Mucoactive Agents for Airway Mucus Hypersecretory Diseases Duncan F Rogers PhD FIBiol Introduction Sputum Profile of Airway Inflammation and Mucus Hypersecretory Phenotype in Asthma, COPD, and CF Which Aspect of Airway Mucus Hypersecretion to Target? Theoretical Requirements for Effective Therapy of Airway Mucus Hypersecretion Current Recommendations for Clinical Use of Mucolytic Drugs Mucoactive Drugs N-Acetylcysteine: How Does it Work? Does it Work? Dornase Alfa Hypertonic Saline Surfactant Analysis Summary Airway mucus hypersecretion is a feature of a number of severe respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). However, each disease has a different airway inflammatory response, with consequent, and presumably linked, mucus hypersecretory phenotype. Thus, it is possible that optimal treatment of the mucus hyper- secretory element of each disease should be disease-specific. Nevertheless, mucoactive drugs are a longstanding and popular therapeutic option, and numerous compounds (eg, N-acetylcysteine, erdosteine, and ambroxol) are available for clinical use worldwide. However, rational recommen- dation of these drugs in guidelines for management of asthma, COPD, or CF has been hampered by lack of information from well-designed clinical trials. In addition, the mechanism of action of most of these drugs is unknown. Consequently, although it is possible to categorize them according to putative mechanisms of action, as expectorants (aid and/or induce cough), mucolytics (thin mucus), mucokinetics (facilitate cough transportability), and mucoregulators (suppress mechanisms underlying chronic mucus hypersecretion, such as glucocorticosteroids), it is likely that any bene- ficial effects are due to activities other than, or in addition to, effects on mucus. It is also noteworthy that the mucus factors that favor mucociliary transport (eg, thin mucus gel layer, “ideal” sol depth, and elasticity greater than viscosity) are opposite to those that favor cough effectiveness (thick mucus layer, excessive sol height, and viscosity greater than elasticity), which indicates that differ- Duncan F Rogers PhD FIBiol is affiliated with the National Heart & The author reports no conflicts of interest related to the content of this Lung Institute, Imperial College London, Dovehouse Street, London, paper. United Kingdom. Dr Rogers presented a version of this paper at the 39th RESPIRATORY Correspondence: Duncan F Rogers PhD FIBiol, Airway Disease, Na- CARE Journal Conference, “Airway Clearance: Physiology, Pharmacol- tional Heart & Lung Institute, Imperial College London, Dovehouse ogy, Techniques, and Practice,” held April 21–23, 2007, in Cancu´n, Street, London SW3 6LY, United Kingdom. E-mail: duncan.rogers@ Mexico. imperial.ac.uk. 1176 RESPIRATORY CARE • SEPTEMBER 2007 VOL 52 NO 9 MUCOACTIVE AGENTS FOR AIRWAY MUCUS HYPERSECRETORY DISEASES ent mucoactive drugs would be required for treatment of mucus obstruction in proximal versus distal airways, or in patients with an impaired cough reflex. With the exception of mucoregulatory agents, whose primary action is unlikely to be directed against mucus, well-designed clinical trials are required to unequivocally determine the effectiveness, or otherwise, of expectorant, mucolytic, and mucokinetic agents in airway diseases in which mucus hypersecretion is a pathophysiological and clinical issue. It is noteworthy that, of the more complex molecules in development, it is simple inhaled hypertonic saline that is currently receiving the greatest attention as a mucus therapy, primarily in CF. Key words: mucus, hypersecretion, asthma, chronic obstructive pulmonary disease, COPD, cystic fibrosis, mucolytic, mucokinetic, expectorant, mucoactive, N-acetylcysteine, erdosteine, ambroxol. [Respir Care 2007;52(9):1176–1193. © 2007 Daedalus Enterprises] Introduction treat the disease, especially if the changes that have led to increased mucus production are irreversible. Nevertheless, Patients with asthma, chronic obstructive pulmonary dis- as discussed above, mucus hypersecretion does contribute ease (COPD), or cystic fibrosis (CF) invariably exhibit to clinical symptoms in certain groups of patients with characteristics of airway mucus hypersecretion, namely asthma, COPD, or CF. This suggests that it is important to sputum production,1,2 excessive mucus in the airway lu- develop drugs that address the airway mucus problem in men3 (Figs. 1 and 2), goblet cell hyperplasia,3–6 and sub- these patients. There are 2 points that need considering mucosal gland hypertrophy.3,5 The pathophysiological se- when developing drugs aimed at reducing airway hyper- quelae of mucus hypersecretion are airway obstruction, secretion: airflow limitation, ventilation-perfusion mismatch, and im- • The nature of the underlying disease process in asthma, pairment of gas exchange. In addition, compromised mu- COPD, and CF, and how this relates to the mucus hy- cociliary function, with reduced mucus clearance, can en- persecretory phenotype in each condition courage bacterial colonization, leading to repeated chest infections and exacerbations, particularly in COPD and • The aspect(s) of mucus hypersecretion that should be CF. In COPD, a city-wide epidemiological study in Copen- targeted hagen showed that a number of clinical variables, includ- This paper considers the validity of using compounds ing deterioration in lung function, risk of hospitalization, with potential beneficial effects on airway mucus as treat- and risk of death, were greater in patients with COPD who ments in asthma, COPD, and CF. To set these drugs in had chronic mucus hypersecretion, compared with patients context, the paper begins with discussion of sputum, air- with either no sputum production or with only a small way mucus, and mucins, followed by an outline of the amount of intermittent sputum production7 (Fig. 3). In characteristics of mucus hypersecretion in asthma, COPD, addition, patients who had chronic airway mucus hyper- and CF, and emphasizes differences between the 3 condi- secretion and were also susceptible to chest infections had tions, and the theoretical requirements for drugs aimed at greater mortality and morbidity, compared with patients effectively inhibiting airway mucus hypersecretion. with mucus hypersecretion but without infections (see Fig. 3). In contrast, the contribution of mucus to patho- physiology and clinical symptoms in asthma or CF is less Sputum well defined. In asthma, excess mucus may not only ob- struct the airway lumen, but also contribute to the devel- Coughing or “hawking” to bring up “phlegm” is a sign opment of airway hyperresponsiveness.8 The latter possi- of respiratory disease.2,10 It indicates airway mucus hyper- bilities led to the suggestion that chronic mucus secretion, coupled with impaired mucus clearance and mu- hypersecretion reflects lack of asthma control, leading in cus retention, and is an aspect of many lung infections, turn to accelerated loss of lung function and increased asthma, COPD, bronchiectasis, and CF. The expectorated mortality.7 In CF, mucus accumulation is associated with excessive secretions are referred to as sputum. The char- airway obstruction and with bacterial colonization of the acteristics of mucus change with infection and inflamma- airways, leading to cycles of infection and exacerbations.9 tion. Inflammation leads to mucus hypersecretion, ciliary The association of airway mucus hypersecretion with dysfunction, and changes in the composition and biophys- asthma, COPD, and CF does not necessarily imply causa- ical properties of airway secretions.11 Inflammatory cells, tion. The excess mucus may merely be a result of the particularly neutrophils, which are recruited to the airway inflammatory processes that cause the disease. Conse- to combat infection, disappear from the airway, either quently, treating the mucus problem will not inevitably through programmed cell death (apoptosis) or by necrosis. RESPIRATORY CARE • SEPTEMBER 2007 VOL 52 NO 9 1177 MUCOACTIVE AGENTS FOR AIRWAY MUCUS HYPERSECRETORY DISEASES Fig. 1. Airway luminal mucus in respiratory diseases. A: Mucus (M) secretions (arrow) in an intrapulmonary bronchus in a patient with asthma. B: Airway mucus “tethering” in asthma. Transverse section through a bronchiole of a patient with asthma, showing incomplete release, or “continuity,” of secreted mucin from airway epithelial goblet cells (arrows). Similar appearances of mucus tethering are not observed in chronic obstructive pulmonary disease (COPD). E ϭ epithelium. C: Mucopurulent secretions in an intrapulmonary bronchus in a patient with COPD. D: Mucus (M) occluding a bronchiole in a patient with cystic fibrosis (CF). E ϭ epithelium. Necrotic neutrophils release pro-inflammatory mediators differences in the features of mucus obstruction in differ- that damage the epithelium and recruit more inflammatory ent hypersecretory conditions. cells. They also release deoxyribonucleic acid (DNA)12 First, although the underlying pulmonary inflammation and filamentous actin (F-actin) from the cytoskeleton. DNA of asthma, COPD, and CF shares many common features, and F-actin copolymerize to form a second rigid network there are specific characteristics unique to each condi- within airway secretions13,14 (Fig. 4). Neutrophil-derived tion.15–17 Asthma is usually an allergic disease that affects myeloperoxidase imparts a characteristic green color to the airways, rather than the lung parenchyma, and in gen- inflamed airway