Pneumology - Reviews Open access

Mucus production and chronic obstructive pulmonary disease, a possible treatment target: zooming in on N-acetylcysteine

Authors

Published
14 January 2025
Section
Pneumology - Reviews
DOI
10.4081/monaldi.2025.3159

Abstract

Mucus hypersecretion is a trait of chronic obstructive pulmonary disease (COPD) associated with poorer outcomes. As it may be present before airway obstruction, its early treatment may have a preventive role. This narrative review of the literature presents the role of mucus dysfunction in COPD, its pathophysiology, and the rationale for the use of N-acetylcysteine (NAC). NAC can modify mucus rheology, improving clearance and reducing damage-induced MUC5AC expression. It exerts a direct and indirect (glutathione replenishment) antioxidant mechanism; it interferes with inflammatory molecular pathways, including inhibition of nuclear factor-kB activation in epithelial airway cells and reduction in the expression of cytokine tumor necrosis factor α, interleukin (IL)-6, and IL-10. Some clinical experiences suggest that the adjunctive use of NAC may reduce symptoms and improve outcomes for patients with COPD. In conclusion, NAC may be a candidate drug for the early treatment of subjects at risk of COPD development.

Keywords

References

  1. Sandelowsky H, Weinreich UM, Aarli BB, et al. COPD– do the right thing. BMC Fam Pract 2021;22:244. DOI: https://doi.org/10.1186/s12875-021-01583-w
  2. Venkatesan P. GOLD COPD report: 2024 update. Lancet Respir Med 2024;12:15-6. DOI: https://doi.org/10.1016/S2213-2600(23)00461-7
  3. Barnes PJ. Endo-phenotyping of COPD patients. Expert Rev Respir Med 2021;15:27-37. DOI: https://doi.org/10.1080/17476348.2020.1804364
  4. Hughes R, Rapsomaniki E, Janson C, et al. Frequent productive cough: symptom burden and future exacerbation risk among patients with asthma and/or COPD in the NOVELTY study. Respir Med 2022;200:106921. DOI: https://doi.org/10.1016/j.rmed.2022.106921
  5. Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256-76. DOI: https://doi.org/10.1164/ajrccm.163.5.2101039
  6. Rodrigues SO, Cunha CMCD, Soares GMV, et al. Mechanisms, pathophysiology and currently proposed treatments of chronic obstructive pulmonary disease. Pharmaceuticals 2021;14:979. DOI: https://doi.org/10.3390/ph14100979
  7. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for prevention, diagnosis and management of COPD: 2024 report. Available from: https://goldcopd.org/2024-gold-report.
  8. Papi A, Alfano F, Bigoni T, et al. N-acetylcysteine treatment in chronic obstructive pulmonary disease (COPD) and chronic bronchitis/pre-COPD: distinct meta-analyses. Arch Bronconeumol 2024;60:269-78. DOI: https://doi.org/10.1016/j.arbres.2024.03.010
  9. Kesimer M, Kirkham S, Pickles RJ, et al. Tracheobronchial air-liquid interface cell culture: a model for innate mucosal defense of the upper airways? Am J Physiol Lung Cell Mol Physiol 2009;296:L92-100. DOI: https://doi.org/10.1152/ajplung.90388.2008
  10. Whitsett JA, Alenghat T. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat Immunol 2015;16:27-35. DOI: https://doi.org/10.1038/ni.3045
  11. Voynow JA, Gendler SJ, Rose MC. Regulation of mucin genes in chronic inflammatory airway diseases. Am J Respir Cell Mol Biol 2006;34:661-5. DOI: https://doi.org/10.1165/rcmb.2006-0035SF
  12. Perez-Vilar J. Mucin granule intraluminal organization. Am J Respir Cell Mol Biol 2007;36:183-90. DOI: https://doi.org/10.1165/rcmb.2006-0291TR
  13. Shah BK, Singh B, Wang Y, et al. Mucus hypersecretion in chronic obstructive pulmonary disease and its treatment. Mediators Inflamm 2023;2023:8840594. DOI: https://doi.org/10.1155/2023/8840594
  14. Radicioni G, Ceppe A, Ford AA, et al. Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med 2021;9:1241-54. DOI: https://doi.org/10.1016/S2213-2600(21)00079-5
  15. Singanayagam A, Footitt J, Marczynski M, et al. Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease. J Clin Invest 2022;132:e120901. DOI: https://doi.org/10.1172/JCI120901
  16. Park KS, Korfhagen TR, Bruno MD, et al. SPDEF regulates goblet cell hyperplasia in the airway epithelium. J Clin Invest 2007;117:978-88. DOI: https://doi.org/10.1172/JCI29176
  17. Wan H, Kaestner KH, Ang SL, et al. Foxa2 regulates alveolarization and goblet cell hyperplasia. Development 2004;131:953-64. DOI: https://doi.org/10.1242/dev.00966
  18. Diaz AA, Orejas JL, Grumley S, et al. Airway-occluding mucus plugs and mortality in patients with chronic obstructive pulmonary disease. JAMA 2023;329:1832-9. DOI: https://doi.org/10.1001/jama.2023.2065
  19. Curran DR, Cohn L. Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease. Am J Respir Cell Mol Biol 2010;42:268-75. DOI: https://doi.org/10.1165/rcmb.2009-0151TR
  20. Boucher RC. Muco-obstructive lung diseases. N Engl J Med 2019;380:1941-53. DOI: https://doi.org/10.1056/NEJMra1813799
  21. Fahy JV, Dickey BF. Airway mucus function and dysfunction. N Engl J Med 2010;363:2233-47. DOI: https://doi.org/10.1056/NEJMra0910061
  22. Yuan S, Hollinger M, Lachowicz-Scroggins ME, et al. Oxidation increases mucin polymer cross-links to stiffen airway mucus gels. Sci Transl Med 2015;7:276ra27. DOI: https://doi.org/10.1126/scitranslmed.3010525
  23. Dunican EM, Elicker BM, Henry T, et al. Mucus plugs and emphysema in the pathophysiology of airflow obstruction and hypoxemia in smokers. Am J Respir Crit Care Med 2021;203:957-68. DOI: https://doi.org/10.1164/rccm.202006-2248OC
  24. Okajima Y, Come CE, Nardelli P, et al. Luminal plugging on chest ct scan: association with lung function, quality of life, and COPD clinical phenotypes. Chest 2020;158:121-30. DOI: https://doi.org/10.1016/j.chest.2019.12.046
  25. Kim V, Dolliver WR, Nath HP, et al. Mucus plugging on computed tomography and chronic bronchitis in chronic obstructive pulmonary disease. Respir Res 2021;22:110. DOI: https://doi.org/10.1186/s12931-021-01712-0
  26. Mettler SK, Nath HP, Grumley S, et al. Silent airway mucus plugs in COPD and clinical implications. Chest 2024;166:1010-9. DOI: https://doi.org/10.1016/j.chest.2023.11.033
  27. Hogg JC, Chu FS, Tan WC, et al. Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am J Respir Crit Care Med 2007;176:454-9. DOI: https://doi.org/10.1164/rccm.200612-1772OC
  28. Mettler SK, Sonavane S, Grumley S, et al. Airway-occluding mucus plugs and cause-specific mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2024;209:1508-10. DOI: https://doi.org/10.1164/rccm.202401-0121LE
  29. Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 2016;138:16-27. DOI: https://doi.org/10.1016/j.jaci.2016.05.011
  30. Li JD, Dohrman AF, Gallup M, et al. Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc Natl Acad Sci U S A 1997;94:967-72. DOI: https://doi.org/10.1073/pnas.94.3.967
  31. Yang D, Xu D, Wang T, et al. Mitoquinone ameliorates cigarette smoke-induced airway inflammation and mucus hypersecretion in mice. Int Immunopharmacol 2021;90:107149. DOI: https://doi.org/10.1016/j.intimp.2020.107149
  32. Milnerowicz H, Ściskalska M, Dul M. Molecular mechanisms of the impact of smoke-oxidants. Exp Toxicol Pathol 2015;67:377-82. DOI: https://doi.org/10.1016/j.etp.2015.04.004
  33. Åstrand ABM, Hemmerling M, Root J, et al. Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition. Am J Physiol Lung Cell Mol Physiol 2015;308:L22-32. DOI: https://doi.org/10.1152/ajplung.00163.2014
  34. Conti V, Corbi G, Manzo V, et al. SIRT1 activity in peripheral blood mononuclear cells correlates with altered lung function in patients with chronic obstructive pulmonary disease. Oxid Med Cell Longev 2018;2018:9391261. DOI: https://doi.org/10.1155/2018/9391261
  35. Rahman I, MacNee W. Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radic Biol Med 2000;28:1405-20. DOI: https://doi.org/10.1016/S0891-5849(00)00215-X
  36. Cazzola M, Calzetta L, Page C, et al. Thiol-based drugs in pulmonary medicine: much more than mucolytics. Trends Pharmacol Sci 2019;40:452-63. DOI: https://doi.org/10.1016/j.tips.2019.04.015
  37. Drost EM, Skwarski KM, Sauleda J, et al. Oxidative stress and airway inflammation in severe exacerbations of COPD. Thorax. 2005;60:293-300. DOI: https://doi.org/10.1136/thx.2004.027946
  38. Santus P, Corsico A, Solidoro P, et al. Oxidative stress and respiratory system: pharmacological and clinical reappraisal of N-acetylcysteine. COPD 2014;11:705-17. DOI: https://doi.org/10.3109/15412555.2014.898040
  39. Agustí A, Celli BR, Criner GJ, et al. Global Initiative for Chronic Obstructive Lung Disease 2023 Report: GOLD Executive Summary. Arch Bronconeumol 2023;59:232-48. DOI: https://doi.org/10.1016/j.arbres.2023.02.009
  40. Kopa-Stojak PN, Pawliczak R. Comparison of the effects of active and passive smoking of tobacco cigarettes, electronic nicotine delivery systems and tobacco heating products on the expression and secretion of oxidative stress and inflammatory response markers. A systematic review. Inhal Toxicol 2024;36:75-89. DOI: https://doi.org/10.1080/08958378.2024.2319315
  41. Di Marco F, Foti G, Corsico AG. Where are we with the use of N-acetylcysteine as a preventive and adjuvant treatment for COVID-19? Eur Rev Med Pharmacol Sci 2022;26:715-21.
  42. Mata M, Ruíz A, Cerdá M, et al. Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats. Eur Respir J 2003;22:900-5. DOI: https://doi.org/10.1183/09031936.03.00018003
  43. Calzetta L, Matera MG, Rogliani P, Cazzola M. Multifaceted activity of N-acetyl-l-cysteine in chronic obstructive pulmonary disease. Expert Rev Respir Med 2018;12:693-708. DOI: https://doi.org/10.1080/17476348.2018.1495562
  44. Zhu L, Xu F, Kang X, et al. The antioxidant N-acetylcysteine promotes immune response and inhibits epithelial-mesenchymal transition to alleviate pulmonary fibrosis in chronic obstructive pulmonary disease by suppressing the VWF/p38 MAPK axis. Mol Med 2021;27:97. DOI: https://doi.org/10.1186/s10020-021-00342-y
  45. Foschino Barbaro MP, Serviddio G, Resta O, et al. Oxygen therapy at low flow causes oxidative stress in chronic obstructive pulmonary disease: Prevention by N-acetyl cysteine. Free Radic Res 2005;39:1111-8. DOI: https://doi.org/10.1080/10715760500250257
  46. Decramer M, Rutten-van Mölken M, Dekhuijzen PN, 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;365:1552-60. DOI: https://doi.org/10.1016/S0140-6736(05)66456-2
  47. 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;144:106-18. DOI: https://doi.org/10.1378/chest.12-2357
  48. Tse HN, Raiteri L, Wong KY, et al. Benefits of high-dose N-acetylcysteine to exacerbation-prone patients with COPD. Chest 2014;146:611-23. DOI: https://doi.org/10.1378/chest.13-2784
  49. Cazzola M, Calzetta L, Page C, et al. Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. Eur Respir Rev 2015;24:451-61. DOI: https://doi.org/10.1183/16000617.00002215
  50. Zheng JP, Wen FQ, Bai CX, 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. DOI: https://doi.org/10.1016/S2213-2600(13)70286-8
  51. Papi A, Zheng J, Criner GJ, et al. Impact of smoking status and concomitant medications on the effect of high-dose N-acetylcysteine on chronic obstructive pulmonary disease exacerbations: a post-hoc analysis of the PANTHEON study. Respir Med 2019;147:37-43. DOI: https://doi.org/10.1016/j.rmed.2018.12.014
  52. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2017). Available from: https://goldcopd.org/archived-reports/.
  53. Micheletto C, Izquierdo JL, Avdeev SN, et al. N-acetylcysteine as a therapeutic approach to post-COVID-19 pulmonary fibrosis adjunctive treatment. Eur Rev Med Pharmacol Sci 2022;26:4872-80.

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