Conference Proceedings

Physiology of Airway Mucus Secretion

and Pathophysiology of Hypersecretion
Duncan F Rogers PhD FIBiol

Introduction
Airway Mucus
Respiratory Tract Mucins
Mucin Genes and Gene Products
Mechanisms of Goblet Cell Exocytosis
Airway Mucus Hypersecretory Phenotype in COPD
Airway Mucus Hypersecretory Phenotype in Asthma
Mechanisms of Airway Goblet Cell Hyperplasia
Summary

Mucus secretion is the first-line defense against the barrage of irritants that inhalation of approx-
imately 500 L of air an hour brings into the lungs. The inhaled soot, dust, microbes, and gases can
all damage the airway epithelium. Consequently, mucus secretion is extremely rapid, occurring in
tens of milliseconds. In addition, mucus is held in cytoplasmic granules in a highly condensed state
in which high concentrations of Ca2ⴙ nullify the repulsive forces of the highly polyanionic mucin
molecules. Upon initiation of secretion and dilution of the Ca2ⴙ, the repulsion forces of the mucin
molecules cause many-hundred-fold swelling of the secreted mucus, to cover and protect the epi-
thelium. Secretion is a highly regulated process, with coordination by several molecules, including
soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) proteins, myris-
toylated alanine-rich C kinase substrate (MARCKS), and Munc proteins, to dock the mucin gran-
ules to the secretory cell membrane prior to exocytosis. Because mucus secretion appears to be such
a fundamental airway homeostatic process, virtually all regulatory and inflammatory mediators
and interventions that have been investigated increase secretion acutely. When given longer-term,
many of these same mediators also increase mucin gene expression and mucin synthesis, and induce
goblet cell hyperplasia. These responses induce (in contrast to the protective effects of acute secre-
tion) long-term, chronic hypersecretion of airway mucus, which contributes to respiratory disease.
In this case the homeostatic, protective function of airway mucus secretion is lost, and, instead,
mucus hypersecretion contributes to pathophysiology of a number of severe respiratory conditions,
including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Key words: mucin,
mucus, asthma, chronic obstructive pulmonary disease, cystic fibrosis. [Respir Care 2007;52(9):1134 –
1146. © 2007 Daedalus Enterprises]

Duncan F Rogers PhD FIBiol is affiliated with the National Heart & Dr Rogers has a financial relationship with Syntaxin Ltd, Porton Down,
Lung Institute, Imperial College London, London, United Kingdom. Salisbury, United Kingdom.

Dr Rogers presented a version of this paper at the 39th RESPIRATORY Correspondence: Duncan F Rogers PhD FIBiol, Airway Disease, Na-
CARE Journal Conference, “Airway Clearance: Physiology, Pharmacol- tional Heart & Lung Institute, Imperial College London, Dovehouse
ogy, Techniques, and Practice,” held April 21–23, 2007, in Cancún, Street, London, United Kingdom, SW3 6LY. E-mail: duncan.rogers@
Mexico. imperial.ac.uk.

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Introduction
Inhalation of approximately 12,000 L of air a day bom-
bards the airway epithelium with up to 25 million particles
an hour.1 Cigarette smoking more than doubles that
amount.2,3 As a result, the airway epithelium has devel-
oped ways to combat this onslaught of soot, dust, mi-
crobes, and allergens. The first-line defense against in-
haled insult impinging on and damaging the epithelium is
the production of mucus. This mucus is a viscoelastic gel
that forms a thin film on the surface of the airways (Fig. 1).
It is an important homeostatic defense mechanism with a
variety of functions (Table 1) that have evolved to reduce
epithelial damage by inhaled irritants. Under normal cir-
cumstances, airway mucus protects the epithelial lining by
entrapping foreign debris, bacteria, and viruses, and clear-
ing them from the airway by ciliary movement, a process
termed mucociliary clearance4 (Fig. 2). In contrast, in clin-
ical conditions associated with airway mucus hypersecre-
tion, such as asthma,5 chronic obstructive pulmonary dis-
ease (COPD),6,7 and cystic fibrosis (CF),8 the mucus shifts
from a protective role to one that contributes to respiratory
disease (see Fig. 2). Excessive production of airway mu-
cus, termed mucus hypersecretion, and changes in the bio-
physical properties of the mucus can impair mucociliary
clearance, with associated accumulation of mucus in the
lungs (Fig. 3), leading to difficulty in breathing, morbidity,
and, in severe cases, mortality. The latter aspects are cov-
ered in the present article, after a general introduction to
airway mucus and the physiology of airway mucus secre-
tion.
Airway Mucus
Airway mucus is a complex dilute aqueous solution of
lipids, glycoconjugates, and proteins. It contains electro-
Fig. 1. Scanning electron micrograph of human bronchus, show-
ing mucus (M), appearing as “rafts” and strands, resting on cilia
(C). (Courtesy of Peter K Jeffery, Department of Gene Therapy,
Royal Brompton Hospital, Imperial College London, United King-
dom.)
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AND PATHOPHYSIOLOGY OF HYPERSECRETION
Table 1. Functions of Airway Mucus
Physical barrier to inhaled airborne particles, irritants, microbes, and to
aspirated foods and liquids
Entrapment of organisms, particles, and irritants
Formation of the vehicle on which irritants are transported by
mucociliary activity for clearance from the airways
Provision of a waterproof layer over the epithelium to limit
dehydration
Humidification of inspired air
Insulation
pH buffering capacity
Lubrication
Neutralization of toxic gases
Selective macromolecular sieve
Source of antibacterial and other protective enzymes, and provision of
extracellular surface for their activity
Source of immunoglobulins, and provision of extracellular surface for
their activity
lytes, enzymes and anti-enzymes, oxidants and antioxi-
dants, exogenous bacterial products, endogenous antibac-
terial secretions, cell-derived mediators and proteins,
plasma-derived mediators and proteins (see Fig. 2), and
cell debris such as deoxyribonucleic acid (DNA). Airway
mucus is believed to form a liquid bi-layer; an upper gel
layer floats above a lower, more watery sol, or periciliary
liquid, layer9 (see Fig. 2). It is likely that a thin layer of
surfactant lies between the sol and gel phases10 (see Fig. 2).
The function(s) of the sol layer is debated, but is presumed
to include “lubrication” of the beating cilia. The surfactant
layer might facilitate spreading of mucus over the epithe-
lial surface. The gel layer traps particles and is moved on
the tips of the beating cilia. The inhaled particles are trapped
in the sticky gel layer and are removed from the airways—a
process termed mucociliary clearance. When the mucus
reaches the throat, it is either swallowed and delivered to
the gastrointestinal tract for degradation, or, if excessive,
as in respiratory disease, it is coughed out as “sputum.”4
Respiratory tract mucus requires the correct combina-
tion of viscosity and elasticity (viscoelasticity) for optimal
efficiency of ciliary interaction.6,11 Viscosity is a liquid-
like characteristic and is the resistance to flow and the
capacity to absorb energy when moving. Elasticity is a
solid-like property and is the capacity to store energy that
moves or deforms the fluid. Viscoelasticity is conferred on
the mucus primarily by high-molecular-weight mucous gly-
coproteins, termed mucins.
Respiratory Tract Mucins
In health, mucins comprise up to 2% by weight of the
airway mucus.12 In the airways, mucins are produced by
goblet cells in the epithelium13 (see Figs. 2 and 4) and
sero-mucous glands in the submucosa14 (Fig. 5).
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 PHYSIOLOGY OF AIRWAY MUCUS SECRETION
Fig. 2. Airway mucus secretion and hypersecretion. Upper Panel:
In healthy airways, mucus forms a bi-layer over the epithelium,
with surfactant (dotted line) separating the gel and sol layers. Mu-
cins secreted by goblet cells and submucosal glands confer vis-
coelasticity on the mucus, which facilitates mucociliary clearance
of inhaled particles and irritants. Mucus hydration is regulated by
salt (and, hence, water) flux across the epithelium. The glands also
secrete water. Plasma proteins exuded from the tracheobronchial
microvasculature bathe the submucosa and contribute to the for-
mation of mucus. The above processes are under the control of
nerves and regulatory mediators. Lower Panel: Airway inflamma-
tion (in asthma, chronic obstructive pulmonary disease [COPD],
and possibly cystic fibrosis [CF]) induces changes associated with
a mucus hypersecretory phenotype, including increased plasma
exudation (more predominant in asthma than COPD or CF), goblet
cell hyperplasia, via differentiation from basal cells, and associ-
ated increased mucus synthesis and secretion, and submucosal
gland hypertrophy (with associated increased mucus production),
leading to increased luminal mucus (and airway obstruction).
Mucins are long, thread-like, complex glycoconjugates
(see Fig. 4). A mucin consists of a linear peptide backbone
(termed apomucin), which is encoded by specific mucin
(MUC) genes (see below), to which hundreds of carbohy-
drate side-chains are O-linked, but also with additional
N-linked glycans. The glycosylation pattern is complex
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AND PATHOPHYSIOLOGY OF HYPERSECRETION
and extremely diverse,15 and is associated with comple-
mentary motifs on bacterial cell walls, which facilitates
broad-spectrum bacterial attachment and subsequent clear-
ance.16,17 Within the main protein core are variable num-
bers of tandemly repeated serine-rich and/or threonine-
rich regions, which are unique in size and sequence for
each mucin,4 and represent sites for mucin glycosylation.
These complex glycoproteins are polydisperse, linear poly-
mers that can be fragmented, by reduction, to create mono-
mers (see Fig. 4) termed “reduced subunits.”18 –21 There
are at least 2 structurally and functionally distinct classes
of mucin, namely, the membrane-associated mucins (Ta-
ble 2) and the secreted mucins (either gel-forming or non-
gel-forming) (Tables 3 and 4). Membrane-tethered mu-
cins, which have a hydrophobic domain that anchors the
mucin in the plasma membrane, contribute to the forma-
tion of the epithelial surface.4 Secretory mucins are stored
intracellularly in secretory granules and are released at the
apical surface of the cell in response to a stimulus (see
below). It would appear that mucus production is such a
fundamental homeostatic process that virtually all the in-
terventions that have been investigated trigger airway mu-
cin secretion (Table 5). In addition, many of these same
mediators when administered longer-term not only induce
mucin secretion but also up-regulate MUC gene expres-
sion, with concomitant increases in mucin synthesis and
associated goblet cell hyperplasia (see Table 5).
Mucin Genes and Gene Products
Twenty human MUC genes have so far been identified
(see Tables 2– 4). Of these, only nine, namely, MUC1,
MUC2, MUC4, MUC5AC, MUC5B, MUC7, MUC8,
MUC11, and MUC13, are expressed in the human respi-
ratory tract.4 Of these, only MUC2, MUC5AC, and MUC5B
(the classic gel-forming mucins, see Fig. 4), are found in
airway secretions. MUC5AC and MUC5B glycoproteins,
localized adjacent to each other on chromosome 11p15.5,
are considered the major gel-forming mucins in both nor-
mal respiratory tract secretions and airway secretions from
patients with respiratory diseases. 22–27 Interestingly,
MUC5B appears to be unique in that it is not polymorphic.
Small amounts of MUC2 may, however, be found in se-
cretions from “irritated” airways (see below).
In general, the MUC gene products are poorly charac-
terized biochemically and biophysically.12 The predicted
sequences of the MUC1, 3A, 3B, 4, 11–12, 13, 15–18, and
20 gene products suggest they are membrane-bound, with
an extracellular mucin domain and a hydrophobic mem-
brane-spanning domain (see Table 2). In contrast, MUC2,
5AC, 5B, 6 –9, and 19 gene products are secreted mucins
(see Tables 3 and 4). The technology for studying the
contribution to physiology and pathophysiology of the in-
dividual MUC gene products lags well behind that of in-
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Fig. 3. Mucus obstruction of the airways in asthma and chronic obstructive pulmonary disease (COPD). A: Mucus plugging in asthma.
Complete occlusion by mucus (M) plugs of an intrapulmonary bronchus (arrow), cut in longitudinal section, in a patient who died of an acute
severe asthma attack. B: Mucus (M) partially obstructing an extrapulmonary bronchus (transverse section: arrow) of an elderly, male,
long-term cigarette smoker. C: Bronchoconstriction and luminal mucus in fatal asthma. Intrapulmonary airway (transverse section) of a
patient who died of an acute severe asthma attack, showing airway epithelium (arrow) thrown into folds by smooth-muscle contraction, and
occlusion by mucus (M) of remaining luminal space. This relatively small amount of mucus would not be expected to significantly reduce
airflow in a relaxed, nonconstricted airway. D: Mucus (M) blocking an intrapulmonary airway (transverse section) of an elderly, male,
long-term cigarette smoker (a different patient than that in panel B). Note the lack of airway constriction (in contrast to panel B) and the
cellular infiltrate in the mucus. The arrow points to the epithelium.

vestigation of gene expression.4 MUC1, 2, and 8 genes are
expressed in both the epithelium and submucosal glands,
whereas MUC4, 5AC and 13 are expressed primarily in
the epithelium. In contrast, MUC5B and MUC7 genes are
expressed primarily in the glands. Use of currently avail-
able antibodies confirms that the MUC5AC gene product
is a goblet cell mucin, whereas MUC5B predominates in
the glands, albeit that some MUC5AC (and possibly MUC7)
is also usually present.12 Interestingly, MUC4 mucin lo-
calizes to the ciliated cells.
The mucin content of secretions from patients with hy-
persecretory respiratory diseases may differ from normal.
For example, MUC5AC mucin, initially isolated as a tra-
cheobronchial mucin,28 is found in airway secretions pooled

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Fig. 4. Airway mucin and mucin secretion. A: Goblet cell (GC) and ciliated cell (CC) in human bronchus. M ⫽ mucin-containing granules.
C ⫽ cilia. L ⫽ lumen. B: Visualization of mucin exocytosis by a guinea pig tracheal goblet cell. Fusion of an intracellular mucin granule (arrow)
with the apical membrane of the cell (arrow head) leads to the formation of a bi-membrane-spanning pore that rapidly opens out to form
an “omega” (⍀) profile (shown), which allows release of stored mucin (M). In this image the mucin is retained in the granule, due to the use
of tannic acid fixation. C: Predominant airway mucin gene products: modular motifs in amino acid backbones. MUC2, MUC5AC, and
MUC5B are cysteine-rich secretory mucins. See Reference 4 for details of modular motifs. D: Mucin subunit. Each subunit (approximately
500 nm in length) comprises an amino acid backbone with highly glycosylated (linear) domains and folded regions, stabilized via disulphide
bonds, with little or no glycosylation. Glycosylation is via O-linkages and is highly diverse. E: Mature mucin molecule. In secretions, the
mucin subunits are joined end-to-end by disulphide bonds (S-S) to form long, thread-like mature mucin molecules.

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Fig. 5. Airway submucosal glands. A: Isolated dog tracheal gland, showing complex structure of secretory acini that feed secretions into
a collecting duct, which are then wafted out via the ciliated duct. Mucus is seen being secreted from the top of the gland. (Courtesy of Sanae
Shimura, First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan). B: Computer-generated image of
human bronchial gland. Serial histological sections were translated into a false-colored reconstruction of the gland. The distal serous acini
produce relatively watery secretions that contain antibacterial enzymes (lysozyme, lactoferrin). It has been proposed that they wash over
the more viscous mucin secretions produced by the more proximal mucous acini and flush them into the collecting duct. (Courtesy of
William F Whimster [deceased], Department of Histopathology, King’s College School of Medicine, London, United Kingdom.)

from healthy individuals,24,22 and increased levels are
present in the airways of patients with asthma.29 The ex-
pression of many genes, such as MUC5AC, in airway
epithelial cells is regulated by various neurohumoral fac-
tors and inflammatory mediators (see Table 5). MUC5B
mucins are a major component of tenacious mucus plugs
from the lungs of a patient who died in status asthmati-
cus,25,30 and in sputum from patients with chronic bron-
chitis.26
From the above it appears that, in healthy individuals,
MUC5B is mainly expressed in the airway submucosal
glands, which are restricted to the more proximal, car-
tilaginous airways. In contrast, MUC5AC expression is
generally restricted to goblet cells in the upper and lower
respiratory tracts.31,32 Thus, the composition of normal
mucus can be altered, depending on the relative contri-
bution to the secretions of these different cellular sourc-
es.33 In respiratory diseases associated with airway mu-
cus hypersecretion, such as asthma, COPD, and CF,
further changes in the composition of the mucus, and in
the mucus secretory phenotype in general, are observed
(see below).
Mechanisms of Goblet Cell Exocytosis
Exocytosis is an evolutionarily conserved and ubiqui-
tous process whereby hormones, mediators, and other mol-
ecules are released from cells. For exocytosis of most
vesicles to occur, a soluble N-ethyl-maleimide-sensitive
factor attachment protein receptor (SNARE) complex has
to be formed, which links the vesicle (v-SNARE) and the
target cell membrane (t-SNARE) together, to facilitate re-
lease of vesicle content from the cell.34
There are 2 general mechanisms by which exocytosis
occurs, and these apply also to mucin exocytosis:
• Constitutive (basal) secretion: this secretion is unreg-
ulated and of a low level.
• Stimulated secretion: regulated exocytosis of granules
in response to extracellular stimuli.

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Table 2. Human MUC Genes That Produce Membrane-Associated Table 5. Inducers of Airway Mucus Secretion, Goblet Cell
Mucins Hyperplasia, and Mucin Gene Expression/Mucin Synthesis

Gene Tissue Distribution Stimulant Secretion* Hyperplasia MUC Gene

MUC 1 Lung, cornea, salivary glands, esophagus, stomach, Cytokines

pancreas, large intestine, breast, prostate, ovary, IL-1␤ ⫹ NR NR
kidney, uterus, cervix, dendritic cells IL-6 ⫹ NR Yes
MUC 3A Thymus, small intestine, colon, kidney IL-9 NR NR Yes
MUC 3B Small intestine, colon IL-13 (IL-4) ⫹ Yes Yes
MUC 4 Lung, cornea, salivary glands, esophagus, small TNF-␣ ⫹⫹ Yes† Yes1
intestine, kidney, endocervix
MUC 11 Lung, middle ear, thymus, small intestine, pancreas, Gases
colon, liver, kidney, uterus, prostate Irritant gases (eg, cigarette ⫹⫹ Yes Yes
MUC 12 Middle ear, pancreas, colon, uterus, prostate smoke)
MUC 13 Lung, conjunctiva, stomach, small intestine, colon, Nitric oxide NE/⫹ NR NR
kidney Reactive oxygen species 0/⫹ NR NR
MUC 15 Conjunctiva, tonsils, thymus, lymph node, breast,
Inflammatory mediators
small intestine, colon, liver, spleen, prostate, testis,
Bradykinin ⫹ NR NR
ovary, leukocytes, bone marrow
Cysteinyl leukotrienes ⫹⫹ NR NR
MUC 16 Conjunctiva, ovary
Endothelin 0/⫹ NR NR
MUC 17 Intestinal cells, conjunctival epithelium
Histamine ⫹ NR NR
MUC 18 Prostate
Platelet activating factor ⫹ Yes1 Yes†
MUC 20 Lung, liver, kidney, colon, placenta, prostate
Prostaglandins 0/⫹ NR NR
Proteinases ⫹⫹⫹ Yes NR
Purine nucleotides ⫹⫹ NR NR
Table 3. Human MUC Genes That Produce Secreted, Cysteine-Rich
(Gel-Forming) Mucins Neural pathways
Cholinergic nerves ⫹⫹ NR NR
Gene Tissue Distribution Cholinoceptor agonists ⫹⫹ Yes NR
MUC 2 Lung, conjunctiva, middle ear, stomach, small Nicotine ⫹⫹ Yes NR
intestine, colon, nasopharynx, prostate Tachykininergic nerves ⫹ NR NR
MUC 5AC Lung, conjunctiva, middle ear, stomach, gall bladder, Substance P ⫹⫹ NR NR
nasopharynx Neurokinin A ⫹ NR NR
MUC 5B Lung, middle ear, sublingual gland, laryngeal
Miscellaneous
submucosal glands, esophageal glands, stomach,
Epidermal growth factor NR Yes Yes
duodenum, gall bladder, nasopharynx
(⫹ TNF-␣)
MUC 6 Stomach, duodenum, gall bladder, pancreas, kidney
Sensitization followed by ⫹ Yes Yes
MUC 19 Lung, salivary gland, kidney, liver, colon, placenta,
challenge
prostate
*⫹⫹⫹ ⫽ highly potent, ⫹⫹ ⫽ marked effect, ⫹ ⫽ lesser effect, 0 ⫽ minimal effect, NE ⫽
no effect, NR ⫽ effect not reported.
† Effect only observed with platelet activating factor and tumor necrosis factor alpha (TNF-␣)
Table 4. Human MUC Genes That Produce Secreted, Cysteine-Poor in combination.
Mucins IL ⫽ interleukin

Gene Tissue Distribution

MUC 7 Lung, lachrymal glands, salivary glands, nose

MUC 8 Oviduct
MUC 9 Submandibular glands
Mucin granules are present in the cytoplasm of airway
mucin-secreting cells (see Fig. 4). Mucins are first synthe-
sized on the rough endoplasmic reticulum, then oligomerized
and sent to the Golgi for glycosylation and subsequent pack-
aging and budding into mature mucin granules. The granules
are stored in the cytoplasm, in preparation for release.
In airway goblet cells, exocytosis of mucin involves the
movement of the mucin granule to the apical surface of the
goblet cell. This movement is dependent upon many fac-
tors, including chaperoning to the plasma membrane via
myristoylated alanine-rich C-kinase substrate (MARCKS)
protein. Upon stimulation, MARCKS is phosphorylated
by protein kinase C, released from the plasma membrane,
and de-phosphorylated by protein phosphatase 2A, acti-
vated by protein kinase G. This allows MARCKS to be
unbound and ready for actin/myosin binding to form an
interaction with the secretory vesicle. Targeting to the se-
cretory vesicle is mediated by its chaperone protein,
Hsp70.35 Binding allows MARCKS to chaperone the mu-
cin-containing vesicle to the apical membrane of the gob-

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let cell. As a result of MARCKS phosphorylation, the

actin/myosin contracts, which allows the vesicle to fuse
with the plasmalemma, and release mucin out of the cell.
Munc-18 is also required for syntaxin binding to the plas-
malemma. Docked granules have to mature to fusion-com-
petence before they can undergo exocytosis. Munc-13– 4
participates in this “priming” of airway goblet cell gran-
ules.36 Once at the plasma membrane, the mucin-contain-
ing granule forms a SNARE complex, irreversibly tether-
ing the granule. Correct and complete formation of this
MARCKS-guided SNARE complex has to occur before
mucin exocytosis can take place, which forms an open
conformation with the profile of an omega symbol (⍀),
that links the mucin granule and apical cell membranes37
(see Fig. 4).
Once initiated, goblet cell mucin exocytosis obeys first-
order kinetics: it is extremely rapid, taking only tens of
milliseconds, during which time the released mucin ex-
pands many hundred-fold38 (Fig. 6). Rapid expansion oc-
curs because the mucin is highly condensed within the
granules, with the mucin threads bound together by high Fig. 6. Kinetics of airway mucin secretion. A: Highly polyanionic
intragranular concentrations of Ca2⫹, which acts as a shield- mucin molecules repel each other to form a tangled network that
ing cation. Mucin granules are polyanioic, so without the spreads over the epithelial surface. For packaging into intracellular
mucin granules, high concentrations of intragranular Ca2⫹ act as a
calcium present within the mucin matrix, such close pack- shielding cation to nullify anionic repulsion and allow condensa-
aging could not occur. Upon exocytosis, the Ca2⫹ is pro- tion of the mucin in the granules. For mucin secretion, after pore
gressively diluted, allowing electrostatic expulsion to oc- formation and expansion into an omega profile (see Fig. 4), water
cur, a process accelerated by water uptake, resulting in enters the granule and progressively dilutes out the Ca2⫹, with
consequent loss of capacity to nullify anionic repulsion, which
expansion of the mucin into the airways. This is a normal, allows the mucin to undergo a Donnan shift and expand out of the
homeostatic process. However, excessive and prolonged cell, in the manner of a “jack-in-the-box.” B: Kinetics of mucin
exocytosis results in airway mucus hypersecretion, as seen expansion. Condensed intragranular mucin undergoes size ex-
in respiratory diseases such as COPD and asthma. pansion of many hundred-fold upon secretion, reaching a plateau
expansion in tens of milliseconds. C: Mucin secretion from a guinea
pig secretory epithelial cell. The arrowheads point to mucin, exo-
Airway Mucus Hypersecretory Phenotype in COPD cytosed in sequence from different individual granules, around the
cell. Note the relative size of the mucin “globules” to the cell,
indicating large, post-secretory size expansion. The whole se-
quence for the 4 exocytotic events is 40 s.
COPD comprises 3 overlapping conditions, namely,
chronic bronchitis (airway mucus hypersecretion), chronic
bronchiolitis (small airways disease), and emphysema (air Airway Mucus Hypersecretory Phenotype in Asthma
space enlargement due to alveolar destruction).39 The fol-
Asthma is a chronic inflammatory condition of the air-
lowing discussion considers the “bronchitic” component
ways, characterized by variable airflow limitation that is at
of COPD. The airways of patients with COPD contain
least partially reversible, either spontaneously or with treat-
excessive amounts of mucus40 (see Fig. 3), which is mark-
ment.47,48 It has specific clinical and pathophysiological
edly increased above that in control subjects.41,42 The ex- features,49 including mucus obstruction of the airways.50
cessive luminal mucus is associated with increased amounts There is more mucus in the central and peripheral airways
of mucus-secreting tissue. Goblet cell hyperplasia is a car- in patients with chronic or severe asthma than in control
dinal feature of chronic bronchitis,40 with increased num- subjects.51 The increased luminal mucus reflects an in-
bers of goblet cells in the airways of cigarette smokers, crease in the amount of airway secretory tissue, due to
either with chronic bronchitis and chronic airflow limita- both goblet cell hyperplasia29,51 and submucosal gland hy-
tion,43 or with or without productive cough.44 Submucosal pertrophy,52 although the latter is not characteristic of all
gland hypertrophy also characterizes chronic bronchi- patients with asthma.51
tis,40,41,45,46 and the amount of gland correlates with the Airway mucus obstruction in asthma is particularly ev-
amount of luminal mucus.41 ident in a proportion of patients who die in status asth-

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Fig. 7. Airway plasma exudation in asthma. Patients with seasonal
allergic asthma underwent a bronchoalveolar lavage (BAL) before
and then immediately after local challenge of the airways with
allergen. BAL fluid concentrations of low- and high-molecular-
weight proteins were expressed as a ratio of total BAL protein, and
then expressed as a ratio of serum proteins (again as a ratio of
total serum protein). Compared with pre-challenge BAL, allergen
challenge caused a greater increase in BAL low-molecular-weight
proteins (plasma markers) (double-headed arrow) compared with
high-molecular-weight markers of secretion (arrows), which indi-
cates increased plasma exudation in response to allergen chal-
lenge. ␣1AT ⫽ alpha-1 antitrypsin. Alb ⫽ albumin. Trans ⫽ trans-
ferrin. Cer ⫽ ceruloplasmin. Fib ⫽ fibrinogen. ␣2M ⫽ alpha-2
macroglobulin. (Redrawn using data in Reference 57.)
maticus, where many airways are occluded by mucus
plugs52–54 (see Fig. 3). The plugs are highly viscous and
contain large amounts of plasma proteins (such as serum
albumin), as well as DNA, cells, proteoglycans,55 and mu-
cins.30,52,55 The plasma proteins are a result of increased
plasma exudation56,57 (Fig. 7), which is a pathophysiolog-
ical feature of asthma.58 Importantly, incomplete mucus
plugs are found in the airways of asthmatic subjects who
have died from causes other than asthma,59 which indi-
cates that plug formation is a chronic, progressive process.
The increased viscosity of the airway mucus in asthma
could be due to an intrinsic abnormality in the secreted
mucins30 or to interactions between mucins and plasma,
whereby plasma synergistically increases the viscosity of
mucus60,61 (Fig. 8). The mechanisms underlying the latter
increased viscosity are unclear, but may be due to plasma-
induced rupturing of hydrogen bonds between adjacent
mucin molecules, which promotes greater inter-tangling
between mucin and albumin molecules, or to plasma lim-
iting the normal hydration and swelling of secreted mu-
cin.62 In addition to its thickening effect on mucin, luminal
plasma would directly contribute to the increased amount
of airway mucus, and may itself induce mucin secretion,63
leading to further increases in luminal mucus with high
viscosity (see Fig. 8).
1142
AND PATHOPHYSIOLOGY OF HYPERSECRETION
Fig. 8. Effect of mucin secretion and plasma exudation on airway
mucus. Mucus secretion and plasma exudation both increase the
volume of luminal liquid. In addition, plasma can induce mucin
secretion, which further increases the volume of liquid. Plasma
and mucin interact such that plasma proteins (eg, albumin) syn-
ergistically increase the viscosity of mucin. Thus, mucin secretion
coupled with plasma exudation potentially results in a greater vol-
ume of more viscous liquid than either mucin secretion or plasma
exudation alone.
Mechanisms of Airway Goblet Cell Hyperplasia
Airway goblet cell hyperplasia is a prominent patho-
physiological feature of COPD, asthma, and CF (see above),
and is an often-used end point in animal models of respi-
ratory disease.64 The cellular composition of the airway
epithelium can alter both by cell division and by differen-
tiation of one cell into another.65 There are at least 8 cell
types in the airway epithelium of the conducting airways.
In terms of goblet cell hyperplasia, differentiation is the
major pathway for production of new goblet cells, and cell
division is the major carcinoma pathway. The basal serous
and Clara cells are considered the primary progenitor cells,
because they have the capacity to undergo division, fol-
lowed by differentiation into “mature” ciliated or goblet
cells. In specific experimental conditions (eg, exposure to
cigarette smoke), goblet cell division contributes in part to
the hyperplasia. However, differentiation of nongranulated
airway epithelial cells is a major route for production of
new goblet cells.65– 67 In experimental animals, production
of goblet cells is usually at the “expense” of the progenitor
cells, most notably serous and Clara cells, which decrease
in number as goblet cell numbers increase. Serous-like
cells and Clara cells are found in macroscopically normal
bronchioles in human lung.68 Whether there is a reduction
in number in respiratory disease has not been reported, but
merits investigation. Reduction in the relative proportion
of serous and Clara cells has pathophysiological impor-
tance because they produce a number of anti-inflamma-
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 PHYSIOLOGY OF AIRWAY MUCUS SECRETION AND PATHOPHYSIOLOGY OF HYPERSECRETION

Fig. 9. Pathophysiology of airway mucus hypersecretion. Initiating factors, including allergen exposure (in asthma), cigarette smoking (in
chronic obstructive pulmonary disease [COPD]), defects in the cystic fibrosis (CF) transmembrane-conductance regulator (CFTR), and
bacterial infection (COPD and CF), set up a cycle of inflammation, and are also associated with nerve activation. The inflammation of asthma
(predominantly Th2 lymphocytes [T] and eosinophils [E]) differs from that in COPD or CF (predominantly macrophages [M] and neutrophils
[N]). Secretagogues produced during inflammation and nerve activation induce a number of signaling pathways associated with increased
mucin secretion, mucin gene expression, and mucin synthesis, which, in turn, are associated with secretory cell hyperplasia, airway mucus
hypersecretion and respiratory problems. EGF-R ⫽ epidermal growth factor receptor. MAP ⫽ mitogen-activated protein (kinases). hCLCA1 ⫽
human calcium-activated chloride channel. RAR ⫽ retinoic acid receptor.

tory, immunomodulatory, and antibacterial molecules vital
to host defense.69,70 For example, serous cells produce
lysozyme, lactoferrin, secretory immunoglobin A, perox-
idase, and at least 2 protease inhibitors. Clara cells pro-
duce Clara cell 10-kDa protein (also known as uteroglobu-
lin), Clara cell 55-kDa protein, Clara cell tryptase,
␤-galactoside-binding lectin, possibly a specific phospho-
lipase, and surfactant proteins A, B, and D. Thus, in re-
spiratory diseases associated with airway mucus hyperse-
cretion it seems that not only is there goblet cell hyperplasia,
with associated mucus hypersecretion, but also a reduction
in serous and Clara cells, with concomitant impaired po-
tential for host defense.
Some of the mechanisms for development of airway
goblet cell hyperplasia and the associated mucus hyperse-
cretory phenotype in asthma and COPD are becoming clear-
er.50,71 Many regulatory and inflammatory mediators and
enzymes increase mucus secretion and induce MUC gene
expression, mucin synthesis, and goblet cell hyperplasia in
experimental systems (see Table 5). These mediators are
intermediates in a cascade of pathophysiological events
leading from initiating factors (such as allergen exposure
in asthma) to a chronic inflammatory/repair response, which
in turn leads to mucus hypersecretion and associated air-
way obstruction and clinical symptoms (Fig. 9). A small
number of key molecules may be involved in translating
the actions of the different inflammatory mediators into
airway mucus hypersecretion, namely, epidermal growth
factor and its receptor tyrosine signaling pathway,72 the
mitogen activated kinase and extracellular signal-regulated
kinase (MEK/ERK) pathway,73 calcium-activated chloride
channels,74,75 and the retinoic acid receptor (RAR)-␣ sig-
naling pathway.76 A wide variety of small molecule an-
tagonists and inhibitors of these pathways are currently in
pharmacotherapeutic development.77
Summary
Secretion of airway mucus is a vital homeostatic mech-
anism that protects the respiratory tract from a barrage of

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 PHYSIOLOGY OF AIRWAY MUCUS SECRETION
inhaled insult. The mucus has to be of the correct viscosity
and elasticity for optimal interaction with the cilia and
effective mucociliary clearance of particles from the lungs.
Presumably because of the potential damage that inhaled
irritants can do to the airway epithelium, the process of
secretion is extremely rapid. In addition, because of the
marked condensation of intragranular mucins, deconden-
sation and subsequent secretion releases vast amounts of
mucin onto the airway surface. However, over and above
the rapid secretion in response to temporary inhaled insult,
long-term, chronic increased secretion of airway mucus
contributes to respiratory disease. In this case, the homeo-
static, protective function of airway mucus secretion is lost
and, instead, mucus hypersecretion contributes to disease.
Airway obstruction by mucus is a common feature of a
number of severe respiratory conditions, including asthma,
COPD, and CF. To a certain extent, each disease has a
particular hypersecretory phenotype, although a number of
pathophysiological features are shared (eg, submucosal
gland hypertrophy and goblet cell hyperplasia). Goblet cell
hyperplasia, and the associated mucus hypersecretion, are
particularly important in small airways. Mucus in these
airways cannot be cleared by cough and tends to accumu-
late and cause obstruction. Goblet cell hyperplasia is at the
expense of serous cells and Clara cells. The loss of the
various anti-inflammatory, immunomodulatory, and anti-
bacterial molecules normally secreted by these cells fur-
ther compromises host defense.
In summary, mucus secretion is homeostatic, and mucus
hypersecretion is not. Where the division lies between
secretion and hypersecretion is not clear, but needs to be
delineated for more precise and clinically useful diagnosis
of airway mucus hypersecretory diseases.
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Discussion
MacIntyre: That was terrific. For
somebody who doesn’t deal with this
very often, that was very clear, thank
you. I have 2 somewhat separate ques-
tions. Number one, and this is proba-
bly oversimplified, but you described
secretions—a normal secretion and a
hypersecretion. You say normal is nor-
mal and hypersecretion is abnormal.
Is there not a state in the middle where
a little hypersecretion is appropriate?
It’s sort of like the sepsis cascade. You
know, we think of these inflammatory
mediators as all being bad.
Well, as a matter of fact, we evolved
into creatures where this increased in-
flammatory response in sepsis is prob-
ably protective, and it’s only bad when
it starts spinning out of control. So
there probably is a hypersecretion state
that is good, and protects us against
viral infections and other infections,
and stuff like that. I guess the ques-
tion is that it’s not normal versus ab-
normal; it’s like normal at rest, nor-
mal hypersecretion, and then abnormal
hypersecretion. Does that make sense?
Rogers: I couldn’t agree more with
that. That’s the basis of the last ques-
tion on my final slide. The airway ep-
ithelium has got to have mucus on it:
mucus is clearly protective. It does all
these wonderful things. Not least that
it provides a barrier. We’re inhaling
about 12,000 liters of air a day. In
central London, where I work, it’s
bringing millions upon millions of par-
ticulate matter into the airways on an
hourly basis, and we’ve got to have
airway mucus. It’s got viscoelasticity
for mucociliary clearance, as well as
the other protective mechanisms that
it provides. And when, for example,
asthmatics inhale pollen or other irri-
tant, acute production of mucus is pre-
sumably protection against the inhaled
pollen. But then the secretion subsides;
so there is only transitory mucus hy-
persecretion, after which mucus secre-
tion returns to “baseline.” So you’ve
got normal mucus secretion, and
you’ve got protective, transitory mu-
cus hypersecretion.
MacIntyre: Which is good.
Rogers: Which is good; and abso-
lutely what you want. But at some
stage, if your airways are being re-
peatedly challenged by inhaled partic-
ulates, which in turn are setting up a
chronic inflammatory response lead-
ing to airway remodeling into a mu-
cus hypersecretory phenotype (eg,
goblet cell hyperplasia and submuco-
sal gland hypertrophy), you must reach
a cutoff point where protective, tran-
sitory mucus hypersecretion shifts
over into a chronic mucus hypersecre-
tory phenotype, whereby the perpet-
ual presence of excess mucus in the
airways is pathophysiological. I don’t
know where that cutoff point will be,
because the chronic mucus hyperse-
cretion will still be trying to be pro-
tective, but will merge into being non-
protective: but, where is that merge
point?
MacIntyre: Can I ask you another
question? I am struck by the fact that
emphysema doesn’t have any mucus.
As you go down the human tracheo-
bronchial tree, where do you start los-
ing mucus glands? Emphysematous
patients are dyspneic, but they cer-
tainly don’t cough mucus.
Rogers: This is the thing. You can
visualize COPD as 3 interlinked
Olympic rings set in a triangle.1 One
is chronic bronchitis, or mucus hy-
persecretion; one is small airways
disease, which is fibrosis, and the
resultant stenosis, of the bronchioli;
and the third is alveolar destruction,
or emphysema. Clearly, in any one
patient, you will not necessarily
know the relative contribution of
those 3 components to the patho-
physiology and clinical symptom-
atology of the patient, unless they
are hawking up great quantities of
sputum. In the paper by Aikawa et
al, the patients just had emphysema;
they weren’t producing sputum. 2
They had alveolar destruction, with
big holes in their lungs. So, they
didn’t seem to have the bronchitic
component to their COPD, for what-
ever reason; but it might be genetic.
1. Rogers DF. Mucoactive agents for airway
mucus hypersecretory diseases. Respir Care
2007;52(9):1176-1193.
2. Aikawa T, Shimura S, Sasaki H, Takishima
T, Yaegashi H, Takahashi T. Morphometric
analysis of intraluminal mucus in airways in
chronic obstructive pulmonary disease. Am
Rev Respir Dis 1989;140(2):477-482.
MacIntyre: But anatomically,
where do you lose mucus glands?
Rubin: You go down until you lose
cartilage, so you’ve got mucus glands
until you’ve got cartilage.
MacIntyre: And how far down is
that? 20. . .?
Rubin: Not that far down. I’m not
sure how far, but I don’t think it’s that
far.

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 PHYSIOLOGY OF AIRWAY MUCUS SECRETION
Rogers: Terminal bronchioles don’t
have cartilage and don’t have glands,
so in general you have glands where
you have cartilage.
Rubin: The corollary to that is that
some of the animal models that are
used don’t have submucosal glands–
typically, mice, rodents. So one of the
reasons we think that there may be no
air lung disease in the CF mouse model
is the complete lack of submucosal
glands, except for a single little sub-
mucosal gland right below the vocal
cords. So there are very significant spe-
cies differences, which makes it hard
to extrapolate some of these things.
Very nicely done, Duncan.
Also, to Neil: There are accumulat-
ing data now that there are conditions
that are associated with decreased mu-
cus secretion that may lead to more
chronic infection inflammation. 1,2
And primary mucus hyposecretion
may actually be pathophysiologic in
some of the diseases that we know of.
But for asthma, in the last couple of
years there’s been an interest in this
entity called “secretory hyperrespon-
siveness” where patients with asthma
are given methacholine as a challenge,
and some of them clearly get a bron-
choconstrictive element and then bron-
chodilate. Others still get a drop, but
don’t respond to bronchodilators.
If you look at this, these are the
patients who appear to respond more
to cholinergic agent by producing
these buckets of mucus, presumably
something may be related to these pa-
tients, whether it’s the presence of neu-
trophil elastase, which can induce this
phenotype, that may lead the really
bad asthmatics to end up drowning in
their secretions, because you’ve shown
that. Have you any more information
on what would make somebody have
a hypersecretory response to these ir-
ritants, as opposed to a bronchospas-
tic response?
1. Henke MO, Renner A, Huber RM, Seeds
MC, Rubin BK. MUC5AC and MUC5B mu-
cins are decreased in cystic fibrosis airway
RESPIRATORY CARE • SEPTEMBER 2007 VOL 52 NO 9
AND PATHOPHYSIOLOGY
secretions. Am J Respir Cell Mol Biol 2004;
31:86-91.
2. Henke MO, Gerrit J, Germann M, Linde-
mann H, Rubin BK. MUC5AC and MUC5B
mucins increase in cystic fibrosis airway se-
cretions during a pulmonary exacerbation.
Am J Respir Crit Care Med 2007;175:816-
821.
Rogers: Yes, that’s a very interest-
ing question. It’s something that fas-
cinates me, and I’ve spoken about it
with some of my clinical colleagues.
There are clearly patients who have a
more bronchospastic response with
less secretion. In contrast, other pa-
tients produce a lot of mucus com-
pared with the smooth muscle con-
traction. I’m not sure why that is,
because the nerves go to the 2 differ-
ent structures, to the airway submu-
cosal glands and the smooth muscle.
I’m not sure why there should be a
difference.
Some patients certainly have “bron-
chorrhea,” which is a Japanese term,
and one we don’t usually use in En-
gland or the USA. Bronchorrhea may
be associated with excessive water se-
cretion. Submucosal glands secrete
water and, in experimental studies,
cholinergic stimulation of glands will
induce mucus secretion and also wa-
ter secretion; this is via interaction with
muscarinic M3 receptors. It could be
that these patients have a polymor-
phism in the receptor whereby they
produce more water in the secretion
than mucus. Bronchorrhea secretions
are excessive and certainly more wa-
tery than a typical mucus secretion,
indicating a preferential stimulation of
water than of mucus. Why that would
be, I don’t know.
One possibility is that there’s a dis-
proportionate change in the glands,
whereby you get an increase in serous
cells, which produce a more watery
secretion, compared with mucous
cells, which produce a more viscous
secretion. Human glands comprise
both serous and mucous acini. In
COPD, there are many patients who
demonstrate a disproportionate in-
crease in mucus cells compared to se-
OF HYPERSECRETION
rous cells. So there is the possibility
of the reverse situation: a dispropor-
tionate increase in serous cells. It
would be very interesting to make a
histological study of the airway glands
of patients with bronchorrhea.
Rubin: I know that Ruben Restrepo
will be talking about adrenergic agents,
but some of us have been interested
that as asthmatics have come in with
this hypersecretion, they may begin
with very watery secretions, very much
the way your nose runs during the al-
lergy season. But during severe
asthma, they develop these massively
viscous secretions, and the concern
might be that this may be a result of
flogging in the airways with the ␤ ago-
nists. You showed a number of years
ago that ␤-adrenergic stimulation pro-
duces a very viscous secretion. And I
wonder if some of our asthmatics who
are up in the critical care unit are do-
ing so because they’ve been given such
massive doses of ␤ agonists.
Rogers: That’s a possibility. One of
the things about ␤ agonists is what
you’ve alluded to already with your
reference to the mouse, is that animals
and human beings respond differently
to drugs, and ␤ agonists are one ex-
ample. It’s very easy in research ani-
mals to show that ␤ agonists stimulate
mucus secretion. ␤ agonists will do it,
␣-adrenergic agonists will do it, and
you can show various interactions.
However, in human airways, it’s much
more difficult to demonstrate a secre-
tory response to ␤ agonists. It may
depend on the distribution of recep-
tors on the cells.
For example, cholinergic stimula-
tion was once considered to induce
submucosal gland secretion from both
mucous and serous acini. In contrast,
␤-receptor stimulation would stimu-
late the mucus cells, whilst ␣-adren-
ergic stimulation causes the serous
cells to secrete. But it depends on the
distribution of the relevant receptors,
and that will presumably have a ge-
netic component. So, theoretically,
1147
 PHYSIOLOGY OF AIRWAY MUCUS SECRETION
there is a scenario where there may be
preferential stimulation of mucus
rather than serous secretion. But I don’t
think that’s been systematically looked
at.
Homnick: I’m interested in this con-
cept of “tethered mucus” in asthma. I
think it’s tethered to the goblet cells,
is that correct?
Rogers: Yes, yes. I’m going to be
showing a slide of that in my next
talk. But we can discuss it now.
Homnick: I’d like to know, what is
the mechanism? Is it incomplete exo-
cytosis, or what is it?
Rogers: Well, that’s a very interest-
ing question. In asthma there’s some-
thing strange about either the mucus
itself, or the secretory process that re-
fuses to release the mucus when it’s
being extruded from the goblet cells.1
There is continuity of mucus between
the lumen and the cells. This incom-
plete release is not found in the air-
ways of patients with COPD. So
there’s something about asthma that
leads to this phenotype. And the ex-
planation by the authors was that in
asthma the airway inflammatory cell
profile comprises Th2 lymphocytes
and eosinophils, whereas in COPD,
macrophages and neutrophils predom-
inate. The macrophages and neutro-
phils produce proteases, including
elastase and matrix metalloproteases.
And the hypothesis is that these pro-
teases cleave the mucus, once it has
been secreted, away from the goblet
cells.
In contrast, lymphocytes and eosin-
ophils do not produce appropriate pro-
teases to cleave away the secreted mu-
cus from the goblet cells— hence the
tethering. But you would have to look
at the kinetics of the system and at
how the COPD protease enzymes ac-
tually work. For example, are they
likely to cleave mucin molecules? Al-
ternatively, it could be something more
fundamental, like a difference in the
1148
AND PATHOPHYSIOLOGY
exocytotic mechanism between
asthma and COPD. But it hasn’t been
explored.
1. Rogers DF. Mucoactive agents for airway
mucus hypersecretory diseases. Respir Care;
2007;52(9):1176-1193.
Restrepo: What is the importance
of the regional distribution of the se-
rous cells or the mucus secretion? The
reason why I ask is because, when
you look at the studies for sympatho-
mimetics and anticholinergics, they al-
ways talk about these regions of in-
terest. And they will divide these areas
of radioaerosol penetration and clear-
ings into peripheral, transitional, and
central regions. It looked to me, based
on this computerized picture, that the
serous cells and the mucus cells don’t
have any homogenous distribution.
Rogers: That distribution is theo-
retically very important. The serous
cells are at the periphery of the gland;
moving in from there are the mucus
cells that are producing mucus; then
there is the collecting duct and cili-
ated duct. Based on this distribution
of the different secretory acini, the the-
ory is that on the outside there are the
serous cells, which produce a more
watery secretion (containing antibac-
terial enzymes). Inside of them are the
mucus cells, which produce a more
viscous secretion (ie, mucin). And the
theory is that the more watery secre-
tion washes the more viscous mucus
secretion into the collecting duct and
out of the top of the gland. In addi-
tion, the glands have got smooth mus-
cle bundles around them, which makes
the glands contract, for example, in
response to cholinergic stimulation.
That contraction, combined with the
more watery secretion flooding over
the more viscous secretion, would help
force the secretions out.
Restrepo: I guess the clinical im-
portance of this distribution is because
the sympathomimetics have the ten-
dency to distribute toward the periph-
ery, which actually correlates very well
RESPIRATORY CARE • SEPTEMBER 2007 VOL 52 NO 9
OF HYPERSECRETION
with the pathological changes of pa-
tients with COPD or chronic obstruc-
tive airway disease.
Rubin: Ruben, I think Dr Rogers
was talking about the periphery in the
center of an individual gland, distrib-
uted throughout the airways . . .
Restrepo: Oh, I’m sorry . . .
Rubin: . . . You’re discussing small
airways having greater ␤ agonist re-
ceptors and proximal to the trachea
having cholinergic receptors, I think,
so when we’re talking periphery, we’re
using the term differently.
Restrepo: I was actually talking
about the lung distribution. When you
have this computerized version of the
distribution of the. . .
Rogers: That was an individual
gland. Professor Bill Whimster cut nu-
merous histological sections through
a human airway, and found that he’d
also fortuitously cut sections through
a submucosal gland. He “recon-
structed” the gland using a computer-
based image analysis system.1
1. Rogers DF. Physiology of airway mucus se-
cretion and pathophysiology of hypersecre-
tion. Respir Care 2007;52(9):1134-1146.
Restrepo: Well, if that is the case,
what is the importance of the lung dis-
tribution of these cells? Are they ho-
mogenously distributed throughout the
lung, or is there any difference on the
regional distribution?
Rogers: That’s an interesting ques-
tion, but it’s not really been addressed
because of the magnitude of the task:
sampling a whole lung to determine
the regional distribution of the glands
would be prohibitively demanding.
However, many years ago, Restrepo
and Heard1,2 did a lot of work with
submucosal glands, but not extensive
investigation of regional distribution
along the airways.
 PHYSIOLOGY OF AIRWAY MUCUS SECRETION
1. Restrepo GL, Heard BE. The size of the
bronchial glands in chronic bronchitis.
J Pathol Bacteriol 1963;85:305-310.
2. Restrepo GL, Heard BE. Mucous gland en-
largement in chronic bronchitis: extent of
enlargement in the tracheo-bronchial tree.
Thorax 1963;18:334-339.
Schechter: I’d like to ask about the
proposition that some patients are mu-
cus hypersecretors. That’s an interest-
ing concept, and you even showed a
slide indicating that there were differ-
ences in mortality, depending upon
how these patients were categorized.
How does one categorize a patient as
a mucus hypersecretor? What criteria
do you use for that classification? Are
there specific criteria, or is it just a
gestalt classification?
Rogers: It was what we might call a
gestalt evaluation. There was a ques-
tionnaire, and one question asked, “Do
you produce a lot of sputum?” They
either did or they didn’t. So that was
RESPIRATORY CARE • SEPTEMBER 2007 VOL 52 NO 9
AND PATHOPHYSIOLOGY
the definition of mucus hypersecre-
tion in the metric. The data from the
Copenhagen Heart Study where the
population of Copenhagen was sam-
pled. Originally, it was primarily a
heart study, and acquired as much in-
formation as they could from every-
body in Copenhagen, mostly by ques-
tionnaire. Professor Jorgen Vestbo and
colleagues looked at the data from the
perspective of respiratory epidemiol-
ogists interested in the respiratory pa-
rameters, one of which was chronic
mucus hypersecretion, and how it re-
lated to parameters such as mortality,
infection, hospitalization.1
1. Vestbo J. Epidemiological studies in mucus
hypersecretion. Novartis Found Symp 2002;
248:3-12.
Schechter: So that creates a prob-
lem with interpretation. Even if there
was some objective measure of se-
cretion that would allow you to cat-
egorize patients as hypersecretors,
OF HYPERSECRETION
the problem would still be that the
underlying disease process rather
that the individual patient character-
istics may be the cause of the mucus
hypersecretion. So the cause of in-
creased mortality might be the dis-
ease that is causing it rather than the
presence or absence of the mucus
per se.
Rogers: I agree. I’m not an epide-
miologist, nor would I want to be; they
have a very difficult job— dealing with
populations is just too complex.
Schechter: Well, this is the point I
am trying to make. We can have in-
teresting discussions that focus at the
molecular and at the cellular level, but
the jump from the cellular level to the
patient outcome level is one that we
must make with caution.
Rogers: Absolutely!
1149