The Role of Mucus in Chronic
Pulmonary Disease*
Adam
Wanner,
M.D.,
Chronic
bronchitis
function
resulting
cilia
and
the
F.C.C.P
is
characterized
from
structural
secretory
hypersecretion
and
interaction
to
the
in
play
a
ciliary
role
excessive
the
airway
lower
natural
exacerbations.
In
compromise
altered
in the
production
and
not
surprising
the
the
mucociliary
apparatus
of the
subject
of intense
investigation.’
agreement
that
that
the
actions
cigarette
fects on mucociliary
responsible
for the
function.
cigarette
has
Some
smoke
of patients
Epidemiologic
airflow.
with
chronic
reported
to
or not productive
term
study
has
obstructive
lung
sputum
22-year
mortality
shown
not only
(eg, FEVL/FVC)
chronic
ciated
of lower
smoke
on
School
are
detrimental
survival
the
to
the
Division
of Medicine,
other
hand,
Miamni.
Disease,
University
and
of physical
lower
to evaluate
maneuvers
airway
di-
secretions
is
objectively.
FEy,.
assorisk
of
Miami
Even
do not have
a major
obstructive
if excessive
lower
airway
effect on the progression
pulmonary
disease
(COPD),
accumulation
FUNCTION
of
mucus
in
the
conducting
airways
is thought
cretion
combined
Both component
have been
shown
to result
from epithelial
hypersewith
a defect
in ciliary
function.
functions
of mucociliary
interaction
to be impaired
in cigarette
smokers
and
chronic
patients
with
of Cigarette
relation
effects
varying
hum,
an
bronchitis.
Snzoke
to
chronic
of long-term
of special
interest.
in the
airways
a
production
was
only
1.35
but
when
corrected
for age, smoking
of Pulmonary
and
excessive
MUCOCILIARY
In
has
survey
of more
than 1 ,000 men has
that the severity
of airflow
obstruction
is correlated
with
mortality,
btmt that
sputum
significant
could
irritants
review
Effects
bronchitis
limits
conflicting.
In patients
On
secretions
inhaled
they
could
transiently
obstruct
the airways
during
acute
exacerbations
and hence
contribute
to morbidity. This possibility
is the subject
of the second
part of
The
be directly
related
to FEy1
whether
cough
is present.2
Likewise,
a longfound
that
death
rates
in chronic
disease
are not significantly
related
production.3
and
ef-
of the mechanisms
and chronic
bron-
disease,
agents
difficult
habits,
secretions
this
chronic
lung
airway
to
There
removing
of chronic
have been
is general
phlegm
production
is also significantly
with
mortality.
The
increased
relative
related
remained
5Frm
data
obstructive
been
to initial
with
at
therefore
chitis-associated
mucociliary
dysfunction
have been
elucidated.
The
first part
of this brief
review
deals
with
this defect.
Another
important
question,
however,
must
be
whether
the presence
of excessive
mucus
in the
airways
agents.
pharmacologic
rected
is the single most
and it is therefore
There
excessive
responses
in the
clearance
airways
from
airway
are currently
no direct,
noninvasive
methods
available
to assess
the quantity
and
distribution
of airway
secretions
in vivo. Indirect
indices
such as cough
frequency,
sputum
volume,
respiratory
function,
and mucociiary
clearance
are nonspecific
and
subject
to misinterpretation.
The clinical
utility
of mucotropic
they
acute
as chronic
implies
an
of cigarette
smoke
the
minor
deposition
airway
secretions.
Cigarette
smoking
common
cause of chronic
bronchitis,
pharmacologic
chronic
only
clinically
definition
of
of
While
have
aerosol
hronic
bronchitis
is defined
productive
cough.
This
abnormality
of
dysfunction.
may
the
appears
of airflow obstruction,
airway function
during
course
addition,
smoke
pathogenesis
secretions
resulting
influence
disruption
to
accumulation
Cigarette
mucociliary
effects
on the
could transiently
C
in
the
airways
of
dys-
defects
combination
leads
hence
airways.
bronchitis-associated
mucociliary
The
impairment
and
lower
critical
by
and functional
apparatus.
of mucociliary
secretions
Obstructive
bronchitis,
exposure
the
to cigarette
mucociliary
smoke
are
There
are typical
histologic
changes
of cigarette
smokers
consisting
of
degrees
of denudation
increase
in the
of the ciliated
epithenumnber
of goblet
cells,
submucosal
gland
hypertrophy,
and squamous
metaplasia.
Morphometric
studies
in smokers
have demonstrated
an increased
quantity
of mucus
in the airway
lumen
without
histologic
evidence
of coexistent
emphysema
or history
of obstructive
whereas
this is not observed
in the
nonsmokers.
Electron
microscopic
ciliated
tained
epithelium
from cigarette
abnormalities
axoneme,
in surgical
lung
smokers
has also
consisting
intracytoplasmic
CHEST
/ 97
of
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compound
microtubular
1990
lung
disease,
lungs
of healthy
examination
of
specimens
revealed
cilia,
doublets,
I Supplement
obciliary
single
and
uS
cilia
within
have
sure
been
observed
in animals
to cigarette
smoke.8’
The
of
periciliary
the
respiratory
cigarette
cigarette
smoke
smokers
mucocihiary
onstrated,
and
sheaths.7
mucosa
be
for one
species
animals
exposed
to
been
clearly
demto the production
in ciliary
beat frequency
of hamsters
exposed
under
cihiary
of cihiary
inactivity
because
this
effect
rats
also
almost
identical
beat frequency,
has been
to cigarette
appears
to
exposed
for
conditions
exhibit
although
with zones
or discoordination.
Examinations
of airway
secretions
in healthy
for long periods
of time;
biochemrevealed
the
presence
of serum
have cihioinhibitory
effects.”
Mucociliary
rette smoke
Interaction:
on mucocihiary
have
investigated
been
discrete
evidence
alters
these
with
aerosol
onset.’2”3
has
after
one
Partial
been
be
Both
the
smoke
mentioned.
For
agents
the
healthy
cihiotoxicity
months
the particulate
underlying
characterized,
inflammatory
reduce
of
in
cessation
for three
week of cessation.
of cigarette
Although
incompletely
recovery
observed
to
impair
of tobacco
to protect
the
animals
goblet
cell
proliferation
induced
mucosa.’4”5
play a role
also
been
reported
to
cigarette
or more,
and
inhibit
but
gaseous
function.
addition
been
of
smoke,
and
the
treat-
smokerespiratory
on
concept
the
might
concerning
hypersecretion
in the
airways
imbalance
In hamsters,
bronchial
been
experimentally
by
of a crude
instillation
or purified
human
human
neutrophil
an early
discharge
secretory
cretions
Cigarette
cell metaplasia.’
contain
an acid-stable
smoke
has
been
proteinase
because
inhibitor
in vitro
airway
secretions
granules
followed
and probably
of smokers
than
secretions
for a neutrophil
Bronchitis
it is difficult
to separate
the
smoke
on mucociliary
transport
the pathophysiologic
changes
bronchitis,
it is useful
to describe
chronic
bronchitis
separately
be present
in exsmokers.
same
apparatus
as those
hypertrophy
and
glands,
an increase
the
chronic
in healthy
direct
effects
from those
of chronic
abnormalities
because
Histologic
in
found
bronchitis
are
smokers
hyperplasia
in the number
of
and
the
submucosal
and redistribution
length
has
been
patients
visible
with
chronic
bronchitis.’
The
respiratory
secretions
is a frequent
finding
in patients
with
in the
chronic
creased
amounts
of bronchial
on pathologic
sections
of the
the
include
goblet
cell
metaplasia
in
of the columnar
epithehium,
metaplasia.2l
A decrease
ciliated
cells
and
the mean
noted
in
they
may also
changes
of the
of goblet
cells,
airways,
atrophy
spotty
squamous
the number
of
also
of
be met in the
to goblet
cell
Although
of cigarette
related
to
mucocihiary
by
also in vivo,
contain
the
elastase/antielastase
imbalance
could
of cigarette
smokers
leading
metaplasia
and mucous
hypersecretion.
in Chronic
of human
elastase.’
can produce
Human
lower
airway
seproteinase
inhibitor.’8
shown
to inhibit
this
airways
Abnormalities
secreinduced
extract
neutrophil
elastase
of secretory
is
in the
pathogenesis
of COPD.
tory cell metaplasia
has
tracheal
be
cigarette
lower
protease-antiprotease
larger
smaller
and
in both
ciliary
airways
of
presence
endoscopic
of
bronchitis,
secretions
and
can
be
inseen
lung.21
Cilia: In vitro examination
of ciliated
lower
airway
epithelial
cells
obtained
by brushings
from
patients
with chronic
bronchitis
has failed
to reveal
an abnormality
in beat frequency.
However,
the in vitro study
of ciliary
function
is of limited
inflammation
Cigarette
might
smoke
the ciliated
cells are
and are not exposed
adenylate
kinase
explain
activity
in ciliated
tracheal
cells of hamsters
exposed
to cigarette
smoke
for up to nine
months.
i6 Because
inhibition
of this enzyme
leads to a decreased
generation of adenosine
triphosphate,
the energy
source
for
12S
based
activity
to
to tobacco
has been
cigarette
in
anti-
shown
exposure
agent
against
This
suggests
that
in mucous
hypersecretion.
that
after
have been
only
of them
deserve
has
ment of rats undergoing
long-term
smoke
with
an anti-inflammatory
shown
and
year
mucociliary
mechanisms
several
and
bulk
of
smoking
mucociliary
phase
example,
tobacco
ciga-
clearance
transport
mechanisms
occur
as early
as one
Mechanisms:
has
of
subjects
mucocihiary
changes
can
smokers
not after
to
effects
in human
transport
techniques.
The
that long-term
cigarette
transport
phase
Long-term
function
marker
indicates
smoking
promising
ciliary
inhibitor
at a lower
concentration
nonsmokers.’
Therefore,
conditions
smokers
have not been carried
out, primarily
because
these
subjects
do not have a productive
cough.
However, mucous
hypersecretion
has been clearly
demonstrated
in the airways
of several
animal
species
exposed
to cigarette
smoke
ical analysis
has
proteins
that might
decreased
smoke-induced
neutrophils
In addition,
year.’#{176}However,
one year
increased
bending,
expected.
The most
and
in human
the presence
of
This has
with respect
dependent
Mucus:
in
cihiary
expochanges
of mucus.
Cilia: A decrease
found
in the airways
smoke
abnormalities
for a long
period
strongly
suggest
dysfunction.
particularly
clearance
Similar
after
long-term
morphologic
a study
bronchitis.n
the discrepancy
involving
In that
informative
suspended
to their
between
rats
study,
value
in an artificial
natural
milieu.
the
human
study
with
experimental
ciliary
motion
was
in vivo, and discoordination
were observed.
and
Role
zonal
of Mucus
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21607/ on 06/17/2017
and
chronic
observed
akinesia
in COPD
since
medium
This may
(Adam
of cilia
Wanner)
Mucus:
and
To our knowledge,
rheologic
the distribution,
properties
of mucus
amount,
within
the
have
not been
studied
in chronic
bronchitis,
extensive
literature
exists
on the biochemistry
rheology
of expectorated
sputum.
Data Ofl this
must
be
interpreted
been
identified
in the
bronchitis,
their
of
function.
has
been
shown
that
at a given
airflow,
the deposition
of 3- and 5-pm
aerosol
is higher
by one to two orders
of magnitude
coated
tubes
than
in
dry
tubes;
that
particles
in mucusthe
airflow
random
have
because
airway
it
ical characteristics
chronic
partly
but
and
subject
impair
models,
contamination
with
saliva
and
the
rapid
physical
alteration
of expectorated
sputum,
and partly
because
normal
respiratory
secretions
for comparison
are virtually impossible
to obtain.
Although
special
biochemwith
caution,
can
In airway
resistance
is higher
in the presence
ofmucous
simulant
than
in the absence
of mucous
simulant;
and that
aerosol
deposition
and airflow
resistance
is higher
for
mucous
simulants
with high viscosity
and low elasticity.5’
A plausible
explanation
for these
findings
is a
of patients
with
secretions
airways
sputum
effect
on
mucociliary
interaction
has not been
established.
In
contrast,
rheologic
abnormalities
of respiratory
secretions
may contribute
to the impairment
of mucus
transport.
viscosity
A deviation
and elasticity
properties
may
from
an ideal
ratio
and changes
in other
prevent
an
optimal
interaction
tween
cilia and mucus.
For example,
higher
sputum
viscosity
and lower values
of sputum
have been
observed
during
exacerbations
bronchitis
rheologic
in vitro
between
rheologic
be-
values
of
elasticity
of chronic
than
during
clinical
stability,
and
such
alterations
have been
shown
to impair
the
transportability
of sputum
on the frog pal-
Mucociliary
inhaled
Interaction:
aerosols
M ucocihiary
and
tracheal
healthy
smokers
tion.
However,
not the same;
ciliary
patients
exhibit
with
in patients
has devel-
with
chronic
an impaired
transport
rates
has
with
been
in young
FEy,.
within
BETWEEN
this
disor-
bronchitis
observed
and
fine-
in smokers
bronchitis
AND
AIRWAY
AIRWAY
than
in
MUCUS
FUNCTION
airflow
and alter aerosol
deposition.
While
excessive
secretions
in the lower airways
can be seen endoscopically and on pathologic
specimens
of the lung,
it has
been
difficult
to determine
the degree
to which
the
COPD
secretions
narrow
the airway
to airflow
obstruction
in whom
other
are also operative.
models
and animals
mechanisms
However,
strongly
was
and
lumen
and
in patients
of airflow
observations
suggest
that
hence
with
limitation
in airway
excessive
aerosol
total
smoke-induced
inversely
increasing
a beneficial
deposition
aerosol
bronchitis
related
to
have
irritants
and
agent.
protect
limit
the
agents
to the airway
possibility,
dogs with
been
shown
Conversely,
the airway
access
compensate
carbachol
These
a thickened
from
inhaled
therapeutic
decreased
responses
However,
obstructive
the distribuairway
must
of sheep.3’
aerosol
to
This has been
examined
mucus
into one or both
The
deposition
mucous
and
siveness
to the bronchoconstrictor
given by inhalation
but not when
When
the
increase
in pulmonary
inhaled
carbachol
was normalized
increase
actually
mucus
by
irritants
or
dose of an
of inhaled
to exhibit
bronchi
with
effect
tissues.
In support
of the latter
S02-induced
chronic
bronchitis
also be taken
into account.
by instilling
artificial
airway
total
adverse
of inhaled
the airway
inhaled
bronchoconstrictors.2
tion of inhaled
aerosol
in the
main
in patients
an
the total lung burden
effect by enhancing
therapeutic
layer could
have
technique.
deposition
could
inhaled
mucous
increased
The change
in airway
geometry
induced
by excessive mucus
could
theoretically
increase
resistance
to
luminal
contribute
subjects
sensitive
of the
RELATIONSHIP
of cigarette
However,
patients
with simple
bronchitis
(FEy,
tile predicted
normal
range)
also had increased
chronic
does not
a similar
been
re-
mucociliary
chronic
degrees
disease
and in normal
control
subjects.u
Total
deposition
was somewhat
higher
in old subjects
Increased
the magnitude
of the impairment
is
a greater
impairment
of tracheal
muco-
and nonsmokers
healthy
smokers.’3
in varying
by the
smokers
the
deposition
and increase
airflow
resisactions
of excessive
airway
mucus
on
and aerosol
deposition
have been confirmed
in
studies3132
aerosol
deposition
in the lung has been
meas-
airway
aerosol
than
under
of
ported
both
tired
simulant
an irregular
mucous
This
would
both
as
bronchitis,
cessation
of smoking
slowing
of mucociliary
clearance;
of mucociliary
transport
has
der.’3’27
Thus,
aerosol
These
airflow
animal
Total
mucous
velocity
oped chronic
reverse
the
impairment
exsmokers
enhance
tance.1
of the
clearance
mucous
surface
markers
are altered
bronchitis.
Once
a subject
and
motion
of airflow,
creating
causes
turbulence.
total
aerosol
deposition
as compared
with
normal
controls,
again suggesting
that excessive
airway
secretion can cause airway
obstniction
that is only detected
assessed
by
with chronic
in
wave
the influence
surface
that
simulant
airway
respon-
carbachol
when
given intravenously.
resistance
after
for the concomitant
in deposition,
airway
responsiveness
was
decreased.
However,
the protective
effect
of
against
inhaled
carbachol
was insufficient
to
for the
deposition.
observations
enhancing
provide
effect
strong,
of
mucus
albeit
on
indirect,
evidence
for airflow
obstruction
and increased
deposition
of inhaled
particulates
(eg, pollutants)
resulting
CHEST
I 97 I 2 I FEBRUARY,
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1990
I Supplement
‘13S
from
excessive
airway
secretions
in
patients
cilia
with
facilitating
bacterial
colonization
of the airway.
the mucociliary
dysfunction
related
cough
and
production
are
bothersome
by
perceived
symptoms.
the
clinician
chitis.
Although
the value
This
treating
by
the
deserves
with
has
been
in the
lower
direct
methods
to assess.
quantifying
airways
after
for
drug
mucus
10
measuring
airway
secretions
at the
function
mucolytic
tests
are
efficacy
airways
production
same
involved
Lack
in airways
of objective
efficacy
necessarily
of
rate
has
as their
abate,
therapy
symptoms
be
abandoned.
should
tests
to tracheal
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14
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1990
I Supplement
15S