Effect of high-dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD patients

Jan De Backer, Wim Vos, Cedric Van Holsbeke, Samir Vinchurkar, Rita Claes, Paul M Parizel, Wilfried De Backer, Jan De Backer, Wim Vos, Cedric Van Holsbeke, Samir Vinchurkar, Rita Claes, Paul M Parizel, Wilfried De Backer

Abstract

Background: Previous studies have demonstrated the potential beneficial effect of N-acetylcysteine (NAC) in chronic obstructive pulmonary disease (COPD). However, the required dose and responder phenotype remain unclear. The current study investigated the effect of high-dose NAC on airway geometry, inflammation, and oxidative stress in COPD patients. Novel functional respiratory imaging methods combining multislice computed tomography images and computer-based flow simulations were used with high sensitivity for detecting changes induced by the therapy.

Methods: Twelve patients with Global Initiative for Chronic Obstructive Lung Disease stage II COPD were randomized to receive NAC 1800 mg or placebo daily for 3 months and were then crossed over to the alternative treatment for a further 3 months.

Results: Significant correlations were found between image-based resistance values and glutathione levels after treatment with NAC (P = 0.011) and glutathione peroxidase at baseline (P = 0.036). Image-based resistance values appeared to be a good predictor for glutathione peroxidase levels after NAC (P = 0.02), changes in glutathione peroxidase levels (P = 0.035), and reduction in lobar functional residual capacity levels (P = 0.00084). In the limited set of responders to NAC therapy, the changes in airway resistance were in the same order as changes induced by budesonide/formoterol.

Conclusion: A combination of glutathione, glutathione peroxidase, and imaging parameters could potentially be used to phenotype COPD patients who would benefit from addition of NAC to their current therapy. The findings of this small pilot study need to be confirmed in a larger pivotal trial.

Trial registration: ClinicalTrials.gov NCT00969904.

Keywords: N-acetylcysteine; chronic obstructive pulmonary disease; computational fluid dynamics; computed tomography; functional respiratory imaging.

Figures

Figure 1
Figure 1
Changes in iRaw and iVaw for all patients. Abbreviations: iRaw, image-based resistance; iVaw, image-based volume.
Figure 2
Figure 2
Changes in iRaw after 3 months of treatment with NAC (top) and placebo (bottom) in iRaw responders. Abbreviations: NAC, N-acetylcysteine; iRaw, image-based resistance.
Figure 3
Figure 3
Changes in iRaw after 3 months of treatment with NAC (top) and placebo (bottom) in an iRaw nonresponder. Abbreviations: NAC, N-acetylcysteine; iRaw, image-based resistance.
Figure 4
Figure 4
Significant correlation between change in computational fluid dynamics-based resistance of the central airways, iRawcent, and glutathione levels after NAC treatment. Abbreviations: iRaw, image-based resistance; GSH, glutathione; NAC, N-acetylcysteine.
Figure 5
Figure 5
Significant correlation between change in computational fluid dynamics-based resistance of the distal airways iRawdist and level of GPx at baseline (top) and after placebo (bottom). Abbreviations: iRaw, image-based resistance; GPx, glutathione peroxidase.
Figure 6
Figure 6
Glutathione after NAC treatment was significantly different for patients who experienced a decrease in iRawcent (top) and an increase in iVawcent (bottom). Abbreviations: iRaw, image-based resistance; GSH, glutathione; iVaw, image-based volume.
Figure 7
Figure 7
Significant difference in change in GPx between responders and nonresponders in terms of iRawtot (top) and no significant difference in change in GPx between responders and nonresponders in terms of FEV1 (bottom). Abbreviations: iRaw, image-based resistance; GPx, glutathione peroxidase; FEV1, forced expiratory volume in one second.
Figure 8
Figure 8
Significant difference in reduction of hyperinflation (lobar FRC volumes) between responders and nonresponders in terms of iRawdist. Abbreviations: iRaw, image-based resistance; FRC, forced residual capacity.

References

    1. Hogg JC. Chronic obstructive pulmonary disease: an overview of pathology and pathogenesis. Novartis Found Symp. 2001;234:4–19.
    1. Kuwano K, Bosken CH, Paré PD, Bai TR, Wiggs BR, Hogg JC. Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1993;148(5):1220–1225.
    1. Bosken CH, Wiggs BR, Paré PD, Hogg JC. Small airway dimensions in smokers with obstruction to airflow. Am Rev Respir Dis. 1990;142(3):563–570.
    1. Sadowska AM, Van Overveld FJ, Górecka D, et al. The interrelationship between markers of inflammation and oxidative stress in chronic obstructive pulmonary disease: modulation by inhaled steroids and antioxidant. Respir Med. 2005;99(2):241–249.
    1. 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(4):425–434.
    1. Sadowska AM, Manuel-y-Keenoy B, Vertongen T, et al. Effect of N-acetylcysteine on neutrophil activation markers in healthy volunteers: in vivo and in vitro study. Pharmacol Res. 2006;53(3):216–225.
    1. Sadowska AM, Luyten C, Vints A-M, Verbraecken J, Van Ranst D, De Backer WA. Systemic antioxidant defences during acute exacerbation of chronic obstructive pulmonary disease. Respirology. 2006;11(6):741–747.
    1. Decramer M, Rutten-van Mölken M, Dekhuijzen PNR, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365(9470):1552–1560.
    1. Sadowska AM, Manuel-Y-Keenoy B, 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(1):9–22.
    1. De Backer LA, Vos W, De Backer J, Van Holsbeke C, Vinchurkar S, De Backer W. The acute effect of budesonide/formoterol in COPD: a multi-slice computed tomography and lung function study. Eur Respir J. 2012;40(2):298–305.
    1. De Backer JW, Vos WG, Gorlé CD, et al. Flow analyses in the lower airways: patient-specific model and boundary conditions. Med Eng Phys. 2008;30(7):872–879.
    1. Vinchurkar S, Backer LD, Vos W, Holsbeke CV, Backer JD, Backer WD. A case series on lung deposition analysis of inhaled medication using functional imaging based computational fluid dynamics in asthmatic patients: effect of upper airway morphology and comparison with in vivo data. Inhal Toxicol. 2012;24(2):81–88.
    1. De Backer JW, Vos WG, Vinchurkar SC, et al. Validation of computational fluid dynamics in CT-based airway models with SPECT/CT. Radiology. 2010;257(3):854–862.
    1. De Rochefort L, Vial L, Fodil R, et al. In vitro validation of computational fluid dynamic simulation in human proximal airways with hyperpolarized 3He magnetic resonance phase-contrast velocimetry. J Appl Physiol. 2007;102(5):2012–2023.
    1. De Backer JW, Vos WG, Devolder A, et al. Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation. J Biomech. 2008;41(1):106–113.
    1. De Backer L, Vos W, Salgado R, et al. Functional imaging using computer methods to compare the effect of salbutamol and ipratropium bromide in patient-specific airway models of COPD. Int J Chron Obstruct Pulmon Dis 2011. 2011;6:637–646.
    1. Lappas M, Permezel M, Rice GE. N-Acetyl-cysteine inhibits phospholipid metabolism, proinflammatory cytokine release, protease activity, and nuclear factor-kappaB deoxyribonucleic acid-binding activity in human fetal membranes in vitro. J Clin Endocrinol Metabol. 2003;88(4):1723–1729.
    1. Ungheri D, Pisani C, Sanson G, et al. Protective effect of n-acetylcysteine in a model of influenza infection in mice. Int J Immunopathol Pharmacol. 2000;13(3):123–128.
    1. Cai S, Chen P, Zhang C, Chen J-B, Wu J. Oral N-acetylcysteine attenuates pulmonary emphysema and alveolar septal cell apoptosis in smoking-induced COPD in rats. Respirology. 2009;14(3):354–359.
    1. Dekhuijzen PN, Van Beurden WJ. The role for N-acetylcysteine in the management of COPD. Int J Chron Obstruct Pulmon Dis. 2006;1(2):99–106.
    1. Stav D, Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study. Chest. 2009;136(2):381–386.
    1. Celli B. COPD, inflammation and its modulation by phosphodiesterase 4 inhibitors: time to look beyond the FEV1. Chest. 2006;129(1):5–6.
    1. Jones PW. Health status measurement in chronic obstructive pulmonary disease. Thorax. 2001;56(11):880–887.
    1. Wedzicha J, Decramer M, Seemungal T. The role of bronchodilator treatment in the prevention of exacerbations of COPD. Eur Respir J. 2012;40(6):1545–1554.
    1. Come CE, Divo MJ, San José Estépar R, et al. Lung deflation and oxygen pulse in COPD: results from the NETT randomized trial. Respir Med. 2012;106(1):109–119.

Source: PubMed

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