Airway Mucosal Defense: Mucins, Innate Immunity, and Contemporary Mucoactive Strategies

Mucins are highly glycosylated proteins that form the structural basis of mucus and represent a key component of innate immunity at mucosal surfaces, particularly in the respiratory tract. Beyond their mechanical barrier function, mucins actively participate in pathogen trapping, regulation of mucociliary clearance, modulation of inflammatory responses, and maintenance of epithelial homeostasis. Dysregulation of mucin synthesis, composition, or transport contributes to mucus hypersecretion, impaired airway clearance, and chronic inflammation in respiratory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. This review summarizes current insights into mucin biology, including their biosynthesis, structure, classification, and regulation, with emphasis on the gel-forming mucins MUC5AC and MUC5B. The role of mucins in mechanical protection, host–pathogen interactions, control of inflammation, and coordination of innate immune responses is reviewed. Attention is given to the interplay between mucins, immune cells, and microbial communities in maintaining airway barrier integrity. The article further examines mucoactive therapeutic strategies aimed at restoring mucus barrier function. Expectorants, mucolytics, mucoregulators, and mucokinetic agents are reviewed with respect to their mechanisms of action and clinical relevance. Established drugs, including N-acetylcysteine, carbocysteine, dornase alfa, ambroxol, and hypertonic solutions, are considered alongside emerging molecular targets such as NF-κB-dependent regulation of mucin expression, calcium-activated chloride channels, MARCKS-mediated mucin exocytosis, purinergic signaling pathways, and NO/cGMP signaling. Non-pharmacological approaches, including airway clearance techniques and respiratory rehabilitation, are covered concisely. Conclusions: Overall, this review highlights mucins as dynamic regulators of innate immunity and underscores the need for mechanism-based, personalized mucoactive therapies to improve outcomes in chronic inflammatory airway diseases.