Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure to high levels of inspired oxygen leads to respiratory failure and death in many animal models. Endothelial cell death is an early finding, before the onset of respiratory failure. Vascular endothelial growth factor (VEGF) is highly expressed in the lungs of adult animals. In the present study, adult Sprague-Dawley rats were exposed to >95% FiO2 for 24 or 48 hours. Northern blot analysis revealed a marked reduction in VEGF mRNA abundance by 24 hours, which decreased to less than 50% of control by 48 hours. In situ hybridization revealed that VEGF was highly expressed in distal airway epithelial cells in controls but disappeared in the oxygen-exposed animals. Immunohistochemistry and Western blot analyses demonstrated that VEGF protein was decreased at 48 hours. TUNEL staining demonstrated the presence of apoptotic cells coincident with the decline in VEGF. Abundance of VEGF receptor mRNAs (Flt-1 and KDR/Flk) decreased in the late time points of the study (48 hours), possibly secondary to the loss of endothelial cells. We speculate that VEGF functions as a survival factor in the normal adult rat lung, and its loss during hyperoxia contributes to the pathophysiology of oxygen-induced lung damage.
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PMID:Exposure to hyperoxia decreases the expression of vascular endothelial growth factor and its receptors in adult rat lungs. 1007 60

Surfactant protein B (SP-B) is a 79-amino acid hydrophobic surfactant protein that plays a critical role in postnatal lung function. Homozygous SP-B (-/-)-deficient mice die of respiratory failure at birth, associated with severe pulmonary dysfunction and atelectasis. Heterozygous SP-B (+/-)-deficient mice have 50% less SP-B protein, proprotein, and SP-B mRNA compared with control mice and are highly susceptible to oxygen-induced lung injury. In the current study, we tested whether the susceptibility of SP-B (+/-) mice to hyperoxia was restored by intratracheal administration of exogenous SP-B. After exposure to 95% oxygen for 3 d, opening pressures were increased and maximal lung volumes were significantly decreased in SP-B (+/-) mice compared with SP-B (+/+) mice. SP-B (+/-) mice were administered purified bovine SP-B (2%) with DL-alpha dipalmitoyl phosphatidylcholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-( -glycerol)] (POPG) phospholipids or DPPC and POPG phospholipids intratracheally and exposed to 95% oxygen. SP-B-treated SP-B (+/-) mice survived longer in 95% oxygen. Although decreased lung function in SP-B (+/-) mice exposed to oxygen was not altered by administration of DPPC and POPG, administration of lipids containing 2% purified bovine SP-B restored lung function when assessed after 3 d in oxygen. Abnormalities in pulmonary function in SP-B (+/-) mice after oxygen exposure were associated with increased alveolar capillary leak, which was corrected by administration of SP-B with DPPC and POPG. Likewise, histologic abnormalities caused by oxygen-induced lung injury were improved by administration of SP-B with DPPC and POPG. Administration of phospholipids with the active SP-B peptide was sufficient to restore pulmonary function and prevent alveolar capillary leak after oxygen exposure, demonstrating the protective role of SP-B during oxygen-induced lung injury.
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PMID:Surfactant protein B corrects oxygen-induced pulmonary dysfunction in heterozygous surfactant protein B-deficient mice. 1059 28

We studied interrelationships between exercise endurance, ventilatory demand, operational lung volumes, and dyspnea during acute hyperoxia in ventilatory-limited patients with advanced chronic obstructive pulmonary disease (COPD). Eleven patients with COPD (FEV(1.0) = 31 +/- 3% predicted, mean +/- SEM) and chronic respiratory failure (Pa(O(2)) 52 +/- 2 mm Hg, Pa(CO(2 ))48 +/- 2 mm Hg) breathed room air (RA) or 60% O(2) during two cycle exercise tests at 50% of their maximal exercise capacity, in randomized order. Endurance time (T(lim)), dyspnea intensity (Borg Scale), ventilation (V E), breathing pattern, dynamic inspiratory capacity (IC(dyn)), and gas exchange were compared. Pa(O(2)) at end-exercise was 46 +/- 3 and 245 +/- 10 mm Hg during RA and O(2), respectively. During O(2), T(lim) increased 4.7 +/- 1.4 min (p < 0.001); slopes of Borg, V E, V CO(2), and lactate over time fell (p < 0.05); slopes of Borg-V E, V E-V CO(2), V E-lactate were unchanged. At a standardized time near end-exercise, O(2) reduced dyspnea 2.0 +/- 0.5 Borg units, V CO(2) 0.06 +/- 0.03 L/min, V E 2.8 +/- 1.0 L/min, and breathing frequency 4.4 +/- 1.1 breaths/min (p < 0.05 each). IC(dyn) and inspiratory reserve volume (IRV) increased throughout exercise with O(2) (p < 0.05). Increased IC(dyn) was explained by the combination of increased resting IRV and decreased exercise breathing frequency (r(2) = 0.83, p < 0.0005). In conclusion, improved exercise endurance during hyperoxia was explained, in part, by a combination of reduced ventilatory demand, improved operational lung volumes, and dyspnea alleviation.
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PMID:Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. 1128 62

Although the surface properties of surfactant protein (SP)-B and SP-C are similar, the contributions that either protein may make to lung function have not been identified in vivo. Mutations in SP-B cause lethal respiratory failure at birth; however, SP-B null mice are deficient in both SP-B and SP-C. To identify potential contributions of SP-C to lung function in vivo, the following transgenic mice were generated and exposed to 95% O(2) for 3 days: (SP-B(+/+),SP-C(+/+)), (SP-B(+/+), SP-C(-/-)), (SP-B(+/-),SP-C(+/+)), (SP-B(+/-),SP-C(+/-)), and (SP-B(+/-),SP-C(-/-)). Hyperoxia altered pressure-volume curves in mice that were heterozygous for SP-B, and these values were further decreased in (SP-B(+/-),SP-C(-/-)) mice. Likewise, alveolar interleukin (IL)-6 and IL-1 beta were maximally increased by O(2) exposure of (SP-B(+/-),SP-C(-/-)) mice compared with the other genotypes. Lung hysteresivity was lower in the (SP-B(+/-),SP-C(-/-)) mice. Surfactant isolated from (SP-B(+/+),SP-C(-/-)) and (SP-B(+/-),SP-C(-/-)) mice failed to stabilize the surface tension of microbubbles, showing that SP-C plays a role in stabilization or recruitment of phospholipid films at low bubble radius. Genetically decreased levels of SP-B combined with superimposed O(2)-induced injury reveals the distinct contribution of SP-C to pulmonary function in vivo.
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PMID:Deficiency of SP-B reveals protective role of SP-C during oxygen lung injury. 1179 59

Therapy with high oxygen concentrations (hyperoxia) is often necessary to treat patients with respiratory failure. However, hyperoxia may exacerbate the development of acute lung injury, perhaps by increasing lung epithelial cell death. Therefore, interrupting lung epithelial cell death is an important protective and therapeutic strategy. In the present study, hyperoxia (95% O(2)) results in murine lung epithelium cell death by DNA-laddering, terminal deoxynucleotidyltransferase dUTP nick end labeling, and Annexin V-fluorescein isothiocyanate flow cytometry assay. We show that hyperoxia increases superoxide production, as assessed by nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity and flow cytometric assay, and increases phospho-extracellular signal-regulated kinase (ERK)1/2 by Western blot analysis. These processes are inhibited by a reactive oxygen species inhibitor, diphenylene iodonium (DPI), and by an inhibitor of the mitogen-activated protein (MAP) or ERK kinase (MEK)/ERK1/2 pathway, PD98059. ERK1/2 activation in hyperoxia is also inhibited by DPI. Hyperoxia-induced cell death is associated with cytochrome c release, subsequent caspase 9 and 3 activation, and poly (ADP-ribosyl) polymerase cleavage, which can all be suppressed by DPI and PD98059. However, the broad caspase inhibitor z-VAD-FMK protects cells from death without affecting superoxide generation and ERK1/2 activation. Taken together, our data suggest that hyperoxia, by virtue of activating NADPH oxidase, generates reactive oxygen species (ROS), which mediates cell death of lung epithelium via ERK1/2 MAPK activation, and functions upstream of caspase activation in lung epithelial cells.
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PMID:Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase mediate hyperoxia-induced cell death in lung epithelium. 1259 56

Administration of high concentrations of oxygen (hyperoxia) is a mainstay of supportive treatment for patients suffering from severe respiratory failure. However, hyperoxia, by generating excess systemic reactive oxygen species (ROS), can exacerbate organ failure by causing cellular injury. Therefore, a better understanding of the signal transduction pathways in hyperoxia may provide the basis for effective therapeutic interventions. The major biological effects of hyperoxia include cell death, induction of stress responses, inflammation, and modulation of cell growth. Major signaling pathways that appear to be involved include the mitogen-activated protein kinases (MAPKs), AP-1, and NF-kappa B, which converge, ultimately, to the expression of a range of stress response genes, cytokines, and growth factors.
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PMID:Pathways of cell signaling in hyperoxia. 1289 37

Patients with Pneumocystis pneumonia often develop respiratory failure after entry into medical care, and one mechanism for this deterioration may be increased alveolar epithelial cell injury. In vitro, we previously demonstrated that Pneumocystis is not cytotoxic for alveolar epithelial cells. In vivo, however, infection with Pneumocystis could increase susceptibility to injury by stressors that, alone, would be sublethal. We examined transient exposure to hyperoxia as a prototypical stress that does cause mortality in normal mice. Mice were depleted of CD4+ T cells and inoculated intratracheally with Pneumocystis. Control mice were depleted of CD4+ T cells but did not receive Pneumocystis. After 4 weeks, mice were maintained in normoxia, were exposed to hyperoxia for 4 days, or were exposed to hyperoxia for 4 days followed by return to normoxia. CD4-depleted mice with Pneumocystis pneumonia demonstrated significant mortality after transient exposure to hyperoxia, while all uninfected control mice survived this stress. We determined that organism burdens were not different. However, infected mice exposed to hyperoxia and then returned to normoxia demonstrated significant increases in inflammatory cell accumulation and lung cell apoptosis. We conclude that Pneumocystis pneumonia leads to increased mortality following a normally sublethal hyperoxic insult, accompanied by alveolar epithelial cell injury and increased pulmonary inflammation.
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PMID:Pneumocystis pneumonia increases the susceptibility of mice to sublethal hyperoxia. 1450 May 17

Exposure of animals to hyperoxia results in respiratory failure and death within 72 h. Histologic evaluation of the lungs of these animals demonstrates epithelial apoptosis and necrosis. Although the generation of reactive oxygen species (ROS) is widely thought to be responsible for the cell death observed following exposure to hyperoxia, it is not clear whether they act upstream of activation of the cell death pathway or whether they are generated as a result of mitochondrial membrane permeabilization and caspase activation. We hypothesized that the generation of ROS was required for hyperoxia-induced cell death upstream of Bax activation. In primary rat alveolar epithelial cells, we found that exposure to hyperoxia resulted in the generation of ROS that was completely prevented by the administration of the combined superoxide dismutase/catalase mimetic EUK-134 (Eukarion, Inc., Bedford, MA). Exposure to hyperoxia resulted in the activation of Bax at the mitochondrial membrane, cytochrome c release, and cell death. The administration of EUK-134 prevented Bax activation, cytochrome c release, and cell death. In a mouse lung epithelial cell line (MLE-12), the overexpression of Bcl-XL protected cells against hyperoxia by preventing the activation of Bax at the mitochondrial membrane. We conclude that exposure to hyperoxia results in Bax activation at the mitochondrial membrane and subsequent cytochrome c release. Bax activation at the mitochondrial membrane requires the generation of ROS and can be prevented by the overexpression of Bcl-XL.
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PMID:Reactive oxygen species are required for hyperoxia-induced Bax activation and cell death in alveolar epithelial cells. 1462 74

Pulmonary surfactant, a complex of lipids and proteins, maintains alveolar integrity and participates in the control of host defense and inflammation in the lung. Surfactant proteins A, B, C, and D are important components of surfactant that play diverse roles in the surface tension reducing as well as host defense and inflammation control functions of surfactant. Hyperoxia or exposure of cells/tissues to elevated levels of oxygen occurs when high levels of oxygen are used to treat a variety of pulmonary disorders that include respiratory distress syndrome of premature infants, emphysema, sarcoidosis, end-stage lung diseases, and others. The lung serves as a primary target organ in hyperoxia, and hyperoxic lung injury is characterized by pulmonary edema, inflammation, and respiratory failure. Hyperoxic lung injury is associated with significant changes in the expression of surfactant proteins that likely serves as an adaptive response to elevated oxygen levels. In most animal species studied, hyperoxia increases the tissue expression of surfactant protein mRNAs. A limited number of studies have indicated that the increased tissue expression of surfactant protein mRNAs is associated with increased levels of surfactant proteins in the bronchoalveolar lavage.
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PMID:Regulation of surfactant protein gene expression by hyperoxia in the lung. 1471 50

Respiratory failure is a serious consequence of lung cell injury caused by treatment with high inhaled oxygen concentrations. Human lung microvascular endothelial cells (HLMVEC) are a principal target of hyperoxic injury (hyperoxia). Cell stress can cause release of ATP, and this extracellular nucleotide can activate purinoreceptors and mediate responses essential for survival. In this investigation, exposure of endothelial cells to an oxidative stress, hyperoxia, caused rapid but transient ATP release (20.03 +/- 2.00 nm/10(6) cells in 95% O(2) versus 0.08 +/- 0.01 nm/10(6) cells in 21% O2 at 30 min) into the extracellular milieu without a concomitant change in intracellular ATP. Endogenously produced extracellular ATP-enhanced mTOR-dependent uptake of glucose (3467 +/- 102 cpm/mg protein in 95% oxygen versus 2100 +/- 112 cpm/mg protein in control). Extracellular addition of ATP-activated important cell survival proteins like PI 3-kinase and extracellular-regulated kinase (ERK-1/2). These events were mediated primarily by P2Y receptors, specifically the P2Y2 and/or P2Y6 subclass of receptors. Extracellular ATP was required for the survival of HLMVEC in hyperoxia (55 +/- 10% surviving cells with extracellular ATP scavengers [apyrase + adenosine deaminase] versus 95 +/- 12% surviving cells without ATP scavengers at 4 d of hyperoxia). Incubation with ATP scavengers abolished ATP-dependent ERK phosphorylation stimulated by hyperoxia. Further, ERK activation also was found to be important for cell survival in hyperoxia, as treatment with PD98059 enhanced hyperoxia-mediated cell death. These findings demonstrate that ATP release and subsequent ATP-mediated signaling events are vital for survival of HLMVEC in hyperoxia.
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PMID:Extracellular ATP-mediated signaling for survival in hyperoxia-induced oxidative stress. 1476 47


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