Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Respiratory Research
Published in: Respiratory Research 1/2017

Open Access 01-12-2017 | Research

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

Authors: Mario Cazzola, Luigino Calzetta, Francesco Facciolo, Paola Rogliani, Maria Gabriella Matera

Published in: Respiratory Research | Issue 1/2017

Login to get access

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.
Literature
1.
Matera MG, Calzetta L, Cazzola M. Oxidation pathway and exacerbations in COPD: the role of NAC. Expert Rev Respir Med. 2016;10:89–97.CrossRefPubMed
2.
Drost EM, Skwarski KM, Sauleda J, Soler N, Roca J, Agusti A, et al. Oxidative stress and airway inflammation in severe exacerbations of COPD. Thorax. 2005;60:293–300.CrossRefPubMedPubMedCentral
3.
Tse HN, Raiteri L, Wong KY, Yee KS, Ng LY, Wai KY, et al. High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest. 2013;144:106–18.CrossRefPubMed
4.
Zheng JP, Wen FQ, Bai CX, Wan HY, Kang J, Chen P, et al. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir med. 2014;2:187–94.CrossRefPubMed
5.
Cazzola M, Calzetta L, Page C, Jardim J, Chuchalin AG, Rogliani P, et al. Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. Eur Respir Rev. 2015;24:451–61.CrossRefPubMed
6.
Sadowska AM, Verbraecken J, Darquennes K, De Backer WA. Role of N-acetylcysteine in the management of COPD. Int J Chron Obstruct Pulmon Dis. 2006;1:425–34.PubMedPubMedCentral
7.
Sadowska AM, Manuel YKB, De Backer WA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther. 2007;20:9–22.CrossRefPubMed
8.
Kharitonov S, Sjöbring U. Lipopolysaccharide challenge of humans as a model for chronic obstructive lung disease exacerbations. Models of Exacerbations in Asthma and COPD.  Contrib Microbiol. Basel: Karger Publishers; 2007. vol 14, pp. 83–100.
9.
Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P, Caramori G, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173:1114–21.CrossRefPubMed
10.
Vernooy JH, Dentener MA, van Suylen RJ, Buurman WA, Wouters EF. Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology. Am J Respir Cell Mol Biol. 2002;26:152–9.CrossRefPubMed
11.
Doe C, Bentley R, Behm DJ, Lafferty R, Stavenger R, Jung D, et al. Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J Pharmacol Exp Ther. 2007;320:89–98.CrossRefPubMed
12.
Cazzola M, Calzetta L, Page CP, Rinaldi B, Capuano A, Matera MG. Protein prenylation contributes to the effects of LPS on EFS-induced responses in human isolated bronchi. Am J Respir Cell Mol Biol. 2011;45:704–10.CrossRefPubMed
13.
Hippenstiel S, Soeth S, Kellas B, Fuhrmann O, Seybold J, Krull M, et al. Rho proteins and the p38-MAPK pathway are important mediators for LPS-induced interleukin-8 expression in human endothelial cells. Blood. 2000;95:3044–51.PubMed
14.
Moldeus P, Cotgreave IA, Berggren M. Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration. 1986;50 Suppl 1:31–42.PubMed
15.
Villagrasa V, Cortijo J, Marti-Cabrera M, Ortiz JL, Berto L, Esteras A, et al. Inhibitory effects of N-acetylcysteine on superoxide anion generation in human polymorphonuclear leukocytes. J Pharm Pharmacol. 1997;49:525–9.CrossRefPubMed
16.
Cortijo J, Marti-Cabrera M, de la Asuncion JG, Pallardo FV, Esteras A, Bruseghini L, et al. Contraction of human airways by oxidative stress protection by N-acetylcysteine. Free Radic Biol Med. 1999;27:392–400.CrossRefPubMed
17.
Matera MG, Calzetta L, Peli A, Scagliarini A, Matera C, Cazzola M. Immune sensitization of equine bronchus: glutathione, IL-1beta expression and tissue responsiveness. Respir Res. 2005;6:104.CrossRefPubMedPubMedCentral
18.
Reddy S, Finkelstein EI, Wong PS, Phung A, Cross CE, van der Vliet A. Identification of glutathione modifications by cigarette smoke. Free Radic Biol Med. 2002;33:1490–8.CrossRefPubMed
19.
Oltmanns U, Chung KF, Walters M, John M, Mitchell JA. Cigarette smoke induces IL-8, but inhibits eotaxin and RANTES release from airway smooth muscle. Respir Res. 2005;6:74.CrossRefPubMedPubMedCentral
20.
Matera MG, Calzetta L, Passeri D, Facciolo F, Rendina EA, Page C, et al. Epithelium integrity is crucial for the relaxant activity of brain natriuretic peptide in human isolated bronchi. Br J Pharmacol. 2011;163:1740–54.CrossRefPubMedPubMedCentral
21.
Calzetta L, Spina D, Cazzola M, Page CP, Facciolo F, Rendina EA, et al. Pharmacological characterization of adenosine receptors on isolated human bronchi. Am J Respir Cell Mol Biol. 2011;45:1222–31.CrossRefPubMed
22.
Binks AP, Paydarfar D, Schachter SC, Guz A, Banzett RB. High strength stimulation of the vagus nerve in awake humans: a lack of cardiorespiratory effects. Respir Physiol. 2001;127:125–33.CrossRefPubMed
23.
Ouadrhiri Y, Pilette C, Monteiro RC, Vaerman JP, Sibille Y. Effect of IgA on respiratory burst and cytokine release by human alveolar macrophages: role of ERK1/2 mitogen-activated protein kinases and NF-kappaB. Am J Respir Cell Mol Biol. 2002;26:315–32.CrossRefPubMed
24.
Iyengar R, Stuehr DJ, Marletta MA. Macrophage synthesis of nitrite, nitrate, and N-nitrosamines: precursors and role of the respiratory burst. Proc Natl Acad Sci U S A. 1987;84:6369–73.CrossRefPubMedPubMedCentral
25.
Motulsky H, Christopoulos A. Fitting models to biological data using linear and nonlinear regression : a practical guide to curve fitting. Oxford: Oxford University Press; 2004.
26.
27.
Mitzner W. Airway smooth muscle: the appendix of the lung. Am J Respir Crit Care Med. 2004;169:787–90.CrossRefPubMed
28.
Fredberg JJ. Counterpoint: airway smooth muscle is not useful. J Appl Physiol. 2007;102(1709):8750–7587.
29.
Seow CY, Fredberg JJ. Historical perspective on airway smooth muscle: the saga of a frustrated cell. J Appl Physiol. 2001;91:938–52.PubMed
30.
Mitchell HW. Airway smooth muscle contraction - perspectives on past, present and future. Pulm Pharmacol Ther. 2009;22:363–9.CrossRefPubMed
31.
Lazaar AL, Panettieri Jr RA. Airway smooth muscle as a regulator of immune responses and bronchomotor tone. Clin Chest Med. 2006;27:53–69. vi.CrossRefPubMed
32.
Borger P, Tamm M, Black JL, Roth M. Asthma: is it due to an abnormal airway smooth muscle cell? Am J Respir Crit Care Med. 2006;174:367–72.CrossRefPubMed
33.
Calzetta L, Luongo L, Cazzola M, Page C, Rogliani P, Facciolo F, et al. Contribution of sensory nerves to LPS-induced hyperresponsiveness of human isolated bronchi. Life Sci. 2015;131:44–50.CrossRefPubMed
34.
Calzetta L, Soggiu A, Roncada P, Bonizzi L, Pistocchini E, Urbani A, et al. Propofol protects against opioid-induced hyperresponsiveness of airway smooth muscle in a horse model of target-controlled infusion anaesthesia. Eur J Pharmacol. 2015;765:463–71.CrossRefPubMed
35.
36.
Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014;141:150–9.CrossRefPubMed
37.
Zafarullah M, Li WQ, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci. 2003;60:6–20.CrossRefPubMed
38.
Desaki M, Takizawa H, Kasama T, Kobayashi K, Morita Y, Yamamoto K. Nuclear factor-kappa b activation in silica-induced interleukin 8 production by human bronchial epithelial cells. Cytokine. 2000;12:1257–60.CrossRefPubMed
39.
De Laurentiis A, Candolfi M, Pisera D, Seilicovich A. Effects of lipopolysaccharide on neurokinin A content and release in the hypothalamic-pituitary axis. Regul Pept. 2003;111:91–5.CrossRefPubMed
40.
41.
Tsikas D, Sandmann J, Ikic M, Fauler J, Stichtenoth DO, Frolich JC. Analysis of cysteine and N-acetylcysteine in human plasma by high-performance liquid chromatography at the basal state and after oral administration of N-acetylcysteine. J Chromatogr B Biomed Sci Appl. 1998;708:55–60.CrossRefPubMed
42.
Allegra L, Dal Sasso M, Bovio C, Massoni C, Fonti E, Braga PC. Human neutrophil oxidative bursts and their in vitro modulation by different N-acetylcysteine concentrations. Arzneimittelforschung. 2002;52:669–76.PubMed
Metadata
Title
Pharmacological investigation on the anti-oxidant and anti-inflammatory activity of N-acetylcysteine in an ex vivo model of COPD exacerbation
Authors
Mario Cazzola
Luigino Calzetta
Francesco Facciolo
Paola Rogliani
Maria Gabriella Matera
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2017
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-016-0500-y

Other articles of this Issue 1/2017

Respiratory Research 1/2017 Go to the issue

Letter to the Editor

Electronic applications for the CFQ-R scoring

Commentary

Vitamin K deficiency: the linking pin between COPD and cardiovascular diseases?

Research

Fibrocyte measurement in peripheral blood correlates with number of cultured mature fibrocytes in vitro and is a potential biomarker for interstitial lung disease in Rheumatoid Arthritis

Letter to the Editor

Novel insights in cough and breathing patterns of patients with idiopathic pulmonary fibrosis performing repeated 24-hour-respiratory polygraphies

Letter to the Editor

Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis

Research

Exposure to ambient particulate matter alters the microbial composition and induces immune changes in rat lung

ACC 2024 Congress Coverage

Cardiology Video

Highlights from the ACC 2024 Congress

Watch now

Watch official videos from the ACC congress summarizing key highlights from the last year in heart failure, cardiomyopathies, valvular disease, pulmonary vascular disease, and pediatric cardiology.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits