Impact of N-Acetylcysteine on Mucus Hypersecretion in the Airways: A Systematic Review

Paola Rogliani,1 Gian Marco Manzetti,1 Shima Gholamalishahi,1 Mario Cazzola,1 Luigino Calzetta2 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, Parma, ItalyCorrespondence: Paola Rogliani, Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, Rome, 00133, Italy, Email [email protected]: Mucus clearance is crucial for airway protection, and its dysfunction leads to chronic obstructive pulmonary disease (COPD) characterized by mucus hypersecretion (MHS) and impaired clearance. MUC5AC and MUC5B mucin proteins are key components of airway mucus, with MUC5AC being particularly responsive to environmental stimuli, making it a potential COPD biomarker. N-acetylcysteine (NAC) is a mucolytic agent with known effects on mucus viscosity and clearance, but its precise mechanisms in COPD remain unclear. This systematic review evaluated the impact of NAC on MHS in the airways, reporting significant inhibitory effects on MUC5AC and MUC5B gene and protein expression, as well as a reduction in the number of goblet cells. NAC has demonstrated efficacy in vitro and in animal models of MHS, including COPD models, but data on human bronchial tissue are lacking. This systematic review suggests that NAC acts as a mucolytic and a mucoregulator, directly inhibiting mucus secretion and goblet cell hyperplasia. Given the critical role of MHS in COPD progression, exacerbations, and mortality, these findings highlight the potential of NAC as a targeted therapy for hypersecretion COPD phenotypes. However, further studies are needed to confirm the results of this systematic review, even in human bronchial tissue, to provide translatable evidence in clinical settings. Understanding the intimate mechanism of NAC versus MHS regulation may pave the way for more effective treatments targeting airway mucus dysfunction in COPD, ultimately improving patient outcomes and reducing morbidity and mortality associated with chronic mucus hypersecretion.Keywords: COPD, mucus hypersecretion, N-acetylcysteine, systematic review