N-acetylcysteine by metered dose inhaler in thetreatment of chronic bronchitis: a multi-centre study

Dueholm, Margit; Nielsen, Casper; Thorshauge, H.; Evald, T; Hansen, Niels Chr.; Madsen, Hanne

doi:10.1016/s0954-6111(06)80220-9

Cited by 52 publications

(35 citation statements)

References 5 publications

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“…The reason for this effect is not known but presumably NAC acts as a sink for ROS, which are increased in these patients [1]. However, a multicentre study using NAC delivered by metered dose inhalers in patients with chronic cough failed to show a positive effect on wellbeing, sensation of dyspnoea, cough or lung function [191].…”

Section: N-acetyl-l-cysteinementioning

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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Section: N-acetyl-l-cysteinementioning

confidence: 99%

Oxidative stress and redox regulation of lung inflammation in COPD

Rahman

Adcock²

2006

Eur Respir J

783

599

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“…The mechanism for this effect of NAC on H 2 O 2 is not known but presumably NAC acts as a sink for ROS, which are increased in these patients (Rahman, 2005). However, a multicentre study using NAC delivered by metered dose inhalers in patients with chronic cough failed to show a positive effect on wellbeing, sensation of dyspnoea, cough or lung function (Dueholm et al, 1992). Recently, NAC has been shown to downregulate inflammatory responses in CF patients (Tirouvanziam et al, 2006)…”

Section: Therapies/clinical Trials With Gsh Analogsmentioning

confidence: 99%

Environmental toxicity, redox signaling and lung inflammation: The role of glutathione

Biswas

Rahman

2009

Molecular Aspects of Medicine

292

198

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Glutathione (γ-glutamyl-cysteinyl-glycine, GSH) is the most abundant intracellular antioxidant thiol and is central to redox defense during oxidative stress. GSH metabolism is tightly regulated and has been implicated in redox signaling and also in protection against environmental oxidant-mediated injury. Changes in the ratio of the reduced and disulfide form (GSH/GSSG) can affect signaling pathways that participate in a broad array of physiological responses from cell proliferation, autophagy and apoptosis to gene expression that involve H2O2 as a second messenger. Oxidative stress due to oxidant/antioxidant imbalance and also due to environmental oxidants is an important component during inflammation and respiratory diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and asthma. It is known to activate multiple stress kinase pathways and redox sensitive transcription factors such as Nrf2, NF-κB and AP-1, which differentially regulate the genes for pro-inflammatory cytokines as well as the protective antioxidant genes. Understanding the regulatory mechanisms for the induction of antioxidants, such as GSH, versus pro-inflammatory mediators at sites of oxidant-directed injuries may allow for the development of novel therapies which will allow pharmacological manipulation GSH synthesis during inflammation and oxidative injury. This article features the current knowledge about the role of GSH in redox signaling, GSH biosynthesis and particularly the regulation of transcription factor Nrf2 by GSH and downstream signaling during oxidative stress and inflammation in various pulmonary diseases. We also discussed the current therapeutic clinical trials using GSH and other thiol compounds, such as N-acetyl-L-cysteine, fudosteine, carbocysteine, erdosteine in environment-induced airways disease.

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“…[94][95][96][97] On the other hand, it had relatively minor effects on lung GSH homeostasis. [98][99][100] Both controlled studies and a systematic review with NAC in COPD have shown a small reduction in exacerbations. 101 102 Other compounds with NAC-like activity have been tested in many laboratories including N-acystelyn, GSH esters and GSH precursors, but there are no studies on these compounds in human smokers with COPD.…”

Section: Potential Exogenous Antioxidants and Antioxidant Mimetics Inmentioning

confidence: 99%

Focus on antioxidant enzymes and antioxidant strategies in smoking related airway diseases

Kinnula¹

2005

Thorax

115

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N-acetylcysteine by metered dose inhaler in thetreatment of chronic bronchitis: a multi-centre study

Cited by 52 publications

References 5 publications

Oxidative stress and redox regulation of lung inflammation in COPD

Oxidative stress and redox regulation of lung inflammation in COPD

Environmental toxicity, redox signaling and lung inflammation: The role of glutathione

Focus on antioxidant enzymes and antioxidant strategies in smoking related airway diseases

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