receptor 1 (Cxcr1) inhibits the release of reactive oxygen species (ROS) from neutrophils and synergistically enhances the ability of endothelial cells to eliminate ROS. We also combine transcriptome, proteome, and metabolome analysis and find that CXCR1 knockdown promotes glutamine metabolism and leads to reduced glutathione by upregulating the expression of malic enzyme 1. This preclinical evidence suggests that a conservative oxygen strategy should be recommended and indicates that targeting CXCR1 has the potential to restore redox homeostasis by reducing oxygen toxicity when inspiratory hyperoxia treatment is necessary.

The role of rhIGF-1/BP3 in the prevention of pulmonary hypertension in bronchopulmonary dysplasia and its underlying mechanism

BackgroundThis study aimed to determine whether postnatal treatment with recombinant human IGF-1 (rhIGF-1)/binding peptide 3 (BP3) ameliorates lung injury and prevents pulmonary hypertension (PH) in bronchopulmonary dysplasia (BPD) models.MethodsWe used two models of BPD in this study: one model that was associated with chorioamnionitis (CA), stimulated by intra-amniotic fluid and exposure to lipopolysaccharide (LPS), whereas the other was exposed to postnatal hyperoxia. Newborn rats were treated with rhIGF-1/BP3 (0.2 mg/Kg/d) or saline via intraperitoneal injection. The study endpoints included the wet/dry weight (W/D) ratio of lung tissues, radial alveolar counts (RACs), vessel density, right ventricular hypertrophy (RVH), lung resistance, and lung compliance. Hematoxylin and eosin (H&E) and Masson staining were used to evaluate the degree of lung injury and pulmonary fibrosis. IGF-1 and eNOS expression were detected using western blotting or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The levels of SP-C, E-cadherin, N-cadherin, FSP1, and Vimentin in the lung tissues were detected by immunofluorescence.ResultsLPS and hyperoxia treatment increased lung injury and pulmonary fibrosis, enhanced RVH and total respiratory resistance, and decreased RAC, pulmonary vascular density and pulmonary compliance in young mice (all p < 0.01). Simultaneously, LPS and hyperoxia induced an increase in epithelial-mesenchymal transition (EMT) in airway epithelial cells. However, rhIGF-1/BP3 treatment reduced lung injury and pulmonary fibrosis, decreased RVH and total respiratory resistance, and enhanced RAC, pulmonary vascular density and pulmonary compliance, as well as inhibited EMT in airway epithelial cells in LPS and hyperoxia treated mice.ConclusionPostnatal rhIGF-1/BP3 treatment relieved the effects of LPS or hyperoxia on lung injury and prevented RVH, providing a promising strategy for the treatment of BPD.

INTERVAL HYPOXIC HYPEROXIC TREATMENT IN THE REHABILITATION OF POST-COVID-19 PATIENTS

The aim of the study is to reveal the main pathogenetic mechanisms of the effectiveness of interval hypoxic hyperoxic treatment in the rehabilitation of post-COVID-19 patients.&#x0D; Materials and Methods. Hypo-Oxy, hypoxic therapy device produced by Oxyterra (Russia) was used to generate a hypoxic mixture with different oxygen content. Hypoxic periods followed the hyperoxic ones (30 % O2). To determine individual sensitivity to hypoxia, patients underwent a hypoxic test, the results of which were used to select the optimal oxygen content in the hypoxic mixture, the duration of hypoxic effects and the number of sessions. The authors determined the parameters of the functional respiratory system, oxygen regimen, lipid peroxidation, antioxidant system, exhaled air condensate and coagulation system. Statistical processing was carried out in accordance with the rules of mathematical statistics using Microsoft Excel and Statistica 6.0 for Windows. When conducting parametric analysis, paired and unpaired Student's t-tests were used. All numerical data were presented as the arithmetic mean and standard error of the mean (M±m). Differences were considered statistically significant at p&lt;0.05. &#x0D; Results. Interval hypoxic hyperoxic treatment has proven to be an effective way to rehabilitate post-COVID-19 patients (medium severity). After hypoxic therapy, there was a decrease in respiratory, circulatory, hemic and tissue hypoxia, and an improvement in the parameters of the prooxidant and antioxidant systems. Hypoxic therapy had a normalizing effect on the hemostasis system: platelet count in the blood increased (p&lt;0.05) (it was low before hypoxic therapy). Activated partial thromboplastin time, international normalized ratio, and antithrombin III content also increased. Prothrombin index, fibrinogen and D-dimer content in the blood serum showed a decreased risk of thrombosis. &#x0D; Conclusion. The conducted studies have proven the high efficiency of interval hypoxic hyperoxic treatment in the rehabilitation of post-COVID-19 patients.

Oxygen therapy accelerates apoptosis induced by selenium compounds via regulating Nrf2/MAPK signaling pathway in hepatocellular carcinoma

Selenium has good antitumor effects in vitro, but the hypoxic microenvironment in solid tumors makes its clinical efficacy unsatisfactory. We hypothesized that the combination with oxygen therapy might improve the treatment efficacy of selenium in hypoxic tumors through the changes of redox environment. In this work, two selenium compounds, Na2SeO3 and CysSeSeCys, were selected to interrogate their therapeutic effects on hepatocellular carcinoma (HCC) under different oxygen levels. In tumor-bearing mice, both selenium compounds significantly inhibited the tumor growth, and combined with oxygen therapy further reduced the tumor volume about 50 %. In vitro HepG2 cell experiments, selenium induced autophagy and delayed apoptosis under hypoxia (1 % O2), while inhibited autophagy and accelerated apoptosis under hyperoxia (60 % O2). We found that, in contrast to hypoxia, the hyperoxic environment facilitated the H2Se, produced by the selenium metabolism in cells, to be rapidly oxidized to generate H2O2, leading to inhibit the expression level of Nrf2 and to increase that of phosphorylation of p38 and MKK4, resulting in inhibiting autophagy and accelerating apoptosis. Once the Nrf2 gene was knocked down, selenium compounds combined with hyperoxia treatment would further activate the MAPK signaling pathway and further increase apoptosis. These findings highlight oxygen can significantly enhance the anti-HCC effect of selenium compounds through regulating the Nrf2 and MAPK signaling pathways, thus providing novel therapeutic strategy for the hypoxic tumors and pave the way for the application of selenium in clinical treatment.

Author Response: Normobaric Hyperoxia Combined With Endovascular Treatment for Patients With Acute Ischemic Stroke: A Randomized Controlled Clinical Trial

We appreciate the comments from Penckofer and Siegler.1 The differential outcome of our study vs the cited stroke oxygen study is due to the fact that ours is normobaric hyperoxia (NBO) and endovascular treatment (EVT), whereas the study by Roffe et al.1,2 is NBO only. Without EVT, NBO benefits will only be temporary. We agree that certain specific subgroups may benefit more than others from NBO + EVT intervention and that stroke severity and timing of treatment could influence the efficacy of oxygen therapy. Owing to the small sample size, our study did not conduct subgroup analyses.

Hyperbaric oxygen improves depression-like behaviors in chronic stress model mice by remodeling gut microbiota and regulating host metabolism.

There is growing evidence that the gut microbiota plays a significant part in the pathophysiology of chronic stress. The dysbiosis of the gut microbiota closely relates to dysregulation of microbiota-host cometabolism. Composition changes in the gut microbiota related to perturbations in metabolic profiles are vital risk factors for disease development. Hyperbaric oxygen therapy is commonly applied as an alternative or primary therapy for various diseases. Therefore, a metabolic and gut bacteria perspective is essential to uncover possible mechanisms of chronic stress and the therapeutic effect of hyperbaric oxygenation. We determined that there were significantly disturbed metabolites and disordered gut microbiota between control and chronic stress group. The study aims to offer further information on the interactions between host metabolism, gut microbiota, and chronic stress. At present, chronic unpredictable mild stress is considered the most widespread method of modeling chronic stress in animals, so we used a chronic unpredictable mild stress mouse model to characterize changes in the metabolome and microbiome of depressed mice by combining 16S rRNA gene sequencing and UHPLC-MS/MS-based metabolomics. Pearson's correlation-based clustering analysis was performed with above metabolomics and fecal microbiome data to determine gut microbiota-associated metabolites. We found that 18 metabolites showed a significant correlation with campylobacterota. Campylobacterota associated metabolites were significantly enriched mainly in the d-glutamate and d-glutamine metabolism. Hyperoxia treatment may improve depression-like behaviors in chronic stress model mice through regulating the disrupted metabolites. Hyperbaric oxygen improves depression-like behaviors in chronic stress model mice by remodeling Campylobacterota associated metabolites.

Retinal microglia protect against vascular damage in a mouse model of retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a common cause of blindness in preterm babies. As a hypoxia-induced eye disease characterized by neovascularization, its association with retinal microglia has been noted but not well documented. We performed a comprehensive analysis of retinal microglia and retinal vessels in mouse oxygen-induced retinopathy (OIR), an animal model of ROP. In combination with a pharmacological inhibitory strategy, the role of retinal microglia in vascular network maintenance was investigated. Postnatal day (P) 7 C57BL/6J mouse pups with their nursing mother were exposed to 75% oxygen for 5 days to induce OIR. Age-matched room air-treated pups served as controls. On P12, P17, P21, P25, and P30, retinal microglia and vessels were visualized and quantified based on their location and activation status. Their relationship with retinal vessels was also analyzed. On P5 or P12, retinal microglia inhibition was achieved by intravitreal injection of liposomes containing clodronate (CLD); retinal vasculature and microglia were examined in P12 and P17 OIR retinae. The number of retinal microglia was increased in the superficial areas of OIR retinae on P12, P17, P21, P25, and P30, and most of them displayed an amoeboid (activated) morphology. The increased retinal microglia were associated with increased superficial retinal vessels in OIR retinae. The number of retinal microglia in deep retinal areas of OIR retinae also increased from P17 to P30 with a ramified morphology, which was not associated with reduced retinal vessels. Intravitreal injection of liposomes-CLD caused a significant reduction in retinal microglia. Loss of retinal microglia before hyperoxia treatment resulted in increased vessel obliteration on P12 and subsequent neovascularization on P17 in OIR retinae. Meanwhile, loss of retinal microglia immediately after hyperoxia treatment on P12 also led to more neovascularization in P17 OIR retinae. Our data showed that activated microglia were strongly associated with vascular abnormalities upon OIR. Retinal microglial activation continued throughout OIR and lasted until after retinal vessel recovery. Pharmacological inhibition of retinal microglia in either hyperoxic or hypoxic stage of OIR exacerbated retinal vascular consequences. These results suggested that retinal microglia may play a protective role in retinal vasculature maintenance in the OIR process.

P311 knockdown alleviates hyperoxia-induced injury by inactivating the Smad3 signaling pathway in type II alveolar epithelial cells.

P311 is associated with alveolar formation and development. However, the role and possible mechanism of P311 in hyperoxia-induced injury in type II alveolar epithelial cells (AEC II) need to be elucidated. In our study, rat AEC II (RLE-6TN) were exposure to normoxia (21% O2 and 5% CO2) or hyperoxia (95% O2 and 5% CO2) for 24h, followed by determination of P311 expression. After knockdown of P311 and hyperoxic treatment, cell viability, cell cycle progression, apoptosis and the Smad3 signaling pathway were examined. Rat AEC II were pretreated with SIS3 HCl for 4h and then subjected to P311 overexpression plasmid transfection and hyperoxic exposure. Then, cell viability, apoptosis and the Smad3 signaling pathway were determined. The results showed that hyperoxic exposure significantly elevated P311 levels in rat AEC II. P311 knockdown increased cell viability, accelerated cell cycle progression and inhibited apoptosis, as well as suppression of the Smad3 signaling pathway in hyperoxia-exposed AEC II. Additionally, we found that P311 overexpression enhanced the effects of hyperoxia. Interestingly, SIS3 HCl incubation blocked the effects of P311 overexpression on rat AEC II function under hyperoxic condition, as evidenced by an increase in cell viability, and suppressions of apoptosis and the Smad3 signaling pathway. These results indicate that P311 knockdown may ameliorate hyperoxia-induced injury by inhibiting the Smad3 signaling pathway in rat AEC II. P311 may be a novel target for the treatment of hyperoxia-induced lung injury and even bronchopulmonary dysplasia (BPD).

Normobaric hyperoxia plays a neuroprotective role after cerebral ischemia by maintaining the redox homeostasis and the level of connexin43 in astrocytes.

IntroductionAcute cerebral ischemia is caused by an insufficient blood supply to brain tissue. Oxygen therapy, which is able to aid diffusion to reach the ischemic region, has been regarded as a possible treatment for cerebral ischemia. Recent animal and pilot clinical studies have reported that normobaric hyperoxia (NBO) showed neuroprotective effects if started soon after the onset of stroke. However, little is known about the role and mechanism of NBO treatment in astrocytes. Connexin43, one of the main gap junction proteins in astrocytes, is extremely sensitive to hypoxia and oxidative stress after cerebral ischemia.AimsIn the present study, we used sutures to develop an ischemia/reperfusion model in rats to mimic clinical recanalization and investigated the role of connexin43 in NBO‐treated stroke rats, as well as the underlying mechanism of NBO therapy.ResultsNormobaric hyperoxia treatment maintained the homeostasis of oxidoreductases: glutathione peroxidase 4 (GPX4) and NADPH oxidase 4 (two important oxidoreductases) and rescued the ischemia/reperfusion‐induced downregulation of connexin43 protein in astrocytes. Furthermore, NBO treatment attenuated cerebral ischemia‐induced cytochrome c release from mitochondria and was involved in neuroprotective effects by regulating the GPX4 and connexin43 pathway, using Ferrostatin‐1 (an activator of GPX4) or Gap27 (an inhibitor of connexin43).ConclusionsThis study showed the neuroprotective effects of NBO treatment by reducing oxidative stress and maintaining the level of connexin43 in astrocytes, which could be used for the clinical treatment of ischemic stroke.

Inspiratory hyperoxia suppresses lung cancer metastasis through a MYC/SLC1A5-dependent metabolic pathway.

The lack of knowledge about the effect of inspiratory hyperoxia on the lung-specific tumour microenvironment and progression of lung cancer has attracted considerable attention. This study proposes that inspiratory hyperoxia has special significance for the malignant phenotype of lung cancer cells. The effects of different oxygenation parameters on the proliferation, apoptosis, invasion and migration of lung cancer cells were systematically evaluated in vitro and in vivo Our results reveal that inspiratory hyperoxia treatment (60% oxygen, 6 h·day-1) not only has no tumour progression-promoting effects, but also suppresses lung cancer metastasis and promotes long-term survival. In addition, we combined transcriptome, proteome and metabolome analysis and found that hyperoxia treatment induced significant intracellular metabolic changes in lung cancer cells. Overall, we established that MYC/SLC1A5-induced metabolic reprogramming and glutamine addiction is a new mechanism that drives lung cancer metastasis, which can be significantly suppressed by inspiratory hyperoxia treatment. These findings are relevant to the debate on the perils, promises and antitumour effect of inspiratory hyperoxia, especially for patients with lung cancer.

Effects of chronic mild hyperoxia on retinal and choroidal blood flow and retinal function in the DBA/2J mouse model of glaucoma.

PurposeTo test the hypothesis that mild chronic hyperoxia treatment would improve retinal function despite a progressive decline in ocular blood flow in the DBA/2J mouse model of glaucoma.Materials and methodsDBA/2J mice were treated with chronic mild hyperoxia (30% O2) beginning at 4.5 months of age or were untreated by giving normal room air. Retinal and choroidal blood flow (RBF and ChBF, respectively) were measured at 4, 6, and 9 months of age by MRI. Blood flow was additionally measured under hypercapnia challenge (5% CO2 inhalation) to assess vascular reactivity. Intraocular pressure (IOP) was measured using a rebound tonometer at the same time points. Scotopic flash electroretinograms (ERGs) were recorded at 9 months of age.ResultsBoth ChBF and RBF were reduced and significantly affected by age (p < 0.01), but neither were significantly affected by O2-treatment (p > 0.05). ChBF significantly increased in response to hypercapnia (p < 0.01), which was also unaffected by O2-treatment. Significant effects of age (p < 0.001) and of the interaction of age with treatment (p = 0.028) were found on IOP. IOP significantly decreased in O2-treated mice at 6 months compared to 4 months of age (p < 0.001), while IOP trended to increase with age in untreated mice. The amplitude of the b-wave from ERG was significantly increased in O2-treated DBA/2J compared to the untreated mice (p = 0.012), while the a-wave and oscillatory potentials were not significantly affected (p > 0.05).ConclusionThis study investigated the effects of chronic mild hyperoxia on retinal function and on retinal and choroidal blood flow in a mouse model of glaucoma. Retinal function was improved in the O2-treated mice at late stage, despite a progressive decline of RBF and ChBF with age that was comparable to untreated mice.

The impacts of oxygen and pentoxifylline in hypoxic condition

Introduction:Among major trauma patients in the emergency department, the leading cause of morbidity and mortality is a hemorrhagic shock. The low oxygen flow with hypovolemia in trauma patients is believed to play a significant role. Hence, oxygen supply is essential in severe trauma patients with massive hemorrhage. This study aimed to investigate the effect of oxygen supply in hypoxic condition and variable treatments such as pentoxifylline (PTX), glycerol, hypertonic saline (HTS), protease inhibitor, and dexamethasone (DEXA) in macrophage and T cells. Method:Nitric oxide synthase (iNOS) and macrophage migration inhibitory factor (MIF) were measured for macrophage. MIF, interleukin (IL)-2, and IL-8 were measured for T cells. T cell viability was measued by MTT assay. Results: Pentoxifylline decreased iNOS expression mostly followed by glycerol under hypoxia. Under the hyperoxia, PTX and other treatments decreased iNOS expressions in macrophage. MIF expression was lowered with PTX under hypoxia. PTX, glycerol, HTS, and protease inhibitor were effective under hyperoxia in macrophage. PTX increased T cell survival under hypoxia. Under the hyperoxia, IL-2 expressions were upregulated with PTX, glycerol, and HTS. PTX and other treatments were effective for IL-8. Our results indicate that the PTX and the other agents tested reversed the effects of stimulation of lipopolysaccharide, PGE2in hypoxia or hypoxia. Conclusion:Our study demonstrated potential usefulness in improving immune systems during severe inflammatory conditions similar to septic shock possibly caused by massive hemorrhage.

A two-hit model of sepsis plus hyperoxia causes lung permeability and inflammation.

Mouse models of acute lung injury (ALI) have been instrumental for studies of the biological underpinnings of lung inflammation and permeability, but murine models of sepsis generate minimal lung injury. Our goal was to create a murine sepsis model of ALI that reflects the inflammation, lung edema, histological abnormalities, and physiological dysfunction that characterize ALI. Using a cecal slurry (CS) model of polymicrobial abdominal sepsis and exposure to hyperoxia (95%), we systematically varied the timing and dose of the CS injection, fluids and antibiotics, and dose of hyperoxia. We found that CS alone had a high mortality rate that was improved with the addition of antibiotics and fluids. Despite this, we did not see evidence of ALI as measured by bronchoalveolar lavage (BAL) cell count, total protein, C-X-C motif chemokine ligand 1 (CXCL-1) or by lung wet:dry weight ratio. Addition of hyperoxia [95% fraction of inspired oxygen ([Formula: see text])] to CS immediately after CS injection increased BAL cell counts, CXCL-1, and lung wet:dry weight ratio but was associated with 40% mortality. Splitting the hyperoxia treatment into two 12-h exposures (0-12 h and 24-36 h) after CS injection increased survival to 75% and caused significant lung injury compared with CS alone as measured by increased BAL total cell count (92,500 vs. 240,000, P = 0.0004), BAL protein (71 vs. 103 µg/mL, P = 0.0030), and lung wet:dry weight ratio (4.5 vs. 5.5, P = 0.0005), and compared with sham as measured by increased BAL CXCL-1 (20 vs. 2,372 pg/mL, P < 0.0001) and histological lung injury score (1.9 vs. 4.2, P = 0.0077). In addition, our final model showed evidence of lung epithelial [increased BAL and plasma receptor for advanced glycation end products (RAGE)] and endothelial (increased Syndecan-1 and sulfated glycosaminoglycans) injury. In conclusion, we have developed a clinically relevant mouse model of sepsis-induced ALI using intraperitoneal injection of CS, antibiotics and fluids, and hyperoxia. This clinically relevant model can be used for future studies of sepsis-induced ALI.