Effect of hyperoxia on glutathione levels and glutamic acid uptake in endothelial cells

Deneke, Susan M.; Šteiger, Vladimír; Fanburg, B. L.

doi:10.1152/jappl.1987.63.5.1966

Cited by 52 publications

(25 citation statements)

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“…The importance of GSH in normal functioning of cellular defense mechanisms is well recognized, and depletion of GSlI by fasting, restricting dietary sources of divalent sulfur or treatment with L-buthionine-[S.R]-sulfoximine has been reported to enhance the sensitivity of experimental animals to the adverse effects of hyperoxia (17)(18)(19)(20) and other potentially damaging challenges such as has been characterized for toxic doses of acetaminophen (31). In addition to the stresses created by increased oxidation of GSH to GSSG.…”

Section: Methodsmentioning

confidence: 99%

Oxidant Stress Responses in Premature Infants during Exposure to Hyperoxia

et al. 1993

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ABSTRACT. To assess oxidant stress responses in newborn infants treated with elevated concentrations of oxygen, we measured plasma concentrations of glutathione (GSH) and glutathione disulfide (GSSG) in newborn infants ranging from 23 to 42 wk gestational age. All infants recruited into the study were mechanically ventilated and had catheters placed in their umbilical arteries a s part of their normal clinical management. Blood samples were obtained on d 1,3, and 5 and weekly thereafter or until the catheters were removed. W e observed plasma concentrations of GSSG in these infants that were frequently an order of magnitude higher than the 0.1 to 0.3 pM we find in adults. Interestingly, plasma GSSG concentrations were inversely correlated to the inspired oxygen tensions. This effect appeared to arise from the patient selection criteria whereby, of the infants studied, those breathing the lowest partial pressures of oxygen were the smallest and gestationally youngest. A second observation was that plasma concentrations of G S H in the premature infants were substantially, indeed often dramatically, lower than we have observed in adult humans (6 to 10 pM). Finally, we found that in patients with both umbilical arterial and umbilical venous catheters arterial GSSG concentrations were consistently higher than venous concentrations; conversely, arterial GSI4 concentrations were lower than venous concentrations. The elevated GSSG concentrations we observed in these infants indicate marked oxidant stress responses in prematurely born infants, even in those infants exposed only to room air. The positive arteriovenous gradients of GSSG concentrations across the lungs of these infants suggest that a t least some of the increased plasma GSSG originates in the lung. The low plasma G S H concentrations we observed in these same infants suggest deficiencies in an antioxidant that has been shown in numerous animal studies to be critical for prevention of hyperoxia-induced lung injury. Finally, the negative arteriovenous gradients of G S H concentrations across the lung provide the first evidence in humans for pulmonary uptake of GSH. (Pediatr Res 34: 360-365,1993) Abbreviations Fi02, fraction inspired oxygen GGT, y-glutamyltranspeptidase GSH, glutathione GSSG, glutathione disulfide PAO~, alveolar oxygen tension Pao2, arterial oxygen tension

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Section: Methodsmentioning

confidence: 99%

Oxidant Stress Responses in Premature Infants during Exposure to Hyperoxia

et al. 1993

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“…Oxidants (hyperoxia and H 2 O 2 ), and agents such as sodium arsenite, cadmium, electrophilic compounds and diethyl maleate, also induce cystine transport in various lung cells, macrophages and erythrocytes that is analogous to the X c --transport system, a sodium-independent inducible system specific to the intracellular transport of cystine and glutamate [130±133]. It has been shown that exposure of rats to hyperoxia results in increases in total lung GSH within 24 h [6,134]. It is, therefore, possible that induction of cystine or cysteine transport could contribute to the increased GSH levels in lungs after exposure to hyperoxia [6,134].…”

Section: Role Of C-glutamyl Transpeptidase In the Regulation Of Glutamentioning

confidence: 99%

“…It has been shown that exposure of rats to hyperoxia results in increases in total lung GSH within 24 h [6,134]. It is, therefore, possible that induction of cystine or cysteine transport could contribute to the increased GSH levels in lungs after exposure to hyperoxia [6,134].…”

Section: Role Of C-glutamyl Transpeptidase In the Regulation Of Glutamentioning

confidence: 99%

Oxidative stress and regulation of glutathione in lung inflammation

Rahman¹,

MacNee²

2000

Eur Respir J

808

555

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Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox‐sensitive transcription factors such as nuclear factor‐κB, and activator protein‐1 (AP‐1), which regulate the genes for pro‐inflammatory mediators and protective antioxidant genes. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra‐ and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro‐inflammatory processes in the lungs. Recent findings have suggested that GSH is important in immune modulation, remodelling of the extracellular matrix, apoptosis and mitochondrial respiration. The rate‐limiting enzyme in GSH synthesis is γ‐glutamylcysteine synthetase (γ‐GCS). The human γ‐GCS heavy and light subunits are regulated by AP‐1 and antioxidant response elements and are modulated by oxidants, phenolic antioxidants, growth factors, and inflammatory and anti‐inflammatory agents in lung cells. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant γ‐GCS and pro‐inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. Knowledge of the mechanisms of GSH regulation and balance between the release and expression of pro‐ and anti‐inflammatory mediators could lead to the development of novel therapies based on the pharmacological manipulation of the production as well as gene transfer of this important antioxidant in lung inflammation and injury. This review describes the redox control and involvement of nuclear factor‐κB and activator protein‐1 in the regulation of cellular glutathione and γ‐glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant‐mediated susceptibility/tolerance, γ‐glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

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“…In the liver, both transport systems have been found, but only the sodium-independent system was inducible [37]. In bovine pulmonary artery endothelial cells (BPAEC), the x c -system was found to be sodium-independent and inducible by diethyl maleate (DEM), arsenite and 1,3-bis(2-chloroethyl)-1-nitrosurea (BCNU) [23,24,39,40]. In human fibroblasts is rather complex, and our knowledge of it is far from complete, especially with regard to the type II pneumocytes.…”

Section: Glutathione In Perspectivementioning

confidence: 99%

“…The activity of transsulphuration differs in isolated liver cells from the in vivo situation, in that isolated liver cells (like other cell types in vitro) usually lack the transsulphuration pathway, and thus require exogenous cysteine or cystine [22]. Cysteine is one of the three components of GSH, and the ratelimiting substrate for GSH synthesis in various cell types in culture, especially under conditions of oxidative stress [22][23][24]. Glutamate or glycine are rarely rate-limiting [22,25].…”

Section: Amino Acid Transport Systems and Gsh Synthesis (Fig 3)mentioning

confidence: 99%

Cellular glutathione turnover in vitro, with emphasis on type II pneumocytes

Klaveren¹,

Demedts²,

Nemery³

1997

Eur Respir J

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The most important extracellular antioxidant in the lung is glutathione (GSH). The epithelial lining fluid of normal lungs contains very high concentrations of this tripeptide, about 100 times higher than that found in the extracellular fluid of many other tissues. How these high extracellular GSH levels are established and the mechanisms for increases (e.g. smokers) or decreases (e.g. lung fibrosis) are still unknown, but more insight into the regulation of GSH turnover in type II pneumocytes has recently become available.The purpose of this review is to give an overview of the literature concerning cellular GSH turnover for different cell types in vitro, with an emphasis on alveolar type II epithelial cells. The main messages of this review are that: 1) GSH is, in fact, an important vehicle for stabilizing, detoxifying and transferring cysteine; 2) cysteine is the rate-limiting substrate for GSH synthesis, especially under conditions of oxidative stress; 3) various transport systems exist for the uptake of the constituents of GSH, of which γ-glutamyltransferase appears to be important; 4) intracellular GSH levels of the type II cells are governed by different factors, including, probably, the extracellular redox state; and 5) a more reduced extracellular redox state appears to favour GSH efflux, whilst an oxidized state leads to retention of GSH inside the cell.These concepts should lead to reconsideration of some of the conventional approaches to increasing intracellular glutathione levels.

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Effect of hyperoxia on glutathione levels and glutamic acid uptake in endothelial cells

Cited by 52 publications

References 0 publications

Oxidant Stress Responses in Premature Infants during Exposure to Hyperoxia

Oxidant Stress Responses in Premature Infants during Exposure to Hyperoxia

Oxidative stress and regulation of glutathione in lung inflammation

Cellular glutathione turnover in vitro, with emphasis on type II pneumocytes

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