Pharmacological investigation on the anti-oxidant and anti-inflammatory activity of N-acetylcysteine in an ex vivo model of COPD exacerbation

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Abstract

Background

Oxidative stress is recognized to be one of predisposing factor in the pathogenesis of COPD. The oxidant/antioxidant imbalance is significantly pronounced in patients with COPD exacerbation. N-acetylcysteine (NAC) seems to be able to reduce COPD exacerbations by modulating the oxidative stress in addition to its well-known mucolytic activity, but there are discordant findings on the actual anti-oxidant activity of NAC.

Methods

The anti-oxidant effect of NAC and its impact on the inflammatory response have been pharmacologically characterized on a human ex vivo model of COPD exacerbation induced by lipopolysaccharide (LPS).

Results

NAC prevented the desensitization induced by LPS incubation on the contractile tone in linear concentration-response manner. Concentrations of NAC ≥1 μM reduced the pro-oxidant response (peroxidase activity, hydrogen peroxide, malondialdehyde, nitric oxide), and improved the anti-oxidant response (total anti-oxidant capacity, glutathione, superoxide dismutase) induced by LPS. Lower concentrations of NAC (<1 μM) did not modulate the bronchial oxidative imbalance. Concentrations of NAC ≥300 μM inhibited the inflammatory response (release of IL-1β, IL-8, and TNF-α) of human airways induced by the overnight stimulation with LPS, whereas lower concentrations of NAC (≥1 μM) were sufficient to reduce the release of IL-6 elicited by LPS. Both the anti-oxidant effect and the anti-inflammatory effect of NAC were inversely correlated with the release of NKA.

Conclusions

The findings of this study suggest that NAC may have a role in modulating the detrimental effect induced by LPS in course of COPD exacerbation. It may elicit both anti-oxidant and anti-inflammatory effects when administered at high concentrations.

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Most cited references 36

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Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits.

Gordon Rushworth, Ian L Megson (2014)

N-acetyl-l-cysteine (NAC) has long been used therapeutically for the treatment of acetaminophen (paracetamol) overdose, acting as a precursor for the substrate (l-cysteine) in synthesis of hepatic glutathione (GSH) depleted through drug conjugation. Other therapeutic uses of NAC have also emerged, including the alleviation of clinical symptoms of cystic fibrosis through cysteine-mediated disruption of disulfide cross-bridges in the glycoprotein matrix in mucus. More recently, however, a wide range of clinical studies have reported on the use of NAC as an antioxidant, most notably in the protection against contrast-induced nephropathy and thrombosis. The results from these studies are conflicting and a consensus is yet to be reached regarding the merits or otherwise of NAC in the antioxidant setting. This review seeks to re-evaluate the mechanism of action of NAC as a precursor for GSH synthesis in the context of its activity as an "antioxidant". Results from recent studies are examined to establish whether the pre-requisites for effective NAC-induced antioxidant activity (i.e. GSH depletion and the presence of functional metabolic pathways for conversion of NAC to GSH) have received adequate consideration in the interpretation of the data. A key conclusion is a reinforcement of the concept that NAC should not be considered to be a powerful antioxidant in its own right: its strength is the targeted replenishment of GSH in deficient cells and it is likely to be ineffective in cells replete in GSH. © 2013.

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Oxidative stress and airway inflammation in severe exacerbations of COPD.

A Agusti, J Roca, K Skwarski … (2005)

A study was undertaken to assess both oxidative stress and inflammation in the lungs of patients with chronic obstructive pulmonary disease (COPD) during severe and very severe exacerbations compared with those with stable COPD, healthy smokers, and non-smokers. Two sites within the lungs were compared: the large airways (in sputum) and the peripheral airways (by bronchoalveolar lavage (BAL)). BAL fluid cell numbers and levels of tumour necrosis factor (TNFalpha) and interleukin (IL)-8 were measured as markers of airway inflammation and glutathione (GSH) levels as a marker of antioxidant status. Nuclear translocation of the pro-inflammatory transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) were also measured by electromobility shift assay in BAL fluid leucocytes and lung biopsy samples. Influx of inflammatory cells into the peripheral airways during exacerbations of COPD was confirmed. Increased IL-8 levels were detected in BAL fluid from patients with stable COPD compared with non-smokers and healthy smokers, with no further increase during exacerbations. In contrast, IL-8 levels in the large airways increased during exacerbations. GSH levels were increased in the BAL fluid of smokers (444%) and patients with stable COPD (235%) compared with non-smokers and were reduced during exacerbations (severe 89.2%; very severe 52.3% compared with stable COPD). NF-kappaB DNA binding in BAL leucocytes was decreased in healthy smokers compared with non-smokers (41.3%, n = 9, p<0.001) but did not differ in COPD patients, whereas AP-1 DNA binding was significantly decreased during exacerbations of COPD. There is evidence of increased oxidative stress in the airways of patients with COPD that is increased further in severe and very severe exacerbations of the disease. This is associated with increased neutrophil influx and IL-8 levels during exacerbations.

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Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology.

J H Vernooy, Klaas van Gisbergen, Wim A Buurman … (2001)

Lipopolysaccharide (LPS), a major proinflammatory glycolipid component of the gram-negative bacterial cell wall, is one of the agents ubiquitously present as contaminant on airborne particles, including air pollution, organic dusts, and cigarette smoke. Chronic exposure to significant levels of LPS is reported to be associated with the development and/or progression of many types of lung diseases, including asthma, chronic bronchitis, and progressive irreversible airflow obstruction, that are all characterized by chronic inflammatory processes in the lung. In the present study, pathologic effects of long-term LPS exposure to the lung were investigated in detail. To this end, a murine model in which mice were exposed to repeated intratracheal instillation of Escherichia coli LPS was developed. We show that long-term LPS instillation in mice results in persistent chronic pulmonary inflammation, characterized by peribronchial and perivascular lymphocytic aggregates (CD4(+), CD8(+), and CD19(+)), parenchymal accumulation of macrophages and CD8(+) T cells, and altered cytokine expression. Furthermore, airway and alveolar alterations such as mucus cell metaplasia, airway wall thickening, and irreversible alveolar enlargement accompanied the chronic inflammatory response. Interestingly, the observed inflammatory and pathologic changes mimic changes observed in human subjects with chronic inflammatory lung diseases, especially chronic obstructive pulmonary disease (COPD), suggesting that this murine model could be applicable to dissect the role of inflammation in the pathogenesis of these disease conditions.

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Author and article information

Contributors

Mario Cazzola: mario.cazzola@uniroma2.it

Luigino Calzetta: +39 06 7259 6666 , luigino.calzetta@uniroma2.it

Francesco Facciolo: facciolo@ifo.it

Paola Rogliani: roglianp@uniroma2.it

Maria Gabriella Matera: mariagabriella.matera@unina2.it

Journal

Journal ID (nlm-ta): Respir Res

Journal ID (iso-abbrev): Respir. Res

Title: Respiratory Research

Publisher: BioMed Central (London )

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Electronic): 24 January 2017

Publication date PMC-release: 24 January 2017

Publication date (Print): 2017

Volume: 18

Electronic Location Identifier: 26

Affiliations

[1 ]ISNI 0000 0001 2300 0941, GRID grid.6530.0, Department of Systems Medicine, Chair of Respiratory Medicine, , University of Rome Tor Vergata, ; Via Montpellier 1, 00133 Rome, Italy

[2 ]ISNI 0000 0004 1760 5276, GRID grid.417520.5, , Regina Elena National Cancer Institute, Thoracic Surgery Unit, ; Rome, Italy

[3 ]ISNI 0000 0001 2200 8888, GRID grid.9841.4, Department of Experimental Medicine, Unit of Pharmacology, , Second University of Naples, ; Naples, Italy

Article

Publisher ID: 500

DOI: 10.1186/s12931-016-0500-y

PMC ID: 5260037

PubMed ID: 28118826

SO-VID: d16b5f0a-712e-46f4-8bc3-66e129aab6f1

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 3 November 2016

Date accepted : 29 December 2016

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ScienceOpen disciplines: Respiratory medicine

Keywords: anti-inflammatory effect,anti-oxidant effect,copd,lipopolysaccharide,n-acetylcysteine

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ScienceOpen disciplines: Respiratory medicine

Keywords: anti-inflammatory effect, anti-oxidant effect, copd, lipopolysaccharide, n-acetylcysteine

Pharmacological investigation on the anti-oxidant and anti-inflammatory activity of N-acetylcysteine in an ex vivo model of COPD exacerbation

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Conclusions

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Biomarkers for Inflammatory Lung Disease

Most cited references 36

Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits.

Oxidative stress and airway inflammation in severe exacerbations of COPD.

Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology.

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