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HBOT increases the proportion of dissolved oxygen in the blood, generating hyperoxia. This increased oxygen diffuses into the mitochondria, which consume the majority of inhaled oxygen and constitute the epicenter of HBOT effects. In this way, the oxygen entering the mitochondria can reverse tissue hypoxia, activating the electron transport chain to generate energy. Furthermore, intermittent HBOT is sensed by the cell as relative hypoxia, inducing cellular responses such as the activation of the HIF-1α pathway, which in turn, activates numerous cellular processes, including angiogenesis and inflammation, among others. These effects are harnessed for the treatment of various pathologies. This review summarizes the evidence indicating that the use of medium-pressure HBOT generates hyperoxia and activates cellular pathways capable of producing the mentioned effects. The possibility of using medium-pressure HBOT as a direct or adjunctive treatment in different pathologies may yield benefits, potentially leading to transformative therapeutic advancements in the future.
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Oxigenoterapia Hiperbárica , Hiperóxia , Humanos , Oxigênio , Hipóxia , InflamaçãoRESUMO
The objectives of this research were to investigate the impact of hypobaria, hyperoxia, and nitrogen form on the growth and nutritional quality of plants. Pre-culture 20-day-old lettuce (Lactuca sativa L. var. Rome) seedlings grew for 25 days under three levels of total atmospheric pressure (101, 54, and 30 kPa), two levels of oxygen partial pressure (21 and 28 kPa), and two forms of nitrogen (NO3N and NH4N). The ratios of NO3N to NH4N included 3: 1, 4: 0, 2: 2, and 0: 4. The nitrogen quantity included two levels, i.e. N1, 0.1 g N kg-1 dry matrix and N2, 0.2 g N kg-1 dry matrix. The growth status of lettuce plants in different treatments differentiated markedly. Regardless of the nitrogen factor, the growth status of lettuce plants treated with total atmospheric pressure/oxygen partial pressure at 54/21 was equivalent to the treatment of 101/21. Under the hypobaric condition (54 kPa), compared with 21 kPa oxygen partial pressure, hyperoxia (28 kPa) significantly inhibited the growth of lettuce plants and the biomass (fresh weight) decreased by 60.9%-69.9% compared with that under 101/21 treatment. At the N1 level, the sequence of the biomass of lettuce plants supplied with different ratios of NO3N to NH4N was 3: 1 > 4: 0 > 2: 2 > 0: 4, and there were higher concentrations of chlorophyll and carotenoid of lettuce plants supplied with the higher ratio of NO3 to NH4. At the N2 level, the effects of different ratios of NO3N to NH4N on lettuce plants were similar to those at the N1 level. The high nitrogen (N2) promoted the growth of lettuce plants such as 54/21/N2 treatments. Both form and nitrogen level did not affect the stress resistance of lettuce plants. Hypobaria (54 kPa) increased the contents of N, P, and K and hyperoxia (28 kPa) decreased the content of organic carbon in lettuce plants. The high nitrogen (N2) improved the content of total N and the N uptake. The ratios of NO3N to NH4N were 4: 0 and 3: 1, lettuce could absorb and utilize N effectively. This study demonstrated that hyperoxia (28 kPa) inhibited the growth of lettuce plants under the hypobaric condition (54 kPa), and high level of nitrogen (0.2 g N kg-1 dry matrix) and NO3N: NH4N at 3: 1 markedly enhanced the growth, the contents of mineral elements and the nutritional quality of lettuce plants.
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Hiperóxia , Lactuca , Nitrogênio , Valor Nutritivo , OxigênioRESUMO
Acute hyperbaric O2 (HBO) therapy after spinal cord injury (SCI) can reduce inflammation and increase neuronal survival. To our knowledge, it is unknown if these benefits of HBO require hyperbaric vs. normobaric hyperoxia. We used a C4 lateralized contusion SCI in adult male and female rats to test the hypothesis that the combination of hyperbaria and 100% O2 (i.e. HBO) more effectively mitigates spinal inflammation and neuronal loss, and enhances respiratory recovery, as compared to normobaric 100% O2. Experimental groups included spinal intact, SCI no O2 therapy, and SCI + 100% O2 delivered at normobaric pressure (1 atmosphere, ATA), or at 2- or 3 ATA. O2 treatments lasted 1-h, commenced within 2-h of SCI, and were repeated for 10 days. The spinal inflammatory response was assessed with transcriptomics (RNAseq) and immunohistochemistry. Gene co-expression network analysis showed that the strong inflammatory response to SCI was dramatically diminished by both hyper- and normobaric O2 therapy. Similarly, both HBO and normobaric O2 treatments reduced the prevalence of immunohistological markers for astrocytes (glial fibrillary acidic protein) and microglia (ionized calcium binding adaptor molecule) in the injured spinal cord. However, HBO treatment also had unique impacts not detected in the normobaric group including upregulation of an anti-inflammatory cytokine (interleukin-4) in the plasma, and larger inspiratory tidal volumes at 10-days (whole body-plethysmography measurements). We conclude that normobaric O2 treatment can reduce the spinal inflammatory response after SCI, but pressured O2 (i.e., HBO) provides further benefit.
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Oxigenoterapia Hiperbárica , Traumatismos da Medula Espinal , Ratos , Masculino , Feminino , Animais , Doenças Neuroinflamatórias , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/patologia , Inflamação/metabolismo , Oxigênio/metabolismoRESUMO
BACKGROUND: Breast cancer is the most common cancer among women, and melanoma is the most dreadful type of skin cancer. Due to the side effects of chemotherapy drugs, the development of new herbal nano-medicines has been considered. METHODS: This study first investigated the chemical composition of Ferula gummosa essential oil using GC-MS analysis; ß-pinene, with 61.57%, was the major compound. Next, alginate nanoparticles containing ß-pinene and the essential oil with particle sizes of 174 ± 7 and 137 ± 6 nm were prepared. Meanwhile, their zeta potentials were 12.4 ± 0.7 and 28.1 ± 1 mV. Besides, the successful loading of ß-pinene and the essential oil in nanoparticles was confirmed using ATR-FTIR analysis. After that, their effects on viability and apoptotic index of human melanoma and breast cancer cells were investigated in normoxia and normobaric hyperoxia (NBO) conditions. RESULTS: The best efficacy on A-375 and MDA-MB-231 cells was achieved by alginate nanoparticles containing the EO at hyperoxic and normoxia conditions; IC50 76 and 104 µg/mL. Besides, it affected apoptosis-involved genes; as Bax/Bcl-2 ratio was higher than 1, conditions for induction of apoptosis were obtained. Higher sensitivity was observed in the A-375 cell line treated with Alg-EO in the NBO model. CONCLUSIONS: Alginate nanoparticles containing F. gummosa EO could be considered for further investigation in anticancer studies. Also, it may be expected that NBO can be a new strategy for delaying cancer progression and improving nanotherapy efficacy.
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Neoplasias da Mama , Ferula , Hiperóxia , Melanoma , Óleos Voláteis , Humanos , Feminino , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Ferula/química , Alginatos , Neoplasias da Mama/tratamento farmacológico , Melanoma/tratamento farmacológico , Proliferação de CélulasRESUMO
Hyperoxia exposure of immature lungs contributes to lung injury and airway hyperreactivity. Up to now, treatments of airway hyperreactivity induced by hyperoxia exposure have been ineffective. The aim of this study was to investigate the effects of quercetin on hyperoxia-induced airway hyperreactivity, impaired relaxation, and lung inflammation. Newborn rats were exposed to hyperoxia (FiO2 > 95%) or ambient air (AA) for seven days. Subgroups were injected with quercetin (10 mg·kg-1·day-1). After exposures, tracheal cylinders were prepared for in vitro wire myography. Contraction to methacholine was measured in the presence or absence of organ bath quercetin and/or Nω-nitro-L-arginine methyl ester (L-NAME). Relaxation responses were evoked in preconstricted tissues using electrical field stimulation (EFS). Lung tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß) levels were measured by enzyme-linked immunosorbent assay (ELISA). A P < 0.05 was considered statistically significant. Contractile responses of tracheal smooth muscle (TSM) of hyperoxic animals were significantly increased compared with AA animals (P < 0.001). Treatment with quercetin significantly reduced contraction in hyperoxic groups compared with hyperoxic control (P < 0.01), but did not have any effect in AA groups. In hyperoxic animals, relaxation of TSM was significantly reduced compared with AA animals (P < 0.001), while supplementation of quercetin restored the lost relaxation in hyperoxic groups. Incubation of preparations in L-NAME significantly reduced the quercetin effects on both contraction and relaxation (P < 0.01). Treatment of hyperoxic animals with quercetin significantly decreased the expression of TNF-α and IL-1ß compared with hyperoxic controls (P < 0.001 and P < 0.01, respectively).The findings of this study demonstrate the protective effect of quercetin on airway hyperreactivity and suggest that quercetin might serve as a novel therapy to prevent and treat neonatal hyperoxia-induced airway hyperreactivity and inflammation.
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Asma , Hiperóxia , Ratos , Animais , Ratos Sprague-Dawley , Animais Recém-Nascidos , Quercetina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Hiperóxia/complicações , Hiperóxia/patologia , Fator de Necrose Tumoral alfa/metabolismo , Pulmão/patologia , Asma/metabolismo , Suplementos NutricionaisRESUMO
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.
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Hiperóxia , Lesão Pulmonar , Receptores de Interleucina-8A , Humanos , Células Endoteliais/metabolismo , Glutamina/metabolismo , Hiperóxia/complicações , Hiperóxia/metabolismo , Pulmão/metabolismo , Lesão Pulmonar/terapia , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Camundongos , Receptores de Interleucina-8A/metabolismoRESUMO
Zinc (Zn) has antioxidant, anti-inflammatory and anti-proliferative actions, with Zn dysregulation associated with coronary ischemia/reperfusion injury and smooth muscle cell dysfunction. As the majority of studies concerning Zn have been conducted under non-physiological hyperoxic conditions, we compare the effects of Zn chelation or supplementation on total intracellular Zn content, antioxidant NRF2 targeted gene transcription and hypoxia/reoxygenation-induced reactive oxygen species generation in human coronary artery smooth muscle cells (HCASMC) pre-adapted to hyperoxia (18 kPa O2) or normoxia (5 kPa O2). Expression of the smooth muscle marker SM22-α was unaffected by lowering pericellular O2, whereas calponin-1 was significantly upregulated in cells under 5 kPa O2, indicating a more physiological contractile phenotype under 5 kPa O2. Inductively coupled plasma mass spectrometry established that Zn supplementation (10 µM ZnCl2 + 0.5 µM pyrithione) significantly increased total Zn content in HCASMC under 18 but not 5 kPa O2. Zn supplementation increased metallothionein mRNA expression and NRF2 nuclear accumulation in cells under 18 or 5 kPa O2. Notably, NRF2 regulated HO-1 and NQO1 mRNA expression in response to Zn supplementation was only upregulated in cells under 18 but not 5 kPa. Furthermore, whilst hypoxia increased intracellular glutathione (GSH) in cells pre-adapted to 18 but not 5 kPa O2, reoxygenation had negligible effects on GSH or total Zn content. Reoxygenation-induced superoxide generation in cells under 18 kPa O2 was abrogated by PEG-superoxide dismutase but not by PEG-catalase, and Zn supplementation, but not Zn chelation, attenuated reoxygenation-induced superoxide generation in cells under 18 but not 5kPaO2, consistent with a lower redox stress under physiological normoxia. Our findings highlight that culture of HCASMC under physiological normoxia recapitulates an in vivo contractile phenotype and that effects of Zn on NRF2 signaling are altered by oxygen tension.
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Vasos Coronários , Hiperóxia , Humanos , Vasos Coronários/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/metabolismo , Superóxidos/metabolismo , Zinco/farmacologia , Zinco/metabolismo , Hipóxia/metabolismo , Miócitos de Músculo Liso/metabolismo , Hiperóxia/metabolismo , Glutationa/metabolismo , RNA Mensageiro/metabolismo , Suplementos NutricionaisRESUMO
AIMS: Pulmonary oxygen toxicity is caused by exposure to a high fraction of inspired oxygen, which damages multiple cell types within the lung. The cellular basis for pulmonary oxygen toxicity includes mitochondrial dysfunction. The aim of this study was to identify the effects of hyperoxic exposure on mitochondrial bioenergetic and dynamic functions in pulmonary cells. MAIN METHODS: Mitochondrial respiration, inner membrane potential, dynamics (including motility), and distribution of mitochondrial bioenergetic capacity in two intracellular regions were quantified using cultured human lung microvascular endothelial cells, human pulmonary artery endothelial cells and A549 cells. Hyperoxic (95 % O2) exposures lasted 24, 48 and 72 h, durations relevant to mechanical ventilation in intensive care settings. KEY FINDINGS: Mitochondrial motility was altered following all hyperoxic exposures utilized in experiments. Inhomogeneities in inner membrane potential and respiration parameters were present in each cell type following hyperoxia. The partitioning of ATP-linked respiration was also hyperoxia-duration and cell type dependent. Hyperoxic exposure lasting 48 h or longer provoked the largest alterations in mitochondrial motility and the greatest decreases in ATP-linked respiration, with a suggestion of decreases in respiration complex protein levels. SIGNIFICANCE: Hyperoxic exposures of different durations produce intracellular inhomogeneities in mitochondrial dynamics and bioenergetics in pulmonary cells. Oxygen therapy is utilized commonly in clinical care and can induce undesirable decrements in bioenergy function needed to maintain pulmonary cell function and viability. There may be adjunctive or prophylactic measures that can be employed during hyperoxic exposures to prevent the mitochondrial dysfunction that signals the presence of oxygen toxcity.
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Hiperóxia , Humanos , Hiperóxia/metabolismo , Células Endoteliais/metabolismo , Pulmão/metabolismo , Oxigênio/metabolismo , Metabolismo Energético , Trifosfato de Adenosina/metabolismoRESUMO
The COMEX-30 hyperbaric treatment table is used to manage decompression sickness in divers but may result in pulmonary oxygen toxicity (POT). Volatile organic compounds (VOCs) in exhaled breath are early markers of hyperoxic stress that may be linked to POT. The present study assessed whether VOCs following COMEX-30 treatment are early markers of hyperoxic stress and/or POT in ten healthy, nonsmoking volunteers. Because more oxygen is inhaled during COMEX-30 treatment than with other treatment tables, this study hypothesized that VOCs exhaled following COMEX-30 treatment are indicators of POT. Breath samples were collected before and 0.5, 2, and 4 h after COMEX-30 treatment. All subjects were followed-up for signs of POT or other symptoms. Nine compounds were identified, with four (nonanal, decanal, ethyl acetate, and tridecane) increasing 33-500% in intensity from before to after COMEX-30 treatment. Seven subjects reported pulmonary symptoms, five reported out-of-proportion tiredness and transient ear fullness, and four had signs of mild dehydration. All VOCs identified following COMEX-30 treatment have been associated with inflammatory responses or pulmonary diseases, such as asthma or lung cancer. Because most subjects reported transient pulmonary symptoms reflecting early-stage POT, the identified VOCs are likely markers of POT, not just hyperbaric hyperoxic exposure.
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Introduction: Supplementation with increased inspired oxygen fractions has been suggested to alleviate the harmful effects of tissue hypoxia during hemorrhagic shock (HS) and traumatic brain injury. However, the utility of therapeutic hyperoxia in critical care is disputed to this day as controversial evidence is available regarding its efficacy. Furthermore, in contrast to its hypoxic counterpart, the effect of hyperoxia on the metabolism of circulating immune cells remains ambiguous. Both stimulating and detrimental effects are possible; the former by providing necessary oxygen supply, the latter by generation of excessive amounts of reactive oxygen species (ROS). To uncover the potential impact of increased oxygen fractions on circulating immune cells during intensive care, we have performed a 13C-metabolic flux analysis (MFA) on PBMCs and granulocytes isolated from two long-term, resuscitated models of combined acute subdural hematoma (ASDH) and HS in pigs with and without cardiovascular comorbidity. Methods: Swine underwent resuscitation after 2 h of ASDH and HS up to a maximum of 48 h after HS. Animals received normoxemia (PaO2 = 80 - 120 mmHg) or targeted hyperoxemia (PaO2 = 200 - 250 mmHg for 24 h after treatment initiation, thereafter PaO2 as in the control group). Blood was drawn at time points T1 = after instrumentation, T2 = 24 h post ASDH and HS, and T3 = 48 h post ASDH and HS. PBMCs and granulocytes were isolated from whole blood to perform electron spin resonance spectroscopy, high resolution respirometry and 13C-MFA. For the latter, we utilized a parallel tracer approach with 1,2-13C2 glucose, U-13C glucose, and U-13C glutamine, which covered essential pathways of glucose and glutamine metabolism and supplied redundant data for robust Bayesian estimation. Gas chromatography-mass spectrometry further provided multiple fragments of metabolites which yielded additional labeling information. We obtained precise estimations of the fluxes, their joint credibility intervals, and their relations, and characterized common metabolic patterns with principal component analysis (PCA). Results: 13C-MFA indicated a hyperoxia-mediated reduction in tricarboxylic acid (TCA) cycle activity in circulating granulocytes which encompassed fluxes of glutamine uptake, TCA cycle, and oxaloacetate/aspartate supply for biosynthetic processes. We further detected elevated superoxide levels in the swine strain characterized by a hypercholesterolemic phenotype. PCA revealed cell type-specific behavioral patterns of metabolic adaptation in response to ASDH and HS that acted irrespective of swine strains or treatment group. Conclusion: In a model of resuscitated porcine ASDH and HS, we saw that ventilation with increased inspiratory O2 concentrations (PaO2 = 200 - 250 mmHg for 24 h after treatment initiation) did not impact mitochondrial respiration of PBMCs or granulocytes. However, Bayesian 13C-MFA results indicated a reduction in TCA cycle activity in granulocytes compared to cells exposed to normoxemia in the same time period. This change in metabolism did not seem to affect granulocytes' ability to perform phagocytosis or produce superoxide radicals.
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Hematoma Subdural Agudo , Hiperóxia , Choque Hemorrágico , Animais , Suínos , Glutamina/metabolismo , Ciclo do Ácido Cítrico , Análise do Fluxo Metabólico/métodos , Superóxidos , Teorema de Bayes , Granulócitos/metabolismo , Oxigênio , Glucose/metabolismoRESUMO
INTRODUCTION: Previous studies have highlighted hyperoxia-induced microcirculation modifications, but few have focused on hyperbaric oxygen (HBO) effects. Our primary objective was to explore hyperbaric hyperoxia effects on the microcirculation of healthy volunteers and investigate whether these modifications are adaptative or not. METHODS: This single centre, open-label study included 15 healthy volunteers. Measurements were performed under five conditions: T0) baseline value (normobaric normoxia); T1) hyperbaric normoxia; T2) hyperbaric hyperoxia; T3) normobaric hyperoxia; T4) return to normobaric normoxia. Microcirculatory data were gathered via laser Doppler, near-infrared spectroscopy and transcutaneous oximetry (PtcO2). Vascular-occlusion tests were performed at each step. We used transthoracic echocardiography and standard monitoring for haemodynamic investigation. RESULTS: Maximal alterations were observed under hyperbaric hyperoxia which led, in comparison with baseline, to arterial hypertension (mean arterial pressure 105 (SD 12) mmHg vs 95 (11), P < 0.001) and bradycardia (55 (7) beats·min⻹ vs 66 (8), P < 0.001) while cardiac output remained unchanged. Hyperbaric hyperoxia also led to microcirculatory vasoconstriction (rest flow 63 (74) vs 143 (73) perfusion units, P < 0.05) in response to increased PtcO2 (104.0 (45.9) kPa vs 6.3 (2.4), P < 0.0001); and a decrease in laser Doppler parameters indicating vascular reserve (peak flow 125 (89) vs 233 (79) perfusion units, P < 0.05). Microvascular reactivity was preserved in every condition. CONCLUSIONS: Hyperoxia significantly modifies healthy volunteer microcirculation especially during HBO exposure. The rise in PtcO2 promotes an adaptative vasoconstrictive response to protect cellular integrity. Microvascular reactivity remains unaltered and vascular reserve is mobilised in proportion to the extent of the ischaemic stimulus.
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Oxigenoterapia Hiperbárica , Hiperóxia , Humanos , Microcirculação/fisiologia , Voluntários Saudáveis , Oxigênio , Hemodinâmica/fisiologia , Oxigenoterapia Hiperbárica/métodosRESUMO
A high fiber diet (HFD) and dietary supplementation with acetate have been reported to have beneficial effects in a variety of diseases. We investigated the effects of a HFD and acetate supplementation on the gut microbiota and hyperoxia-induced acute lung injury (HALI) in mice. Mice were fed a control diet, HFD, or acetate supplementation for three weeks, and their gut microbiome composition, lung tissues, and bronchoalveolar lavage fluid (BALF) were examined after exposure to ambient air or hyperoxia. Both the HFD and acetate supplementation modified the gut microbiota community and increased the proportion of acetate-producing bacteria in mice exposed to hyperoxia. The HFD and acetate supplementation also increased the abundance of Bacteroides acidifaciens and reduced gut dysbiosis according to the ratio of Firmicutes to Bacteroidetes. Compared with hyperoxia-exposed mice fed a control diet, both the HFD and acetate supplementation significantly increased the survival time while reducing the severity of pulmonary edema and the concentrations of protein and inflammatory mediators in BALF. Moreover, the HFD and acetate supplementation reduced the production of free radicals, attenuated NF-κB signaling activation, and decreased apoptosis in the lung tissues. Overall, this study indicates that a HFD or acetate supplementation reduces the severity of HALI through alterations in the gut microbiota to exert anti-inflammatory effects.
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Lesão Pulmonar Aguda , Hiperóxia , Camundongos , Animais , Dieta Hiperlipídica , Acetatos , Suplementos Nutricionais , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Premature infants, subjected to supplemental oxygen and mechanical ventilation, may develop bronchopulmonary dysplasia, a chronic lung disease characterized by alveolar dysplasia and impaired vascularization. We and others have shown that hyperoxia causes senescence in cultured lung epithelial cells and fibroblasts. Although miR-34a modulates senescence, it is unclear whether it contributes to hyperoxia-induced senescence. We hypothesized that hyperoxia increases miR-34a levels, leading to cellular senescence. METHODS: We exposed mouse lung epithelial (MLE-12) cells and primary human small airway epithelial cells to hyperoxia (95% O2/5% CO2) or air (21% O2/5% CO2) for 24 h. Newborn mice (< 12 h old) were exposed to hyperoxia (> 95% O2) for 3 days and allowed to recover in room air until postnatal day 7. Lung samples from premature human infants requiring mechanical ventilation and control subjects who were not mechanically ventilated were employed. RESULTS: Hyperoxia caused senescence as indicated by loss of nuclear lamin B1, increased p21 gene expression, and senescence-associated secretory phenotype factors. Expression of miR-34a-5p was increased in epithelial cells and newborn mice exposed to hyperoxia, and in premature infants requiring mechanical ventilation. Transfection with a miR-34a-5p inhibitor reduced hyperoxia-induced senescence in MLE-12 cells. Additionally, hyperoxia increased protein levels of the oncogene and tumor-suppressor Krüppel-like factor 4 (KLF4), which were inhibited by a miR-34a-5p inhibitor. Furthermore, KLF4 knockdown by siRNA transfection reduced hyperoxia-induced senescence. CONCLUSION: Hyperoxia increases miR-34a-5p, leading to senescence in lung epithelial cells. This is dictated in part by upregulation of KLF4 signaling. Therefore, inhibiting hyperoxia-induced senescence via miR-34a-5p or KLF4 suppression may provide a novel therapeutic strategy to mitigate the detrimental consequences of hyperoxia in the neonatal lung.
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Displasia Broncopulmonar , Hiperóxia , Fator 4 Semelhante a Kruppel , MicroRNAs , Animais , Humanos , Camundongos , Animais Recém-Nascidos , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/tratamento farmacológico , Dióxido de Carbono , Senescência Celular , Células Epiteliais/metabolismo , Hiperóxia/genética , Hiperóxia/metabolismo , Fator 4 Semelhante a Kruppel/genética , Fator 4 Semelhante a Kruppel/metabolismo , Pulmão/metabolismo , MicroRNAs/metabolismoRESUMO
Oxygen is a powerful trigger for cellular reactions, but there are few comparative investigations assessing the effects over a large range of partial pressures. We investigated a metabolic response to single exposures to either normobaric (10%, 15%, 30%, 100%) or hyperbaric (1.4 ATA, 2.5 ATA) oxygen. Forty-eight healthy subjects (32 males/16 females; age: 43.7 ± 13.4 years, height: 172.7 ± 10.07 cm; weight 68.4 ± 15.7 kg) were randomly assigned, and blood samples were taken before and 2 h after each exposure. Microparticles (MPs) expressing proteins specific to different cells were analyzed, including platelets (CD41), neutrophils (CD66b), endothelial cells (CD146), and microglia (TMEM). Phalloidin binding and thrombospondin-1 (TSP), which are related to neutrophil and platelet activation, respectively, were also analyzed. The responses were found to be different and sometimes opposite. Significant elevations were identified for MPs expressing CD41, CD66b, TMEM, and phalloidin binding in all conditions but for 1.4 ATA, which elicited significant decreases. Few changes were found for CD146 and TSP. Regarding OPB, further investigation is needed to fully understand the future applications of such findings.
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Oxigenoterapia Hiperbárica , Oxigênio , Adulto , Antígeno CD146 , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxigênio/metabolismo , Pressão Parcial , FaloidinaRESUMO
Oxygen supplementation is regularly prescribed to patients to treat or prevent hypoxia. However, excess oxygenation can lead to reduced cerebral blood flow (CBF) in healthy subjects and worsen the neurological outcome of critically ill patients. Most studies on the vascular effects of hyperoxia focus on arteries but there is no research on the effects on cerebral capillary pericytes, which are major regulators of CBF. Here, we used bright-field imaging of cerebral capillaries and modeling of CBF to show that hyperoxia (95% superfused O2) led to an increase in intracellular calcium level in pericytes and a significant capillary constriction, sufficient to cause an estimated 25% decrease in CBF. Although hyperoxia is reported to cause vascular smooth muscle cell contraction via generation of reactive oxygen species (ROS), endothelin-1 and 20-HETE, we found that increased cytosolic and mitochondrial ROS levels and endothelin release were not involved in the pericyte-mediated capillary constriction. However, a 20-HETE synthesis blocker greatly reduced the hyperoxia-evoked capillary constriction. Our findings establish pericytes as regulators of CBF in hyperoxia and 20-HETE synthesis as an oxygen sensor in CBF regulation. The results also provide a mechanism by which clinically administered oxygen can lead to a worse neurological outcome.
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Hiperóxia , Pericitos , Cálcio/metabolismo , Capilares , Circulação Cerebrovascular/fisiologia , Constrição , Constrição Patológica , Endotelina-1/metabolismo , Humanos , Hiperóxia/metabolismo , Oxigênio/metabolismo , Pericitos/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Introduction: The hyperbaric oxygen treatment table 6 (TT6) is widely used to manage dysbaric illnesses in divers and iatrogenic gas emboli in patients after surgery and other interventional procedures. These treatment tables can have adverse effects, such as pulmonary oxygen toxicity (POT). It is caused by reactive oxygen species' damaging effect in lung tissue and is often experienced after multiple days of therapy. The subclinical pulmonary effects have not been determined. The primary aim of this study was to measure volatile organic compounds (VOCs) in breath, indicative of subclinical POT after a TT6. Since the exposure would be limited, the secondary aim of this study was to determine whether these VOCs decreased to baseline levels within a few hours. Methods: Fourteen healthy, non-smoking volunteers from the Royal Netherlands Navy underwent a TT6 at the Amsterdam University Medical Center-location AMC. Breath samples for GC-MS analysis were collected before the TT6 and 30 min, 2 and 4 h after finishing. The concentrations of ions before and after exposure were compared by Wilcoxon signed-rank tests. The VOCs were identified by comparing the chromatograms with the NIST library. Compound intensities over time were tested using Friedman tests, with Wilcoxon signed-rank tests and Bonferroni corrections used for post hoc analyses. Results: Univariate analyses identified 11 compounds. Five compounds, isoprene, decane, nonane, nonanal and dodecane, showed significant changes after the Friedman test. Isoprene demonstrated a significant increase at 30 min after exposure and a subsequent decrease at 2 h. Other compounds remained constant, but declined significantly 4 h after exposure. Discussion and Conclusion: The identified VOCs consisted mainly of (methyl) alkanes, which may be generated by peroxidation of cell membranes. Other compounds may be linked to inflammatory processes, oxidative stress responses or cellular metabolism. The hypothesis, that exhaled VOCs would increase after hyperbaric exposure as an indicator of subclinical POT, was not fulfilled, except for isoprene. Hence, no evident signs of POT or subclinical pulmonary damage were detected after a TT6. Further studies on individuals recently exposed to pulmonary irritants, such as divers and individuals exposed to other hyperbaric treatment regimens, are needed.
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The antioxidant and anti-inflammatory effects of electrophilic nitrated fatty acid (NFA); 10-nitrooleate, have been reported. The present study investigated whether 10-nitrooleate has a protective role against hyperoxic-induced acute lung injury (HALI). Using a C57BL/6 mice model of HALI, we investigated the protective effect of 10-nitrooleate. C57BL/6 mice were administered with NFA intratracheally, exposed to hyperoxia for 48 h to induce HALI, and kept at room air for 24 h. Bronchoalveolar lavage (BAL) fluid and lung samples were collected after 24 h of post hyperoxia to analyze markers associated with HALI. Intratracheal (IT) and intraperitoneal (IP) administration of NFA notably attenuated hyperoxia-induced infiltration of inflammatory cells, alveolar-capillary leakage, upregulation of proinflammatory cytokine levels (IL-6 and TNFα) into the BAL fluid, and resolution of inflammation in the lung. Western blot analyses showed that 10-nitrooleate reduced the expression of the inflammatory transcription factor NFκB p65 subunit and increased antioxidant proteins HO-1 and NQO1 expression in the lung tissues compared to vehicle-treated animals. Moreover, 10-nitrooleate reversed the hyperoxia-induced expression of mitophagy-associated markers (PINK1 and p62/SQSTM1), thereby protecting the HALI/ acute respiratory distress syndrome (ARDS). IT and IP delivery of 10-nitrooleate reduces hyperoxia-induced ALI/ARDS by regulating the antioxidant pathways and restoring the mitochondrial homeostasis by regulating mitophagy. It is suggested that NFAs can be further evaluated as supplementary therapy for critically ill patients like COVID-19/ARDS.
Assuntos
Lesão Pulmonar Aguda , COVID-19 , Hiperóxia , Lesão Pulmonar , Síndrome do Desconforto Respiratório , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Ácidos Graxos/metabolismo , Humanos , Hiperóxia/complicações , Hiperóxia/metabolismo , Pulmão/metabolismo , Lesão Pulmonar/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nitratos/efeitos adversos , Nitratos/metabolismoRESUMO
Iron is an essential metal for cellular metabolism and signaling, but it has adverse effects in excess. The physiological consequences of iron deficiency are well established, yet the relationship between iron supplementation and pericellular oxygen levels in cultured cells and their downstream effects on metalloproteins has been less explored. This study exploits the metalloprotein geNOps in cultured HEK293T epithelial and EA.hy926 endothelial cells to test the iron-dependency in cells adapted to standard room air (18 kPa O2) or physiological normoxia (5 kPa O2). We show that cells in culture require iron supplementation to activate the metalloprotein geNOps and demonstrate for the first time that cells adapted to physiological normoxia require significantly lower iron compared to cells adapted to hyperoxia. This study establishes an essential role for recapitulating oxygen levels in vivo and uncovers a previously unrecognized requirement for ferrous iron supplementation under standard cell culture conditions to achieve geNOps functionality.
Assuntos
Técnicas Biossensoriais , Metaloproteínas , Células Endoteliais/metabolismo , Células HEK293 , Humanos , Ferro/metabolismo , Metaloproteínas/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/metabolismoRESUMO
Hyperoxia, is often used in preterm supportive care, leading to high oxygen exposure in neonates. Coenzyme Q10 (CoQ10) is a free radical scavenger that has been studied in older children but never be investigated for its role in preterm care. We hypothesize that the administration of exogenous CoQ10 would raise serum concentrations of CoQ10 and mitigate the adverse effects of hyperoxia on the organs by reducing oxygen-free radicals and inflammation. The aim of this study was to evaluate the effects of oxidative stress, inflammatory response, and survival in neonatal rats after CoQ10 treatment. Neonatal rats delivered from four pregnant Wistar rats were randomly divided into four groups: (a) control, (b) CoQ10, (c) hyperoxia (O2 group), and (d) treatment (CoQ10 + O2 ) groups. The dose of CoQ10 injected was 30 mg/kg. The CoQ9, CoQ10, cytokines, oxidative stress, and antioxidant enzyme activity were measured. Tissue samples were histologically examined and mortality was monitored for 16 days. The level of CoQ9 significantly increased in the liver, kidney, and plasma, while the level of CoQ10 significantly increased in most organ tissues in the CoQ10 + O2 group. Additionally, CoQ10 decrease oxidative stress in the liver, increase antioxidant enzyme activity in the heart, kidney, and brain, and reverse an inclined level of hematopoietic growth factors. However, CoQ10 had no effect on inflammation, organ damage, or mortality. Therefore, the use of CoQ10 in potential adjuvant therapy for neonatal hyperoxia requires further research.