Glutamate-cysteine ligase modulatory subunit in BAL alveolar macrophages of healthy smokers

Neurohr, C; Lenz, Anke‐Gabriele; Ding, Isabelle; Leuchte, Hanno; Kolbe, Tanja; Behr, Jürgen

doi:10.1183/09031936.03.00080403

Cited by 36 publications

(25 citation statements)

References 42 publications

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“…There are studies showing that several genes of the glutathione pathway are upregulated in smoker9s lung [20,32], although in these studies the protein expressions or functional enzyme activities were not analysed. In contrast, the current authors [1] and others [33] have shown that the immunoreactive protein of c-glutamyl cysteine synthetase was lower in smoker9s lung and COPD than in nonsmokers. To the knowledge of the present authors, no other H 2 O 2 -scavenging antioxidant enzymes have been investigated in COPD with variable disease severity.…”

Section: Discussioncontrasting

confidence: 71%

Manganese superoxide dismutase is increased in the airways of smokers' lungs

Harju

Kaarteenaho‐Wiik²,

Sirviö³

et al. 2004

Eur Respir J

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Oxidant stress is a key mechanism for smoking-induced chronic obstructive pulmonary disease (COPD). Smoking has been shown to upregulate several antioxidant enzymes, with potential effects on the prevention of the disease and/or its progression. Superoxide dismutases (SOD)s are the only enzymes capable of consuming superoxide radicals. The purpose of the present study was to investigate SODs in the lungs of nonsmokers, smokers and COPD patients.Manganese superoxide dismutase (MnSOD), copper zinc SOD (CuZnSOD), and extracellular SOD (ECSOD), were investigated by immunohistochemistry in the airways of 13 nonsmokers, 20 smokers and 22 COPD patients with mild-to-moderate disease. Lung tissue homogenates of three nonsmokers and four smokers were used for Western blot and enzyme activity analysis.The expression of MnSOD was higher in the central bronchial epithelium of smokers with COPD and in the alveolar epithelium of smokers without or with COPD than in nonsmokers. Lung MnSOD immunoreactivity, evaluated by Western blotting and specific activity, were 33% and 51% higher, respectively, in smokers than in nonsmokers. No major changes could be observed in lung CuZnSOD or ECSOD immunoreactivities.Manganese superoxide dismutase is elevated in the alveolar epithelium of cigarette smokers, probably due to the increased oxidant burden in smokers9 lungs. Eur Respir J 2004; 24: 765-771.

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Section: Discussioncontrasting

confidence: 71%

Manganese superoxide dismutase is increased in the airways of smokers' lungs

Harju

Kaarteenaho‐Wiik²,

Sirviö³

et al. 2004

Eur Respir J

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“…A number of studies have shown that high ELF GSH concentrations similar to those found in smokers protect cultured epithelial cells against oxidative stress (6,33,34). We found that mice exposed to 16 weeks of ETS had increased ELF GSH steady-state levels that were blocked in the M. pneumoniae group.…”

Section: Discussionsupporting

confidence: 48%

Mycoplasma pneumoniae Infection and Environmental Tobacco Smoke Inhibit Lung Glutathione Adaptive Responses and Increase Oxidative Stress

et al. 2008

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Chronic cigarette smoking evokes a lung glutathione (GSH) adaptive response that results in elevated GSH levels in the lung epithelial lining fluid (ELF). Currently, little is known about how the lung regulates or maintains steady-state levels of ELF GSH. Pathogens such as Mycoplasma pneumoniae can exacerbate airway inflammation and oxidative stress. The present study examined whether M. pneumoniae infections synergize with environmental tobacco smoke (ETS) to disrupt lung GSH adaptive responses. Mice were exposed separately and in combination to ETS and M. pneumoniae for 16 weeks. ETS exposure resulted in a doubling of ELF GSH levels, which was blocked in the M. pneumoniae-exposed mice. In addition, the ETS-plus-M. pneumoniaeexposed mice had elevated levels of oxidized glutathione (GSSG), resulting in a dramatic change in the ELF redox state that corresponded with an increase in lung tissue DNA oxidation. Similar findings were observed in human lung epithelial cells in vitro. Cells exposed separately or in combination to cigarette smoke extract and M. pneumoniae for 48 h had elevated apical levels of GSH compared to control cells, and these increases were blocked by M. pneumoniae and were also associated with increased cellular DNA oxidation. Further studies showed that M. pneumoniae exposure blocked ETS-induced increases in GSH reductase, an enzyme that recycles GSSG back to GSH, both in vitro and in vivo. These studies suggest that M. pneumoniae infection synergizes with ETS and suppresses the lung's ability to respond appropriately to environmental challenges leading to enhanced oxidative stress.

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“…HARJU et al [168] have found that glutamate cysteine ligase immunoreactivity was decreased (possibly leading to decreased GSH levels) in the airways of smokers compared with nonsmokers, suggesting that cigarette smoke predisposes lung cells to ongoing oxidant stress. In addition, NEUROHR et al [169] recently showed that decreased GSH levels in BAL fluid cells of chronic smokers were associated with a decreased expression of glutamate cysteine ligase-light subunit without a change in glutamate cysteine ligase-heavy subunit expression.…”

Section: Thiol Compoundsmentioning

confidence: 99%

Oxidative stress and redox regulation of lung inflammation in COPD

Rahman

Adcock²

2006

Eur Respir J

783

599

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Reactive oxygen species, either directly or via the formation of lipid peroxidation products, may play a role in enhancing inflammation through the activation of stress kinases (cJun activated kinase, extracellular signal-regulated kinase, p38) and redox-sensitive transcription factors, such as nuclear factor (NF)-kB and activator protein-1. This results in increased expression of a battery of distinct pro-inflammatory mediators. Oxidative stress activates NF-kBmediated transcription of pro-inflammatory mediators either through activation of its activating inhibitor of kB-a kinase or the enhanced recruitment and activation of transcriptional coactivators. Enhanced NF-kB-co-activator complex formation results in targeted increases in histone modifications, such as acetylation leading to inflammatory gene expression.Emerging evidence suggests the glutathione redox couple may entail dynamic regulation of protein function by reversible disulphide bond formation on kinases, phosphatases and transcription factors. Oxidative stress also inhibits histone deacetylase activity and in doing so further enhances inflammatory gene expression and may attenuate glucocorticoid sensitivity.The antioxidant/anti-inflammatory effects of thiol molecules (glutathione, N-acetyl-L-cysteine and N-acystelyn, erdosteine), dietary polyphenols (curcumin-diferuloylmethane, cathechins/ quercetin and reserveratol), specific spin traps, such as a-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (extracellular superoxide dismutase (SOD) mimetic, SOD mimetic M40419 and SOD, and catalase manganic salen compound, eukarion-8), porphyrins (AEOL 10150 and AEOL 10113) and theophylline have all been shown to play a role in either controlling NF-kB activation or affecting histone modifications with subsequent effects on inflammatory gene expression in lung epithelial cells.Thus, oxidative stress regulates both key signal transduction pathways and histone modifications involved in lung inflammation. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in chronic obstructive pulmonary disease are also discussed.

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Glutamate-cysteine ligase modulatory subunit in BAL alveolar macrophages of healthy smokers

Cited by 36 publications

References 42 publications

Manganese superoxide dismutase is increased in the airways of smokers' lungs

Manganese superoxide dismutase is increased in the airways of smokers' lungs

Mycoplasma pneumoniae Infection and Environmental Tobacco Smoke Inhibit Lung Glutathione Adaptive Responses and Increase Oxidative Stress

Oxidative stress and redox regulation of lung inflammation in COPD

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