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PubMed2004

Amplification by hyperoxia of coronary vasodilation induced by propofol.

UNLABELLED: We tested the hypothesis that in vitro coronary and myocardial effects of propofol (10-300 microM) should be significantly modified in an isolated and erythrocyte-perfused rabbit heart model in the absence (PaO(2) = 137 +/- 16 mm Hg, n = 12) or in the presence (PaO(2) = 541 +/- 138 mm Hg, n = 12) of hyperoxia. The induction of hyperoxia provoked a significant coronary vasoconstriction (-13% +/- 7%). Propofol induced increased coronary vasodilation in the presence of hyperoxia. Because high oxygen tension has been reported to induce a coronary vasoconstriction mediated by the closure of adenosine triphosphate-sensitive potassium channels, we studied the effects of propofol in 2 additional groups of hearts (n = 6 in each group) pretreated by glibenclamide (0.6 microM) and cromakalim (0.5 microM) in the absence and presence of hyperoxia, respectively. The pretreatment by glibenclamide induced a coronary vasoconstriction (-16% +/- 7%) which did not affect propofol coronary vasodilation. The pretreatment by cromakalim abolished the amplification of propofol coronary vasodilation in the presence of hyperoxia. Propofol induced a significant decrease in myocardial performance for a concentration >100 micro M both in the absence and presence of hyperoxia. We conclude that propofol coronary vasodilation is amplified in the presence of hyperoxia. This phenomenon is not explained by the previous coronary vasoconstriction induced by glibenclamide. However, the pretreatment of hearts by cromakalim abolished the amplification of propofol coronary vasodilation in the presence of hyperoxia. The myocardial effects of propofol were not affected by the presence of hyperoxia. IMPLICATIONS: Propofol induced a coronary vasodilation that was amplified in the presence of hyperoxia. This phenomenon does not seem to be related to previous coronary vasoconstriction. The myocardial effects of propofol were not significantly modified in the presence of hyperoxia.

ATP-Binding Cassette Transporters↗
PubMed2004

[Pulmonary apoptosis and necrosis in hyperoxia-induced acute mouse lung injury].

OBJECTIVE: To investigate the pathways to cell death in hyperoxia-induced lung injury and the functional significance of apoptosis in vivo in response to hyperoxia. METHODS: Seventy-two mice were exposed in sealed cages > 98% oxygen (for 24 - 72 h) or room air, and the severity of lung injury and epithelium sloughing was evaluated. The extent and location of apoptosis in injured lung tissues were studied by terminal transferase dUTP end labeling assay (TUNEL), reverse transcript-polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: Hyperoxia caused acute lung injury; the hyperoxic stress resulted in marked epithelium sloughing. TUNEL assay exhibited increased apoptosis index both in alveolar epithelial cells and bronchial epithelial cells in sections from mice after 48 h hyperoxia compared with their control group (0.51 +/- 0.10, 0.46 +/- 0.08 verse 0.04 +/- 0.02, 0.02 +/- 0.01). This was accompanied by increased expression of caspase-3 mRNA in lung tissues after 48 h hyperoxia compared with their control group (0.53 +/- 0.09 verse 0.34 +/- 0.07), the expression was higher at 72 h of hyperoxia (0.60 +/- 0.08). Immunohistochemistry study showed caspase-3 protein was located in cytoplasm and nuclei of airway epithelial cells, alveolar epithelial cells and macrophage in hyperoxia mice. The expression of caspase-3 protein in airway epithelium significantly increased at 24 h of hyperoxia compared with their control group (41.62 +/- 3.46 verse 15.86 +/- 1.84), the expression level was highest at 72 h of hyperoxia (55.24 +/- 6.80). CONCLUSIONS: Both apoptosis and necrosis contribute to cell death during hyperoxia. Apoptosis plays an important role in alveolar damage and cell death from hyperoxia.

Acute Disease↗
PubMed1989

Hyperoxia and the antimicrobial susceptibility of Escherichia coli and Pseudomonas aeruginosa.

We have tested the ability of hyperoxia (98% O2-2% CO2 at 2.8 atmospheres absolute [ca. 284.6 kPa]) to enhance killing of Escherichia coli (serotype O18 or ATCC 25922) by nitrofurantoin, sulfamethoxazole, trimethoprim, gentamicin, and tobramycin. We have also looked for interactions between hyperoxia and the aminoglycosides against Pseudomonas aeruginosa ATCC 27853. Hyperoxia significantly enhanced bacteriostatic activity of nitrofurantoin and trimethoprim as measured by MIC testing. The possibility exists that these effects might be due to the method required to tests MICs under hyperoxic conditions rather than to the effect of hyperoxia itself. In addition, hyperoxia enhanced killing of bacteria by trimethoprim as measured by MBC testing. Hyperoxia decreased numbers of E. coli by 1.3 log10 and P. aeruginosa by 2.7 log10 in cation-supplemented Mueller-Hinton broth medium. The bacteriostatic effects of hyperoxia did not affect MICs of gentamicin or tobramycin. The lack of interaction between hyperoxia and gentamicin or tobramycin was confirmed by determining the number of viable bacteria remaining after 24 h of exposure to hyperoxia by using a pour plate method. We conclude that hyperoxia potentiates the antimicrobial activity of the reduction-oxidation-cycling antibiotic tested (nitrofurantoin) and of one of the antimetabolites tested (trimethoprim). Hyperoxia does not enhance the bactericidal effects of gentamicin and tobramycin, which require oxidative metabolism for transport into bacterial cells.

Anti-Bacterial Agents↗
PubMed1990

Complex effects of in vitro hyperoxia on alveolar macrophage arachidonic acid metabolism.

Metabolites of arachidonic acid (AA) released into bronchoalveolar lavage fluid of animals exposed to hyperoxia have previously been implicated as mediators of pulmonary oxygen toxicity. The alveolar macrophage (AM) represents an important potential source of these eicosanoids. We have therefore investigated the effects of in vitro hyperoxia (95% O2/5% CO2) versus normoxia (95% air/5% CO2) on the metabolism of AA in the AM of the rat. Exposure to 95% O2 for up to 72 h did not impair the viability or affect the protein content of cultured AMs. Hyperoxia for 24 to 72 h increased the accumulation of free AA liberated from endogenous stores in cultures of resting AMs. Despite this increase in free AA, no changes in synthesis of thromboxane B2, prostaglandin (PG) E2, PGF2 alpha, leukotriene (LT) B4, or LTC4 were observed in resting AMs exposed to hyperoxia for up to 72 h. This was not due to degradation of eicosanoids in hyperoxia. However, formation of cyclooxygenase metabolites from exogenously supplied AA was reduced in hyperoxia-incubated AMs, suggesting that hyperoxia inhibited the cyclooxygenase enzyme. In AMs stimulated with calcium ionophore A23187, both AA release and synthesis of cyclooxygenase and lipoxygenase eicosanoids were augmented after incubation in hyperoxia for 24 to 72 h. The increase in A23187-stimulated LTB4 synthesis caused by hyperoxia was inhibited by the antioxidants catalase, superoxide dismutase, and the intracellular cysteine loading agent L-2-oxothiazolidine-4-carboxylic acid, suggesting that the augmentation by hyperoxia of A23187-induced AA metabolism was mediated by reactive oxygen metabolites. Thus, hyperoxia has complex effects on AA metabolism in the AM, which include the ability to augment the release of AA and formation of bioactive eicosanoids. These findings support a possible role for eicosanoid synthesis by the AM in the pathogenesis of oxygen toxicity of the lung.

Animals↗
PubMed2004

Extracellular signal-regulated kinase activation delays hyperoxia-induced epithelial cell death in conditions of Akt downregulation.

Hyperoxia (fraction of inspired oxygen = 95%) induces death of lung epithelial cells. The duration of cell survival in the setting of hyperoxia depends on hyperoxia-induced activation of intracellular survival pathways. Two survival pathways with known effects on lung epithelial cells are the propidium iodide 3-kinase/Akt and extracellular signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinase pathways. We investigated the effect of hyperoxia on activity of both the Akt and ERK pathways in the A549 lung epithelial cell line. Hyperoxia-exposed cells show progressive loss of Akt activation and total Akt protein. Hyperoxia decreases Akt mRNA, consistent with the loss of total Akt. In addition, hyperoxia induces ERK activation. Inhibition of ERK with the MAP kinase kinase 1/2 inhibitor, U0126, shortens the survival time of cells in hyperoxia, suggesting that increased ERK activity partially compensates for the hyperoxia-induced Akt downregulation. Our findings show, for the first time, that hyperoxia has divergent effects on two survival pathways (Akt and ERK), and that ERK activity compensates for the loss of the Akt survival effects, delaying the death of hyperoxia-exposed lung epithelial cells.

Apoptosis↗
PubMed2006

Modulation of pulmonary cytochrome P4501A1 expression by hyperoxia and inhaled nitric oxide in the newborn rat: implications for lung injury.

Inhaled nitric oxide (iNO), with supplemental oxygen, is used in the treatment of hypoxic respiratory failure of the newborn. In this study, we tested the hypothesis that exposure of newborn rats to iNO, hyperoxia, or iNO + hyperoxia would modulate the expression of pulmonary cytochrome P450 (CYP)1A1 in relation to acute lung injury. Newborn Fischer 344 rats were maintained in room air, or exposed to iNO, hyperoxia (>95%), or iNO (20 or 40 ppm) + hyperoxia for up to 168 h, and lung injury parameters and CYP1A1 expression were studied. Animals given iNO (40 ppm) + hyperoxia were more susceptible to lung injury than those exposed to hyperoxia or iNO alone. On the other hand, animals exposed to iNO (20 ppm) + hyperoxia did not elicit lung damage. Pulmonary CYP1A1 protein and mRNA expression were induced by hyperoxia, iNO (20 or 40 ppm), or iNO (20 ppm) + hyperoxia for up to 168 h, compared with air-breathing controls. In animals given iNO (40 ppm) + hyperoxia, pulmonary CYP1A1 was enhanced at 48 h, followed by down-regulation at later time points. Immunohistochemistry experiments showed localization of CYP1A1 in the pulmonary epithelial and endothelial cells. In conclusion, because previous studies have shown beneficial effects of CYP1A1 induction in hyperoxic lung injury, our current observations showing maintenance of pulmonary CYP1A1 induction by iNO (20 ppm) + hyperoxia through the 168-h period support the hypothesis that this phenomenon may contribute to the protective effects of iNO against hyperoxic injury.

Animals↗
PubMed2002

Hyperoxia-induced apoptosis does not require mitochondrial reactive oxygen species and is regulated by Bcl-2 proteins.

Exposure of animals to hyperoxia results in lung injury that is characterized by apoptosis and necrosis of the alveolar epithelium and endothelium. The mechanism by which hyperoxia results in cell death, however, remains unclear. We sought to test the hypothesis that exposure to hyperoxia causes mitochondria-dependent apoptosis that requires the generation of reactive oxygen species from mitochondrial electron transport. Rat1a cells exposed to hyperoxia underwent apoptosis characterized by the release of cytochrome c, activation of caspase-9, and nuclear fragmentation that was prevented by the overexpression of Bcl-X(L.) Murine embryonic fibroblasts from bax(-/-) bak(-/-) mice were resistant to hyperoxia-induced cell death. The administration of the antioxidants manganese (III) tetrakis (4-benzoic acid) porphyrin, ebselen, and N-acetylcysteine failed to prevent cell death following exposure to hyperoxia. Human fibrosarcoma cells (HT1080) lacking mitochondrial DNA (rho(0) cells) that failed to generate reactive oxygen species during exposure to hyperoxia were not protected against cell death following exposure to hyperoxia. We conclude that exposure to hyperoxia results in apoptosis that requires Bax or Bak and can be prevented by the overexpression of Bcl-X(L). The mitochondrial generation of reactive oxygen species is not required for cell death following exposure to hyperoxia.

Animals↗
PubMed2004

NADPH oxidase and ERK signaling regulates hyperoxia-induced Nrf2-ARE transcriptional response in pulmonary epithelial cells.

Oxidative stress plays a major role in hyperoxia-induced acute lung injury. We have shown previously that mice lacking the Nrf2 are more susceptible to hyperoxia than are wild-type mice. Nrf2 activates antioxidant response element (ARE)-mediated gene expression involved in cellular protection against toxic insults. The present study was designed to investigate the mechanisms that control the activation of Nrf2 by hyperoxia using a non-malignant murine alveolar epithelial cell line, C10. No significant alteration in the levels of Nrf2 mRNA and protein was found following exposure to hyperoxia. In contrast, hyperoxia caused the translocation of Nrf2 from the cytoplasm to the nucleus within 30-60 min of exposure. Consistent with these observations, gel shift and reporter analyses demonstrated a correlation between the hyperoxia-enhanced ARE DNA-binding activity of Nrf2 and an up-regulation of ARE-driven transcription. Inhibition of NADPH oxidase with diphenyleneiodonium (DPI) blocked both Nrf2 translocation and ARE-mediated transcription. Inhibition of the MEK/ERK pathway caused a similar effect. Consistent with this finding, hyperoxia stimulated ERK-1 and ERK-2 phosphorylation, whereas DPI or N-acetyl-l-cysteine blocked such activation. Hyperoxia stimulated the phosphorylation of endogenous Nrf2, but not in the presence of U0126, suggesting a critical role for ERK signaling in the activation of Nrf2. Consistent with this notion, hyperoxia did not stimulate the phosphorylation of Nrf2 in fibroblasts lacking the ERK-1. Collectively, our findings suggest that hyperoxia-induced, ARE-driven, Nrf2-dependent transcription is controlled by NADPH oxidase and ERK-1 signaling.

Active Transport, Cell Nucleus↗
PubMed2002

Ablation of the heat shock factor-1 increases susceptibility to hyperoxia-mediated cellular injury.

High concentrations of oxygen (hyperoxia) are known to cause cellular injury and death. The heat shock response is a highly conserved cellular defense mechanism that protects cells against various environmental stressors, including hyperoxia. Herein we determined the role of heat shock factor-1 (HSF-1), a major component of the heat shock response, in protecting cells against hyperoxia. Embryonic fibroblasts from HSF-1-null mutant mice (HSF-1 -/- cells) were compared to wild-type embryonic fibroblasts (HSF-1 +/+ cells) following 24 hours' exposure to room air or hyperoxia (95% O(2)). Acute survival in hyperoxia was decreased in HSF-1 -/- cells as compared to HSF-1 +/+ cells. Intracellular ATP levels were significantly lower in the HSF-1 -/- cells as compared to the HSF-1 +/+ cells exposed to hyperoxia. Isoprostane levels, a marker of membrane lipid peroxidation, were significantly higher in the HSF-1 -/- cells as compared to the HSF-1 +/+ cells exposed to hyperoxia. Restoration of HSF-1 in the HSF-1 -/- cells by stable transfection with a HSF-1 expression plasmid improved survival in hyperoxia when compared to HSF-1 -/- cells stably transfected with the empty expression vector. Hyperoxia increased activation of HSF-1 in HSF-1 +/+ cells and in HSF-1 -/- cells stably transfected with the HSF-1 expression plasmid. These data demonstrate that HSF-1 plays an important role in conferring resistance to hyperoxia in vitro.

Adenosine Triphosphate↗
PubMed2002

Vitamin C prevents hyperoxia-mediated vasoconstriction and impairment of endothelium-dependent vasodilation.

High arterial blood oxygen tension increases vascular resistance, possibly related to an interaction between reactive oxygen species and endothelium-derived vasoactive factors. Vitamin C is a potent antioxidant capable of reversing endothelial dysfunction due to increased oxidant stress. We tested the hypotheses that hyperoxic vasoconstriction would be prevented by vitamin C, and that acetylcholine-mediated vasodilation would be blunted by hyperoxia and restored by vitamin C. Venous occlusion strain gauge plethysmography was used to measure forearm blood flow (FBF) in 11 healthy subjects and 15 congestive heart failure (CHF) patients, a population characterized by endothelial dysfunction and oxidative stress. The effect of hyperoxia on FBF and derived forearm vascular resistance (FVR) at rest and in response to intra-arterial acetylcholine was recorded. In both healthy subjects and CHF patients, hyperoxia-mediated increases in basal FVR were prevented by the coinfusion of vitamin C. In healthy subjects, hyperoxia impaired the acetylcholine-mediated increase in FBF, an effect also prevented by vitamin C. In contrast, hyperoxia had no effect on verapamil-mediated increases in FBF. In CHF patients, hyperoxia did not affect FBF responses to acetylcholine or verapamil. The addition of vitamin C during hyperoxia augmented FBF responses to acetylcholine. These results suggest that hyperoxic vasoconstriction is mediated by oxidative stress. Moreover, hyperoxia impairs acetylcholine-mediated vasodilation in the setting of intact endothelial function. These effects of hyperoxia are prevented by vitamin C, providing evidence that hyperoxia-derived free radicals impair the activity of endothelium-derived vasoactive factors.

Acetylcholine↗
PubMed2004

Interferon-gamma: a key contributor to hyperoxia-induced lung injury in mice.

Hyperoxia-induced lung injury complicates the care of many critically ill patients who receive supplemental oxygen therapy. Hyperoxic injury to lung tissues is mediated by reactive oxygen species, inflammatory cell activation, and release of cytotoxic cytokines. IFN-gamma is known to be induced in lungs exposed to high concentrations of oxygen; however, its contribution to hyperoxia-induced lung injury remains unclear. To determine whether IFN-gamma contributes to hyperoxia-induced lung injury, we first used anti-mouse IFN-gamma antibody to blockade IFN-gamma activity. Administration of anti-mouse IFN-gamma antibody inhibited hyperoxia-induced increases in pulmonary alveolar permeability and neutrophil migration into lung air spaces. To confirm that IFN-gamma contributes to hyperoxic lung injury, we then simultaneously exposed IFN-gamma-deficient (IFN-gamma-/-) mice and wild-type mice to hyperoxia. In the early phase of hyperoxia, permeability changes and neutrophil migration were significantly reduced in IFN-gamma-/- mice compared with wild-type mice, although the differences in permeability changes and neutrophil migration between IFN-gamma-/- mice and wild-type mice were not significant in the late phase of hyperoxia. The concentrations of IL-12 and IL-18, two cytokines that play a role in IFN-gamma induction, significantly increased in bronchoalveolar lavage fluid after exposure to hyperoxia in both IFN-gamma-/- mice and wild-type mice, suggesting that hyperoxia initiates upstream events that result in IFN-gamma production. Although there was no significant difference in overall survival, IFN-gamma-/- mice had a better early survival rate than did the wild-type mice. Therefore, these data strongly suggest that IFN-gamma is a key molecular contributor to hyperoxia-induced lung injury.

Animals↗
PubMed2007

Hyperoxia reduces bone marrow, circulating, and lung endothelial progenitor cells in the developing lung: implications for the pathogenesis of bronchopulmonary dysplasia.

Hyperoxia disrupts vascular and alveolar growth of the developing lung and contributes to the development of bronchopulmonary dysplasia (BPD). Endothelial progenitor cells (EPC) have been implicated in repair of the vasculature, but their role in lung vascular development is unknown. Since disruption of vascular growth impairs lung structure, we hypothesized that neonatal hyperoxia impairs EPC mobilization and homing to the lung, contributing to abnormalities in lung structure. Neonatal mice (1-day-old) were exposed to 80% O(2) at Denver's altitude (= 65% at sea level) or room air for 10 days. Adult mice were also exposed for comparison. Blood, lung, and bone marrow were harvested after hyperoxia. Hyperoxia decreased pulmonary vascular density by 72% in neonatal but not adult mice. In contrast to the adult, hyperoxia simplified distal lung structure neonatal mice. Moderate hyperoxia reduced EPCs (CD45-/Sca-1+/CD133+/VEGFR-2+) in the blood (55%; P < 0.03), bone marrow (48%; P < 0.01), and lungs (66%; P < 0.01) of neonatal mice. EPCs increased in bone marrow (2.5-fold; P < 0.01) and lungs (2-fold; P < 0.03) of hyperoxia-exposed adult mice. VEGF, nitric oxide (NO), and erythropoietin (Epo) contribute to mobilization and homing of EPCs. Lung VEGF, VEGF receptor-2, endothelial NO synthase, and Epo receptor expression were reduced by hyperoxia in neonatal but not adult mice. We conclude that moderate hyperoxia decreases vessel density, impairs lung structure, and reduces EPCs in the circulation, bone marrow, and lung of neonatal mice but increases EPCs in adults. This developmental difference may contribute to the increased susceptibility of the developing lung to hyperoxia and may contribute to impaired lung vascular and alveolar growth in BPD.

Aging↗
PubMed1996

Increased nitric oxide synthesis and action preclude choroidal vasoconstriction to hyperoxia in newborn pigs.

We tested the hypothesis that hyperoxia does not cause adequate constriction of choroidal vessels of the newborn (1 to 5 days old) pig, resulting in increased O2 delivery to the retina, possibly due to excess production and/or effects of vasodilators such as nitric oxide (NO). Hyperoxia (100% O2, 45 minutes) led to a decrease in retinal blood flow (RBF) of both newborn and juvenile (5 to 6 weeks old) pigs and also reduced choroidal blood flow (ChBF) in juvenile but not in newborn pigs; the absence of hyperoxia-induced ChBF response in the newborn was associated with a rise in choroidal O2 delivery. Ibuprofen (prostaglandin G/H synthase inhibitor) and 1,3-dimethyl-2-thiourea (a free radical scavenger) did not modify the choroidal hemodynamic responses to hyperoxia in newborn pigs. However, in newborn animals treated with the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME), hyperoxia caused a decrease in blood flow and O2 delivery to the choroid. Consistent with these effects of L-NAME, hyperoxia induced an increase in choroidal cGMP in newborn pigs ventilated with 100% O2 and stimulated nitrite production in isolated choroids exposed to hyperoxia from newborn but not juvenile pigs; these effects were inhibited by NOS blockers. Also, both constitutive and inducible NOS activities were higher in choroidal tissues from newborn than from juvenile animals. In addition, the vasorelaxant effect of the NO donor sodium nitroprusside in vitro was also greater on choroids from newborn than from juvenile pigs. Finally, L-NAME prevented the hyperoxia-induced increase in peroxidation products in the choroid of newborns. It is concluded that hyperoxia does not lead to a decrease in blood flow and O2 delivery to the choroid of the newborn because of increased NO synthesis and effects; since the choroid is the main source of O2 supply to the retina, the present data contribute in providing an explanation for the increased susceptibility of the immature neonate to hyperoxia-induced retinopathy.

Animals↗
PubMed2001

[Hyperoxia-induced liberation of big-endothelin into jugular venous blood of electric neurosurgical patients].

The use of hyperoxia in emergency situations is generally accepted, but the routine and uncritical application of higher oxygen concentrations is criticized. The influence of short-term application of hyperoxia on cerebral oxygenation, cerebral lactate and BIG-endothelin (BIG-ET) was studied. After approval by the Ethics Committee of the University of Leipzig, 22 patients (hyperoxia group n = 16, normoxia, control group n = 6) undergoing an elective craniotomy were included in the study. After induction of a total intravenous anaesthesia (sufentanil and propofol), a fibre-optic catheter was inserted into the bulb of the jugular vein. The inspiratory concentration of oxygen was raised from 0.4 to 1.0 for 15 minutes. Before, during and after hyperoxia, a blood gas analysis and analysis of lactate and BIG-ET were performed from arterial and jugularvenous blood. Hyperoxia caused a significant increase in jugularvenous oxygen saturation (sjO2) from 60.4 +/- 8.8% to 68.6 +/- 10.4% and jugularvenous oxygen content (cjvO2) from 10.27 +/- 2.06 vol% to 11.76 +/- 2.16 vol%. These changes were reversible after the end of hyperoxia. The jugularvenous lactate decreased significantly (9%) from 1.20 +/- 0.48 mmol/l to 1.10 +/- 0.45 mmol/l after the end of hyperoxia. Hyperoxia led to a significant increase in jugularvenous BIG-ET from 3.35 +/- 0.61 pg/ml to a maximum of 3.82 +/- 0.95 pg/ml and a decrease in the arterio-jugularvenous difference of BIG-ET from 0.19 +/- 0.53 pg/ml to a minimum -0.11 +/- 0.32 pg/ml. The changes in lactate and BIG-ET were also seen after the end of the hyperoxia. In the control group (normoxia, FiO2 0.4), no significant changes in sjO2, oxygen content, lactate and BIG-ET were observed. The increase in jugularvenous BIG-ET and the decrease in the arterio-jugularvenous difference of BIG-ET following hyperoxia indicate a higher cerebral release of BIG-ET.

Adult↗
PubMed2004

[Study on effect of dexamethasone on the expression of matrix metalloproteinase and its tissue inhibitors in hyperoxia-induced lung injury].

OBJECTIVE: To observe the effect of dexamethasone on the mRNA expression of matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinase (TIMPs) in the lung tissue and to explore the protective mechanism of dexamethasone in hyperoxia-induced lung injury. METHODS: Thirty-two two-week old Wistar rats were randomly divided into atmospheric-air group (n=16) and hyperoxia group (n=16). After 7 days of continuous exposure to high concentration O (2)(>95%), the lung wet/dry(W/D) ratio, the protein content in bronchoalveolar lavage fluid(BALF) and histopathological changes of the lung were measured in 16 rats(8 in each group). The lung tissue specimens of the other 16 rats were cultured, 8 among which served as atmospheric-air control group, the remainder in the hyperoxia group were divided into hyperoxia control group,hyperoxia+dexamethasone (1 x 10(-8) mol/L) group, hyperoxia+dexamethasone (1 x 10(-6) mol/L) group, and hyperoxia+dexamethasone (1 x 10(-4) mol/L) group. Eight samples were examined in each group. After cultured for 24 hours, the lung tissue were collected and its mRNA expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 were determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: 1. Pulmonary edema, hemorrhage and extensive inflammatory cells infiltration were observed in hyperoxia group, but no such changes were found in the atmospheric-air group. The lung W/D and the protein content in BALF in hyperoxia group were significantly higher than those in atmospheric air groups. 2. The mRNA expressions of MMP-2, MMP-9, TIMP-1, TIMP-2 and the ratio of MMP-2/TIMP-2, MMP-9/TIMP-1 were significantly higher in the hyperoxic group than those in the atmospheric-air group. 3. Dexamethasone could down-regulate the mRNA expressions of MMP-2 and MMP-9 in a concentration dependent manner. The mRNA expressions of TIMP-1, TIMP-2 also could be reduced by dexamethasone. Decreasing ratios of MMP-2/TIMP-2 and MMP-9/TIMP-1 were found in correlation with increasing concentration of dexamethasone. CONCLUSION: Dexamethasone can reduce the mRNA expressions of MMPs as well as regulate the balance of MMPs/TIMPs, which may be one of the mechanism of its protective effect on hyperoxia-induced lung injury.

Animals↗
PubMed2006

[Expression and modulation of aquaporin 5 in hyperoxia induced lung injury].

OBJECTIVE: To explore the expression and the modulation of aquaporin 5(AQP5) in hyperoxia induced lung injury. METHODS: Sixty four Wistar rats of 2 weeks old, were randomly assigned to following groups (n=8): air group, hyperoxia 3, 7, 14 days groups, air + dexamethasone (Dex), hyperoxia 3, 7, 14 days + Dex groups. The rats were kept in oxygen chamber at normal pressure (O(2)> or =95%) in hyperoxia groups, and in normal pressure air (O(2)=21%) in room-air group, and the rats in Dex groups were injected with Dex (5 mg.kg(-1).d(-1)) intraperitoneally for 3 consecutive days in room-air or hyperoxia exposure. The expression of AQP5 mRNA level and the location were detected by reverse transcription-polymerase chain reaction and immunohistochemistry respectively. RESULTS: AQP5 was strongly labeled in alveolar epithelial type I cells, and was also expressed in the secretory epithelium plasma membrane in the airway. The location of AQP5 in hyperoxia groups was not changed, but the expression of AQP5 mRNA had a notable gradual decline when the time of hyperoxia exposure was prolonged, compared to control group (all P<0.05). There was no difference in AQP5 mRNA level between hyperoxia groups and hyperoxia + Dex groups at different time points (all P<0.05). CONCLUSION: The significant decrease in AQP5 may be an important factor of pulmonary edema formation in hyperoxia-induced lung injury. Dex does not have effect on modulating the AQP5 expression in acute lung injury.

Animals↗
PubMed2005

Cellular factors required for protection from hyperoxia toxicity in Saccharomyces cerevisiae.

Prolonged exposure to hyperoxia represents a serious danger to cells, yet little is known about the specific cellular factors that affect hyperoxia stress. By screening the yeast deletion library, we have identified genes that protect against high-O2 damage. Out of approx. 4800 mutants, 84 were identified as hyperoxia-sensitive, representing genes with diverse cellular functions, including transcription and translation, vacuole function, NADPH production, and superoxide detoxification. Superoxide plays a significant role, since the majority of hyperoxia-sensitive mutants displayed cross-sensitivity to superoxide-generating agents, and mutants with compromised SOD (superoxide dismutase) activity were particularly vulnerable to hyperoxia. By comparison, factors known to guard against H2O2 toxicity were poorly represented amongst hyperoxia-sensitive mutants. Although many cellular components are potential targets, our studies indicate that mitochondrial glutathione is particularly vulnerable to hyperoxia damage. During hyperoxia stress, mitochondrial glutathione is more susceptible to oxidation than cytosolic glutathione. Furthermore, two factors that help maintain mitochondrial GSH in the reduced form, namely the NADH kinase Pos5p and the mitochondrial glutathione reductase (Glr1p), are critical for hyperoxia resistance, whereas their cytosolic counterparts are not. Our findings are consistent with a model in which hyperoxia toxicity is manifested by superoxide-related damage and changes in the mitochondrial redox state.

Gene Expression Regulation, Fungal↗
PubMed2003

Hyperoxia induces macrophage cell cycle arrest by adhesion-dependent induction of p21Cip1 and activation of the retinoblastoma protein.

Hyperoxia induces growth arrest, apoptosis, necrosis, and morphological changes (spreading and adhesion) in various types of cells. The mechanism of hyperoxia-induced cell growth arrest has not been well elucidated, especially in macrophages. One possible mechanism is a role of cell adhesion in hyperoxia-induced cell cycle arrest. To evaluate this finding, macrophages were cultured in normoxia (21% O2) or hyperoxia (95% O2) in adhesion or low adhesion conditions. Incubation of macrophages in hyperoxia induced cell cycle arrest. The hyperoxia-induced cell cycle arrest was prevented by low adhesion conditions. To evaluate pathways potentially involved in hyperoxia-induced growth arrest, we measured extracellular regulated kinase and retinoblastoma protein activation and p21Cip1 and p53 accumulation. Hyperoxia strongly induced activation of extracellular regulated kinase and retinoblastoma protein as well as up-regulation of p21Cip1. These effects of hyperoxia were attenuated under low adhesion conditions, suggesting a role for integrin-dependent signaling. The induction of p21Cip1 and activation of retinoblastoma protein occurred via a p53-independent mechanism. These results suggest that adhesion-dependent pathways are required for hyperoxia-induced cell cycle arrest in macrophages.

Animals↗