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
2
in which high concentrations of Ca nullify the repulsive forces of the highly polyanionic mucin
2
molecules. Upon initiation of secretion and dilution of the Ca , 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 R ESPIRATORY 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 2123, 2007, in Cancun, Street, London, United Kingdom, SW3 6LY. E-mail: duncan.rogers@
Mexico. imperial.ac.uk.

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 PHYSIOLOGY OF AIRWAY MUCUS SECRETION
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, layer 9
(see Fig. 2). It is likely that a thin layer of surfactant lies
between the sol and gel phases 10 (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 airwaysa 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).
1135
 PHYSIOLOGY OF AIRWAY MUCUS SECRETION AND PATHOPHYSIOLOGY OF HYPERSECRETION
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
1136
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.2227 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, 1112, 13, 1518, 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, Kings 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
Gases
MUC 11 Lung, middle ear, thymus, small intestine, pancreas,
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
MUC 16 Conjunctiva, ovary Cysteinyl leukotrienes NR NR
MUC 17 Intestinal cells, conjunctival epithelium Endothelin 0/ NR NR
MUC 18 Prostate Histamine NR NR
MUC 20 Lung, liver, kidney, colon, placenta, prostate Platelet activating factor Yes1 Yes
Prostaglandins 0/ NR NR
Proteinases Yes NR
Purine nucleotides NR NR
Table 3. Human MUC Genes That Produce Secreted, Cysteine-Rich Neural pathways
(Gel-Forming) Mucins
Cholinergic nerves NR NR
Gene Tissue Distribution Cholinoceptor agonists Yes NR
Nicotine Yes NR
MUC 2 Lung, conjunctiva, middle ear, stomach, small 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 submucosal Miscellaneous
glands, esophageal glands, stomach, duodenum,
Epidermal growth factor NR Yes Yes
gall bladder, nasopharynx
( TNF- )
MUC 6 Stomach, duodenum, gall bladder, pancreas, kidney MUC 19
Sensitization followed by Yes Yes
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- ) in
Table 4. Human MUC Genes That Produce Secreted, Cysteine-Poor 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 intragranular Fig. 6. Kinetics of airway mucin secretion. A: Highly polyanionic mucin
2 molecules repel each other to form a tangled network that spreads
concentrations of Ca , which acts as a shield-ing cation.
over the epithelial surface. For packaging into intracellular mucin
Mucin granules are polyanioic, so without the calcium
granules, high concentrations of intragranular Ca 2 act as a shielding
present within the mucin matrix, such close pack-aging could cation to nullify anionic repulsion and allow condensa-tion of the
2
not occur. Upon exocytosis, the Ca is pro-gressively diluted, mucin in the granules. For mucin secretion, after pore formation and
allowing electrostatic expulsion to oc-cur, a process expansion into an omega profile (see Fig. 4), water enters the granule

accelerated by water uptake, resulting in expansion of the
mucin into the airways. This is a normal, homeostatic
process. However, excessive and prolonged exocytosis
results in airway mucus hypersecretion, as seen in respiratory
diseases such as COPD and asthma.
Airway Mucus Hypersecretory Phenotype in COPD
COPD comprises 3 overlapping conditions, namely,
chronic bronchitis (airway mucus hypersecretion), chronic
bronchiolitis (small airways disease), and emphysema (air
space enlargement due to alveolar destruction).39 The fol-
lowing discussion considers the bronchitic component of
COPD. The airways of patients with COPD contain
excessive amounts of mucus40 (see Fig. 3), which is mark-
edly increased above that in control subjects. 41,42 The ex-
cessive luminal mucus is associated with increased amounts
of mucus-secreting tissue. Goblet cell hyperplasia is a car-
dinal feature of chronic bronchitis, 40 with increased num-
bers of goblet cells in the airways of cigarette smokers, either
with chronic bronchitis and chronic airflow limita-tion, 43 or
with or without productive cough.44 Submucosal gland
hypertrophy also characterizes chronic bronchi-tis, 40,41,45,46
and the amount of gland correlates with the amount of
luminal mucus.41
and progressively dilutes out the Ca 2 , with consequent loss of
capacity to nullify anionic repulsion, which allows the mucin to
undergo a Donnan shift and expand out of the cell, in the manner of a
jack-in-the-box. B: Kinetics of mucin expansion. Condensed
intragranular mucin undergoes size ex-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-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.
Airway Mucus Hypersecretory Phenotype in Asthma
Asthma is a chronic inflammatory condition of the air-
ways, characterized by variable airflow limitation that is at
least partially reversible, either spontaneously or with treat-
ment.47,48 It has specific clinical and pathophysiological
features,49 including mucus obstruction of the airways. 50
There is more mucus in the central and peripheral airways in
patients with chronic or severe asthma than in control
subjects.51 The increased luminal mucus reflects an in-crease
in the amount of airway secretory tissue, due to both goblet
cell hyperplasia29,51 and submucosal gland hy-pertrophy,52
although the latter is not characteristic of all patients with
asthma.51
Airway mucus obstruction in asthma is particularly ev-
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
plugs5254 (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 mucins 30 or to
interactions between mucins and plasma, whereby plasma
synergistically increases the viscosity of mucus 60,61 (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
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 AND PATHOPHYSIOLOGY OF HYPERSECRETION
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 doesnt 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
secretionsa 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? Its
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 its 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 its not normal versus ab-normal;
its like normal at rest, nor-mal
hypersecretion, and then abnormal
hypersecretion. Does that make sense?
Rogers: I couldnt agree more with
that. Thats 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. Were inhaling about
12,000 liters of air a day. In central
London, where I work, its bringing
millions upon millions of par-ticulate
matter into the airways on an hourly
basis, and weve got to have airway
mucus. Its 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 youve
got normal mucus secretion, and
youve 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 dont
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 doesnt 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 dont cough mucus.
Rogers: This is the thing. You can
visualize COPD as 3 interlinked
1
Olympic rings set in a triangle. 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 werent producing sputum.
2
They had alveolar destruction, with
big holes in their lungs. So, they
didnt 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 youve got mucus glands
until youve got cartilage.
MacIntyre: And how far down is
that? 20. . .?
Rubin: Not that far down. Im not
sure how far, but I dont think its that
far.

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 PHYSIOLOGY OF AIRWAY MUCUS SECRETION AND PATHOPHYSIOLOGY OF HYPERSECRETION
Rogers: Terminal bronchioles dont
have cartilage and dont 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 dont 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
1,2
chronic infection inflammation. 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
theres 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
dont 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 its 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 youve 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
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.
Rubin: I know that Ruben Restrepo
Rogers: Yes, thats a very interest-
ing question. Its something that fas-
cinates me, and Ive 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. Im 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.
Im not sure why there should be a
difference.
Some patients certainly have bron-
chorrhea, which is a Japanese term,
and one we dont 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 dont know.
One possibility is that theres 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-
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.
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 theyve been given such
massive doses of agonists.
Rogers: Thats a possibility. One of the
things about agonists is what youve
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.
Its 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, its 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 AND PATHOPHYSIOLOGY OF HYPERSECRETION
there is a scenario where there may
be preferential stimulation of mucus
rather than serous secretion. But I
dont think thats been systematically
looked at.
Homnick: Im interested in this con-
cept of tethered mucus in asthma. I
think its tethered to the goblet cells,
is that correct?
Rogers: Yes, yes. Im going to be
showing a slide of that in my next
talk. But we can discuss it now.
Homnick: Id like to know, what is
the mechanism? Is it incomplete exo-
cytosis, or what is it?
Rogers: Well, thats a very interest-
ing question. In asthma theres some-
thing strange about either the mucus
itself, or the secretory process that re-
fuses to release the mucus when its
1 Rogers: That was an individual gland.
being extruded from the goblet cells.
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
theres 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
exocytotic mechanism between
asthma and COPD. But it hasnt 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 dont
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
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, Im sorry . . .
Rubin: . . . Youre discussing small
airways having greater agonist re-
ceptors and proximal to the trachea
having cholinergic receptors, I think,
so when were talking periphery,
were using the term differently.
Restrepo: I was actually talking
about the lung distribution. When
you have this computerized version
of the distribution of the. . .
Professor Bill Whimster cut nu-merous
histological sections through a human
airway, and found that hed also
fortuitously cut sections through a
submucosal gland. He recon-structed
the gland using a computer-based
1
image analysis system.
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: Thats an interesting ques-tion,
but its 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
1,2
and Heard did a lot of work with
submucosal glands, but not extensive
investigation of regional distribution
along the airways.
 PHYSIOLOGY OF AIRWAY MUCUS SECRETION AND PATHOPHYSIOLOGY OF HYPERSECRETION
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: Id like to ask about the
proposition that some patients are mu-
cus hypersecretors. Thats 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 didnt. So that was
RESPIRATORY CARE SEPTEMBER 2007 VOL 52 NO 9
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,
1
infection, hospitalization.
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,
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. Im 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