Treatment of airway mucus hypersecretion

Abstract

Airway mucus hypersecretion is now recognized as a key pathophysiological feature in many patients with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapies, including anticholinergics, β₂‐adrenoceptor agonists, corticosteroids, mucolytics and macrolide antibiotics, have variable efficacy in inhibiting airway mucus hypersecretion, and are less effective in COPD than in asthma. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g. large conductance calcium‐activated potassium, BK_Ca, channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g. benzafibrate), inhibitors of mucin exocytosis (e.g. anti‐myristoylated alanine‐rich C kinase substrate (MARCKS), peptide and Munc‐18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g. epidermal growth factor (EGF), receptor tyrosine kinase inhibitors, p38 mitogen‐activated protein (MAP), kinase inhibitors, MAP kinase kinase/extracellular signal‐regulated kinase (MEK/ERK), inhibitors, human calcium‐activated chloride (hCACL2), channel blockers and retinoic acid receptor‐α antagonists), inducers of goblet cell apoptosis (e.g. Bax inducers or Bcl‐2 inhibitors), and purinoceptor P_2Y2 antagonists to inhibit mucin secretion or P_2Y2 agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in asthma from that in COPD. More information is required on these differences to identify specific therapeutic targets which, in turn, should lead to rational design of anti‐hypersecretory drugs for treatment of airway mucus hypersecretion in asthma and COPD.

• Asthma
• chronic bronchitis
• chronic obstructive pulmonary disease
• COPD
• epidermal growth factor
• MUC gene
• mucin
• protease
• protease inhibitor

Introduction

Mucus secretion in the airways normally represents first‐line defence of the respiratory tract and is an important part of innate immunity. However, if secretion becomes abnormal, mucus accumulates and may obstruct the airway lumen (Figure 1). Long‐term and excessive mucus production, termed chronic mucus hypersecretion, can lead to significant airflow limitation in a number of severe respiratory conditions including asthma 1, chronic obstructive pulmonary disease (COPD) 2,3 and cystic fibrosis (CF) 4. It should be noted, however, that the impact of airway mucus hypersecretion on morbidity and mortality is not unequivocal or pertinent to all patients. Nevertheless, there are certain groups of patients, for example those with COPD who have mucus hypersecretion and are prone to chest infections 5, where a causal association has been demonstrated. Consequently, there is the perception that inhibiting mucus hypersecretion should have clinical benefit in hypersecretory conditions of the airways. Numerous pharmaceutical and other treatments are available or in development that are aimed, either directly or indirectly, at inhibiting mucus hypersecretion. However, although asthma and COPD share mucus obstruction as a clinical feature, the pathophysiological mechanisms underlying the impairment in mucus clearance may be different, to a greater or lesser extent, for each condition. For example, there are real and theoretical differences in the pathophysiology of airway mucus hypersecretion between asthma and COPD (Figure 2). In addition, the features of airway inflammation and remodelling that uniquely characterize different respiratory diseases are also factors that influence mucus hypersecretion. Consequently, no single therapy is likely to be effective across the spectrum of mucus obstructive conditions of the respiratory tract. It is possible that disease specific therapy will be more successful.

Figure 1. Mucus obstruction of the airways in asthma and COPD: gross pathology. A: Lung from an asthmatic patient cut through to show gelatinous plugs (P) in the large airways (arrows). Courtesy Dr Catherine Corbishley (thumb, T, and finger, F, holding specimen). B: Luminal mucus (M) partially blocking an extrapulmonary bronchus (arrow) in a long‐term elderly male cigarette smoker with chronic sputum production.

Figure 2. Putative differences in pathophysiology of the airway mucus hypersecretory phenotype in asthma, chronic obstructive pulmonary disease(COPD) and cystic fibrosis (CF). Compared with normal, in asthma there is airway inflammation, increased luminal mucus, with an increased ratio of MUC5B (low charge glycoform (lcgf)) to MUC5AC, possibly small amounts of MUC2 present in the mucus, epithelial ‘fragility’ with loss of ciliated cells, marked goblet cell hyperplasia, submucosal gland hypertrophy (although without a marked increase in mucous to serous ratio), ‘tethering’ of mucus to goblet cells, and plasma exudation. In COPD, there is airway inflammation, increased luminal mucus, goblet cell hyperplasia, submucosal gland hypertrophy (with an increased proportion of mucous to serous acini), an increased ratio of lgcf MUC5B to MUC5AC above that in asthma, possibly small amounts of MUC2 in the mucus, and a susceptibility to infection. In CF, there is airway inflammation, increased luminal mucus, goblet cell hyperplasia, submucosal gland hypertrophy, an increased ratio of lgcf MUC5B to MUC5AC, small amounts of MUC2 in the mucus, and a marked susceptibility to infection. Many of these differences require confirmation (or otherwise) by data from greater numbers of subjects.

The present review discusses airway mucus hypersecretion, using asthma and COPD as examples of respiratory conditions that share excess airway mucus as a clinical feature but with specific differences in mucus pathophysiology. Cystic fibrosis will be briefly mentioned where appropriate for comparative purposes as a third respiratory condition with its own pathophysiology and mucus problems. However, the mucus problems in CF pertain predominantly to the genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) and the associated abnormality in sodium channels, and are beyond the scope of the present article. The interested reader is referred to two recent reviews 4,6. Factors involved in the rational design of pharmacotherapeutic compounds to inhibit airway mucus hypersecretion in asthma and COPD will be considered. A brief description of airway mucus is given first.

Airway mucus, mucins and MUC genes

Airway luminal mucus is a complex dilute aqueous solution of lipids, glycoconjugates and proteins. It comprises salts, enzymes and anti‐enzymes, oxidants and antioxidants, exogenous bacterial products, endogenous antibacterial agents, cell‐derived mediators and proteins, plasma‐derived mediators and proteins, and cell debris such as DNA. Airway mucus is considered to form a liquid bi‐layer whereby an upper gel layer floats above a lower, more watery sol, or periciliary liquid, layer 6. The gel layer traps particles and is moved on the tips of the cilia. Respiratory tract mucus requires the correct combination of viscosity and elasticity for optimal efficiency of ciliary interaction. Viscoelasticity is conferred on the mucus primarily by high molecular weight mucous glycoproteins, termed mucins, which comprise up to 2% by weight of the mucus 7. In the airways, mucins are produced by goblet cells in the epithelium 8 and sero‐mucous glands in the submucosa 9. Mucins are thread‐like molecules comprising a linear peptide sequence (termed apomucin), often with tandemly repeated regions, that is highly glycosylated, predominantly via O‐linkages (Figure 3). Apomucins are encoded by specific mucin (MUC) genes, with 19 human MUC genes currently recognized, namely MUC1, 2, 3A, 3B, 4, 5AC, 5B, 6–9, 11–13 and 16–20 10–15. Of these, however, it is only the MUC5AC and MUC5B gene products that comprise the major gel‐forming mucins in respiratory secretions from normal subjects. The mucin content of secretions from patients with hypersecretory respiratory diseases may differ from normal (see below).

Figure 3. Schematic representation of a gel‐forming mucin molecule. The mucin subunit (∼500 nm in length) comprises an amino acid backbone with highly glycosylated areas and folded regions, stabilized via disulphide bonds, with little or no glycosylation. Glycosylation is via O‐linkages and is highly diverse. In secretions, the subunits are joined end‐to‐end by disulphide bonds (S‐S) into long thread‐like mature mucin molecules.

Key messages

• Airway mucus hypersecretion is now recognized as an important contributor to morbidity and mortality in many patients with severe chronic lung diseases.

• The airway mucus hypersecretory phenotypes of asthma, COPD and cystic fibrosis have many important differences.

• Effective novel pharmacotherapy of airway mucus hypersecretion may have to be disease specific.

Mucus obstruction of the airways in asthma and COPD

Asthma and COPD are chronic, severe inflammatory conditions of the airways in which mucus hypersecretion is a pathophysiological feature. The increase in airway luminal mucus is associated with increases in amount of mucus‐secreting tissue.

Asthma

Asthma is a chronic inflammatory condition of the airways that has specific clinical and pathophysiological features 16, including mucus obstruction of the airways 17 (Figure 2). The latter is particularly evident in a proportion of patients who die in status asthmaticus, where many airways are occluded by tenacious mucus plugs 18–20. There is also more mucus in the central and peripheral airways of both chronic and severe asthmatics compared with control subjects 21. The increased amount of luminal mucus reflects an increase in amount of airway secretory tissue, due to both goblet cell hyperplasia 21,22, and submucosal gland hypertrophy 19, although the latter is not characteristic of all patients with asthma 21.

COPD

COPD comprises three overlapping conditions, namely chronic obstructive bronchitis (commonly associated with increased airway mucus hypersecretion), chronic bronchiolitis (small airways disease) and emphysema (airspace enlargement due to alveolar destruction) 23. The following discussion considers the ‘bronchitic’ component of COPD. The airways of patients with COPD contain excessive amounts of mucus 24, which is markedly increased above that in control subjects 25,26 (Figure 2). The increased mucus is linked specifically with an increase in MUC5B in the bronchiolar lumen 27. The excessive luminal mucus is associated with increased amounts of mucus‐secreting tissue, namely goblet cell hyperplasia 24,28,29 and submucosal gland hypertrophy 24,25,30,31. The amount of gland correlates with the amount of luminal mucus 25.

Differences in pathophysiology relating to mucus obstruction in asthma, COPD and CF

In order to develop appropriate models of airway mucus hypersecretion and develop drugs to inhibit hypersecretion, it is necessary to understand the similarities and differences in the features of mucus obstruction for different hypersecretory conditions. There are a number of differences in the pathophysiology of mucus hypersecretion between asthma, COPD and CF (Figure 2). Firstly, although the underlying pulmonary inflammation of asthma and COPD share many common features, there are specific characteristics unique to each condition 32–35. Asthma is invariably an allergic disease that affects the airways, rather than the lung parenchyma, and is characterized by Th2‐lymphocytic orchestration of pulmonary eosinophilia. In contrast, COPD is currently perceived as predominantly a neutrophilic disorder governed largely by macrophages and epithelial cells. It is associated primarily with cigarette smoking. The differences between asthma and COPD in their profile of airway inflammation and remodelling may in turn exert different influences on the development of airway mucus obstruction in the two conditions.

Airway mucus in asthma is more viscous than in COPD or CF, with the airways of asthmatic patients tending to develop, and subsequently become blocked by, gelatinous ‘mucus’ plugs 17. Whether or not mucus in asthma has an intrinsic biochemical abnormality is unclear. In general terms, sputum from patients with asthma is more viscous than that from patients with chronic bronchitis or bronchiectasis 36–38. Mucus plugs in asthma differ from airway mucus gels in chronic bronchitis and CF in that they are stabilized by non‐covalent interactions between extremely large mucins assembled from conventionally sized subunits 39. This suggests an intrinsic defect in assembly of the mucin molecules, and could account for the increased viscosity of the mucus plugs in asthma. Plug formation may also be due, at least in part, to increased airway plasma exudation in asthma compared with COPD 40. In addition, and in direct contrast to COPD, exocytosed mucins in asthma are not released fully from the goblet cells, leading to ‘tethering’ of luminal mucins to the airway epithelium 41. This tethering may also contribute to plug formation. One explanation of mucus tethering is that, in COPD, neutrophil proteases cleave goblet cell‐attached mucins, whereas in asthma the inflammatory cell profile, predominantly an eosinophilia, does not generate the appropriate proteases to facilitate mucin release.

Different MUC gene products may be present in respiratory secretions in asthma and COPD. MUC5AC and a low‐charge glycoform of MUC5B are the major mucin species in airway secretions from patients with asthma, COPD and CF 42–46. There is significantly more of the low‐charge glycoform of MUC5B in the respiratory diseases than in normal control secretions 46. Interestingly, there is a proportional increase in the MUC5B mucin over the MUC5AC mucin in airway secretions from patients with COPD or CF, compared with secretions from patients with asthma 42. The significance of the change in MUC5B glycoforms to bacterial colonization between the different diseases is unclear. However, it is interesting that it is observed in COPD and CF, where patients are prone to bacterial chest infections 4,23, rather than in asthma where patients are not notably prone to infection.

In contrast to normal airways, there is upregulation of MUC5AC in the airway epithelium of patients with COPD compared with smoking (and non‐smoking) controls 27. Goblet cells in the airways from patients with COPD contain not only MUC5AC but also MUC5B 44,47 and MUC2 7,48. The latter distribution is different to that in the airways of patients with asthma or CF, where MUC5AC and MUC5B show a similar localization to that in normal subjects 49,50. It is noteworthy that although MUC2 is located in goblet cells in irritated airways, and MUC2 mRNA is found in the airways of smokers 26, MUC2 mucin is either not found in airway secretions from normal subjects or patients with chronic bronchitis 43, or is found only in very small amounts in asthma, COPD and CF 46,51. The significance of the above combined observations is unclear, but suggests that there are differences in goblet cell phenotype between asthma and COPD.

Another notable difference between asthma and COPD is in the bronchial submucosal glands 52. In asthma, although hypertrophied, the glands are morphologically normal with an even distribution of mucous and serous cells. In contrast, in chronic bronchitis, gland hypertrophy is characterized by an increased number of mucous cells relative to serous cells, particularly in severe bronchitis 52.

From the above, it may be seen that there are theoretical and actual differences in the nature of airway mucus between asthma and COPD. How these differences relate to pathophysiology and clinical symptoms in the two conditions is, for the most part, unclear. However, these dissimilarities suggest that different treatments may be required for effective treatment of airway mucus obstruction in asthma and COPD.

Pharmacotherapy of airway mucus hypersecretion

The prevalence of patient presentation with cough and expectoration of sputum and the perceived importance of mucus in the pathophysiology of severe lung conditions, such as asthma and COPD, have led to development of drugs intended to treat airway mucus hypersecretion 53. There are two objectives for treatment of airway mucus obstruction: short‐term relief of symptoms and long‐term benefit (Table I). Pharmacotherapy of airway mucus hypersecretion in asthma and COPD has been discussed in detail recently 17,54 and is summarized below and in Table II. Essentially, pharmacotherapy divides into two sections. The first is anti‐inflammatory treatment of airway inflammation, probably the most beneficial therapy overall. The second is therapies directed specifically at different aspects of the pathophysiology of mucus hypersecretion, from inhibition of the secretagogue effects of specific endogenous inflammatory secretagogues to aiding expectoration of sputum by use of mucolytics.

Table I. Objectives for effective pharmacotherapy of mucus pathophysiology in chronic airway hypersecretory diseases.

Overall objective	Component objective
Facilitate mucus clearance (short‐term relief of symptoms)	Reduce viscosity (? increase elasticity)
	Increase ciliary function
	Induce cough
	Facilitate release of ‘tethered’ goblet cell mucin (asthma)
	Treat pulmonary infection (COPD)
Reverse hypersecretory phenotype (long‐term benefit)	Treat airway/pulmonary inflammation
	Reduce goblet cell number
	Reduce submucosal gland size
	Correct increased gland mucous:serous cell ratio (COPD)
	Reverse increased MUC5B:MUC5AC ratio (especially in COPD)
	Inhibit plasma exudation (asthma)
	Inhibit production of MUC2
	Inhibit development of epithelial ‘fragility’ (asthma)

Table II. Potential therapeutic targets and inhibitors of airway mucus hypersecretion.

Target	Inhibitor(s)
Airway inflammation	Glucocorticosteroids, PDE4 inhibitors, suplatast tosilate, cytokine/chemokine blockers/receptor antagonists, ?macrolide antibiotics
Mucus properties:
Thickened mucus	Mucolytic drugs (e.g. N‐acetylcysteine)
P2Y2 receptors	Selective agonists for mucus hydration (e.g. INS37217)
Goblet cell hyperplasia:
Bcl‐2	Antisense oligonucleotides (e.g. G3139, aka Genasense, oblimersen), Bax mimetics
hCLCA1	Talniflumate
EGFR tyrosine kinase	AG1478, BIBX1522, ZD1839 (Iressa)
ERK	MEK inhibitors (e.g. PD98059, U0126)
MUC gene expression	18‐mer MUC antisense oligonucleotide
NKCC1	Bumetanide
p38 MAPK	p38 MAPK inhibitors (e.g. SB 203580)
PI‐3K	PI‐3K inhibitors (e.g. LY‐294002)
RAR‐α	RAR‐α antagonists (e.g. RO‐41‐5253)
Inflammatory mediators:
Bradykinin (B2 receptors)	Icatibant
Cysteinyl leukotrienes (Cys‐LT1 receptors)	Montelukast, zafirlukast
Endothelin‐1 (ETA receptors)	Bosentan
Mast cell tryptase	APC‐366, BABIM
Neutrophil elastase	Elastase inhibitors (e.g. batimastat, suramin and macrolide antibiotics such as erythromycin and flurythromycin)
PAF	Apafant, modipafant
Purine nucleotides (e.g. ATP, UTP)	P2Y2 antagonists (none yet available)
Mucin exocytosis:
MARCKS	MARCKS inhibitors (e.g. MANS peptide)
Munc‐18B	Munc‐18B inhibitors (antisense oligomer)
SNARE proteins	Re‐targeted clostridial endopeptidase fusion proteins (e.g. EGF‐LHN‐C)
Neural pathways:
Muscarinic (M3) receptors	Anticholinergics (e.g. ipratropium bromide, tiotropium bromide)
Nerve activation	VR‐1 receptor antagonists (e.g. anandamide, capsazepine)
Neurotransmitter release	BKCa channel activators (e.g. NS 1619), CB2 receptor agonists (e.g. AM1241, SR144528)
Tachykinin NK1 receptors	Tachykinin NK1 receptor antagonists (e.g. CP99,994, RP67580, nolpitantium; dual NK1/NK2 and triple NK1/NK2/NK3 antagonists)

Abbreviations: aka = also known as; BABIM = bis(5‐amidino‐2‐benzimidazo‐lyl)methane; Bax = endogenous pro‐apoptotic factor; Bcl‐2 = endogenous antiapoptotic factor; CB = cannabinoid (receptor); EGFR = epidermal growth factor receptor; ERK = extracellular signal‐regulated kinase; MAPK = mitogen activated protein kinase; MARCKS = myristoylated alanine‐rich C kinase substrate; MEK = MAPK kinase (‘upstream’ of ERK); MUC = mucin; NK = neurokinin; NKCC = Na⁺‐K⁺‐Cl⁻ cotransporter; PAF = platelet activating factor; PI‐3K = phosphatidylinositol 3‐kinase; PDE = phosphodiesterase; RAR = retinoic acid receptor; SNARE = soluble N‐ethyl‐maleimide‐sensitive factor attachment protein receptor; VR = vanilloid receptor.

Conventional pharmacotherapy

The medications used currently in clinical management of COPD and asthma, namely bronchodilators (anticholinergics, β₂‐adrenoceptor agonists and methylxanthines) and anti‐inflammatories (primarily glucocorticosteroids), are not administered necessarily to target airway hypersecretion, but may nevertheless exert some of their beneficial effects via actions on mucus 55.

Decreasing the viscosity of airway mucus with mucolytic drugs should improve mucus clearance, both by mucociliary transport and by cough. However, although numerous mucolytic drugs are available worldwide, their effectiveness in treatment of asthma and COPD has not been clearly established 56. Similarly, although antibiotics are recommended in clinical management of exacerbations of COPD, there is no evidence for prophylactic antibiotic treatment of stable COPD 23,57.

Novel pharmacotherapy

There is a range of novel pharmacotherapeutics in development for inhibition of airway mucus hypersecretion, including inhibitors of mucin exocytosis and inhibitors of goblet cell hyperplasia (Figure 4).

Figure 4. Possibilities for novel inhibition of airway mucus hypersecretion in chronic obstructive pulmonary disease(COPD). Theoretically, recruitment and activation of neutrophils and inhalation of cigarette smoke increases the lung burden of proteases and oxidants, which in turn activate the epidermal growth factor (EGF) intracellular signalling pathway leading to increased mucin (MUC) gene expression and mucin synthesis, mucous metaplasia (goblet cell hyperplasia and submucosal gland hypertrophy) and increased mucin secretion (via myristoylated alanine‐rich C kinase substrate (MARCKS)). The neutrophil chemotactic activity of interleukin (IL)‐8 and leukotriene (LT) B₄ can be inhibited by selective antagonists at the receptors for CXC chemokines (CXCR2 antagonists) and for LTB₄ (BLT antagonists), respectively, and neutrophil activity can be inhibited by inhibitors of phosphodiesterase (PDE) 4. The activity of proteases and oxidants can be inhibited by protease inhibitors and antioxidants. The EGF receptor and mitogen activated protein kinase cascade, as well as MARCKS activity, can be inhibited by appropriate inhibitors.

Exocytosis inhibitors

Inhibition of mucin exocytosis is a therapeutic option for mucus hypersecretion in asthma and COPD. Myristoylated alanine‐rich C kinase substrate (MARCKS) protein is a key intracellular molecule involved in intracellular movement and exocytosis of mucin granules 58. Blockade of MARCKS by a synthetic peptide to its N‐terminal region (MANS peptide) inhibited mucin secretion by normal human bronchial epithelial cells in vitro58 and by mouse airway epithelium in vivo59. The Sec1/Munc18 family are critical to exocytosis in airway goblet cells, and experimental induction of Munc18B (mammalian homologue of the nematode unc‐18 gene product, also known as syntaxin‐binding protein 1) induces a marked airway hypersecretory phenotype 60. Clostridium botulinum neurotoxins (BoNT) inhibit neurotransmitter (e.g. acetylcholine) release by cleaving soluble N‐ethyl‐maleimide‐sensitive factor attachment protein receptor (SNARE) proteins in the nerve terminal 61. Conversely, BoNTs could be re‐targeted to airway secretory cells via a fusion ligand to selectively inhibit mucin exocytosis, and thereby reduce mucus output. For example, the LH_N fragment (representing the light chain and the N‐terminal domain of the heavy chain coupled via a single disulphide bond) of BoNT‐C fused to EGF (termed EGF‐LH_N‐C) as targeting ligand for the EGF‐R on airway epithelial cells markedly inhibits stimulated mucin output from a human respiratory epithelial cell line 62.

Inhibition of mucin synthesis and goblet cell hyperplasia

Increased MUC gene expression, mucin synthesis and goblet cell hyperplasia appear to be linked processes that are regulated by a number of inflammatory mechanisms. For example, airway epidermal growth factor receptor (EGF‐R) upregulation and signalling via EGF‐R tyrosine kinase is a key signalling event for induction of mucin synthesis and goblet cell hyperplasia 63,64. Inhibitors of EGF‐R tyrosine kinase block these responses. One of these, gefitinib (Iressa), is in clinical trial for cancer, but not yet for asthma or COPD.

The p38 mitogen‐activated protein (MAP) kinase pathway, the MEK/ERK pathway, and the phosphatidylinositol 3‐kinase pathway are all involved, to a greater or lesser extent, in intracellular events leading to mucin synthesis and goblet cell hyperplasia 65–68. Inhibitors of these pathways inhibit mucus hypersecretory endpoints in experimental systems.

Calcium‐activated chloride (CLCA) channels appear to be critically involved in development of an airway hypersecretory phenotype 69. In mice, suppression of mCLCA3 inhibits goblet cell hyperplasia, whilst overexpression increases goblet cell number 70. Talniflumate is a small molecule putative inhibitor of hCLCA1 which is currently being developed as a mucoregulatory treatment for asthma and COPD 71.

Retinoic acid (vitamin A) acting on the RAR‐α receptor appears to be involved in mucin expression 72–74 and in the development and maintenance of a hypersecretory phenotype 74. RAR‐α antagonists, such as RO‐41‐5253, inhibit a number of these activities 75.

Antisense technology is also being explored as a new approach to inhibition of goblet cell hyperplasia. For example, an 18‐mer MUC antisense oligomer suppressed mucin gene expression and wood smoke‐induced epithelial metaplasia in rabbit airways 76.

Hyperplastic airway goblet cells in COPD models express the antiapoptotic factor Bcl‐2 77. Reduction of Bcl‐2 expression by antisense oligonucleotides induces a dose‐dependent resolution of hyperplasia.

P_2Y2 agonists and antagonists

Adenosine 5'‐triphosphate (ATP) and uridine triphosphate (UTP) increase airway mucin and water secretion via interaction with P_2Y2 purinoceptors 78,79. Consequently, P_2Y2 antagonists might inhibit airway hypersecretion 80. However, mucus hydration is associated with improved mucociliary clearance, and stimulation of water secretion may have greater therapeutic potential than inhibition of P_2Y2‐mediated mucin secretion 6. Consequently, there is considerable interest in development of P_2Y2 agonists 78.

Conclusions

Mucus secretion in the airways is a vital homeostatic mechanism that protects the respiratory tract from a barrage of inhaled insult. However, abnormal production of mucus can contribute to respiratory disease. Airway obstruction by mucus is a common feature of a number of severe respiratory conditions, including asthma, COPD and CF. These diseases share pulmonary inflammation and remodelling as a pathophysiological characteristic. They also each have a number of unique features that characterize their airway mucus obstruction. For example, mucus plug formation and mucus tethering are features of asthma, whereas submucosal gland hypertrophy with a disproportionate increase in the ratio of mucous to serous cells is a significant feature in COPD. Understanding of the relative importance of the differences and similarities in the pathophysiology of mucus obstruction between different respiratory diseases should lead to rational development of therapeutic interventions.