In healthy individuals, mucus is secreted by airway epithelial cells and submucosal glands and plays a major role in preventing water loss and removing inhaled particles from the respiratory tract [1], [2]. Indeed, the surface of the airways is mainly dominated by ciliated and secretory cell types [3]. The latter are responsible for the production of airway surface liquid (ASL) and are classified based on microscopic appearance including proteic, serous and neuroendocrine characteristics [4]. In fact, ASL secreted by the mucous membranes and glands serves as a lubricant and protective blanket for the pulmonary epithelium. It is constituted by two layers: (i) the periciliary layer and (ii) the mucus layer [5]. The periciliary layer allows the cilia to beat and propels the blanket to the mouth [6]. Mucus, for its part, is a viscoelastic hydrogel. It is mostly composed of water and mucin glycoproteins. In the pulmonary level, MUC5B and MUC5AC are the main mucins that are released by submucosal glands and goblet cells, respectively [7]. Other compounds like antimicrobial molecules such as defensin or lysozyme, cellular components, including deoxyribonucleic acid (DNA) and actin, and protective factors, such as trefoil factors, can also be found [8]. Altogether, they form a complex network, as presented in Figure 1. However, during the inflammation process, mucus alteration occurs and the amount of extracellular fragments of DNA and filamentous actin increases. Furthermore, bacterial colonization can appear, reinforcing mucus purulence [9]. When expectorated, the mucus is called sputum.

Mucus hypersecretion is a feature reported in various severe respiratory diseases [10]. The pathophysiological impact is airway obstruction. This obstruction leads to airflow limitation, ventilation-perfusion mismatch and an alteration in gas exchange. Moreover, in some pathologies like Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF), mucociliary function is compromised and encourages bacterial colonization, leading to repeated infections and exacerbations [10]. Each of these diseases has different airway inflammatory responses and unique mucus hypersecretory phenotype. It is necessary to identify those phenotypes in order to deliver the most optimal treatment for each disease. Therefore, developing disease-specific therapies is the most efficient solution to cure those pathologies. Moreover, treating chronic pathologies like these two requires multiple and repeated treatments over time, at the risk of causing more side effects. Thus, therapeutic approaches must have an important tolerance to avoid side effects and long-term consequences for patients.

As described previously, the drug administration pathway represents another important factor in the development of new treatments capable of reaching their therapeutic targets at an efficient concentration [11]. Inhaled drug delivery has great potential for the treatment of pulmonary diseases [12]. This delivery route can directly and efficiently address a high quantity of drugs to the target site. This localized administration reduces systemic exposure and, therefore, side effects while avoiding first-pass hepatic effects [13]. However, airway mucus and its disease-related alterations represent a critical obstacle to develop new therapies capable of properly delivering their active compounds. For decades, mucoactive drugs, especially mucolytic, have been investigated as a therapeutic approach to treat pulmonary diseases [14]. This type of medication showed great promise as a pre-treatment to improve the efficiency and distribution of other therapies, such as gene therapy, in obstructive diseases. Here, we review and discuss the characteristics of these mucoactive drugs and their use as therapeutic agents, with a special focus on their applications in challenging muco-obstructive diseases: COPD and CF.