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Hoi Nam Tse, MBChB, FCCP; Luca Raiteri, MD; King Ying Wong, MBBS, FCCP; Lai Yun Ng, MBChB; Kwok Sang Yee, MBBS
Author and Funding Information

From the Kwong Wah Hospital (Drs Tse and Ng); the Wong Tai Sin Hospital (Drs Wong and Yee); and the Medical Department (Dr Raiteri), Innovation and Medical Sciences, Zambon SpA.

Correspondence to: Hoi Nam Tse, MBChB, FCCP, Medical and Geriatric Department, Kwong Wah Hospital, Waterloo Rd, Yau Ma Tei, Hong Kong, China; e-mail: drhoinam@gmail.com


Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Raiteri was an employee at Zambon SpA during the period of this study. Drs Tse, Wong, Ng, and Yee have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(1):194-195. doi:10.1378/chest.13-2620
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Published online
To the Editor:

We would like to thank Dr Wu and colleagues for their response to our article1 and for raising the question about alternate mechanisms explaining the action of N-acetylcysteine (NAC) in reducing COPD exacerbations. In a human lung model2 NAC could restore the antiviral cytokine response and prevent the inhibitory effect of cigarette smoke extract (CSE) on the viral-mediated retinoic acid-inducible gene (RIG-I), which is an important pattern recognition receptor that senses influenza. This dose-dependent effect of NAC on the innate immune response further supported the use of higher-dose NAC in the treatment of patients with chronic COPD, as shown in our previous The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of Chronic Obstructive Pulmonary Disease—a Double-Blinded, Randomized, Placebo-Controlled Trial (HIACE).1

We have reservations in concluding that its effect on the innate immune system is the major mechanism for reducing COPD exacerbations. First, influenza infection is not the sole cause of COPD exacerbations; in fact, other respiratory viruses (human rhinovirus, respiratory syncytial virus, human metapneumovirus, coronavirus, and adenoviruses) were recognized during exacerbations. The majority of our patients with COPD in the HIACE1 were ex-smokers; it is unknown whether cigarette smoking has a sustained long-term suppressive effect on the innate immune response. Moreover, at present, there are still limited clinical data in patients with COPD that demonstrate the interaction between cigarette smoking and NAC in “virus-induced exacerbation.” To extrapolate the in vivo results to patients with COPD, it seems that further clinical studies are warranted, especially to demonstrate the attenuated innate immune response in patients with COPD and the clinical effect of NAC in enhancing innate response as well as reducing virus-induced exacerbations in patients with COPD.

In fact, exacerbation of COPD is multifactorial. NAC may act on various target sites, resulting in the reduction of exacerbations. In addition to its mucolytic effect, antioxidant and antiinflammatory properties of NAC could attenuate the chronic airway inflammation as well as improve small airways function and reduce air trapping. For example, patients with COPD are characterized by overexpression of adhesion molecules (eg, intercellular adhesion molecule-1, which causes excessive transmigration of neutrophils). It was shown in an in vitro study3 that NAC could exert its anti-inflammatory effect by inhibiting cytokines that stimulated IL-8 and intercellular adhesion molecule-1 in endothelial and epithelial cells. Other effects that were demonstrated by NAC include (1) reductions of lysozyme and lactoferrin concentrations in smokers,4 (2) reduction in the activation and number of neutrophils and macrophages in BAL fluid in smokers,5 and (3) inhibition of the adherence of bacteria to ciliated epithelial cells in vitro.6

Nevertheless, the authors’ comments have definitely shed light on the potential mechanism for our previous observation that NAC could reduce exacerbation in patients with COPD. Further clinical studies are warranted to confirm the hypothesis.

References

Tse HN, Raiteri L, Wong KY, et al. High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest. 2013;144(1):106-118. [CrossRef] [PubMed]
 
Wu W, Patel KB, Booth JL, Zhang W, Metcalf JP. Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung. Am J Physiol Lung Cell Mol Physiol. 2011;300(6):L821-L830. [CrossRef] [PubMed]
 
Radomska-Leśniewska DM, Sadowska AM, Van Overveld FJ, Demkow U, Zieliński J, De Backer WA. Influence of N-acetylcysteine on ICAM-1 expression and IL-8 release from endothelial and epithelial cells. J Physiol Pharmacol. 2006;57(suppl 4):325-334. [PubMed]
 
Linden M, Wieslander E, Eklund A, Larsson K, Brattsand R. Effects of oral N-acetylcysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers. Eur Respir J. 1988;1(7):645-650. [PubMed]
 
Eklund A, Eriksson O, Håkansson L, et al. Oral N-acetylcysteine reduces selected humoral markers of inflammatory cell activity in BAL fluid from healthy smokers: correlation to effects on cellular variables. Eur Respir J. 1988;1(9):832-838. [PubMed]
 
Riise GC, Qvarfordt I, Larsson S, Eliasson V, Andersson BA. Inhibitory effect of N-acetylcysteine on adherence of Streptococcus pneumoniae and Haemophilus influenzae to human oropharyngeal epithelial cells in vitro. Respiration. 2000;67(5):552-558. [CrossRef] [PubMed]
 

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Tables

References

Tse HN, Raiteri L, Wong KY, et al. High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest. 2013;144(1):106-118. [CrossRef] [PubMed]
 
Wu W, Patel KB, Booth JL, Zhang W, Metcalf JP. Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung. Am J Physiol Lung Cell Mol Physiol. 2011;300(6):L821-L830. [CrossRef] [PubMed]
 
Radomska-Leśniewska DM, Sadowska AM, Van Overveld FJ, Demkow U, Zieliński J, De Backer WA. Influence of N-acetylcysteine on ICAM-1 expression and IL-8 release from endothelial and epithelial cells. J Physiol Pharmacol. 2006;57(suppl 4):325-334. [PubMed]
 
Linden M, Wieslander E, Eklund A, Larsson K, Brattsand R. Effects of oral N-acetylcysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers. Eur Respir J. 1988;1(7):645-650. [PubMed]
 
Eklund A, Eriksson O, Håkansson L, et al. Oral N-acetylcysteine reduces selected humoral markers of inflammatory cell activity in BAL fluid from healthy smokers: correlation to effects on cellular variables. Eur Respir J. 1988;1(9):832-838. [PubMed]
 
Riise GC, Qvarfordt I, Larsson S, Eliasson V, Andersson BA. Inhibitory effect of N-acetylcysteine on adherence of Streptococcus pneumoniae and Haemophilus influenzae to human oropharyngeal epithelial cells in vitro. Respiration. 2000;67(5):552-558. [CrossRef] [PubMed]
 
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