Response.

To the Editor

We would like to thank Dr Wu and colleagues for their response to our article and for raising the question about alternate mechanisms explaining the action of N-acetylcysteine (NAC) in reducing COPD exacerbations. In a human lung model 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).

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 HIACE 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 study 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, (2) reduction in the activation and number of neutrophils and macrophages in BAL fluid in smokers, and (3) inhibition of the adherence of bacteria to ciliated epithelial cells in vitro.

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.