mucoactive agents for airway mucus hypersecretory diseases.pdf

Mucoactive Agents for Airway Mucus Hypersecretory Diseases

Duncan F Rogers PhD FIBiol

IntroductionSputumProfile of Airway Inflammation and Mucus Hypersecretory Phenotypein Asthma, COPD, and CF

Which Aspect of Airway Mucus Hypersecretion to Target?Theoretical Requirements for Effective Therapy of Airway MucusHypersecretion

Current Recommendations for Clinical Use of Mucolytic DrugsMucoactive Drugs

N-Acetylcysteine: How Does it Work? Does it Work?Dornase AlfaHypertonic SalineSurfactant

AnalysisSummary

Airway mucus hypersecretion is a feature of a number of severe respiratory diseases, includingasthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). However, eachdisease 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 alongstanding 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 hamperedby lack of information from well-designed clinical trials. In addition, the mechanism of action ofmost of these drugs is unknown. Consequently, although it is possible to categorize them accordingto putative mechanisms of action, as expectorants (aid and/or induce cough), mucolytics (thinmucus), mucokinetics (facilitate cough transportability), and mucoregulators (suppress mechanismsunderlying 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 noteworthythat 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 (thickmucus layer, excessive sol height, and viscosity greater than elasticity), which indicates that differ-

Duncan F Rogers PhD FIBiol is affiliated with the National Heart &Lung Institute, Imperial College London, Dovehouse Street, London,United Kingdom.

Dr Rogers presented a version of this paper at the 39th RESPIRATORY

CARE Journal Conference, “Airway Clearance: Physiology, Pharmacol-ogy, Techniques, and Practice,” held April 21–23, 2007, in Cancun,Mexico.

The author reports no conflicts of interest related to the content of thispaper.

Correspondence: Duncan F Rogers PhD FIBiol, Airway Disease, Na-tional Heart & Lung Institute, Imperial College London, DovehouseStreet, London SW3 6LY, United Kingdom. E-mail: [email protected].

1176 RESPIRATORY CARE • SEPTEMBER 2007 VOL 52 NO 9

ent mucoactive drugs would be required for treatment of mucus obstruction in proximal versusdistal airways, or in patients with an impaired cough reflex. With the exception of mucoregulatoryagents, whose primary action is unlikely to be directed against mucus, well-designed clinical trialsare required to unequivocally determine the effectiveness, or otherwise, of expectorant, mucolytic,and mucokinetic agents in airway diseases in which mucus hypersecretion is a pathophysiologicaland clinical issue. It is noteworthy that, of the more complex molecules in development, it is simpleinhaled 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

Patients with asthma, chronic obstructive pulmonary dis-ease (COPD), or cystic fibrosis (CF) invariably exhibitcharacteristics of airway mucus hypersecretion, namelysputum production,1,2 excessive mucus in the airway lu-men3 (Figs. 1 and 2), goblet cell hyperplasia,3–6 and sub-mucosal gland hypertrophy.3,5 The pathophysiological se-quelae of mucus hypersecretion are airway obstruction,airflow limitation, ventilation-perfusion mismatch, and im-pairment of gas exchange. In addition, compromised mu-cociliary function, with reduced mucus clearance, can en-courage bacterial colonization, leading to repeated chestinfections and exacerbations, particularly in COPD andCF. In COPD, a city-wide epidemiological study in Copen-hagen showed that a number of clinical variables, includ-ing deterioration in lung function, risk of hospitalization,and risk of death, were greater in patients with COPD whohad chronic mucus hypersecretion, compared with patientswith either no sputum production or with only a smallamount of intermittent sputum production7 (Fig. 3). Inaddition, patients who had chronic airway mucus hyper-secretion and were also susceptible to chest infections hadgreater mortality and morbidity, compared with patientswith mucus hypersecretion but without infections (seeFig. 3). In contrast, the contribution of mucus to patho-physiology and clinical symptoms in asthma or CF is lesswell defined. In asthma, excess mucus may not only ob-struct the airway lumen, but also contribute to the devel-opment of airway hyperresponsiveness.8 The latter possi-bilities led to the suggestion that chronic mucushypersecretion reflects lack of asthma control, leading inturn to accelerated loss of lung function and increasedmortality.7 In CF, mucus accumulation is associated withairway obstruction and with bacterial colonization of theairways, leading to cycles of infection and exacerbations.9

The association of airway mucus hypersecretion withasthma, COPD, and CF does not necessarily imply causa-tion. The excess mucus may merely be a result of theinflammatory processes that cause the disease. Conse-quently, treating the mucus problem will not inevitably

treat the disease, especially if the changes that have led toincreased mucus production are irreversible. Nevertheless,as discussed above, mucus hypersecretion does contributeto clinical symptoms in certain groups of patients withasthma, COPD, or CF. This suggests that it is important todevelop drugs that address the airway mucus problem inthese patients. There are 2 points that need consideringwhen developing drugs aimed at reducing airway hyper-secretion:

• The nature of the underlying disease process in asthma,COPD, and CF, and how this relates to the mucus hy-persecretory phenotype in each condition

• The aspect(s) of mucus hypersecretion that should betargeted

This paper considers the validity of using compoundswith potential beneficial effects on airway mucus as treat-ments in asthma, COPD, and CF. To set these drugs incontext, the paper begins with discussion of sputum, air-way mucus, and mucins, followed by an outline of thecharacteristics of mucus hypersecretion in asthma, COPD,and CF, and emphasizes differences between the 3 condi-tions, and the theoretical requirements for drugs aimed ateffectively inhibiting airway mucus hypersecretion.

Sputum

Coughing or “hawking” to bring up “phlegm” is a signof respiratory disease.2,10 It indicates airway mucus hyper-secretion, coupled with impaired mucus clearance and mu-cus retention, and is an aspect of many lung infections,asthma, COPD, bronchiectasis, and CF. The expectoratedexcessive secretions are referred to as sputum. The char-acteristics of mucus change with infection and inflamma-tion. Inflammation leads to mucus hypersecretion, ciliarydysfunction, and changes in the composition and biophys-ical properties of airway secretions.11 Inflammatory cells,particularly neutrophils, which are recruited to the airwayto combat infection, disappear from the airway, eitherthrough programmed cell death (apoptosis) or by necrosis.

MUCOACTIVE AGENTS FOR AIRWAY MUCUS HYPERSECRETORY DISEASES

RESPIRATORY CARE • SEPTEMBER 2007 VOL 52 NO 9 1177

Necrotic neutrophils release pro-inflammatory mediatorsthat damage the epithelium and recruit more inflammatorycells. They also release deoxyribonucleic acid (DNA)12

and filamentous actin (F-actin) from the cytoskeleton. DNAand F-actin copolymerize to form a second rigid networkwithin airway secretions13,14 (Fig. 4). Neutrophil-derivedmyeloperoxidase imparts a characteristic green color toinflamed airway secretions, which are termed mucopuru-lent. Excessive infection turns the secretions dark yellow,green, or brown, and these are termed purulent.

Profile of Airway Inflammationand Mucus Hypersecretory Phenotype

in Asthma, COPD, and CF

Asthma, COPD, and CF, although all are inflammatoryconditions of the airways, are different diseases with dif-ferent pathophysiological and clinical characteristics.15

These differences and similarities extend to the mucushypersecretory phenotype (Fig. 5). In order to developappropriate models of airway mucus hypersecretion anddesign drugs to address the mucus problems in these dis-eases, it is necessary to understand the similarities and

differences in the features of mucus obstruction in differ-ent hypersecretory conditions.

First, although the underlying pulmonary inflammationof asthma, COPD, and CF shares many common features,there are specific characteristics unique to each condi-tion.15–17 Asthma is usually an allergic disease that affectsthe airways, rather than the lung parenchyma, and in gen-eral is characterized by Th2 (CD4�) lymphocyte orches-tration of pulmonary eosinophilia. In contrast, in severeasthma, or when patients are on chronic corticoid treat-ment, neutrophilia often predominates. The reticular layerbeneath the basement membrane is markedly thickened,and the airway epithelium is fragile, which are features notusually associated with COPD or CF. Neutrophils are gen-erally sparse in stable disease, but may play a role insevere disease.

In contrast to asthma, COPD and CF are predominantlyneutrophilic disorders orchestrated largely by macrophagesand epithelial cells. In addition, and in contrast to asthma,CD8� T lymphocytes predominate, and pulmonary eosin-ophilia is generally associated with exacerbations. COPDis associated primarily with cigarette smoking, whereasCF is associated with abnormalities in the CF transmem-

Fig. 1. Airway luminal mucus in respiratory diseases. A: Mucus (M) secretions (arrow) in an intrapulmonary bronchus in a patient withasthma. B: Airway mucus “tethering” in asthma. Transverse section through a bronchiole of a patient with asthma, showing incompleterelease, or “continuity,” of secreted mucin from airway epithelial goblet cells (arrows). Similar appearances of mucus tethering are notobserved in chronic obstructive pulmonary disease (COPD). E � epithelium. C: Mucopurulent secretions in an intrapulmonary bronchus ina patient with COPD. D: Mucus (M) occluding a bronchiole in a patient with cystic fibrosis (CF). E � epithelium.



brane-conductance regulator.9,18 COPD comprises 3 con-ditions, namely, chronic bronchitis (mucus hypersecretion),bronchiolitis (also known as small airways disease), andemphysema (alveolar destruction) (Fig. 6). The latter 2pathophysiologies are not associated with asthma or, ingeneral, with CF. The contribution to clinical symptoms ofbronchitis, bronchiolitis, and emphysema in any one pa-tient is uncertain, and, therefore, the contribution of mucusobstruction to airflow limitation is unclear (Fig. 6). Asthma,COPD, and CF have a characteristic “portfolio” of inflam-matory mediators and enzymes, many of which differ be-tween the conditions.19,20 At a simplified level, histamine,interleukin-4, and eotaxin are associated with asthma,whereas interleukin-8, neutrophil elastase, and matrix met-alloproteinases are associated with COPD and CF. Thus,there are specific differences in airway inflammation andremodeling between asthma on the one hand, and, to acertain extent, COPD and CF together on the other hand.These differences may in turn exert different influences onthe development of airway mucus obstruction in the 3conditions (see Fig. 5).

Airway mucus in asthma is more viscous than in COPDor CF. In asthma the airways tend to develop and becomeblocked by gelatinous “mucus” plugs.8 Interestingly, CFsputum is less viscous than either normal secretions orsputum from patients with asthma or COPD, possibly due

to less mucin in CF sputum.21,22 Whether mucus in asthmahas an intrinsic biochemical abnormality is unclear. Ingeneral terms, sputum from patients with asthma is moreviscous than that from patients with chronic bronchitis orbronchiectasis.23–25 Mucus plugs in asthma differ from air-way mucus gels in chronic bronchitis or CF, in that theyare stabilized by noncovalent interactions between ex-tremely large mucins assembled from conventional-sizesubunits.26 This suggests an intrinsic abnormality in themucus due to a defect in assembly of the mucin molecules,and could account for the increased viscosity of the mucusplugs in asthma. Plug formation may also be due, at leastin part, to increased airway plasma exudation in asthma,compared with COPD or CF.27 In addition, and in directcontrast to COPD, exocytosed mucins in asthma are notreleased fully from the goblet cells, leading to “tethering”of luminal mucins to the airway epithelium.28 This tether-ing may also contribute to plug formation. One explana-tion of mucus tethering is that neutrophil proteases (thepredominant inflammatory cell in COPD29) cleave goblet-cell-attached mucins. In asthma, the inflammatory cell pro-file, predominantly airway eosinophilia,30 does not gener-ate the appropriate proteases to facilitate mucin release.

Different mucin gene (MUC) products, or at least dif-ferent proportions of these mucins, appear to be present inrespiratory tract secretions in COPD, asthma, and CF.

Fig. 2. Relative amounts of airway luminal mucus in different airway diseases. A. Lungs from patients dying of causes other than lungdisease (controls, C), or from emphysema (Emph), chronic bronchitis (CB), chronic asthma (Chr. A) or acute-severe asthma (A-S. A) werecut into histological sections, which were stained for mucin (M). The stained sections were viewed by light microscopy and intrapulmonaryairways assessed for amount of luminal mucus. E � bronchial epithelium. B. Airways of interest were subjected to computer-based imageanalysis. The irregular perimeter of the bronchial epithelium was digitally-converted to a circle, from which the area of mucus (AM) wasexpressed as a ratio of the area of the bronchus (AB), to give a mucus-occupying ratio, MOR (AM/AB), as shown in panel C. *p � 0.01,**p � 0.01 compared with controls. (Redrawn from data in References 3 and 4.)



MUC5AC and MUC5B are the major mucin species inairway secretions from patients with COPD, asthma, orCF.31–35 In general, there is significantly more of the low-charge glycoform of MUC5B in respiratory disease than innormal control secretions.35 An interesting difference isthat there is a proportional increase in the low-charge gly-coform of MUC5B mucin over the MUC5AC mucin inairway secretions from patients with COPD, comparedwith secretions from patients with asthma.31 These datarequire confirmation in more samples.

The importance of the difference in MUC5B glyco-forms between asthma and COPD is unclear, but it mayrelate to differences in propensity for bacterial coloniza-tion of the lungs. It is noteworthy that COPD patients areprone to pulmonary infections,9,29 and have proportionallyfewer serous cells, in contrast to patients with asthma,who are not so notably prone to chest infection. Possiblyone of the most important differences between asthma,COPD, and CF is that in CF there are markedly fewerMUC5AC and MUC5B mucins in airway secretions,compared with normal control subjects.22 This is in con-trast to asthma and COPD, in which these mucins areabove normal (see above). The reduction in MUC5AC and

MUC5B mucins is not thought to be due to sputum ab-normalities,36 but may reflect disease severity or be due toa primary defect in mucin secretion in CF. For example,for the latter suggestion, CF bronchi secrete less mucinthan do non-CF control tissue in response to a variety ofstimuli.37,38

In contrast to healthy individuals, goblet cells in airwaysfrom patients with COPD contain not only MUC5AC butalso MUC5B33,39 and MUC2.40,41 This distribution is dif-ferent than that in the airways of patients with asthma orCF, where MUC5AC and MUC5B show a similar histo-logical pattern to normal controls.42,43 It is noteworthythat, although MUC2 is located in goblet cells in irritatedairways, and MUC2 messenger ribonucleic acid (mRNA)is found in the airways of smokers,44 MUC2 mucin iseither not found in airway secretions from normal subjectsor patients with chronic bronchitis,32 or is found only invery small amounts in asthma, COPD, or CF.35,45 Theimportance of the above combined observations is unclearbut suggests that there are differences in goblet cell phe-notype between asthma, COPD, and CF.

Another notable difference between asthma and COPDis in the bronchial submucosal glands.46 In asthma, al-

Fig. 3. Clinical impact of airway mucus hypersecretion in chronic obstructive pulmonary disease (COPD). The Copenhagen Heart Studyshowed that patients with chronic mucus hypersecretion (CMH), as defined by long-term phlegm production, had an increased risk of death(A), and accelerated decline in lung function (B), a further decline in lung function when linked with pulmonary infection (C), and an increasedrisk of hospitalization (D), when compared with subjects without mucus production (No M) or patients with any mucus production (M) butwithout CMH. (From data in Reference 7.)



though hypertrophied, the glands are morphologically nor-mal and there is an even distribution of mucous and serouscells. In contrast, in chronic bronchitis, gland hypertrophyis characterized by a markedly increased number of mu-cous cells, relative to serous cells, particularly in severebronchitis. The reduction in number of gland serous cellsmay have clinical importance. The serous cells are a richsource of antibacterial enzymes such as lysozyme and lac-toferrin.47 Thus, the airway mucus layer in patients withCOPD may have less antibacterial potential than in pa-tients with asthma. This reduction, coupled with the changein MUC5B glycoforms in COPD (see above), could fur-ther explain, at least in part, the much higher incidence ofbacterial chest infections in COPD, compared with asthma.

Which Aspect of Airway MucusHypersecretion to Target?

From the above it may be seen that there are theoreticaland actual differences in the nature of airway mucus ob-struction between COPD, asthma, and CF. How these re-late to pathophysiology and clinical symptoms in the 3conditions is, for the most part, unclear. However, thesedissimilarities indicate that different treatments are requiredfor effective control of airway mucus obstruction in dif-ferent respiratory diseases. Despite these differences, useof drugs that “thin” mucus (termed mucolytic drugs) is thetraditional pharmacotherapeutic approach to alleviating thesymptoms of airways mucus hypersecretion (coughing,“phlegm” production, and airway obstruction). However,airway hypersecretion in asthma, COPD, and CF is a mul-

tifactorial process that involves increases in the amount ofmucus-producing tissues, changes in phenotype of thesetissues, changes in mucus viscosity, possible changes inexpression of the protein products of MUC genes, andchanges in the interaction of mucus with other componentsof the airway liquid (eg, serum proteins such as albumin).Although these changes are considered to be involved inthe pathophysiology of airway hypersecretion, the relativecontribution of each change to disease development andclinical symptoms is unresolved. Consequently, it is un-clear which pathophysiological aspect(s) should be tar-geted by mucoactive drugs for optimal benefit. It is easilyconceivable that merely thinning mucus is not effectivewithout additional effects on other aspects of hypersecre-tion, such as reducing the amount of mucus-secreting tis-sue.

Theoretical Requirements for Effective Therapyof Airway Mucus Hypersecretion

The discussion above on the characteristics of mucushypersecretion in asthma, COPD, and CF, as well as thaton the differences in hypersecretory phenotype betweenthe 3 conditions (see Fig. 5), demonstrates that effectivelong-term therapy of airway mucus hypersecretion in these3 conditions is likely to entail more than just “thinning” ofmucus, and could be different for each condition. Thereare 2 objectives in treatment of mucus hypersecretion,namely, short-term relief of symptoms and long-term ben-efit (Table 1). The first of these involves facilitating mucusclearance, and entails changing the viscoelasticity of mu-

Fig. 4. Mucin, deoxyribonucleic acid (DNA), and actin interactions in mucus. A: Secreted mucins are thread-like and form a tangled networkon the airway surface, with individual threads linked together by low-energy, noncovalent bonds (dotted lines), including ionic bonds,hydrogen bonds, and van der Waals forces. B: In respiratory conditions in which neutrophilic inflammation is a pathophysiological feature(CF more than in chronic obstructive pulmonary disease or severe asthma, and much more than in stable asthma), necrosing neutrophils(Neut) release DNA, which increases the viscosity of the mucus. Cell-derived filamentous (F) actin also increase the viscosity of the mucus.The DNA and F-actin co-polymerize to form thick bundles,14 although the mucin network is distinct.



cus (the change in viscosity and/or elasticity will dependupon whether mucociliary clearance or cough is “pre-ferred”: see below), increasing ciliary function, and, pos-sibly, encouraging cough. Theoretically, cough clearanceis optimized when there is high viscosity and low tenacity.Tenacity is the product of adhesivity and cohesivity (“stick-iness” and “stringiness”). Decreasing viscosity may notmarkedly change mucus clearance. Of greater importanceis the degree of adhesion of the mucus to the epithelium:decreased adhesion is linked to increased clearance. Inaddition, in asthmatic patients, facilitating the release ofthe tethered goblet cell mucin should improve airflow.Long-term benefit involves reversal of the hypersecretoryphenotype and entails reducing the number of goblet cellsand the size of the submucosal glands. In addition, inasthma it may be useful to inhibit plasma exudation. In

COPD, correction of the increased submucosal gland mu-cous cell to serous cell ratio and the increased MUC5B toMUC5AC ratio may be of benefit. It is unlikely that theactivity of current compounds intended to treat airwaymucus hypersecretion, or even those in development, onthe above variables is clearly defined.

Enhancing mucus clearance, with perceived reductionsin airway obstruction and airflow limitation, is a primaryobjective for short-term relief of symptoms in airway mu-cus hypersecretory diseases. This concept is supported bythe observation that less chronic cough or sputum produc-tion is a predictor of decline in lung function in patientswith asthma.48 The implication is that failure to clear air-way mucus, for whatever reason, is associated with in-creasing airway obstruction. Consequently, aiding clear-ance would seem a viable therapeutic option, by enhancing

Fig. 5. Putative differences in the airway mucus hypersecretory phenotype between asthma, chronic obstructive pulmonary disease(COPD), and cystic fibrosis (CF). Compared with normal, in asthma, there is airway inflammation (predominantly eosinophils and Th2lymphocytes), an increased amount of luminal mucus with an increased content of MUC5AC and MUC5B mucins (large font), with thepossibility of an increased ratio of the low charge glycoform (lcgf) of MUC5B to MUC5AC, the “appearance” of small amounts of MUC2 inthe secretions, epithelial “fragility” with loss of ciliated cells, marked goblet cell hyperplasia, submucosal gland hypertrophy (although, incontrast to COPD or CF [see below], without a marked increase in mucous cell to serous cell ratio), “tethering” of mucus to goblet cells,and plasma exudation. In COPD, there is airway inflammation (predominantly macrophages and neutrophils), increased luminal mucus,increased amounts of MUC5AC and MUC5B mucins (large font), an increased ratio of lcgf MUC5B to MUC5AC above that in asthma, smallamounts of MUC2, goblet cell hyperplasia, submucosal gland hypertrophy (with an increased proportion of mucous to serous cells), anda susceptibility to infection (rod shapes in mucus). In CF, the defect in the cystic fibrosis transmembrane-conductance regulator (CFTR) isassociated with airway inflammation (predominantly macrophages and neutrophils), increased luminal mucus (with increased amounts ofDNA), decreased amounts of MUC5AC and MUC5B (small font) compared with normal, small amounts of MUC2, globlet cell hyperplasia,submucosal gland hypertrophy, and a marked susceptibility to infection. Many of these differences require further investigation in greaternumbers of subjects.



the effectiveness of mucociliary clearance and cough. How-ever, mucociliary clearance and cough exist as a “yin-yang” pairing, in that the mucus variables that favor ef-fective mucociliary clearance are directly opposite to thosethat favor effective cough49 (Table 2). For example, a thinmucus layer and an “ideal” depth of the sol, or periciliary,layer favor mucociliary clearance. The ideal sol depth ispurported to be just less than the height of the cilia, toallow effective coupling between ciliary tips and the sur-face mucus gel layer. In contrast, a thick mucus layer anda sol depth that raises the gel phase away from the ciliafavor cough clearance. Mucus is a non-Newtonian fluid inthat it has both viscous (liquid) and elastic (solid) proper-ties.50 Viscosity represents energy loss, whereas elasticityrepresents energy storage. Consequently, the effectivenessof mucociliary clearance has a direct relationship withelasticity, whereby kinetic energy from beating cilia istransmitted to the mucus, and an indirect relationship withviscosity (limiting energy loss). Conversely, cough effec-tiveness has an indirect relationship with elasticity (to limitelastic recoil of cough-sheared mucus), and a direct rela-tionship with viscosity.51 In addition, low adhesivity ofmucus favors cough due to ease of lifting of the mucus

layer from the airway surface, by allowing “wave” forma-tion in the gel (Fig. 7). High adhesivity hinders waveformation and, to a certain extent, favors mucociliary clear-ance over cough. In addition, mucus depth alters the in-fluence of viscosity, elasticity, and adhesivity on the ef-fectiveness of cough clearance (see Fig. 7). In generalterms, it is easier to clear relatively large amounts of vis-cous mucus with cough, than small amounts of elasticmucus; this is akin to being able to empty a full ketchupbottle with a single shake than one with only a smear ofketchup around the inside (Fig. 8).

From the above it may be reasoned that if the mucusobstruction in any one patient could best be cleared bycough (eg, mucus accumulation in more proximal airways),then drugs that enhance cough would be preferred. Con-versely, if mucus obstruction is in more distal airways, orif a patient has a weak cough reflex, then drugs that favormucociliary clearance would be preferred. The challengesare first, in identifying which patients would benefit fromwhich treatment option, then second, in choice of drug tobest exploit that option.

Current Recommendations for Clinical Useof Mucolytic Drugs

The overt clinical symptoms of cough and expectora-tion, coupled with the concomitant perceived importanceof mucus in pathophysiology of many severe lung condi-tions, including asthma and COPD, have led to worldwidedevelopment of drugs thought to affect respiratory mucus.At present, over 50 compounds have potentially beneficialactions on some aspect of mucus or its secretion (Table 3).In reality, less than a third of these are listed in nationalformularies worldwide.52

Despite the abundance of mucoactive drugs available,few are recommended for use in respiratory hypersecre-tory disease. For example, although the United Kingdom’sNational Institute for Clinical Excellence recommends mu-colytic therapy in clinical management of COPD, mostguidelines for management of COPD do not advocate suchtreatment. Neither the British Thoracic Society53 nor theEuropean Respiratory Society54 currently recommend mu-colytic drugs in treatment. In Canada, mucolytics are listedas one of a number of treatments “under investigation” andare not specifically recommended in disease management.55

The American Thoracic Society suggests that “mucoki-netic” agents be considered in “step 3” as an adjunct tobronchodilators where there is a mild to moderate increasein symptoms, and also in severe exacerbations if sputum is“very viscous.”56 In its asthma management guidelines theBritish Thoracic Society does not mention mucolytic treat-ment,57 whereas the American Thoracic Society makes norecommendations for use of mucolytics or expectorants.58

Fig.6.Componentsofchronicobstructivepulmonarydisease(COPD).A: COPD comprises 3 interlinked conditions, namely, chronic bron-chitis (CB, airway mucus hypersecretion), small airways disease (SAD,chronic bronchiolitis), and emphysema (E, alveolar destruction). Therelative contribution to airway obstruction of each component in anyone patient is often unclear. B: Patient in whom mucus hypersecre-tion predominates (may be identifiable by excessive sputum produc-tion). C: Patient in whom mucus hypersecretion contributes propor-tionally less to airflow limitation than SAD and E.



Mucoactive Drugs

From the above it may be seen that although mucushypersecretion is associated with morbidity and mortalityin asthma, COPD, and CF, there is controversy concerningthe therapeutic value of drugs that affect mucus properties.Nevertheless, there are numerous compounds in develop-ment aimed at alleviating airways mucus hypersecretion.For the most part, the mechanism of action of these com-pounds is either unknown or incompletely characterized.

Useful attempts have been made to precisely categorizecompounds that affect mucus.59,60 However, a more sim-ple classification system is followed herein (Table 4). Com-pounds are classified as expectorants, mucolytics, muco-kinetics, or mucoregulators according to the followingcharacteristics, based loosely on putative mechanism(s) ofaction.61

Expectorants (see Tables 3 and 4) probably increasesecretion of mucins and/or increase mucus hydration to apoint where a sufficient volume of mucus is produced toenable it to be coughed up. These drugs may also beirritants and initiate cough to dislodge mucus.

Mucolytics “lyse,” or reduce the viscosity of, mucus.Respiratory mucins, in common with other mucins, con-tain disulphide bonds that contribute to the long, thread-like structure of mature mucins and aid gel formation.40,62

The term mucolytic refers to compounds with sulfydrylgroups that are able to dissociate disulphide bonds andpotentially reduce mucus viscosity. The “classical” muco-lytic compounds have either “exposed,” or “free,” sulfy-dryl groups (for example N-acetylcysteine) that directlybreak disulphide bonds, or have “blocked” sulfydryl groupsthat are exposed upon metabolism in the body (for exam-ple carbocysteine) (Fig. 9). Other compounds, such as pro-teolytic enzymes and recombinant human deoxyribono-clease (also known as dornase alfa or rhDNase) (seeTable 3), also break up mucus, but do so via mechanismsother than dissociating disulphide bonds in mucin mole-cules, and, as such, are not strictly mucolytic.

Mucokinetic agents increase mucus “kinesis,” effectivelyincreasing the transportability of mucus by cough. Theseagents include �2-adrenoceptor agonist bronchodilators (eg,albuterol) and surfactant. �2 agonists probably increasemucus clearance by increasing airflow and ciliary beat,with consequent effects on mucus movement, as well asincreasing Cl– and, hence, water secretion, and also mucinsecretion (albeit that the latter effect is small), which mayincrease mucus volume and thereby aid cough clearance(see above). Surfactant aids cough clearance by reducingthe adherence of mucus to the epithelium. Drugs such asambroxol (see Fig. 9) may increase cough effectiveness bystimulating surfactant secretion.

Mucoregulators are drugs that do not directly have anygreat influence on airway mucus, but they may reduce the

Table 1. Theoretical Requirements for Pharmacotherapy of Airway Mucus Pathophysiology in Asthma, COPD, and CF

Overall Effect Component Effects*

Facilitate mucus clearance (short-term relief of symptoms) Reduce viscosity (increase elasticity?)Reduce DNA/filamentous actin content of mucus (CF � COPD)Increase ciliary functionInduce coughFacilitate release of “tethered” goblet cell mucin (asthma)Inhibit mucin secretion

Reverse hypersecretory phenotype (long-term benefit) Treat airway/pulmonary inflammationReduce goblet cell numberReduce submucosal gland sizeInhibit plasma exudation (asthma)Correct increased ratio of gland mucous cells to serous cells (COPD)Reverse increased ratio of low-charge glycoform MUC5B to MUC5AC (COPD)

*The relative importance of the individual component effects to airway mucus pathophysiology is unclear. Consequently, it may be unnecessary to meet all theoretical requirements, with inhibition ofonly certain aspects having important clinical benefit.COPD � chronic obstructive pulmonary diseaseCF � cystic fibrosisDNA � deoxyribonucleic acidMUC � mucin gene product

Table 2. Differential Effects of Airway Mucus Properties onMucociliary Clearance and Cough

Favors Mucociliary Clearance Favors Cough

Thin mucus layer Thick mucus layer“Ideal” sol depth Excess sol (height above cilia)Direct relationship with elasticity Indirect relationship with elasticityIndirect relationship with viscosity

(ie, elasticity � viscosity forenergy transfer)

Direct relationship with viscosity(ie, viscosity � elasticity)



process of chronic mucus hypersecretion, either by theiranti-inflammatory activity (including glucocorticosteroidsand macrolide antibiotics) or by inhibiting a particularaspect of mucus physiology (eg, anti-cholinergic drugsthat inhibit cholinergic nerve-induced mucus secretion, inaddition to their anticholinergic bronchodilator activity).

The above terms are useful in categorizing mucoactivedrugs in terms of their putative mechanisms of action.

However, it should be noted that many mucoactive drugshave activities additional to their perceived activity onmucus (eg, antioxidant activity). N-acetylcysteine is a mu-coactive drug with putative mucolytic and antioxidant ac-tivity. It is considered below as an illustration of the originof the doubts raised concerning the therapeutic potential ingeneral of mucoactive drug therapy in mucus hypersecre-tion airway diseases. It highlights the confusion raised by

Fig. 7. Interaction between mucus gel depth and mucus biophysical variables on effectiveness of cough clearance. A: Data from a simulatedcough machine demonstrates that cough-type clearance relates primarily to mucus gel viscosity. B: For a given viscosity, clearance is alsoimpaired by spinnability (the capacity of the mucus to form threads, and an index of large deformation elasticity). Viscous deformation (dueto cough) is reduced by elastic recoil in the mucus. C: At constant viscosity and spinnability, clearance is further impaired by an increasein the adhesivity of the mucus (indicated by reduced capacity of cough airflow to raise the gel into “waves,” which facilitates lifting of themucus from the epithelium). (From data in Reference 51.)

Fig. 8. Mucus volume and cough effectiveness: the ketchup bottle analogy. A: It is easier to empty a full ketchup bottle (left) with a vigorouspalm-slap on the bottom than one containing only a small amount of ketchup (right). (Photograph courtesy of Kate Rogers, author’sdaughter.) B: Large sputum sample coughed out in one episode by a patient with bronchorrhea.



uncertainties about mechanism of action and imprecisionin clinical trial design. In contrast, dornase alfa has a well-defined mechanism of action (ie, degrades DNA) and isconsidered below to contrast with N-acetylcysteine. In ad-dition, hypertonic saline and aerosolized surfactant are alsomentioned below as examples of interventions that arecurrently under consideration as agents with potentiallybeneficial effects on airway mucus.

N-Acetylcysteine: How Does it Work? Does it Work?

N-acetylcysteine is the mucolytic compound most-listedin pharmacopoeias worldwide,52 and has been used formany years in the treatment of patients with a variety ofrespiratory conditions.63 N-acetylcysteine is mentioned inthe COPD guidelines of both the European RespiratorySociety54 and the American Thoracic Society.56 However,although it is considered a mucolytic drug, this activity isnot well documented,64 and after oral dosing it is not foundin airway secretions.65 N-acetylcysteine is also consideredto have antioxidant properties, because it contains freethiol groups. A related compound, N-isobutyrylcysteine,has higher levels of free thiols than N-acetylcysteine. How-ever, unlike N-acetylcysteine,66,67 N-isobutyrylcysteine hadno effect on exacerbation rate in COPD,68 which questionsthe validity of the free thiol hypothesis for N-acetylcyste-ine activity.

The pharmacokinetics of N-acetylcysteine depend uponits route of administration. Aerosolized inhaled N-acetyl-

Table 3. Mucoactive Agents

MucolyticsCysteineN-AcetylcysteineNacystelynEthylcysteineNesosteineDithiothreitolMESNA (2-mercaptoethanesulphonate sodium)ThiopronineUreaTasuldineCarbocysteine*Carbocysteine-Lys*Erdosteine*Fudostein*Letosteine*Stepronin*Usherdex-4 (a low-molecular-weight form of dextran)

Expectorants/MucokineticsAmbroxolAmbroxol-theophylline-7-acetateBromhexineGuaiacol and derivativesGuaifenesinGuaimesalHypertonic solutions (saline)Inorganic iodidesOrganic iodidesIpecacuanhaSobrerolSodium citrateSquillVolatile inhalants and balsams�2-Adrenoceptor agonistsSurfactantYM-40461 (surfactant secretagogue)

Peptide Mucolytics (Enzymes)Bromelain�-ChymotrypsinRecombinant human deoxyribonoclease I (aka, dornase-alfa and

rhDNase)FericaseFicinGelsolinHelicidinLeucine amino peptidaseNeuraminidaseOnopronasePapainSerratopeptidaseStreptodornaseStreptokinaseThymosin beta 4Trypsin

*Metabolized endogenously to form compounds with free sulphydryl groups

Table 4. Mucoactive Agents Putative Mechanisms of Action

Mucoactive Agent Putative Mechanism of Action

Expectorant Increases volume and/or hydration of secretions.May also induce cough (eg, guaifenesin,

hypertonic saline)Mucolytic Reduces viscosity of mucus

Non-peptide (“classical”) mucolytics cleavedisulphide bonds (“free” or “blocked”sulphydryl groups).

Low-molecular-weight saccharide mucolyticsinterfere with non-covalent interactions inmucus, and may osmotically pull water intoairway lumen.

Peptide mucolytics degrade deoxyribonucleicacid (DNA) or actin

Mucokinetic Increases “kinesis” of mucus and facilitatescough “transportability” of mucus

�2-adrenoceptor agonists increase airflow, ciliarybeat, Cl�/water secretion, and mucinsecretion (small effect).

Surfactant reduces mucus adherence toepithelium.

Mucoregulator Reduces process of chronic mucus hypersecretion(eg, glucocorticosteroids, anticholinergics,macrolide antibiotics)



cysteine dissociates mucin disulphide bonds to reduce vis-cosity. In contrast, oral N-acetylcysteine has low bioavail-ability,69 and is de-acetylated to cysteine, whose thiol grouppossesses reducing and antioxidant properties.70 N-acetyl-cysteine is not detected in plasma or bronchoalveolar la-vage fluid following oral dosing for up to 14 days,65,71

although increases in plasma cysteine concentrations werereported.65 Cysteine is a substrate in the biosynthesis ofglutathione, an important intracellular and extracellular an-tioxidant.72 Hence, increased plasma cysteine should befollowed by a concomitant increase in plasma glutathioneconcentrations. Accordingly, oral N-acetylcysteine (600 mgdaily) increased levels of glutathione in both plasma65,71

and lung.65 However, in patients with COPD, plasma con-centrations of glutathione are unchanged following thisdose of N-acetylcysteine, although increases are seen witha higher dose of 600 mg 3 times daily.73 N-acetylcysteine(200 mg orally 3 times daily for 8 weeks) reduces super-oxide radical generation by alveolar macrophages fromhealthy smokers.63

N-acetylcysteine treatment is also associated with a re-duction in airway bacterial load,74 possibly because it re-duces the ability of bacteria to adhere to epithelial cells.75

In an animal model of chronic bronchitis, oral N-acetyl-cysteine inhibited cigarette-smoke-induced goblet cell hy-perplasia,76 and the associated mucus hypersecretion,77 and

speeded resolution of the goblet cell hyperplasia after ces-sation of smoke exposure.78

Thus, from the above, it may be seen that any beneficialclinical effects of N-acetylcysteine are not necessarily dueto mucolytic activity, antioxidant activity, or to direct ben-eficial effects on mucus.

Data from clinical trials of N-acetylcysteine are equallyambiguous. A trial of inhaled N-acetylcysteine in chronicbronchitis found no effect on feelings of well-being, dys-pnea, cough, mucus production and expectoration, or lungfunction after treatment for 16 weeks.79 The trial did notassess effects on exacerbation rate, because of the lownumber reported during the trial. Adverse effects includednausea and stomatitis, whereas hyperresponsive asthmat-ics can develop bronchospasm. Oral dosing is associatedwith dyspepsia, nausea, and diarrhea. Oral N-acetylcyste-ine has been reported to cause changes in sputum compo-sition in patients with chronic bronchitis and excessivesputum production.80 Patients treated with N-acetylcyste-ine had increased sputum volume, decreased sputum thick-ness, and improvements in scores for dyspnea and ease ofexpectoration. The study also reported improvements inpeak expiratory flow and forced expiratory volume in thefirst second (FEV1) in patients treated with N-acetylcys-teine, compared with a placebo group. However, the latterresult should be treated with caution because of differ-

Fig. 9. Structures of some mucolytic, mucokinetic, and expectorant drugs (see text for details).



ences in lung function between the 2 groups at baseline. Alarge placebo-controlled trial in patients with chronic bron-chitis found that oral N-acetylcysteine treatment (200 mgtwice daily) led to changes in sputum composition; thepatients reported lower scores for sputum volume, degreeof purulence, thickness of sputum, difficulty in expecto-ration, and severity of cough.81 These changes in sputumproperties were accompanied by a significant reduction inexacerbations.81,82 In contrast, a further large placebo-con-trolled trial that used a higher dose of oral N-acetylcyste-ine (200 mg 3 times daily) did not find a significant dif-ference in exacerbation rate between the treated and placebogroups, although there was a trend of fewer exacerbationsin the N-acetylcysteine-treated group (p � 0.08).83 Thelatter study differed from the former 2 studies81,82 in thatthe patients had not only chronic bronchitis but also severeairways obstruction. Oral N-acetylcysteine (300 mg twicedaily as slow-release tablets) has also been shown to re-duce days taken off work due to illness in patients withchronic bronchitis.84 There was a significant difference inthe number of sick leave days between the N-acetylcyste-ine and placebo groups, following 4 months of treatment.However, after 6 months, although there were still fewersick leave days in the N-acetylcysteine group (260 d vs739 d with placebo), that difference failed to reach statis-tical significance (p � 0.09). In contrast, a placebo-con-trolled trial of 600 mg twice-daily sustained-release N-ace-tylcysteine reported improvements in “general well-being”in patients with chronic bronchitis.85 This result should beinterpreted with caution, because there was an imbalancebetween the groups’ “well-being” scores at the start of thetrial, and the study found no statistically significant dif-ferences between treatments in subjective symptom scores,lung function, or number or severity of exacerbations.

Dornase Alfa

DNA is released in large amounts from necrotic neu-trophils into the airway mucus. Highly polymerized DNAincreases mucus viscosity in purulent lung secretions (seeabove). Thus, reducing the concentration of highly poly-merized DNA in airway secretions should reduce mucusviscosity. Consequently, dornase alfa has been developedfor treatment of mucus hypersecretion, in particular inCF.86 Dornase alfa reduces the viscosity of purulent spu-tum in CF patients.87 In a number of clinical trials, dailyinhalation of dornase alfa in conjunction with standardtherapies is well tolerated, usually improves the rheologi-cal properties of CF sputum, usually with associated im-provement in cough clearability of secretions, and reliablyimproves lung function.88–91 Similarly, small case studyreports indicate that dornase alfa could be used in clinicalmanagement of lobar atelectasis due to retained secre-tions.92–95 In contrast, in patients with bronchiectasis not

caused by CF, dornase alfa did not alter sputum transport-ability, lung function, dyspnea, or quality of life,96 andmay in fact be potentially harmful.97

In COPD, dornase alfa also reduces the viscosity andfavorably alters the surface properties in vitro of purulentsputum from patients with chronic bronchitis.98 However,phase II and III clinical trials of the effects of dornase alfain COPD are, to date, still only reported in abstract form,with limited data on patient characteristics, disease sever-ity, and concomitant treatment.99–101 The results of thelatter studies are equivocal. Consequently, dornase alfa isnot recommended in clinical management of patients withCOPD.102,103

Hypertonic Saline

Inhaled hypertonic saline is currently routinely used asan expectorant in experimental studies of biomarkers ininduced sputum.104 When used as a mucolytic agent, itmost probably works by reducing the entanglements in theairway mucus gel.105,106 It may also osmotically draw liq-uid through the airway epithelium to dilute the inhaledsaline, and thereby increase the water content of the air-way mucus.107 The hydrated airway mucus may, therefore,be more easily removed by mucociliary clearance, or, ifsufficiently increased in volume, by cough (see above andFig. 8). Hypertonic saline may also separate DNA frommucin in infected mucus, thereby reducing the viscosity ofthe mucus.108

Interest in the potential clinical benefit of hypertonicsaline in airway diseases associated with mucus hyperse-cretion dates back to the 1970s, when it was found that,compared with normal saline, hypertonic saline increasedthe weight of sputum produced and doubled the rate ofmucociliary clearance in patients with chronic bronchi-tis.109 Despite this, current guidelines on clinical manage-ment of COPD do not recommend interventions that pur-port to increase airway mucus clearance.29 Consequently,it is as treatment for the mucus clearance problems in CFthat hypertonic saline is receiving the greatest current in-terest.

Airway surface dehydration has been proposed as theinitiating event in CF lung disease.110,111 The proposalpredicts that airway surface dehydration produces the mu-cus adhesion, inflammation, and bacterial colonizationcharacteristic of CF. Thus, as indicated above, inhaledhypertonic saline should osmotically draw water onto air-way surfaces, thereby improving mucus clearance and pul-monary function, and reducing exacerbations in CF pa-tients. Consequently, a number of clinical studies haveexplored the hypothesis that rehydrating dehydrated CFairways with inhaled hypertonic saline would be therapeu-tically beneficial. Initial short-term (single administrationor up to 2 weeks administration) studies in variable num-



bers (10–52) of patients showed that inhaled hypertonic(7%) saline was well tolerated and increased clearance ofinhaled radioaerosol, lung function, and effectiveness ofchest physiotherapy.112–114 Two more recent longer-termstudies (28 days or 48 weeks of administration), again invariable numbers (24 or 164) of patients, confirmed thatinhaled hypertonic saline was well tolerated and improvedmucus clearance and lung function, and also reduced ex-acerbations.115,116

Surfactant

A thin layer of surfactant is thought to separate thepericiliary and gel layers of airway mucus.117 Theoreti-cally, surfactant decreases the adhesion of mucus to theairway epithelium and, thereby, aids cough-clearance ofmucus. Experimental studies concur, by demonstrating thatphophatidylglycerol distearoyl, the longest chain saturatedfatty acid component of surfactant, significantly improvesexperimentally modeled cough clearance.118 Interestingly,smokers and patients with either chronic bronchitis or CFhave reduced amounts of bronchial surfactant,119 and alsohave abnormal sputum phospholipid composition,120,121

which would tend to increase tenacity and thereby de-crease the efficiency of mucus clearance. Consequently,decreasing mucus adhesivity with surfactant enhances theeffectiveness of cough.122 Thus, in patients with stablechronic bronchitis, aerosolized surfactant (607.5 mg dipa-lymotyl phosphotidal choline/d for 14 d) increased in vitrosputum transportability, improved FEV1 and forced vitalcapacity by more than 10%, and decreased trapped tho-racic gas (ratio of residual volume to total lung capacity)by more than 6%.123 The beneficial effect persisted for atleast a week after the end of treatment.

Analysis

From the standpoint of treatment options for asthma orCOPD, neither the European Respiratory Society,54 theBritish Thoracic Society,53,57 the American Thoracic So-ciety,56,58 nor the Canadian Thoracic Society55 specificallyrecommends mucolytics in clinical management. Despitethis, numerous mucolytic and mucoactive drugs are avail-able worldwide, and N-acetylcysteine, bromhexine, andcarbocysteine are listed extensively in international drugformularies.52 This paper and a recent review124 indicatethat the discrepancy between drug listing and recommendedtreatment is related to the ambiguity in data from clinicaltrials of mucoactive drugs. For example, N-acetylcysteinehas an impressive therapeutic profile in preclinical exper-imental studies, whereas in the 8 clinical studies reportedhere, N-acetylcysteine was beneficial, to a greater or lesserextent, in six, and of no benefit in two. In common withmany clinical studies with other mucoactive drugs, not all

of the studies that found benefit from N-acetylcysteinemeasured an objective end point or were well controlled.This point was highlighted in a recent meta-analysis of theefficacy of N-acetylcysteine in COPD.66 Of 29 reportedtrials, 20 were excluded from the analysis because they didnot meet the inclusion criteria of being double-blind, pla-cebo-controlled, and having data sufficient to calculate anoutcome variable that permits direct comparison of studies(effect size) for both the N-acetylcysteine and placebogroups. A similar exclusion rate was found in a meta-analysis of clinical trials of mucolytics in COPD.125 From72 papers, the authors excluded 57 because they wereeither (1) not double-blind and placebo-controlled withtreatment for at least 8 weeks, and/or (2) did not provideinformation on primary outcome, and/or (3) did not giveerror measures for outcomes. Thus, better clinical studiesare required. Guidelines for clinical trials of mucolyticshighlight the need for studies to be double-blind, placebo-controlled, and randomized, with well-defined primary endpoints, including the effects of drugs over short or longperiods.126,127

It would also be useful to have data on rate of hospitaladmissions in response to mucolytic treatment. Hospitaladmission contributes greatly to the cost of treating severeCOPD. A systematic review analyzed randomized, dou-ble-blind, placebo-controlled studies of oral mucolytics forexacerbations of COPD.67 Of 27 trials identified, 4 wereexcluded because of a lack of information on primary endpoint. The conclusion drawn by those authors, based onthe results of the remaining 23 trials, was that treatment forat least 2 months with oral mucolytic drugs (primarilyN-acetylcysteine, ambroxol, bromhexine, carbocysteine,iodinated glycerol, methylcysteine, or sobrerol) was asso-ciated with a 29% reduction in exacerbation rate, com-pared with the control group. Days of illness also fell, butthere was no effect on lung function.

Another rigorous meta-analysis of trials of oral N-ace-tylcysteine in COPD also found a reduction in exacerba-tions.66 Treatment with N-acetylcysteine for 3–6 monthswas associated with a 23% reduction in exacerbation rate,compared with placebo.

For both of the above meta-analyses it should be notedthat investigation of exacerbations tends to overestimatethe annual rate because more exacerbations occur duringthe winter, when most studies are performed.

The conclusion from the present article and the meta-analyses67,125 is that maintenance treatment with mucoac-tive drugs is not associated with significant improvementsin lung function in patients with asthma or COPD. Untildata from more rigorously conducted trials become avail-able, it is difficult to recommend the use of mucolytic ormucoregulatory drugs in these patient populations. Nev-ertheless, in COPD, treatment with certain mucolytic (andantioxidant) drugs is associated with a reduction in exac-



erbations and days of illness.66,67 However, the cost-effec-tiveness of treatment of this patient group for at least3–6 months a year is debatable.128 It is likely that patientswith more severe COPD, or those who are repeatedly ad-mitted to hospital with exacerbations of COPD, wouldbenefit most from treatment with mucolytics, and that thetreatment would be cost-effective.

Summary

It is unlikely that expectorants, mucolytics, and muco-kinetic agents will play anything other than a relativelyminor role in symptom relief, reduction in exacerbations,or disease modification in asthma, COPD, or CF, althoughstudy of their effects may provide interesting insights intopathophysiology. In CF, the fundamental issue of the de-fect in CF transmembrane-conductance regulator will notbe addressed by mucolytic therapy. In the case of COPD,the major risk factor of cigarette smoking is established,and smoking cessation is the only intervention shown toslow the decline in lung function. Many COPD patientsare asymptomatic until late in their condition, by whichtime they may have lost the greater proportion of theirlung function. Introduction of mucolytic therapy at such alate stage is unlikely to significantly affect the decline inlung function. Similarly, in asthma, inhaled corticosteroidsand �2 agonists are highly effective in improving symp-toms and reducing risk of death.

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Discussion

Rubin: Actually, a bit of clarifica-tion first—those pooled study andmost of the studies that were done withacetylcysteine [NAC] have looked atthe oral form. I believe that aerosolacetylcysteine is very rapidly inacti-vated at the airway. And there are ques-tions as to whether it may be effectiveat all when given as an aerosol. Is thatnot correct?

Rogers: That’s absolutely correct.The thing with N-acetylcysteine is thatit’s been around for a long time, butit’s very difficult to demonstrate thatit works in human airways in vivo.For example, when given orally, it’svery difficult to find N-acetylcysteinewithin mucus in the airways. And evenwhen given by aerosol, again it seemsto be inactivated and/or it doesn’t getinto the mucus. But there are new mol-ecules, for example nalcystelyn,1

which has a variety of biochemicalparameters that make it superior toN-acetylcysteine. So it looks as if thereare developments in the mucolyticfield, based on existing drugs, but mov-ing them onto the next phase to makethem more effective.

1. App EM, Baran D, Dab I, Malfroot A,Coffiner M, Vanderbist F, King M. Dose-finding and 24-h monitoring for efficacy andsafety of aerosolized Nacystelyn in cysticfibrosis. Eur Respir J 2002;19(2):294-302.

Rubin: A follow-up question. Whenyou talked about the potential use ofmucolytics in cystic fibrosis [CF],there were you referring strictly to dor-nase alfa? Are there any data at allthat show that acetylcysteine does any-thing of any value in CF?

Rogers: To find a good clinicalstudy that anyone in here would rec-ognize as a good clinical study for theeffect of N-acetylcysteine in CF is noteasy. Nevertheless, there have beensome reports that it works. However,as it stands at the moment, Dornasealfa is really the mucolytic that standsup to scrutiny in terms of being effec-tive in CF. And, possibly, gelsolin, ifthere is a lot of actin present in themucus. In summary, I think the jury isstill out with N-acetylcysteine in gen-eral, including its effectiveness in CF.

MacIntyre: I’m reminded of the oldtelevision ad: “It’s not nice to foolwith Mother Nature!” And it’s a theme

I brought up earlier. It makes me ner-vous, not only with the mucus story,but with so many things we do in med-icine. We always seem to be operat-ing at the very end of the pathway, atthe manifestations of disease. In con-trast, I keep thinking we’re spendingtime taking care of the manifestationsof respiratory failure. A lot of this phar-macology is monkeying around withreflexes that were put there for a pur-pose. It’s frustrating that we can’t seemto get closer to the actual triggers ofthe disease, as opposed to trying tomanipulate these things at the end ofthe pathway. I guess it’s not really aquestion—it’s more of a comment.

I was really struck by the conflict-ing goals of cough and mucociliaryclearance; that’s a real problem, be-cause if you’re pushing on one, youmay really hamper the other, and thatmay end up doing more harm thangood. Obviously, none of these prod-ucts that we’re discussing are going tobe able to be recommended until theyactually go through real clinical trialsand show a real clinical outcome.

Rogers: I think that’s right. Goodclinical studies are required. But youwill still need to ascertain what as



pects of the mucus problem need ad-dressing—for example, acute, protec-tive hypersecretion versus chronic,nonprotective hypersecretion. Withthe latter, you start to get clinical symp-toms of mucus hypersecretion, fol-lowed by the associated pathologiesyou see in the clinic.

And it is uncertain what parametersof the mucus problem these interven-tions address. At one level—and whatthat may be is uncertain—mucus isclearly protective. But then it switchesover to being not at all protective; infact, it becomes pathophysiological.But where you tip over from it beingsecretion to hypersecretion, physiolog-ical to pathophysiological, is essen-tially unclear at the moment. Unlikebronchospasm, where patients knowif their airways are tightening up. It iseasy to recommend a straight reversalof that process, but less obvious withmucus.

MacIntyre: That’s a good point.

Rogers: I think that it is difficult toidentify exactly what is best to do tothe mucus in any given clinical situ-ation: do you want to make it a bitmore viscous, or a bit more elastic, orboth—or neither—or maybe just lessof it?

Pierson:* I have a question aboutyour ketchup bottles. You showed thenice full bottle on the left, with thecomment that having all that ketchupin there, you could get it out easily,and a nearly empty ketchup bottle onthe right, with perhaps 5% of theketchup left, which drives us all crazygetting that last bit out. Obviously,those 2 ketchup bottles are exactly thesame. One’s got ketchup in it, and theother mostly doesn’t.

My question is: Does the presenceof a lot of ketchup (ie, a lot of mucus

in the airways) somehow facilitateemptying of all the mucus, or is therealways that 5% of residual ketchup?In other words, is having just a rim ofmucus in the airways a particular prob-lem, or does that just represent the lastbit that’s always there after the bulkof the mucus has been expectorated?

Rogers: I think the issue is that in,for example, COPD, where there maybe a relatively thin film of mucus overthe airway epithelium that’s beyondphysiological but isn’t overtly patho-physiological, then it’s going to behard to tell. However, in asthma a dif-ferent scenario is possible because ofthe interaction between mucus andbronchoconstriction.

Airway narrowing can be definedaccording to Poiseuille’s law. Poi-seuille was essentially a Frenchplumber who was interested in the flowof water down pipes, but the same re-lationship can be applied to the flowof air in the bronchi. His law statesthat the resistance to flow is inverselyproportional to the radius of the tube,water pipe, or airway, raised to the 4thpower (ie, 1/r4). It’s the raising to the4th power that is the critical aspect ofthe relationship, and means that air-way resistance is an exponential func-tion of airway patency.

If you have a thin film of mucusaround the inside of an airway, it mightdo very little to airflow under normalcircumstances. However, combinebronchoconstriction with the film ofmucus around the inside of the tube,and because the mucus occupies rel-atively more space in the narrowedlumen, the increase in airway resis-tance rises exponentially. So, the im-pact on airflow of a thin film of mu-cus compared with a thick layer ofmucus will depend on the patientwithin whom that mucus resides, andthen you can make a judgment as tolikely pathology.

Pierson: But back to the ketchupbottle—if I take a brand new full bot-tle of ketchup, can I squirt it all out?

Rogers: Yes.

Pierson: Right then and there. NowI have an empty ketchup bottle. In otherwords, is there a circumstance wherea lot of mucus has been secreted, andbecause it’s all there together, I canget it all out, or is there inevitably arim left? And all you’re seeing whenthere’s lots of mucus is the fact that,yes, lots more comes out.

Rogers: That’s incredibly interest-ing. I don’t know. I don’t think thosesorts of experiments have been done—how much is left when you can get agreat big gob of stuff to come out.Patients can feel very much better af-ter hawking up a large amount of mu-cus.

Wojtczak:† I’m wondering whathappens to these mucus-secreting cellswhen one blocks exocytosis and theextrusion of mucus. Do they eventu-ally just explode? And do you getketchup all over the place?

Rogers: That is the issue! We’veinvestigated this very aspect.1 Un-stimulated secretory cells containstainable mucus. They lose the mucusafter stimulation. At the IC50 of ourinhibitory construct, the cells containmucus because secretion has been in-hibited. If you give the top dose of theconstruct, there is intracellular accu-mulation of mucus, with more mucusin those cells than there is in the con-trol cells. And you would think, asyou suggest and I thought, that theymight eventually explode.

However, we looked at mucin(MUC5AC) gene expression becausewe wondered whether the cells mighttry to turn off mucus production tocompensate for the retained secretions.I was surprised to see that, in fact, asmucus secretion is inhibited, with aprogressive increase in intracellularmucus, there is a concomitant progres-

* David J Pierson MD FAARC, Division ofPulmonary and Critical Care Medicine, Har-borview Medical Center, University of Wash-ington, Seattle, Washington.

† Henry Wojtczak MD, Naval Medical Center,San Diego, California, representing Monaghan/Trudell Medical.



sive inhibition of MUC5AC gene ex-pression. So, it looks as if there’s anegative feedback mechanism be-tween mucin synthesis and secretion.I was very surprised by that.

But, of course it’s absolutely ridic-ulous that I should be surprised, be-cause any cell producing packagedgranules—for example, a mast cell ora neutrophil—must have a physiolog-ical turnoff mechanism. Because, evenunder normal circumstances, cells willneed to register when to stop synthe-sizing intracellular stored product. Pre-sumably, this mechanism holds truein pathophysiological circumstances.In the short-term studies that we’vebeen doing in vitro, the accumulationof intracellular mucin is associatedwith the turning off of the mucin geneand, presumably, mucin synthesis.

1. Adams EJ, Cruttwell CJ, Chaddock JA, Du-rose L, Barnes PJ, Foster KA, Rogers DF.Re-targeted clostridial endopeptidases in-hibit MUC5AC gene expression in respira-tory epithelial cells (abstract). Am J RespirCrit Care Med 2007;175:A751.

Wojtczak: If I could ask you a sec-ond question. Those of us who takecare of CF patients are rapidly adopt-ing hypertonic saline as an aid for air-way clearance, and I think it’s still notclear in my mind, and maybe in theliterature, as to whether it’s just acough stimulant, or whether it’s a hy-drator. I would be interested in yourcomments on that.

Rogers: It’s certainly a cough stim-ulant. And the reasons why it’s a coughstimulant are debated. One of the the-ories is that there are nerves withinthe airway epithelium, and the nervesseem to penetrate between the epithe-lial cells. The theory is that giving hy-pertonic saline takes water out of theepithelium and, therefore, dehydratesit. That dehydration causes the cells toshrink and, thereby, deform, and thattriggers the nerve endings, leading toreflex cough. So, that’s how it couldwork, but it’s essentially unproven.

In terms of what the hypertonic sa-line might do to the mucus, because

positive ions (ie, in Na�) are beingintroduced into the mucus, this couldnullify some of the ionic attraction be-tween the mucus molecules, and sothey will tend to move apart more. Sothere could be thinning of the mucus.The end result could be a thinning ofthe mucus plus a cough response, andthey’re acting synergistically to get ridof mucus from the airway.

Rubin: I’d also like to remind youthat hypertonic challenges with man-nitol or hypertonic saline are extremelypotent secretagogues. And so you canbe increasing the amount of mucusthat’s being generated and sent out intothe airways. A secretagogue can po-tentially improve the ability to expec-torate.

Rogers: So there are various thingsgoing on.

Howard:* We just completed anover-400-subject COPD study usingerdosteine in a couple of differentdoses. I can’t give you all the detailson that, but I think it’s the biggeststudy that’s ever been done with a mu-colytic in COPD patients. And we’llprobably have a report on that in maybe4-6 months. We found some things;no doubt about that, definitely a drugeffect there. But the biggest thing thatwe learned is how tremendously hardit is to quantify how much mucus pro-duction a patient has coming into thestudy. Did you affect that during thestudy? And if you did, did it have anypositive bearing on the health of thesubject? I would say that in all hon-esty, it proved to be much, much,much, much more difficult than weanticipated. The subject is ripe for fur-ther investigation, but I would guess Iwould count myself among the bruisedand cut, trying to look at the effect ofa mucolytic on COPD.

Tecklin:† Just a comment really, al-most amusing, if you will, regardingthe studies on inhaled N-acetylcyste-ine. Most of them were done 45 yearsago, or even longer ago than that, whenit wasn’t as critically important to havedouble-blind randomized controlledtrials. I think when we look back atthose studies today, using today’s cri-teria, the studies don’t bear muchweight and really don’t say much. Butthere must have been something go-ing for folks with CF to have used thatdrug for 20-30 years, anecdotally orotherwise. So I wonder if it might notbe a time to maybe try the N-acetyl-cysteine or its derivatives, again in afairly good trial in CF. Just a com-ment.

Rubin: There has been a prelimi-nary trial of high-dose oral NAC inCF that did show benefit.1 However,to my knowledge all of the studiesthat have been at all well-controlledwith inhaled NAC in CF have notshown benefit, and in fact, there’s beena hint that it may be detrimental. Butthey are going forward with furtherstudies of higher-dose NAC as an an-tioxidant in CF, given as an oral agent.I think that’s what you were alludingto.

1. Tirouvanziam R, Conrad CK, Bottiglieri T,Herzenberg LA, Moss RB, Herzenberg LA.High-dose oral N-acetylcysteine, a glutathi-one prodrug, modulates inflammation in cys-tic fibrosis. Proc Natl Acad Sci U S A 2006;103(12):4628-4633.

Rogers: Just to make the point, Ithink that CF is a tough nut to crackbecause, as well as the airway inflam-mation, there’s the defined genetic de-fect in the CFTR [CF transmembraneconductance regulator], and whateveryou do is only going to be palliativecompared to correcting the CFTR de-fect. You are never going to actuallytreat the disease. It’s just that your

* William W Howard PhD, Adams RespiratoryTherapeutics, Chester, New Jersey.

† Jan S Tecklin PS MSc, Department of Phys-ical Therapy, Arcadia University, Glenside,Pennsylvania, representing Electromed.-



window of opportunity is so much re-duced in CF compared with asthma orCOPD, because the CFTR defect hassuch a fundamental clinical impactover and above treating mucus in iso-lation.

Myers: Duncan, you had men-tioned earlier if we could increasethat surfactant layer in the airways,that additional surfactant may actu-ally enhance mucociliary clearance.Obviously, the problem in the pasthas been the delivery vehicle to getsurfactant into the airways. A re-cently completed Phase 2 trial1,2

looked at aerosolized lucinactant inpremature nonintubated infants. Andit actually was pretty safe and effi-cacious. So could you describe inmore detail what, potentially, thebenefits to increase that surfactantlayer in the airway could be? Be-cause it may be a reality very shortly.And which patients would benefit?

1. Finer N, Merritt T, Bernstein G, et al. Amulticenter pilot study of Aerosurf deliv-ered via nasal continuous positive airwaypressure (nCPAP) to prevent respiratory dis-tress syndrome in preterm neonates (ab-stract). Pediatr Res 2006;59:4840.

2. Mazela J, Merritt TA, Finer NN. Aerosol-ized surfactants. Curr Opin Pediatr 2007;19(2):155-162.

Rogers: Bruce would know moreabout this than I. But I’ll just make afew preliminary comments. Morgen-roth and Bolz1 visualized a surfactantlayer that separates the upper, gelphase of the mucus from the lower,sol phase. Why it is there, I don’t thinkis necessarily clear, but it could bethat it facilitates sliding of the gel phaseduring mucociliary clearance. The ideabehind increasing surfactant volumeis that it may facilitate mucus clear-ance.

However, what you actually wantto do in any one patient takes us backto my previous paradigm of what youwant to achieve. Do you want to favormucociliary clearance, or do you wantto encourage cough? Increasing thesurfactant layer is not necessarily go-

ing to enhance mucociliary clearancebecause you are going to disassociatethe gel from the tips of the cilia. How-ever, if treatment is intended for pa-tients in whom cough is beneficial,raising the surfactant layer would tendto disassociate the gel phase, whichcould then be shifted by cough.

1. Morgenroth K , Bolz J. Morphological fea-tures of the interaction between mucus andsurfactant on the bronchial mucosa. Respi-ration 1985;47(3):225-231.

Rubin: Two things. First, there havebeen studies suggesting that it preventsthose cilia from getting entangled inthe mucus.1 It allows them to pullthrough. But there is surfactant dys-function that’s been well described inasthma, cystic fibrosis, and in COPD.Probably due to endogenous produc-tion of secretory phospholipase A2, aswell as to albumin and other thingsthat lead to breakdown of that and amarked increase in surface tension, orinterfacial tension of airway secre-tions. And there have been studies ofaerosolized surfactant in both COPDand cystic fibrosis that have shownbenefit in lung function.2 So, yourcomment is well taken. With improvedways of delivering surfactant, it’s ter-ribly difficult to nebulize, because ittends to foam, and the like. This maybecome a reality.

1. Anzueto A, Rubin BK. Mucokinetic agentsand surfactants. In: Rubin BK, van der SchansCP, editors. Therapy for mucus clearancedisorders. New York: Marcel Dekker; 2004:307-326.

2. Anzueto A, Jubran A, Ohar JA, Piquette CA,Rennard SI, Colice G, et al. Effects of aero-solized surfactant in patients with stablechronic bronchitis. A prospective random-ized controlled trial. JAMA 1997;278(17):1426-1431.

Wojtczak: Duncan, I was curiousas to whether you think that you canachieve mucolysis with mechanicalmeasures such as vibration, whetheryou’re using an external vibratory de-vice and/or an internal airway vibra-tory device. And does that break thecovalent bonds?

Rogers: I think we will be havingspecific presentations on this topiclater in the meeting. However, in brief,these devices may indirectly work ina similar way to drug interventions.For example, vibrations will probablybreak some of the ionic bonds, hydro-gen bonds, and van der Waal’s forcesholding the mucus molecules together,leading to thinning of the mucus. How-ever, these bonds will re-form becausethey’re not hard and fast. Thus, me-chanical devices may not affect thosesorts of bonds long-term, but may af-fect other types of bonding, and breakup the mucus in that way.

Homnick: Duncan, there are somereports of using dornase alfa in bron-choalveolar lavage fluid for severe mu-cus obstruction in asthma.1,2 I don’tremember specifically if they wereneutrophilic infiltration in those pa-tients or whether it is eosinophilic, butis there any actual benefit in that typeof situation? And if so, is it from thedornase alfa, or simply because of thelavage fluid that’s used?

1. Durward A, Forte V, Shemie SD. Resolu-tion of mucus plugging and atelectasis afterintratracheal rhDNase therapy in a mechan-ically ventilated child with refractory statusasthmaticus. Crit Care Med 2000;28(2):560-562.

2. Greally P. Human recombinant DNase formucus plugging in status asthmaticus. Lan-cet 1995;346(8987):1423-1424.

Rogers: This is put in, is it?

Homnick: Put in. Yes. With a bron-choscope. Right?

Rogers: I don’t really know aboutthat. What has been looked at is theeffect of dornase alfa in patients withCF, where it seems to work, presum-ably by breaking up DNA, and in pa-tients with COPD. As it stands at themoment, clinical studies in patientswith COPD do not demonstrate a ben-eficial effect for dornase alfa. The rea-sons for that are not clear, but perhapsthere is just not enough DNA presentfor any degradation of it to have animpact on overall mucus biophysical



properties. In terms of asthma, I don’tthink dornase alfa has been investi-gated, because you’ve got to haveDNA present in the mucus, becausethe drug works by degrading DNA,and DNA is not a feature of asthmaticairway mucus.

Homnick: These are just case re-ports. And I’m not sure there was anyreal rationale for using it.

Rogers: In CF, there is a lot of air-way pus, meaning lots of neutrophils,which presumably are dying and re-leasing a lot of DNA—you can mea-sure the quantity of DNA in cysticfibrosis sputum, and it’s very high.There is also neutrophilic infiltrationin the airways in COPD, but dornasealfa doesn’t seem to work very well,maybe because there are insufficientneutrophils or they are less chronicallypresent compared with CF.

In asthma, where neutrophilic infil-tration is not a feature of stable dis-ease, there would be no rationale fordornase alfa to work. However, in ex-acerbations of asthma, there is invari-ably marked neutrophilic infiltration,so severe asthma is slightly akin toCOPD and CF. Thus, there could bepotential benefit of dornase alfa in pa-tients with severe asthma.

Restrepo: I just wanted to have abetter understanding about the impor-tance of bulk movement of mucus formucociliary clearance. This is in re-gard to how important it would be tohydrate that high mucin mucus. Sohow much importance would you havewhen you have bulk movement of mu-cus for patients who have adequateviscosity versus low viscosity of themucus?

Rogers: I’m not sure I’m with you.

Restrepo: I guess I’m talking about,let’s say CF patients, with low mucinsecretions versus the hyperviscosity or

high mucin concentration in asthmat-ics. How much of the bulk movement,and again, going to the ketchup . . .

Rogers: All right. It’s the cough as-pect.

Restrepo: So, if that is actually im-portant in impacting mucociliary clear-ance, again, bulk movement and ac-tually having the property of elasticity,due to the mucin, what would be theeffect of just simply hydrating the mu-cus that is actually low in mucin?

Rogers: The hydration issue is veryinteresting. There is dehydration in pa-tients who are intubated, but that isprobably related to the intubation. Oth-erwise, it would appear that, in gen-eral, mucus isn’t necessarily overly de-hydrated in most respiratory diseaseconditions, even in CF. It is all rela-tive and not a special issue. Neverthe-less, if you could hydrate the mucusto cause it to expand—as an interven-tional procedure, to make it more eas-ily cleared, presumably by cough—then that might be a good idea.However, it is very difficult to hy-drate mucus once it has been secreted.

Of interest is an epidemiologicalstudy1 that looked at a whole range ofpredictors of decline in lung functionin asthma and COPD, including coughand mucus. The intriguing observa-tion from the point of view of thismeeting was that in asthma less chroniccough and sputum production was as-sociated with an accelerated declinein lung function. This indicates eitherthat cough and sputum production wasnot relevant in those patients, and theyhad some other pathophysiology, orthat an inability to cough and bring upmucus, for whatever reason—for ex-ample, poor cough reflex or mucusblocking the airways—was actuallycontributing to their decline in lungfunction. The conclusion from thatanalysis is that coughing up sputum isactually a good idea, because at least

you are getting rid of the excess mu-cus.

1. Hesselink AE, van der Windt DAWM, Pen-nix BWJH, Wijnhoven HAH, Twisk JWR,Bouter LM, van Eijk JTM. What predictschange in pulmonary function and quality oflife in asthma or COPD? J Asthma 2006;43(7):513-519.

Rubin: If I could just comment.It’s extraordinarily difficult to hy-drate secretions sitting in an airway.Bill Abraham and Adam Wanner inMiami did a study several years agogiving a lot of additional I.V. fluidto asthmatic sheep.1 This is a prettygood model for human asthma, withtheir airway structure and size. Inproviding additional hydration, theygot their animals much sicker, be-cause most of the fluid extravasatedinto the interstitium, and did noth-ing to the airway.

There have been other studies2

where patients with COPD woulddrink huge amounts of water—abso-lutely no benefit. They were up allnight peeing. And if you’ve ever triedto hydrate secretions when you’ve hada cold, if you’ve ever hawked up lu-gies, for example in a bowl of water,you’ll see it tends to remain fairly co-hesive. It doesn’t very rapidly hydrate.So once it’s there, and once it’s in theairway, it appears to be difficult tohydrate the mucus itself. Even the in-halation of dry powder mannitol orinhaled hyperosmolar saline isthought, perhaps, to hydrate the peri-ciliary fluid, rather than the secretionitself—which would not be a bad thingif you were trying to cough out thesethings coherently.

1. Marchette LC, Marchette BE, Abraham WM,Wanner A. The effect of systemic hydrationon normal and impaired mucociliary func-tion. Pediatr Pulmonol 1985;1(2):107-111.

2. Shim C, King M, Williams MH. Lack ofeffect of hydration on sputum production inchronic bronchitis. Chest 1987;92(4):679-682.



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