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At least 19 recordsLinked to original sources
PubMed2006

Hypoxic ventilatory responses in rats after hypercapnic hyperoxia and intermittent hyperoxia.

Perinatal hyperoxia attenuates the adult hypoxic ventilatory response in rats. Hyperoxia might elicit this plasticity by inhibiting chemoreceptor activity during early life. Thus, we hypothesized that stimulating chemoreceptors with CO(2) during hyperoxia or interrupting hyperoxia with periods of normoxia would reduce the effects of hyperoxia on the hypoxic ventilatory response. Rats were born and raised in 60% O(2) for the first two postnatal weeks. Two groups were simultaneously exposed to either sustained hypercapnia (5% CO(2)) or intermittent hypercapnia (alternating 1-h exposures to 0 and 7.5% CO(2)) while another group was exposed to only intermittent hyperoxia (alternating 1-h exposures to 21 and 60% O(2)). Hypoxic ventilatory responses were assessed at 6-10 weeks of age by whole-body plethysmography. Rats exposed to intermittent hypercapnia during hyperoxia or to intermittent hyperoxia exhibited greater increases in ventilation-to-metabolism ratio ( VE/VO2 ) in response to 12.5% O(2) than rats exposed to hyperoxia alone (both P<0.05), although responses were generally less than those of normoxia-reared controls; a similar trend was observed for rats exposed to sustained hypercapnia during hyperoxia (P=0.053). These data suggest that activity-dependent mechanisms contribute to hyperoxia-induced developmental plasticity, although contributions from additional mechanisms cannot be excluded.

Animals↗
PubMed2006

[Differential response of developing human fetal lung explants to hyperoxia and the effects of dexamethasone on hyperoxia-exposed lungs].

OBJECTIVE: This study aimed to explore the effects of hyperoxia on the development of fetal lung by investigating the changes of morphological and cell proliferation induced by hyperoxia in cultured fetal lungs as well as the effects of dexamethasone on hyperoxia-exposed lungs. METHODS: Human fetal lung explants at the pseudoglandular stage of development were cultured randomly either in normoxia (21% O2/5% CO2) or hyperoxia (95% O2/5% CO2) for 72 hrs. Dexamethasone was added into the feeding medium at the concentration of 10(-6)M. Harvested tissues were stained for pancytokeratin to identify epithelial cells, with Ki-67 as a marker of proliferation. The effects of lung morphometry were analyzed using computer assisted image analysis. The mean airway thickness, the proportion of the surface area occupied by airways, the mean airway surface area and the index of the epithelium proliferation were measured. RESULTS: The lung architectures remained unchanged after 72 hrs normoxia culture, whereas hyperoxia culture resulted in significant dilation of airways and thinning of epithelium, with the surface area of airways of 6662 microm(2) vs 2728 microm(2) and the thickness of airways of 7.8 microm vs 8.1 microm (P < 0.05). Hyperoxia culture also resulted in an increase in the proportion of the surface area occupied by airways than normoxia culture (35.2% vs 23.4%; P < 0.05). The surface area of airways (3174 microm(2)) and the proportion of the surface area occupied by airways (23.9%) decreased significantly in hyperoxia-cultured lungs after dexamethasone administration (P < 0.05). The epithelium proliferation index in hyperoxia-cultured lungs (21.8%) was higher than that in normoxia-cultured lungs (5.1%) and dexamethasone-treated hyperoxia-cultured lungs (7.4%) (P < 0.05). CONCLUSIONS: The exposure of pseudoglandular lungs to hyperoxia modulates the lung architecture to resemble saccular lungs with higher epithelium proliferation index. Dexamethasone may inhibit the effects induced by hyperoxia.

Cell Differentiation↗
PubMed2005

Oxygent as a top load to colloid and hyperoxia is more effective in resuscitation from hemorrhagic shock than colloid and hyperoxia alone.

Perfluorocarbon (PFC) emulsions are intravascular oxygen therapeutics that temporarily enhance tissue oxygenation in dilutional anemia. However, PFC emulsions are not resuscitation fluids because PFCs only work optimally in the presence of high O2 partial pressure (hyperoxia); moreover, because they have no oncotic potential, dosing limitations prevent their use to permanently replace large hemorrhage volumes. Our objective was to clarify whether in the presence of hyperoxia a conventional colloid therapy supplemented by PFC is more efficacious than colloid alone. To answer this question, 22 anesthetized, ventilated dogs were hemorrhaged to a mean arterial pressure of 45 mmHg and were kept at this level until a metabolic O2 debt of 120 mL kg(-1) body weight had evolved. Hyperoxia was established and dogs were randomly allocated to receive colloid (6% HES, Hydroxy Ethyl Starch shed blood volume) or colloid together with Oxygent (perflubron emulsion, 60%, w/v; Alliance Pharmaceutical Corp., San Diego, CA; single dose, 4.5 mL kg(-1); i.e., 2.7 g PFC kg body weight) in a blinded fashion. Hemodynamic and O2 transport parameters, intestinal mucosal blood flow (microspheres), and O2 partial pressure (MDO-Electrode; Eschweiler, Kiel, Germany) were measured at baseline, in shock, and during 3 h post-therapy. In the presence of hyperoxia, Oxygent improved the amount of physically dissolved O2 in plasma and increased the contribution of physically dissolved O2 to global O2 delivery (P < 0.05) and thus whole body O2 consumption when compared with colloid alone (P < 0.05). As a result, Oxygent reduced intestinal mucosal hypoxia and global O2 debt within the first hour post-therapy (P < 0.05). We conclude that under hyperoxic conditions, fluid resuscitation supplemented by Oxygent was more efficacious than colloid and hyperoxia alone. PFC temporarily enhanced intestinal mucosal tissue oxygenation during resuscitation.

Animals↗
PubMed1987

Adaptation to chronic hyperoxia. Biochemical effects and the response to subsequent lethal hyperoxia.

Adult rats were exposed to room air, 50%, 65%, or 80% oxygen for 6 wk. Subsets were sacrificed periodically in order to establish alterations in growth parameters and lung antioxidant responses. Prolonged exposure to 50% or 65% oxygen did not result in weight loss or changes in lung-to-body weight ratios relative to control values. Treatment with 50% oxygen produced delayed increases in nonprotein sulfhydryl (NPSH) content and catalase (CAT) activity, while treatment with 65% oxygen produced delayed increases in NPSH, CAT, and glutathione peroxidase (GPx) content. Rats treated for 6 wk with either 50% or 65% oxygen died significantly earlier than room-air control animals when these groups were subsequently exposed to 100% oxygen. Rats exposed to 80% oxygen had significantly decreased body weight, increased lung-to-body weight ratios, and increased levels of NPSH, CAT, GPx, total superoxide dismutase, and glutathione reductase by 11 days of treatment. At 6 wk they had significantly altered growth parameters and increased GPx catalase, and NPSH levels. Their final antioxidant profile was not significantly different from 65% oxygen-exposed rats. However, these animals survived significantly longer than any group when exposed to 100% oxygen. In summary, lower concentrations of sublethal hyperoxia (less than or equal to 65%) were capable of eliciting significant antioxidant enzyme responses. Levels of antioxidant enzymes in the lungs of rats chronically exposed to sublethal hyperoxia did not appear to be solely responsible for enhanced survival in subsequent lethal hyperoxia.

Adaptation, Physiological↗
PubMed2000

Response of choroidal blood flow in the foveal region to hyperoxia and hyperoxia-hypercapnia.

PURPOSE: Arterial carbon dioxide tension and arterial oxygen tension are important determinants of retinal and cerebral blood flow. In the present study the hypothesis that changes in arterial blood gases also influence choroidal blood flow was tested. METHODS: The effect of breathing different mixtures of oxygen (O(2)) and carbon dioxide (CO(2)) on choroidal blood flow in the foveal region was investigated in healthy subjects. The study was performed in a randomized, double-masked four way cross-over design in 16 subjects. Using a compact laser Doppler flowmeter, red blood cell velocity (ChBVel), volume (ChBVol), and flow (ChBF) in the choroidal vasculature were measured during the breathing of various mixtures of O(2)and CO(2) (hyperoxia-hypercapnia): 100% O(2), 97%O(2)+3%CO(2), 95%O(2)+5%CO(2) (carbogen) and 92%O(2)+8%CO( 2). Arterial oxygen tension (pO(2)) and carbon dioxide tension (pCO(2)) were measured from arterialized blood samples from the earlobe. RESULTS: Breathing 100% O(2) had no significant effect on ChBVel (-3.7%), ChBVol (+1.7%) and ChBF (-4.3%). Addition of 3% CO(2) to O(2) also produced no significant change on these blood flow parameters. In contrast, carbogen significantly increased ChBVel (10.0 +/- 4.4%, 95% CI, p < 0.001) and ChBF (12.5 +/- 11.7%, p = 0.002). The effect of 92% O(2) + 8% CO(2) was more pronounced since it significantly increased ChBVel and ChBF by 15.5 +/- 7.5% (p < 0.001) and 16.2 +/- 11.0% (p < 0.001), respectively. None of the gas mixtures induced a significant change in ChBVol. The increase in ChBF was approximately 1.5% per 1 mmHg increase in pCO(2). CONCLUSIONS: This study demonstrates that, in healthy subjects, pCO(2) is an important determinant of foveal choroidal blood flow, whereas pO(2) has little impact on it.

Administration, Inhalation↗
PubMed2005

[Protective effects of amygdalin on hyperoxia-exposed type II alveolar epithelial cells isolated from premature rat lungs in vitro].

OBJECTIVE: To analyze the effect of hyperoxia on the proliferation and surfactant associated protein messenger RNA levels of type II alveolar epithelial cells (AECIIs) of premature rat, and to investigate the effect of amygdalin on the change resulted from hyperoxia in AECIIs isolated from premature rat lung in vitro. METHODS: The lung tissue of 20-day fetal rat was digested by trypsin and collagenase. AECIIs and lung fibroblasts (LFs) were isolated and purified at different centrifugal force and different adherence, then cultured. The nature of the cultures was identified by cytokeratin staining, vimentin staining and transmission electron micrography. For establishing hyperoxia-exposed cell model, purified AECIIs were cultured for 24 hours after culture flasks were filled with 95% oxygen-5% CO2 at 3 L/min for 10 min, and then sealed. Oxygen concentrations were tested in CYS-1 digital oxygen monitor after 24 hours of exposure. A sample was discarded if its oxygen concentration was < 90%. Cell proliferating vitality was examined by MTT assay after treatment with amygdalin at various concentrations. DNA content, protein expression of proliferating cell nuclear antigen (PCNA) and mRNA levels of SPs of AECIIs were analyzed with flow cytometric assay, Western blot and reverse transcription polymerase chain reaction (RT-PCR) respectively after 24 hours of air or hyperoxia exposure in the presence or absence of 200 micromol/L amygdalin. RESULTS: Excellent yields of highly purified, culturable AECIIs could be obtained from 20-day fetal lungs. The expression of cytokeratin in AECIIs was positive and that of vimentin negative by immunocytochemistry. Those, however, in LFs were just opposite. Lamellar bodies in purified AECIIs were revealed by transmission electron micrography. The established hyperoxia-exposed cell model assured the oxygen concentrations of culture flasks more than 90%. Amygdalin at the concentration range from 50 micromol/L to 200 micromol/L stimulated the proliferation of AECIIs in a dose-dependent manner; however, at the concentration of 400 micromol/L inhibited the proliferation of AECII. Flow cytometric analysis showed that the apoptosis rate and G0/G1 phase percentage increased significantly (P < 0.01), S phase and G2/M phase percentage decreased significantly (P < 0.01), in hyperoxia group compared with that of air group. The apoptosis rate of air plus 200 micromol/L amygdalin group, compared with air group, was not significantly different (P > 0.05); however, G0/G1 phase percentage decreased markedly, S phase percentage increased significantly, G2/M phase percentage did not significantly change (P > 0.05). The apoptosis rate of hyperoxia plus 200 micromol/L amygdalin group was not significantly different (P > 0.05) from that of hyperoxia group, S phase and G2/M phase percentage increased significantly (P < 0.01), G0/G1 phase percentage decreased significantly (P < 0.01). Western blot analysis showed that the protein expression levels of PCNA in all group was significantly different, in turn, hyperoxia group < hyperoxia plus 200 micromol/L amygdalin < air group < air puls 200 micromol/L amygdalin (P < 0.01). SPs mRNA levels were significantly decreased in hyperoxia group, as compared with air group (P < 0.01). After amygdalin was added, SPs mRNA levels were elevated in air plus amygdalin group and hyperoxia plus amygdalin group, as compared with hyperoxia group (P < 0.01, P < 0.05, respectively), but compared with air group, SP mRNA levels were not significantly elevated (P > 0.05). CONCLUSION: AECIIs of premature rats were isolated, purified and cultured successfully. Hyperoxia-exposed cell model was established in AECIIs of premature rat in this experiment. Amygdalin promotes the proliferation of premature rat AECII exposed to air or hyperoxia, the concentration of amygdalin with the best effect was 200 micromol/L. Hyperoxia inhibited the proliferation and decreased SPs mRNAs levels in AECIIs in vitro, which may contribute to hyperoxia-induced lung injury in premature rats. Amygdalin could inhibit the changes of SPs mRNAs levels and cell proliferation of AECIIs resulted from hyperoxia and may play partial protective role in hyperoxia-induced premature lung injury.

Amygdalin↗
PubMed1998

Pulmonary apoptosis in aged and oxygen-tolerant rats exposed to hyperoxia.

Accumulating evidence demonstrates that genotoxic and oxidant stress can induce programmed cell death or apoptosis in cultured cells. However, little is known about whether oxidative stress resulting from the deleterious effects of hyperoxia can induce apoptosis in vivo and even less is known regarding the functional significance of apoptosis in vivo in response to hyperoxia. Using hyperoxia as a model of oxidant-induced lung injury in the rat, we show that hyperoxic stress results in marked apoptotic signals in the lung. Lung tissue sections obtained from rats exposed to hyperoxia exhibit increased apoptosis in a time-dependent manner by terminal transferase dUTP nick end labeling assays. To examine whether hyperoxia-induced apoptosis in the lung correlated with the extent of lung injury or tolerance (adaptation) to hyperoxia, we investigated the pattern of apoptosis with a rat model of age-dependent tolerance to hyperoxia. We show that apoptosis is associated with increased survival of aged rats to hyperoxia and with decreased levels of lung injury as measured by the volume of pleural effusion, wet-to-dry lung weight, and myeloperoxidase content in aged rats compared with young rats after hyperoxia. We also examined this relationship in an alternate model of tolerance to hyperoxia. Lipopolysaccharide (LPS)-treated young rats not only demonstrated tolerance to hyperoxia but also exhibited a significantly lower apoptotic index compared with saline-treated rats after hyperoxia. To further separate the effects of aging and tolerance, we show that aged rats pretreated with LPS did not exhibit a significant level of tolerance against hyperoxia. Furthermore, similar to the hyperoxia-tolerant LPS-pretreated young rats, the nontolerant LPS-pretreated aged rats also exhibited a significantly reduced apoptotic index compared with aged rats exposed to hyperoxia alone. Taken together, our data suggest that hyperoxia-induced apoptosis in vivo can be modulated by both aging and tolerance effects. We conclude that there is no overall relationship between apoptosis and tolerance.

Aging↗
PubMed2006

[Effect of inhaled nitric oxide on surfactant protein A and mannose binding ability in the lung of neonatal rats with hyperoxia-induced lung injury].

OBJECTIVE: To investigate the effect of inhaled nitric oxide (NO) on surfactant protein A (SP-A) and mannose binding ability (MBA) in neonatal rats with hyperoxia-induced lung injury. METHODS: Sixty-four neonatal rats were randomly exposed to room air (Control group), >95% oxygen for 6 days (Hyperoxia group), 10 ppm NO for 24 hrs (NO group), and >95% oxygen for 6 days along with 10 ppm NO for 24 hrs (Hyperoxia + NO group). After 2 and 6 days of exposure, the lung pathologic changes, gene and protein expressions of SP-A and MBA were measured. RESULTS: The rats from the Hyperoxia group presented with obvious lung injuries. The SP-A expressions of mRNA (0.81 +/- 0.04 vs 1.53 +/- 0.25) and protein (59.45 +/- 18.37 vs 89.77 +/- 16.41) in the Hyperoxia group decreased significantly 2 days after exposure but increased significantly 6 days after exposure (SP-A mRNA 0.81 +/- 0.02 vs 0.63 +/- 0.03; SP-A protein 93.57 +/- 13.71 vs 47.73 +/- 21.69) compared with those of the Control group (P < 0.05). NO treatment alleviated the hyperoxia-induced pathologic injuries 2 days after exposure. The SP-A mRNA expression (0.55 +/- 0.91) in the Hyperoxia + NO group was significantly reduced as compared to both the Control and Hyperoxia groups (P < 0.05), and the SP-A protein expression (55.12 +/- 17.53) in the Hyperoxia + NO group was noticeably lower than that of the Control group (P < 0.01) 2 days after exposure. The SP-A protein expression in the Hyperoxia + NO group (67.33 +/- 18.59) was significantly lower than that of the Hyperoxia group 6 days after exposure (P < 0.05). Two days after exposure, the NO group had significantly higher MBA than the Control group (0.821 +/- 0.133 vs 0.58 +/- 0.158); the Hyperoxia + NO group had significantly higher MBA than the Hyperoxia group (0.43 +/- 0.175 vs 0.738 +/- 0.141) (P < 0.05). CONCLUSIONS: Inhaled low dose NO may decrease SP-A protein expression and increase MBA of the lung tissue. This lessens the pathologic lung injury in neonatal rats with hyperoxia.

Administration, Inhalation↗
PubMed2004

Hyperoxia-induced emphysematous changes in subacute phase of endotoxin-induced lung injury in rats.

We examined the effects of prolonged hyperoxia (75% O(2)) on lung structure and collagen metabolism in the subacute phase of lung injury induced by continuous infusion of endotoxin (LPS) in a rat model. Experimental groups included control, endotoxin alone, endotoxin plus hyperoxia, and hyperoxia alone. Endotoxin-treated rats received a bolus of LPS (10 mg/kg i.v.) followed by 500 microg.kg(-1).day(-1) in continuous infusion for 10 days. The bronchoalveolar lavage (BAL) fluid/plasma albumin concentration ratio, an index of capillary permeability, and neutrophil and macrophage counts in BAL fluid were highest in the endotoxin plus hyperoxia group. On pathological examination, prolonged hyperoxia exacerbated destruction of the alveolar wall and caused most prominent emphysematous changes in the endotoxin plus hyperoxia group. Lung tissue hydroxyproline concentration was significantly decreased in the hyperoxia group and increased in the endotoxin group. The latent forms of MMP-2 and MMP-9 increased in BAL fluid of the endotoxin- and/or hyperoxia-treated groups, whereas the activities of collagenase and gelatinase, and the active form of MMP-2 were all increased in the hyperoxia-treated groups. Added to endotoxin, prolonged hyperoxia degraded collagen, the major structural component of basement membranes, and caused emphysematous changes associated with activation of collagenase and MMP-2. Our observations suggest that, in the subacute phase of endotoxin-induced lung injury, prolonged hyperoxia causes pulmonary emphysematous changes with persistent injury to the alveolar capillary barrier. Collagenase and MMP-2 activated by hyperoxia, together with MMP-9, may play prominent roles in disruption of the alveolar basement membranes and degradation of collagen lining the alveolar walls.

Animals↗
PubMed2006

Hyperoxia and apoptosis in developing mouse lung mesenchyme.

Hyperoxia contributes to the development of bronchopulmonary dysplasia in former premature infants. Injurious environmental factors such as hyperoxia may disrupt distal airway branching and alveolar septation, as these critical stages in lung development occur following birth in extremely premature infants. To test if hyperoxia directly inhibited distal airway branching, we cultured E16 fetal mouse lung explants in either 20% (control) or 95% oxygen (hyperoxia). Hyperoxia reduced the number of distal airways to less than 50% of controls. Explants cultured in 95% oxygen also had fewer complex distal airways compared with controls. Mesenchymal cells adjacent to distal airways in hyperoxic explants appeared apoptotic by phase microscopy. Consistent with increased apoptosis, explants cultured in hyperoxia had increased caspase 3/7 activity compared with controls. Hyperoxia also increased mesenchymal caspase 3 expression and annexin V binding within cultured explants as visualized by fluorescence microscopy. We measured increased annexin V binding in isolated primary fetal lung mesenchymal cells cultured in 95% oxygen suggesting a direct effect on cells within the mesenchyme. Hyperoxia can lead to NF-kappaB activation, which mediates inflammatory cascades and may protect cells from apoptosis. We detected NF-kappaB activation and nuclear p65 localization in explants exposed to 48 h of hyperoxia. Inhibition of NF-kappaB prevented the hyperoxia-induced activation of caspase 3. NF-kappaB activation may therefore contribute to apoptosis in the developing fetal mouse lung following hyperoxia exposure. Our data suggest hyperoxia inhibits distal airway branching and directly induces apoptosis of the fetal mouse lung mesenchyme.

Animals↗
PubMed1996

Lung poly(ADP-ribose) and NAD+ concentrations during hyperoxia and niacin deficiency in the Fischer-344 rat.

Sublethal exposure to hyperoxia in vivo induces oxidative damage that leads to destruction of the pulmonary endothelium, pleural effusion, and eventual pulmonary fibrosis. DNA is a potential target for reactive oxygen species in this system; the principle types of damage to DNA during hyperoxia are single-strand breaks and oxidant damage to bases. Poly(ADP-ribosyl)ation, a posttranslational modification of nuclear proteins, is stimulated by strand breaks in DNA and is required for effective repair of many types of DNA lesions. In this study we have measured lung tissue NAD+ and poly(ADP-ribose) concentrations in response to hyperoxia and niacin deficiency in rats. Male weaning Fischer-344 rats consumed niacin-deficient (ND) or niacin-replete pair-fed (PF) diets for 7 d. Rats from each diet group (n = 6) were then housed in normobaric 85% oxygen for 5 d. Normoxic controls were maintained in air. Hyperoxia increased lung poly(ADP-ribose) concentration by 35% in PF rats, but did not significantly increase levels in ND rats. Niacin deficiency decreased lung NAD+ in normoxic rats, but surprisingly, this deficit was partially reversed by hyperoxia. Liver NAD+ levels increased by 21% during hyperoxia in both diet groups. Heart and kidney NAD+ were unaffected by hyperoxia. Blood was the only tissue measured in which NAD+ was decreased by hyperoxia. Dietary treatment did not affect the increase in the lung wt/b. wt. ratio resulting from hyperoxia. This is the first report in the literature of lung tissue poly(ADP-ribose) measurement. Results show that hyperoxia causes a marked increase in lung poly (ADP-ribose) concentration, but also suggest an adaptation of whole-animal NAD+ metabolism to hyperoxia during niacin deficiency.

Animals↗
PubMed2006

Thioredoxin-1 protects against hyperoxia-induced apoptosis in cells of the alveolar walls.

BACKGROUND: The mechanisms of hyperoxia-induced lung injury remain poorly defined. Thioredoxin-1 (TRX-1) is a small ubiquitous protein that acts as an important radical scavenger. We investigated the effect of TRX-1 on apoptosis in hyperoxia-induced lung injury. METHODS: Mice were exposed to 98% O(2) to produce a model of hyperoxia-induced lung injury. Using transgenic mice overexpressing human TRX-1 (hTRX-1), we assessed lung structure (n=4 per group), immunohistochemical staining for 8-hydroxy-deoxyguanosine (n=4 per group), TUNEL staining (n=5 per group), cytokine (n=5 per group) of IL-1beta and IL-6, and protein (n=6 per group) and m-RNA levels (n=4 per group) (or both) of cytochrome c, Bcl-2, Bax, p21, and p53 in the lungs. RESULTS: After exposure to hyperoxia, hTRX-1 transgenic mice had significantly decreased alveolar damage. The apoptotic index was significantly lower in hTRX-1 transgenic mice than in wild-type (WT) mice after exposure to hyperoxia. Protein expression of cytochrome c in the lung was significantly lower in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. Protein expression and m-RNA levels of Bcl-2 in the lung were significantly higher in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. TRX-1 had no effect on the protein and m-RNA levels of Bax and p21. The protein and m-RNA levels of p53 was unaffected by hyperoxia in hTRX-1 transgenic mice. The cytokine level of IL-6 was significantly higher in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. TRX-1 had no effect on cytokine level of IL-1beta. CONCLUSIONS: These findings suggest that overexpression of hTRX-1 protects against hyperoxia-induced apoptosis in cells of the alveolar walls. The up-regulating Bcl-2 protein is considered to be one of antiapoptotic effects of TRX-1 in hyperoxia-induced lung injury.

Animals↗
PubMed2003

Bcl-2 family members make different contributions to cell death in hypoxia and/or hyperoxia in rat cerebral cortex.

Hypoxic brain injury during fetal or neonatal development leads to damaged immature neurons and can result in cognitive or behavioral dysfunction. Hyperoxia therapy (treatment with oxygen) is commonly applied to infants with signs of perinatal hypoxia-anoxia. Both hypoxia and hyperoxia have been shown to result in apoptosis in the brains of rats in several animal models. One determinant of cellular commitment to cell death is the differential expression of the Bcl-2 family of proteins in response to trauma. Here, we characterize cell death and the expression of Bcl-2 homologous proteins in 7-day-old neonatal rat cerebral cortex after hypoxia (5% O(2) for 40 min) and/or hyperoxia (>95% O(2) for 2 h after hypoxia). The expression of Bcl-2 and Bcl-X(L), two anti-apoptotic proteins, decreased at 24 h after hypoxia. Bcl-X(L) increased after either hyperoxia or hypoxia+hyperoxia. We did not detect significant changes in the cytoplasmic levels of pro-apoptotic protein Bax after any of these three treatments. Using cell death ELISA and DNA FragEL assays, we observed increased cell death at 24h after hypoxia, hyperoxia or hypoxia+hyperoxia treatments. At 24 h after either hypoxia, hyperoxia or hypoxia+hyperoxia, caspase 3 activity also increased significantly. Our results suggest that both hypoxia and hyperoxia alone can induce cell death. The Bcl-2 --> cytochrome c --> caspase 3 pathway played a role in hypoxia-induced cell death, while other pathways may be involved in hyperoxia-induced cell death.

Animals↗
PubMed2003

Effect of endogenous nitric oxide on hyperoxia and tumor necrosis factor-alpha-induced leukosequestration and proinflammatory cytokine release in rat airways.

OBJECTIVE: To investigate the effects of endogenous nitric oxide on hyperoxia and tumor necrosis factor-alpha-induced leukosequestration and proinflammatory cytokine release in rat airways. DESIGN: Prospective, randomized, controlled animal study. SETTING: Experimental laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 350-500 g. INTERVENTIONS: The rats were pretreated with N(G)-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) or saline intravenously 4-6 mins before intratracheal administration of tumor necrosis factor-alpha, 95% oxygen, or both, when the vasopressor effect of L-NAME had reached a plateau. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage fluid was recovered from the airway of rats after exposure to 95% oxygen and tumor necrosis factor-alpha for 6 hrs under ventilator support. Neutrophils in lavage fluid were isolated and examined for the inducible nitric oxide synthase expression by flow-cytometric assay. Tumor necrosis factor-alpha and interleukin-1 beta in lavage fluid were measured by enzyme-linked immunosorbent assay. The percentage of neutrophils in bronchoalveolar fluid was significantly higher in rats exposed to hyperoxia + tumor necrosis factor-alpha (29.7 +/- 12.5%) compared with rats with hyperoxia (16.3 +/- 1.2%), tumor necrosis factor-alpha (4.2 +/- 1.1%), or room air (5.0 +/- 1.8%) alone (p <.05). Rats exposed to hyperoxia + tumor necrosis factor-alpha had significantly higher concentrations of inducible nitric oxide synthase of neutrophils (350.1 +/- 75.7 mean fluorescence intensity), compared with rats with hyperoxia (64.9 +/- 1.6 mean fluorescence intensity), tumor necrosis factor-alpha (102.6 +/- 15.3 mean fluorescence intensity), or room air (111.2 +/- 25.8 mean fluorescence intensity) alone (p <.05). Rats exposed to hyperoxia + tumor necrosis factor-alpha significantly produced higher concentrations of tumor necrosis factor-alpha and interleukin-1 beta, compared with rats with tumor necrosis factor-alpha, hyperoxia, or room air alone. Hyperoxia + tumor necrosis factor-alpha also significantly increased growth-related oncogene/cytokine-induced neutrophil chemoattractant (GRO/CINC)-1 in bronchoalveolar fluid, compared with those receiving tumor necrosis factor-alpha alone, hyperoxia alone, or room air alone. L-NAME significantly enhanced the percentage of neutrophil recovery and the production of tumor necrosis factor-alpha, interleukin-1 beta, and GRO/CINC-1 in airways compared with the corresponding hyperoxia + tumor necrosis factor-alpha treatment alone. CONCLUSIONS: Endogenous nitric oxide may be an important endogenous inhibitor of hyperoxia + tumor necrosis factor-alpha-induced leukocyte recruitment and subsequently tumor necrosis factor-alpha, interleukin-1 beta, and GRO/CINC-1 release.

Animals↗
PubMed2001

Induced recovery of hypoxic phrenic responses in adult rats exposed to hyperoxia for the first month of life.

1. Adult rats exposed to hyperoxia for the first month of life have permanently attenuated ventilatory and phrenic nerve responses to hypoxia. We tested the hypothesis that the blunted hypoxic phrenic response in hyperoxia-treated rats (inspired O(2) fraction, F(I,O2) = 0.6 for 28 post-natal days) could be actively restored to normal by intermittent (alternating 12 % O(2)/air at 5 min intervals; 12 h per night for 1 week) or sustained (12 % O(2) for 1 week) hypoxia. 2. Phrenic responses to isocapnic hypoxia (P(a,O2) = 60, 50 and 40 +/- 2 mmHg) were assessed in the following groups of anaesthetized, vagotomized adult Sprague-Dawley rats (age 4 months), treated with a neuromuscular blocking agent and ventilated: control, hyperoxia-treated and hyperoxia-treated exposed to either intermittent or sustained hypoxia as adults. Experiments on intermittent and sustained hypoxia-treated rats were performed on the morning following hypoxic exposures. 3. Both intermittent and sustained hypoxia enhanced hypoxic phrenic responses in hyperoxia-treated rats when expressed as minute phrenic activity (P < 0.05). Increases in phrenic burst amplitude during hypoxia were greater in hyperoxia-treated rats after intermittent hypoxia (P < 0.05), and a similar but non-significant trend was observed after sustained hypoxia. Hypoxia-induced changes in phrenic burst frequency were not significantly different among groups. 4. The estimated carotid body volume in control rats (11.5 (+/- 0.7) x 10(6) microm(3)) was greater than in the other treatment groups (P < 0.05). However, carotid body volume was significantly greater in hyperoxia-treated rats exposed to sustained hypoxia (6.3 (+/- 0.3) x 10(6) microm(3); P < 0.05) compared to hyperoxia-treated rats (3.3 (+/- 0.2) x 10(6) microm(3)) or hyperoxia-treated rats exposed to intermittent hypoxia (3.8 (+/- 0.3) x 10(6) microm(3)). 5. Hypoxic phrenic responses in hyperoxia-treated rats 1 week after intermittent hypoxia were similar to responses measured immediately after intermittent hypoxia, indicating persistent functional recovery. 6. The results indicate that diminished hypoxic phrenic responses in adult rats due to hyperoxia exposure for the first 28 post-natal days can be reversed by intermittent or sustained activation of the hypoxic ventilatory control system. Although the detailed mechanisms of functional recovery are unknown, we suggest that sustained hypoxia restores carotid chemoreceptor sensitivity, whereas intermittent hypoxia primarily augments central integration of synaptic inputs from chemoafferent neurons.

Animals↗
PubMed2006

Recombinant human VEGF treatment transiently increases lung edema but enhances lung structure after neonatal hyperoxia.

Recent studies suggest that VEGF may worsen pulmonary edema during acute lung injury (ALI), but, paradoxically, impaired VEGF signaling contributes to decreased lung growth during recovery from ALI due to neonatal hyperoxia. To examine the diverse roles of VEGF in the pathogenesis of and recovery from hyperoxia-induced ALI, we hypothesized that exogenous recombinant human VEGF (rhVEGF) treatment during early neonatal hyperoxic lung injury may increase pulmonary edema but would improve late lung structure during recovery. Sprague-Dawley rat pups were placed in a hyperoxia chamber (inspired O(2) fraction 0.9) for postnatal days 2-14. Pups were randomized to daily intramuscular injections of rhVEGF(165) (20 microg/kg) or saline (controls). On postnatal day 14, rats were placed in room air for a 7-day recovery period. At postnatal days 3, 14, and 21, rats were killed for studies, which included body weight and wet-to-dry lung weight ratio, morphometric analysis [including radial alveolar counts (RAC), mean linear intercepts (MLI), and vessel density], and lung endothelial NO synthase (eNOS) protein content by Western blot analysis. Compared with room air controls, hyperoxia increased pulmonary edema by histology and wet-to-dry lung weight ratios at postnatal day 3, which resolved by day 14. Although treatment with rhVEGF did not increase edema in control rats, rhVEGF increased wet-to-dry weight ratios in hyperoxia-exposed rats at postnatal days 3 and 14 (P < 0.01). Compared with room air controls, hyperoxia decreased RAC and increased MLI at postnatal days 14 and 21. Treatment with VEGF resulted in increased RAC by 181% and decreased MLI by 55% on postnatal day 14 in the hyperoxia group (P < 0.01). On postnatal day 21, RAC was increased by 176% and MLI was decreased by 58% in the hyperoxia group treated with VEGF. rhVEGF treatment during hyperoxia increased eNOS protein on postnatal day 3 by threefold (P < 0.05). We conclude that rhVEGF treatment during hyperoxia-induced ALI transiently increases pulmonary edema but improves lung structure during late recovery. We speculate that VEGF has diverse roles in hyperoxia-induced neonatal lung injury, contributing to lung edema during the acute stage of ALI but promoting repair of the lung during recovery.

Animals↗
PubMed2000

Hyperoxia synergistically increases TNF-alpha-induced interleukin-8 gene expression in A549 cells.

Interleukin (IL)-8 is an important mediator of acute lung injury. Hyperoxia induces IL-8 production in some cell types, but its effect on IL-8 gene expression in respiratory epithelium is not well described. In addition, IL-8 gene expression resulting from the combined effects of hyperoxia and proinflammatory cytokines has not been well characterized. We treated cultured respiratory epithelial-like cells (A549 cells) with hyperoxia alone, tumor necrosis factor (TNF)-alpha alone, or the combination of TNF-alpha and hyperoxia and evaluated IL-8 gene expression. Hyperoxia alone had a minimal effect on IL-8 gene expression, and TNF-alpha alone increased IL-8 gene expression in a time-dependent manner. In contrast, the combination of TNF-alpha and hyperoxia synergistically increased IL-8 gene expression as measured by ELISA (TNF-alpha alone for 24 h = 769 +/- 89 pg/ml vs. hyperoxia + TNF-alpha for 24 h = 1, 189 +/- 89 pg/ml) and Northern blot analyses. Experiments involving IL-8 promoter-reporter assays, electromobility shift assays, and Western blot analyses demonstrated that hyperoxia augmented TNF-alpha-mediated activation of the IL-8 promoter by a nuclear factor (NF)-kappaB-dependent mechanism and increased the duration of NF-kappaB nuclear translocation after concomitant treatment with TNF-alpha. Additional reporter gene assays demonstrated, however, that increased activation of NF-kappaB does not fully account for the synergistic effect of hyperoxia and that the NF-IL-6 site in the IL-8 promoter is also required for the synergistic effect of hyperoxia. We conclude that hyperoxia alone has a minimal effect on IL-8 gene expression but synergistically increases IL-8 gene expression in the presence of TNF-alpha by a mechanism involving cooperative interaction between the transcription factors NF-kappaB and NF-IL-6.

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