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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The influence of some drugs which affect the dopaminergic system was studied on chemosensory responses to dopamine (DA), acetylcholine (ACh), sodium cyanide NaCN) and hypoxia during experiments on pentobarbitone anaesthetized cats in which chemoreceptor activity was recorded from the peripheral end of a sectioned sinus nerve. 2. Spontaneous chemosensory activity was inhibited in a dose-dependent manner by DA (0.5-5 microgram, I.A.). Higher doses (10-50 microgram) caused a delayed increase in discharge and were associated with inconsistent inhibitory responses. 3. The DA antagonist alpha-flupenthixol (0.2 mg/kg, I.A.) blocked the inhibitory response to DA without affecting either the spontaneous discharge frequency or the response to ACh. The effect of NaCN was potentiated, and during hypoxia chemoreceptor activity increased more rapidly, although the maximum frequency attained was not appreciably different from control values. Similar results were obtained with haloperidol (0.5 and 1.0 mg/kg, I.V.). 4. Higher doses of alpha-flupenthixol (0.5-1.0 mg/kg, I.A.) increased spontaneous chemoreceptor activity, but this was regarded as a non-specific effect of the drug since at these doses the inhibitory effect of 5-hydroxytryptamine (5-HT) was also abolished. 5. The animals were exposed to alternate periods of hypoxia and hyperoxia following administration of the tyrosine hydroxylase inhibitor alpha-methyl p-tyrosine (AMPT, 0.2-10 mg/kg, I.A.). The inhibitory response previously evoked by amphetamine was abolished, and electron microscopic studies showed a great reduction in the number of dense-cored granules, both of which suggested that DA levels in the carotid body had been substantially reduced. Responses to NaCN and hypoxia were slightly potentiated following AMPT, but neither spontaneous activity nor the response to ACh was affected. 6. Apomorphine (0.05-0.2 mg/kg, I.A.) inhibited the chemoreceptor discharge for up to 45 min, an effect which was antagonized by alpha-flupenthixol (0.2 mg/kg, I.A.), implying it resulted from DA receptor stimulation. Although responses to NaCN, hypoxia and higher doses of ACh were reduced following administration of apomorphine, the reduction was not very marked. 7. These results are not compatible with the theory of Osborne & Butler (1975), that in normoxia DA is tonically released in the carotid body and suppresses spontaneous chemosensory activity. 8. It is concluded that DA modulates chemosensory activity by influencing the rate of increase in discharge, without affecting maximum discharge frequency. The mechanism whereby DA is released in response to increased chemosensory activity remains to be established.
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PMID:Inhibitory action of dopamine on cat carotid chemoreceptors. 67 58

1. The peripheral, arterial chemoreceptors in the carotid body are active and responsive in the fetus. At birth, when oxygenation increases, the chemoreceptors are silenced. Over the next few days the sensitivity is reset toward the adult level and the chemoreceptors influence breathing during normal conditions. In order to investigate the underlying mechanisms of this resetting we examined the strength of the chemoreflex in newborn rats and correlated this to the contents of dopamine and noradrenaline in the carotid bodies of the newborn pups and near-term fetuses. Furthermore, turnover rates of dopamine and noradrenaline were determined in newborn rats up to 1 week of age by analysis of catecholamine decreases after inhibition of synthesis with alpha-methyl-p-tyrosine. 2. Chemoreceptor influence was assessed by the method of 'physiological chemodenervation' with hyperoxia of 15-20 s duration in unanaesthetized rat pups. Relative changes in ventilation elicited by hyperoxia were determined by body plethysmography. We found no change in ventilation on the day of birth either in vaginally born rats or in near-term pups delivered by Caesarean section. After 1 day there was a significant decrease in ventilation of -19.4 +/- 2.3% (mean +/- S.E.M.) and at 7 days of age the decrease was -28.8 +/- 2.2%, suggesting an increasing influence from the peripheral chemoreceptors. 3. The contents of dopamine and noradrenaline were measured by high-performance liquid chromatography. Dopamine increased from 3.7 +/- 0.4 pmol (pair of carotid bodies)-1 in the fetus to a peak of 15.9 +/- 2.6, 6-12 h after birth followed by a decline to 7.1 +/- 0.7 at 7 days of age. Noradrenaline levels increased from 1.3 +/- 0.3 in the fetus to 9.6 +/- 1.1 pmol (pair of carotid bodies)-1 after 4 days. The turnover rate of dopamine decreased from 4.4 pmol (pair of carotid bodies)-1 h-1 0-6 h after birth to 1.0 at 6-12 h of age. The turnover rate of noradrenaline also decreased over the first hours following delivery. 4. Since dopamine is an inhibitory neuromodulator in this system, we suggest that the increase in sensitivity seen after the first day of life is, at least in part, due to a decrease in the release of dopamine and thus a removal of an inhibitory mechanism.
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PMID:Development of the arterial chemoreflex and turnover of carotid body catecholamines in the newborn rat. 221 78

Activated alveolar macrophages and epithelial type II cells release both nitric oxide and superoxide which react at near diffusion-limited rate (6.7 x 10(9) M-1s-1) to form peroxynitrite, a potent oxidant capable of damaging the alveolar epithelium and pulmonary surfactant. Peroxynitrite, but not nitric oxide or superoxide, readily nitrates phenolic rings including tyrosine. We quantified the presence of nitrotyrosine in the lungs of patients with the adult respiratory distress syndrome (ARDS) and in the lungs of rats exposed to hyperoxia (100% O2 for 60 h) using quantitative immunofluorescence. Fresh frozen or paraffin-embedded lung sections were incubated with a polyclonal antibody to nitrotyrosine, followed by goat anti-rabbit IgG coupled to rhodamine. Sections from patients with ARDS (n = 5), or from rats exposed to hyperoxia (n = 4), exhibited a twofold increase of specific binding over controls. This binding was blocked by the addition of an excess amount of nitrotyrosine and was absent when the nitrotyrosine antibody was replaced with nonimmune IgG. In additional experiments we demonstrated nitrotyrosine formation in rat lung sections incubated in vitro with peroxynitrite, but not nitric oxide or reactive oxygen species. These data suggest that toxic levels of peroxynitrite may be formed in the lungs of patients with acute lung injury.
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PMID:Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury. 798 97

Hyperoxia is a well-characterized model of injury and repair of the lung. Type 1 cell damage is followed by type 2 cell proliferation and differentiation which restore normal structure and function. The epidermal growth factor receptor (EGFR) network is known to be a potent modulator of epithelial cell growth. Here we examine the EGFR network on isolated rat type 2 cells and SV40T-T2, a type 2 cell line, under normoxic conditions, after 24 and 48 h of in vitro hyperoxia, and after 24 h of normoxic recovery. EGF induces tyrosine phosphorylation of EGFRs in type 2 cells and SV40T-T2 cells, which decreases with hyperoxia and increases above normoxic levels in recovering cells, suggesting biphasic changes in receptor number or function with injury. The EGFR appears to be stimulated in an autocrine fashion in these cells. There is decreased DNA synthesis and proliferation in SV40T-T2 and isolated type 2 cells treated with tyrphostin B56, a specific EGFR inhibitor. Pretreatment with suramin, which binds to growth factor, results in increased EGFR tyrosine phosphorylation after stimulation, suggesting disruption of normal autocrine receptor downregulation. We have also identified transforming growth factor-alpha (TGF-alpha) in conditioned media (CM) from normoxic and hyperoxic SV40T-T2 and type 2 cells. Finally, we show increased EGF bioactivity in both bronchoalveolar lavage (BAL) from hyperoxic rats and CM from hyperoxic cells compared with normoxic controls. These findings support an integral role for an autocrine EGFR network in the type 2 cell response to injury.
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PMID:The epidermal growth factor receptor network in type 2 pneumocytes exposed to hyperoxia in vitro. 877 93

In recent years a body of data has accumulated, linking the development of bronchopulmonary dysplasia (BPD) to increased oxidative stress in the first few days after birth, since high concentrations of metabolites reflecting increased peroxidation products such as pentane, ethane, protein carbonyl, o-tyrosine, allantoin and F2-isoprostanes, as well as low levels of glutathione and sulfhydryl/total protein ratio, also reflecting increased oxidative load, have been found in the premature infants at risk of or developing BPD. Oxidative stress seems to increase lung antioxidants in some experimental models of BPD and hyperoxia affects foetal lung growth. There are similarities between inflammation and hypoxia/reoxygenation, since both activate a number of inflammatory mediators such as cytokines and adhesion molecules, some of which are found in high concentrations in tracheal aspirate fluid of infants developing BPD. Surfactant production and function are also altered by both hyperoxia and reactive oxygen species per se, making the lungs more vulnerable to injury. This new knowledge may result in new and more efficient therapeutic approaches, hopefully leading to the eradication of BPD in the near future.
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PMID:Bronchopulmonary dysplasia and oxidative stress: are we closer to an understanding of the pathogenesis of BPD? 947

The survival of type 2 alveolar epithelial cells (AEC2) in the lung after hyperoxic injury is regulated by signals from the cellular environment. Keratinocyte growth factor and Matrigel can ameliorate the hallmarks of apoptosis seen in hyperoxic AEC2 after 24-h culture on plastic [S. Buckley, L. Barsky, B. Driscoll, K. Weinberg, K. D. Anderson, and D. Warburton. Am. J. Physiol. 274 (Lung Cell. Mol. Physiol. 18): L714-L720, 1998]. We used the same model of in vivo short-term hyperoxia to characterize the protective effects of substrate attachment. Culture of hyperoxic AEC2 on various biological adhesion substrates showed reduced DNA end labeling in cells grown on all biological substrates compared with growth on plastic. In contrast, the synthetic substrate poly-D-lysine conferred no protection. Hyperoxic AEC2 cultured on laminin showed an increased ratio of expression of Bcl-2 to interleukin-1beta-converting enzyme compared with culture on plastic. Laminin also partially restored hyperoxia-depleted glutathione levels and conferred improved optimal mitochondrial viability as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Conversely, attachment to the nonphysiological substrate poly-D-lysine afforded no such protection, suggesting that protection against hyperoxia-induced damage may be associated with integrin signaling. Increased activation of extracellular signal-regulated kinase (ERK), as detected by increased ERK tyrosine phosphorylation, was seen in hyperoxic AEC2 as soon as the cells started to attach to laminin and was sustained after 24 h of culture in contrast to that in control AEC2. To confirm that protection against DNA strand breakage and apoptosis was being conferred by ERK activation, the cells were also plated in the presence of 50 microM PD-98059, an inhibitor of the ERK-activating mitogen-activating kinase. Culture for 24 h with PD-98059 abolished the protective effect of laminin. We speculate that after hyperoxic lung injury, signals through the basement membrane confer specific protection against oxygen-induced DNA strand breakage and apoptosis through an ERK activation-dependent pathway.
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PMID:ERK activation protects against DNA damage and apoptosis in hyperoxic rat AEC2. 1040 43

Inhaled nitric oxide (INO) therapy is currently used clinically to selectively dilate the pulmonary vasculature and to help treat persistent pulmonary hypertension and bronchopulmonary dysplasia in the neonate. However, in the presence of oxygen or superoxide, nitric oxide forms potentially harmful reactive nitrogen species. Using an experimental mice model, we examined the effects of concurrent hyperoxia and INO on protein tyrosine nitration and cysteine S-nitrosylation in pulmonary tissue. Data showed enhanced 3-nitrotyrosine staining within the airway epithelium and alveolar interstitium of mice lungs treated with hyperoxia, which did not increase significantly with INO administration. Within the alveolar interstitium, 3-nitrotyrosine staining was localized to macrophages. S-Nitrosocysteine staining in airway epithelium was significantly enhanced with INO administration regardless of oxygen content. These data suggest that the formation of protein S-nitrosocysteine is the major protein modification during administration of INO.
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PMID:Immunohistochemical localization of protein 3-nitrotyrosine and S-nitrosocysteine in a murine model of inhaled nitric oxide therapy. 1083 41

The purpose of this investigation was to determine the impact of elevated partial pressures of O(2) on the steady state concentration of nitric oxide ((*)NO) in the cerebral cortex. Rodents with implanted O(2)- and (*)NO-specific microelectrodes were exposed to O(2) at partial pressures from 0.2 to 2.8 atmospheres absolute (ATA) for up to 45 min. Elevations in (*)NO concentration occurred with all partial pressures above that of ambient air. In rats exposed to 2.8 ATA O(2) the increase was 692 +/- 73 nM (S.E., n = 5) over control. Changes were not associated with alterations in concentrations of nitric oxide synthase (NOS) enzymes. Based on studies with knock-out mice lacking genes for neuronal NOS (nNOS) or endothelial NOS (eNOS), nNOS activity contributed over 90% to total (*)NO elevation due to hyperoxia. Immunoprecipitation studies indicated that hyperoxia doubles the amount of nNOS associated with the molecular chaperone, heat shock protein 90 (Hsp90). Both (*)NO elevations and the association between nNOS and Hsp90 were inhibited in rats infused with superoxide dismutase. Elevations of (*)NO were also inhibited by treatment with the relatively specific nNOS inhibitor, 7 nitroindazole, by the ansamycin antibiotics herbimycin and geldanamycin, by the antioxidant N-acetylcysteine, by the calcium channel blocker nimodipine, and by the N-methyl-D-aspartate inhibitor, MK 801. Hyperoxia did not alter eNOS association with Hsp90, nor did it modify nNOS or eNOS associations with calmodulin, the magnitude of eNOS tyrosine phosphorylation, or nNOS phosphorylation via calmodulin kinase. Cerebral cortex blood flow, measured by laser Doppler flow probe, increased during hyperoxia and may be causally related to elevations of steady state (*)NO concentration. We conclude that hyperoxia causes an increase in (*)NO synthesis as part of a response to oxidative stress. Mechanisms for nNOS activation include augmentation in the association with Hsp90 and intracellular entry of calcium.
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PMID:Stimulation of nitric oxide synthase in cerebral cortex due to elevated partial pressures of oxygen: an oxidative stress response. 1193 51

We investigated the effect of hyperoxia on phospholipase D (PLD) activation in bovine lung microvascular endothelial cells (BLMVECs). Generation of intracellular reactive oxygen species in BLMVECs exposed to hyperoxia for 2 or 24 h was three-fold higher compared with normoxic cells as measured by dichlorodihydrofluorescein di(acetoxymethyl ester) fluorescence. Exposure of BLMVECs to hyperoxia for 2 or 24 h attenuated 12-O-tetradecanoylphorbol 13-acetate (TPA)-mediated PLD activation compared with normoxic cells, however, hyperoxia did not alter basal PLD activity. Antioxidants, such as propyl gallate and pyrrolidine dithiocarbamate, reversed the effect of hyperoxia on TPA-induced PLD activity. Furthermore, the TPA-induced PLD activation was inhibited not only by the protein kinase C inhibitor, Go6976, but also by the tyrosine kinase inhibitor, genistein, and by the Src kinase specific inhibitor, PP-2, suggesting the involvement of protein kinase C and also tyrosine kinases in TPA-induced PLD activation. Western blot analysis of cell lysates from the hyperoxic (2 or 24 h) BLMVECs stimulated with TPA with anti-phosphotyrosine antibody showed an attenuation in overall tyrosine phosphorylation of proteins. In conclusion, we have demonstrated that hyperoxia enhanced the generation of reactive oxygen species in lung microvascular endothelial cells and attenuated TPA-induced protein tyrosine phosphorylation and PLD activation. As protein tyrosine phosphorylation and PLD play important roles in inflammatory responses, this could provide a mechanism for the regulation of endothelial barrier function during hyperoxic lung injury.
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PMID:Hyperoxia alters phorbol ester-induced phospholipase D activation in bovine lung microvascular endothelial cells. 1271 81

Although nitrated proteins have been repeatedly used as markers of lung injury, little is known about their formation and metabolism under hyperoxia. We therefore measured 3-nitrotyrosine (3NTYR) concentrations in lung tissue and serum of rats with carrageenan-induced pneumonia exposed to hyperoxia. Twenty-nine Wistar male rats were assigned to one of 4 groups. Two experimental groups were treated by intratracheal application of carrageenan (0.5 ml of 0.7 % solution) and then one was exposed to hyperoxia for 7 days (FIO2 0.8), the other to air. Rats of two control groups breathed either hyperoxic gas mixture or air for 7 days. At the end of exposure the ventilation was determined in anesthetized, intubated animals in which 3NTYR concentrations were measured in the lung tissue and nitrites and nitrates (NOx) were estimated in the serum. Carrageenan instillation increased 3NTYR concentrations in lung tissue (carrageenan-normoxic group 147+/-7 pmol/g protein, control 90+/-10 pmol/g protein) and NOx concentration in the serum (carrageenan-normoxic group 126+/-13 ppb, control 78+/-9 ppb). Hyperoxia had no effect on lung tissue 3NTYR concentration in controls (control-hyperoxic 100+/-14 pmol/g protein) but blocked the increase of lung tissue 3NTYR in carrageenan-treated rats (carrageenan-hyperoxic 82+/-13 pmol/g protein), increased NOx in serum (control-hyperoxic 127+/-19 ppb) and decreased serum concentration of 3NTYR in both hyperoxic groups (carrageenan-hyperoxic 51+/-5 pmol/g protein, control-hyperoxic 67+/-7 pmol/g protein, carrageenan-normoxic 82+/-9 pmol/g protein, control 91+/-7 pmol/g protein). The results suggest that hyperoxia affects nitration of tyrosine residues, probably by increasing 3NTYR degradation.
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PMID:Hyperoxia attenuated nitrotyrosine concentration in the lung tissue of rats with experimental pneumonia. 1547 26


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