N-Acetylcysteine Protection in COPD: An Alternative Mechanism of Action

Abstract

We read with interest the study by Tse et al1Shah RJ Diamond JM Cantu E et al.Latent class analysis identifies distinct phenotypes of primary graft dysfunction after lung transplantation.Chest. 2013; 144: 616-622Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar in a recent issue of CHEST (July 2013). In their study, 1-year treatment with high-dose N-acetylcysteine (NAC) resulted in improved small airway function and decreased exacerbation frequency in patients with COPD. The authors proposed that the reduction in COPD exacerbations might be related to antioxidant and antiinflammatory effects of NAC, resulting in improved small airway function in COPD. Additionally, they proposed that NAC might reduce exacerbations by inhibiting bacterial adherence to ciliated epithelial cells and by NAC mucolytic effects. Although we agree with these possibilities, one additional mechanism was not discussed. We propose that a major mechanism of NAC-mediated prevention of COPD exacerbations is through restoration of the normal antiviral innate immune response that is suppressed by cigarette smoking and perhaps in COPD. Cigarette smoking is the major cause of COPD and predisposes patients to severe respiratory tract infections. Respiratory viral infections with rhinoviruses, influenza viruses, and respiratory syncytial virus are the main causes of COPD exacerbations, which are associated with disease progression and loss of lung function.2Christie JD Carby M Bag R Corris P Hertz M Weill D ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition A consensus statement of the International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 2005; 24: 1454-1459Abstract Full Text Full Text PDF PubMed Scopus (622) Google Scholar Specifically, several studies have confirmed the relationship between cigarette smoking and the risk of influenza infection.3Oto T Levvey BJ Snell GI Potential refinements of the International Society for Heart and Lung Transplantation primary graft dysfunction grading system.J Heart Lung Transplant. 2007; 26: 431-436Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Influenza infections are more severe, with more cough, acute and chronic phlegm production, breathlessness, and wheezing in smokers.4Diamond JM Lee JC Kawut SM et al.Clinical risk factors for primary graft dysfunction after lung transplantation.Am J Respir Crit Care Med. 2013; 187: 527-534Crossref PubMed Scopus (417) Google Scholar The mechanism of increased susceptibility to infections in smokers is likely multifactorial but clearly includes an alteration of immunologic host defenses. We have demonstrated that cigarette smoke extract (CSE) suppresses host antiviral activity in a human lung model.5Lederer DJ Kawut SM Wickersham N Lung Transplant Outcomes Group et al.Obesity and primary graft dysfunction after lung transplantation: the Lung Transplant Outcomes Group Obesity Study.Am J Respir Crit Care Med. 2011; 184: 1055-1061Crossref PubMed Scopus (112) Google Scholar Thus, cigarette smoke exacerbates the susceptibility of the host to respiratory infectious diseases and the attendant pathology. We found that CSE treatment inhibited influenza-induced antiviral cytokine expression in our human model. This is associated with CSE-inhibited messenger RNA and protein expression of the major RNA virus sentinel RIG-I that is important in the antiviral host response. However, inhibition of viral-mediated RIG-I induction by CSE was prevented, and antiviral cytokine responses were restored by NAC.5Lederer DJ Kawut SM Wickersham N Lung Transplant Outcomes Group et al.Obesity and primary graft dysfunction after lung transplantation: the Lung Transplant Outcomes Group Obesity Study.Am J Respir Crit Care Med. 2011; 184: 1055-1061Crossref PubMed Scopus (112) Google Scholar The interactions between host immune responses and influenza virus usually determine the outcome of infection. Restoration of these responses by NAC may have been a major mechanism in the decrease in exacerbations demonstrated by Tse et al1Shah RJ Diamond JM Cantu E et al.Latent class analysis identifies distinct phenotypes of primary graft dysfunction after lung transplantation.Chest. 2013; 144: 616-622Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar in patients with COPD. ResponseCHESTVol. 145Issue 1PreviewWe 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). Full-Text PDF