Clin Physiol Funct Imaging (2014) 34, pp171–177 doi: 10.1111/cpf.

12085

INVITED REVIEW

Mucociliary clearance: pathophysiological aspects

Mathias Munkholm1 and Jann Mortensen1,2
1
Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark and 2Department of
Medicine, The Faroese National Hospital, Torshavn, Faroe Islands

Summary

Correspondence
Jann Mortensen, Department of Clinical
Physiology, Nuclear Medicine & PET,
Rigshospitalet, Copenhagen University Hospital,
DK-2100 Copenhagen Ø, Denmark
E-mail: jann.mortensen@regionh.dk
Accepted for publication
Received 05 April 2013;
accepted 21 August 2013
Key words
cough clearance; diagnostic test; mucociliary
clearance; overview
Mucociliary clearance has long been known to be a significant innate defence
mechanism against inhaled microbes and irritants. Important knowledge has been
gathered regarding the anatomy and physiology of this system, and in recent
years, extensive studies of the pathophysiology related to lung diseases character-
ized by defective mucus clearance have resulted in a variety of therapies, which
might be able to enhance clearance from the lungs. In addition, ways to study in
vivo mucociliary clearance in humans have been developed. This can be used as a
means to assess the effect of different pharmacological interventions on clearance
rate, to study the importance of defective mucus clearance in different lung dis-
eases or as a diagnostic tool in the work-up of patients with recurrent airway
diseases. The aim of this review is to provide an overview of the anatomy, physiol-
ogy, pathophysiology, and clinical aspects of mucociliary clearance and to present
a clinically applicable test that can be used for in vivo assessment of mucociliary
clearance in patients. In addition, the reader will be presented with a protocol for
this test, which has been validated and used as a diagnostic routine tool in the
work-up of patients suspected for primary ciliary dyskinesia at Rigshospitalet,
Denmark for over a decade.

used in the assessment and diagnosis of patients with defects

Introduction
When breathing, inhaled particles such as dust and bacteria
inevitably reach the conducting airways. As a respond to this
constant threat of inflammation and infection the airways have
evolved different innate defence mechanisms (Wanner et al.,
1996). Mucociliary clearance is known to be of particular
importance in this first line of defence, which becomes clearly
evident in patients with defects related to this system such as
patients with cystic fibrosis or primary ciliary dyskinesia as
these patients typically present themselves with recurrent
infections of the airways (Robinson et al., 2000; Knowles &
Boucher, 2002; Sagel et al., 2011). In recent years, our under-
standing of the composition and function of this important
defence mechanism has grown, and possible ways to evaluate
as well as enhance mucociliary clearance are currently being
investigated. (Yoo & Koh, 2004; Marthin et al., 2007; Amirav
et al., 2009).
The aim of this review is to give an overview of the anat-
omy, physiology, pathophysiology, and clinical aspects related
to mucociliary clearance and to describe a method that can be
of the mucociliary system.
Anatomy and physiology related to
mucociliary clearance
The cilia
In humans, cilia are found lining the respiratory tract includ-
ing the middle ear and the sinuses, the ductuli efferentes of
males, the Fallopian tubes of females, and the ependyma of
the brain (Meeks & Bush, 2000). Each cilium is about 6 lm
long and has a diameter of 250 nm. The amount of cilia in
the airways is at the level of 109 cilia per cm2 usually being
longer and denser packed in the larger respiratory airways
than in the bronchioles (Livraghi & Randell, 2007). The inner
cytoskeletal structure of the cilia called the axoneme has a dis-
tinctive 9 + 2 microtubule structure as well as some important
microtubular-associated proteins some of which can be seen
with electron microscopy (Fig. 1). They consist of outer and
inner dynein arms, the so-called radial spokes that link the

© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 34, 3, 171–177 171
172 Mucociliary clearance: pathophysiological aspects, M. Munkholm and J. Mortensen
inner microtubules with the outer ones, and the nexin links
linking the outer microtubules to one another (Meeks & Bush,
2000). Especially the dynein arms have been extensively stud-
ied and are known to be essential for normal ciliary move-
ment generated by ATP hydrolyses (Porter & Johnson, 1989).
The function of the cilia in the respiratory tract is to beat in
a synchronized manner thereby propelling mucus as well as
substances trapped within the mucus to the pharynx where
they will be swallowed (Wanner et al., 1996). In health, this
works effectively. However, in a variety of airway diseases, it
will be insufficient, and to a great extent these patients then
have to rely on cough clearance, which means the ability
to shift mucus towards the pharynx by means of coughing.
Both of these clearing mechanisms can be disrupted in differ-
ent ways thus leaving the patient vulnerable to infection
(Meeks & Bush, 2000; Randell & Boucher, 2006; Bennett
et al., 2010).
The mucus layer
Apart from the numerous ciliated cells, the epithelial lining of
the intrapulmonary airways consists mainly of secretory cells.
These cells release different antimicrobial molecules (defen-
sins, lysozyme and IgA), immunomodulatory molecules (e.g.
cytokines) and large glycoproteins called mucins that bind
considerable amounts of water whereby the deformable gel
known as mucus is generated (Evans et al., 2010). The mucus
is lifted away from the cilia by the periciliary liquid layer,
which has two main functions. Because of its low viscosity, it
allows the cilia to beat rapidly, and it prevents the glycopro-
teins of the mucus layer from adhering to the glycocalyx of
the epithelial apical membrane (Knowles & Boucher, 2002).
In healthy individuals, mucus from the airways contains
97% water and only 3% solids of which mucins constitute
around 30% (the rest is non-mucin proteins, lipids, salts and
cellular debris). With this composition, the mucus will have a
consistency resembling egg white and can easily be cleared
from the airways by the ciliary beating. However, this balance
of hydration can be disrupted either by mucin hypersecretion
or dysregulation of the volume of surface liquid resulting in
thicker and more elastic mucus, which will be harder to clear
from the airways (Fahy & Dickey, 2010).
Because of the large amount of water contained in the
mucus layer, it serves as a buffer for the periciliary liquid
© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 34, 3, 171–177
Figure 1 Structure of a normal cilium as
seen under an electronic microscope.
layer so that this layer can maintain its volume during physio-
logical variations of airway hydration (Tarran et al., 2001).
Recently, Button et al. (2012) proposed a more detailed
explanation of the composition of the periciliary liquid layer
formerly thought to consist mainly of water. According to this
new theory, the periciliary liquid layer is occupied by large
amounts of mucins and large glycoproteins both of which are
tethered to the cilia thereby creating a fine mesh. This pre-
vents larger molecules such as inhaled particles and mucins of
the mucus layer from entering the periciliary liquid layer.
Thus, as opposed to the former so-called gel-on-water model,
this new theory (gel-on-brush model) can explain why the
mucus layer and the periciliary liquid layer can exist in such
close proximity without getting mixed up. In addition, this
theory is better at explaining the changes seen in the two lay-
ers in relation to dehydration or excess hydration of the
airway surface. For a more detailed explanation of the gel-
on-brush model, the reader is encouraged to study the article
by Button et al. (2012).
Pathophysiological and clinical aspects of
mucociliary clearance
There are two main reasons why mucociliary clearance could
be hampered. Either the movements of the cilia can be hin-
dered directly, for example by genetic defects in central pro-
teins of the axoneme or by temporary dysfunction caused by
infection or environmental influences (Reimer et al., 1980;
Afzelius, 2004; Escudier et al., 2009; Wang et al., 2012); or
the mucus layer can constitute the main problem when dehy-
dration of the mucus leads to increased viscosity whereby the
ciliary clearance becomes ineffective. Moreover, such dehydra-
tion can cause the periciliary liquid layer to shrink causing the
cilia to become squeezed underneath the mucus layer imped-
ing their movement. If the periciliary liquid layer gets increas-
ingly thin, the mucin glycoproteins of the mucus will bind
to the epithelial glycocalyx much like Velcro impeding both
ciliary and cough clearance radically (Knowles & Boucher,
2002; Boucher, 2007; Fahy & Dickey, 2010).
Aetiology and classification
Conditions directly affecting the movement of the cilia of the
respiratory tract are traditionally divided into primary and
 Mucociliary clearance: pathophysiological aspects, M. Munkholm and J. Mortensen 173

secondary ciliary dyskinesia (PCD and SCD). PCD is usually an
autosomal recessive disorder, but occasionally X-linked or
autosomal-dominant transmission has been reported as well. It
is both phenotypically and genetically a heterogeneous condi-
tion presumably reflecting the molecular complexity of the
axoneme whereby mutations in many different genes can
cause defects of the ciliary movement. To this date, only a
few known mutations have been confirmed to cause PCD; and
as these mutations are causative only in around 25% of the
diagnosed patients, genetic testing is still far from universally
applicable (Chodhari et al., 2004; Bush et al., 2007). Today,
the diagnosis primarily rests on clinical presentation of the
patient (recurring sinopulmonary infections from birth), nasal
NO measurements (low nasal NO points towards PCD), elec-
tron microscopy of ciliary ultrastructure, and microscopy of
ciliary beat pattern and frequency (Bush et al., 2007). In some
centres, these tests are supplemented by other tests, for exam-
ple pulmonary radioaerosol mucociliary clearance, which is
described in detail later in this review.
Secondary ciliary dyskinesia on the other hand includes a
variety of temporary, acquired defects of ciliary movement,
which can be caused by viral or bacterial infection or by air
pollutants such as ozone, aldehydes or cigarette smoke. In
some instances, the condition can be hard to differentiate from
PCD due to overlapping findings in the tests meant for diagnos-
ing PCD (Carson et al., 1980; Reimer et al., 1980; Rautiainen
et al., 1992; Calderon-Garciduenas et al., 2001; Randell &
Boucher, 2006; Livraghi & Randell, 2007; Wang et al., 2012).
Apart from these conditions directly affecting the cilia,
many other diseases have abnormal mucociliary clearance as a
central part of their pathogenesis. For example, this applies
to cystic fibrosis, which is caused by mutations in the gene
encoding the Cl channel known as CFTR. This defect leads to
dehydration of the mucus layer and shrinkage of the pericili-
ary liquid layer, thereby impeding mucus clearance by both
ciliary beating and coughing as described earlier (Fahy & Dic-
key, 2010).
Impaired mucociliary clearance is also seen in patients with
asthma and chronic obstructive pulmonary disease. An impor-
tant part in their pathogenesis is thought to be the hypersecre-
tion of mucin leading to excessive amounts of mucus with an
increased viscosity. This rubbery mucus is hard to clear from
the airways and in severe cases can end up forming mucus
plugs whereby infection or localized atelectasis is likely to fol-
low (Randell & Boucher, 2006; Fahy & Dickey, 2010). An
overview of different conditions affecting mucociliary clear-
ance is presented in Table 1.
Clinical aspects
The primary symptoms of impaired mucociliary clearance are
productive cough and dyspnoea. Dyspnoea is a result of
mucus obstructing airflow in numerous airways, which in
cases of total obstruction can lead to atelectasis (Hogg, 2004;
Bosse et al., 2010; Fahy & Dickey, 2010). As described earlier,
coughing can to some extent substitute for impeded ciliary
clearance. This may help explain why diseases in which only
the cilia are involved (such as PCD) tend to be less severe than
those primarily caused by dehydration of the mucus (e.g. cys-
tic fibrosis) as this will impede both ciliary and cough clear-
ance (Knowles & Boucher, 2002; Livraghi & Randell, 2007;
Fahy & Dickey, 2010).
Recurring sinopulmonary infections starting in early child-
hood are almost universal in patients with substantial and

Table 1 Characteristics of different conditions affecting mucociliary clearance.

Primary ciliary Secondary ciliary Chronic obstructive

dyskinesia dyskinesia Cystic fibrosis pulmonary disease Asthma

Aetiology Genetic defect in gene Temporary Genetic defect in gene Multifactorial disease Multifactorial disease
related to movement dysfunction of the encoding the Cl Smoking is the most Atopi or bronchial
of the cilia cilia caused by viral channel known as common cause hyperresponsiveness
or bacterial infection CFTR plays an important part
or by air pollutants
Primary causes Immotile or dysmotile Temporarily immotile Dehydration of the Goblet cell metaplasia Goblet cell metaplasia
of defective cilia or dysmotile cilia airway mucus and hyperplasia and leading to
mucociliary leading to increased submucosal gland hypersecretion of
clearance mucus viscosity enlargement leading mucin. Thereby
Shrinkage of the to hypersecretion of mucus viscosity is
periciliary liquid mucin. Thereby increased
layer impeding mucus viscosity and Narrowing of airways
ciliary movement amount is increased combined with
rubbery mucus can
form mucus plugs
obstructing
mucociliary clearance

(Afzelius, 2004; Soler-Cataluna et al., 2005; Kondo et al., 2006; Randell & Boucher, 2006; Livraghi & Randell, 2007; Mall, 2008; Fahy & Dickey,
2010; Lommatzsch, 2012).

© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 34, 3, 171–177
174 Mucociliary clearance: pathophysiological aspects, M. Munkholm and J. Mortensen
permanent defects of mucociliary clearance (Sagel et al.,
2011). At least partially, this is thought to be a result of
mucus plugs blocking smaller airways thereby creating a local
environment that promotes bacterial growth (Worlitzsch et al.,
2002; Livraghi & Randell, 2007). Such long-term localized
infection leads to mucus gland hypertrophy and epithelial
damage further impairing mucociliary clearance from that
area. Eventually, the inflammation can lead to bronchiectasis
characterized by permanent dilation of the airway and thick-
ening of the bronchial wall. Because of these changes, areas
like this can function as a seedbed for future infections
(Bilton, 2008; Ilowite et al., 2008; Javidan-Nejad & Bhalla,
2009; King, 2009; Goeminne & Dupont, 2010). Recurring
infections are thought to be the main reason why, in time,
these patients develop a decrease in lung function. However,
the rate of lung function decline of the individual patients can
be difficult to foresee, but tend to appear earlier and to be
more profound in patients with cystic fibrosis compared with
patients with PCD (Livraghi & Randell, 2007). Nevertheless,
all severe chronic diseases involving defective mucociliary
clearance result in substantial morbidity in terms of dyspnoea,
recurring sinopulmonary infections, and frequent and produc-
tive coughs. The amount, frequency and appearance of the
sputum will vary according to the disease, but generally with
increased infection, the amount increases and it gets more
viscous and purulent as often seen in patients with cystic
fibrosis. The close relationship with infection is also evident
in patients with acute infectious exacerbation of chronic
obstructive pulmonary disease where large amounts of dark/
green and viscous sputum are produced (Rubin, 2009; Fahy &
Dickey, 2010; Miravitlles et al., 2010; Stenbit & Flume, 2011).
In severe cases of chronic defective mucociliary clearance,
the decline of lung function can lead to the need for lung
transplantation or early mortality (Livraghi & Randell, 2007;
Marthin et al., 2010).
Measurement of mucociliary clearance
Radioaerosols can be used to study the mucociliary transport
from the ciliated airways. Insoluble 99mTc labelled colloids are
inhaled and deposited, and their subsequent clearance can be
assessed by scintigraphy. If the person does not cough during
the study period, the radioaerosol clearance reflects mucociliary
clearance. However, if the person does cough during measure-
ment, the measured clearance will reflect a combination of mu-
cociliary clearance and cough clearance. Hence, pulmonary
radioaerosol clearance studies can be used for assessment of mu-
cociliary clearance, cough clearance or the combination of both.
Most pulmonary radioaerosol mucociliary clearance studies are
performed to investigate a possible link between mucociliary
dysfunction and pathophysiology of lung diseases or pharmaco-
logical challenges to the mucociliary apparatus. However, as ref-
erence values are available, the technique can also be used as a
diagnostic tool to assess if a person’s mucociliary clearance is
within or outside reference limits. In a patient with recurrent
© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 34, 3, 171–177
infections and/or bronchiectasis, a universal and very slow mu-
cociliary clearance can reflect an underlying PCD, while this is
excluded if mucociliary clearance is normal or only regionally
abnormal. In this case, the radioaerosol is cleared normally from
the lung except at a few sites corresponding to the bronchiecta-
sis (Marthin et al., 2007).
There are only about ten centres in the world that regularly
perform pulmonary radioaerosol mucociliary clearance studies,
and only few of these use it as a diagnostic tool on a routine
basis. There is considerable variation in the specific techniques
applied considering choice of radiocolloid (e.g. albumen/sul-
phur colloids), aerosol generator and particle size, inhalation
technique (slow/fast, depth), gamma camera acquisition per-
iod (0–2, 0–6, 0–24 h) and type (posterior/anterior, static/
dynamic/SPECT), characterization of initial deposition (cen-
tral/peripheral ratio, penetration index), etc. The variation in
the applied techniques reflects the lack of consensus upon the
‘best’ method and that the choice of ‘best’ method depends
upon the specific aim of the test. For example, assessment of
mucociliary clearance from the small and large airways
needs different deposition patterns and timing of acquisition
(Bennett et al., 2010).
The simplified pulmonary radioaerosol mucociliary clearance
technique described in Table 2 has been used as a diagnostic
routine tool in the work-up of patients suspected for PCD in
30–40 patients yearly for more than a decade at Rigshospitalet,
Denmark. This radioaerosol clearance technique was originally
validated in three sequentially performed studies. First, it was
used in a cross-sectional study in patients with established PCD.
Second, it was applied in a prospective blinded trial of patients
referred for suspicion of PCD. Third, it was implemented in a
trial using the method in PCD workup. The results were com-
pared with nasal ciliary motility studies, electron microscopy of
cilia and the final clinical diagnosis (Marthin et al., 2007).
Can mucociliary clearance be enhanced?
As described, mucociliary clearance is crucial in the pathogen-
esis of many different diseases, which has led to the develop-
ment of a wide range of therapies seeking to augment the
clearance of mucus from the airways. Roughly, these therapies
can be divided into two categories as seen below.
Physiotherapeutic regimens
These include postural drainage, positive expiratory pressure,
forced expiration techniques, voluntary coughing and regular
exercise. They are primarily thought to augment clearance
mechanisms largely independent of ciliary function. Thus,
even though these therapies have shown convincing positive
results in a variety of diseases with dysfunctional mucociliary
clearance, this is not thought to be a result of an increase in
ciliary clearance; more it is a result of finding ways to circum-
vent this defect (Mortensen et al., 1991a; Pryor, 1999; Lester
& Flume, 2009).
 Mucociliary clearance: pathophysiological aspects, M. Munkholm and J. Mortensen 175

Table 2 Example of a pulmonary radioaerosol mucociliary clearance protocol.

Preliminary procedure
20 inhalations (slow inspiration/forced expiration) of 99mTc-albumin colloid aerosol (Venticoll, Solco)
Gamma camera measurements of pulmonary radioactivity
Repeated dynamic and static acquisitions for 2 h
A static acquisition after 24 h
A 81mKr ventilation acquisition of the ventilated lung area
Reference values
Lung retention at 1 and 2 h is compared with predicted values calculated from penetration index, age and sex using own reference equations
(Mortensen et al., 1994)
Interpretation
Interpretation is based on visual analysis and quantitative analysis of the radioactivity retention based on the following three measurements
1) Is the bolus transport in the trachea normal?
2) Is lung retention at 1 and 2 h within the predicted values?
3) Is there no focal retention in the airways after 24 h? (Focal retention indicates regional/general impaired mucociliary clearance)
Conclusion of a test
Test results can typically be divided in the following 4 main groupings
Normal mucociliary clearance
It is the case, if all three measurement parameters are normal. Thereby, both PCD and secondary mucociliary defects can be excluded
Abnormal mucociliary clearance
It is the case, if all three measurement parameters are abnormal. This is compatible both with PCD and SCD. Subsequently, nasal ciliary
function testing and electron microscopy can be used to discriminate between these entities
Regional abnormal mucociliary clearance
It is the case, if 1) and 2) are normal while 3) is abnormal. It is compatible with focal SCD, for example bronchiectasis, but excludes PCD
Inconclusive test
It can be due to coughing, too peripheral initial distribution or inconsistency between the three measurement parameters

needed in order to determine the potential usefulness of each

Pharmacological therapies
In recent years, great interest in finding ways to directly stimu-
late mucociliary clearance has led to many different new thera-
pies. Some focus on changing the viscosity of the airway
mucus thereby making it easier to clear either by ciliary move-
ment or by coughing. This includes inhalation of aerosols of
hypertonic saline or a dry powder formulation of mannitol,
which promotes the flux of water across the lung surface. Other
approaches for changing mucus viscosity have been to directly
modulate chloride or sodium channels of the lung in order to
increase hydration of the mucus. Yet another approach has
been to degrade extracellular DNA found in the mucus by inha-
lation of rhDNAse, thereby reducing the mucus viscosity (Yoo
& Koh, 2004; Rogers, 2005; Amirav et al., 2009). Others have
tried to directly stimulate the beating of cilia by b-adrenergic
agents. This has long been known to increase in vitro ciliary beat
frequency, and numerous studies have also shown enhance-
ment of in vivo mucociliary clearance in patients with various
airway diseases although this improvement is generally more
pronounced in the normal lung (Mortensen et al., 1991b; Ben-
nett, 2002; Yoo & Koh, 2004). In addition, some interesting
new therapies, primarily explored in relation to cystic fibrosis,
focus on assisting or repairing the production of certain defec-
tive proteins in epithelial cells of the airways. This kind of treat-
ment is still only on an experimental basis, but shows exciting
potential for future enhancement of chronic defects of mucocil-
iary clearance (Amirav et al., 2009).
In conclusion, several studies have provided preliminary
data supporting the ability of different types of agents to aug-
ment mucociliary clearance. However, further investigation is
therapy in the broad array of different diseases.
Conclusion
Mucociliary clearance is an important airway defence mecha-
nism. Unfortunately, it can be affected by exogenous chal-
lenges such as smoke, dust and infections, and reduced
mucociliary transport is an important part of the pathophysiol-
ogy of many lung diseases.
Today, many different mechanisms have been elucidated
whereby mucociliary clearance can be hampered, and this has
led to a wide variety of approaches to augment the impeded
clearance. However, further investigation is needed before the
usefulness of each therapy in the broad array of different dis-
eases can be determined.
In addition, still many questions remain unanswered espe-
cially regarding the specific gene defects underlying conditions
such as PCD. Further knowledge within this field might facili-
tate the development of therapies able to correct chronic
defects of mucociliary clearance.
Today, scintigraphic clearance of inhaled insoluble radio-
aerosols can be used in the study of mucociliary clearance to
assess the pathophysiology of lung diseases and the impor-
tance of mucociliary dysfunction in this regard. This means
that the procedure can be used as a clinical diagnostic tool in
work-up of patients with recurrent airway infections. Further-
more, effects of physical or pharmacological interventions on
mucociliary transport can be studied by way of this technique,
which may be useful in the clinical testing of novel therapies
aiming to augment mucociliary clearance.

© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 34, 3, 171–177
176 Mucociliary clearance: pathophysiological aspects, M. Munkholm and J. Mortensen
Conflict of interest
The authors declare no conflict of interest.
Reference
Afzelius BA. Cilia-related diseases. J Pathol
(2004); 204: 470–477.
Amirav I, Cohen-Cymberknoh M, Shoseyov
D, Kerem E. Primary ciliary dyskinesia:
prospects for new therapies, building on
the experience in cystic fibrosis. Paediatr
Respir Rev (2009); 10: 58–62.
Bennett WD. Effect of beta-adrenergic agon-
ists on mucociliary clearance. J Allergy Clin
Immunol (2002); 110: S291–S297.
Bennett WD, Daviskas E, Hasani A, Mortensen J,
Fleming J, Scheuch G. Mucociliary and cough
clearance as a biomarker for therapeutic
development. J Aerosol Med Pulm Drug Deliv
(2010); 23: 261–272.
Bilton D. Update on non-cystic fibrosis bron-
chiectasis. Curr Opin Pulm Med (2008); 14:
595–599.
Bosse Y, Riesenfeld EP, Pare PD, Irvin CG. It’s
not all smooth muscle: non-smooth-muscle
elements in control of resistance to airflow.
Annu Rev Physiol (2010); 72: 437–462.
Boucher RC. Cystic fibrosis: a disease of vul-
nerability to airway surface dehydration.
Trends Mol Med (2007); 13: 231–240.
Bush A, Chodhari R, Collins N, Copeland F,
Hall P, Harcourt J, Hariri M, Hogg C, Lucas J,
Mitchison HM, O’Callaghan C, Phillips G. Pri-
mary ciliary dyskinesia: current state of the
art. Arch Dis Child (2007); 92: 1136–1140.
Button B, Cai LH, Ehre C, Kesimer M, Hill
DB, Sheehan JK, Boucher RC, Rubinstein M.
A periciliary brush promotes the lung
health by separating the mucus layer from
airway epithelia. Science (2012); 337: 937–
941.
Calderon-Garciduenas L, Valencia-Salazar G,
Rodriguez-Alcaraz A, Gambling TM, Garcia
R, Osnaya N, Villarreal-Calderon A, Devlin
RB, Carson JL. Ultrastructural nasal pathol-
ogy in children chronically and sequentially
exposed to air pollutants. Am J Respir Cell Mol
Biol (2001); 24: 132–138.
Carson JL, Collier AM, Hu SC. Ultrastructural
observations on cellular and subcellular
aspects of experimental Mycoplasma pneu-
moniae disease. Infect Immun (1980); 29:
1117–1124.
Chodhari R, Mitchison HM, Meeks M. Cilia,
primary ciliary dyskinesia and molecular
genetics. Paediatr Respir Rev (2004); 5: 69–76.
Escudier E, Duquesnoy P, Papon JF, Amselem
S. Ciliary defects and genetics of primary
ciliary dyskinesia. Paediatr Respir Rev (2009);
10: 51–54.
© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 34, 3, 171–177
Evans SE, Xu Y, Tuvim MJ, Dickey BF. Induc-
ible innate resistance of lung epithelium to
infection. Annu Rev Physiol (2010); 72: 413–
435.
Fahy JV, Dickey BF. Airway mucus function
and dysfunction. N Engl J Med (2010); 363:
2233–2247.
Goeminne P, Dupont L. Non-cystic fibrosis
bronchiectasis: diagnosis and management
in 21st century. Postgrad Med J (2010); 86:
493–501.
Hogg JC. Pathophysiology of airflow limita-
tion in chronic obstructive pulmonary dis-
ease. Lancet (2004); 364: 709–721.
Ilowite J, Spiegler P, Chawla S. Bronchiectasis:
new findings in the pathogenesis and treat-
ment of this disease. Curr Opin Infect Dis
(2008); 21: 163–167.
Javidan-Nejad C, Bhalla S. Bronchiectasis.
Radiol Clin North Am (2009); 47: 289–306.
King PT. The pathophysiology of bronchiecta-
sis. Int J Chron Obstruct Pulmon Dis (2009); 4:
411–419.
Knowles MR, Boucher RC. Mucus clearance as
a primary innate defense mechanism for
mammalian airways. J Clin Invest (2002);
109: 571–577.
Kondo M, Tamaoki J, Takeyama K, Isono K,
Kawatani K, Izumo T, Nagai A. Elimination
of IL-13 reverses established goblet cell
metaplasia into ciliated epithelia in airway
epithelial cell culture. Allergol Int (2006); 55:
329–336.
Lester MK, Flume PA. Airway-clearance ther-
apy guidelines and implementation. Respir
Care (2009); 54: 733–750; discussion
751–733.
Livraghi A, Randell SH. Cystic fibrosis and
other respiratory diseases of impaired
mucus clearance. Toxicol Pathol (2007); 35:
116–129.
Lommatzsch M. Airway hyperresponsiveness:
new insights into the pathogenesis. Semin
Respir Crit Care Med (2012); 33: 579–587.
Mall MA. Role of cilia, mucus, and airway
surface liquid in mucociliary dysfunction:
lessons from mouse models. J Aerosol Med
Pulm Drug Deliv (2008); 21: 13–24.
Marthin JK, Mortensen J, Pressler T, Nielsen
KG. Pulmonary radioaerosol mucociliary
clearance in diagnosis of primary ciliary
dyskinesia. Chest (2007); 132: 966–976.
Marthin JK, Petersen N, Skovgaard LT, Niel-
sen KG. Lung function in patients with pri-
mary ciliary dyskinesia: a cross-sectional
and 3-decade longitudinal study. Am J Respir
Crit Care Med (2010); 181: 1262–1268.
Meeks M, Bush A. Primary ciliary dyskinesia
(PCD). Pediatr Pulmonol (2000); 29: 307–316.
Miravitlles M, Marin A, Monso E, Vila S, de la
Roza C, Hervas R, Esquinas C, Garcia M,
Millares L, Morera J, Torres A. Colour of
sputum is a marker for bacterial colonisa-
tion in chronic obstructive pulmonary dis-
ease. Respir Res (2010); 11: 58.
Mortensen J, Falk M, Groth S, Jensen C. The
effects of postural drainage and positive
expiratory pressure physiotherapy on tra-
cheobronchial clearance in cystic fibrosis.
Chest (1991a); 100: 1350–1357.
Mortensen J, Groth S, Lange P, Hermansen F.
Effect of terbutaline on mucociliary clearance
in asthmatic and healthy subjects after inhala-
tion from a pressurised inhaler and a dry pow-
der inhaler. Thorax (1991b); 46: 817–823.
Mortensen J, Lange P, Nyboe J, Groth S. Lung
mucociliary clearance. Eur J Nucl Med (1994);
21: 953–961.
Porter ME, Johnson KA. Dynein structure and
function. Annu Rev Cell Biol (1989); 5:
119–151.
Pryor JA. Physiotherapy for airway clearance in
adults. Eur Respir J (1999); 14: 1418–1424.
Randell SH, Boucher RC. Effective mucus
clearance is essential for respiratory health.
Am J Respir Cell Mol Biol (2006); 35: 20–28.
Rautiainen M, Nuutinen J, Kiukaanniemi H,
Collan Y. Ultrastructural changes in human
nasal cilia caused by the common cold and
recovery of ciliated epithelium. Ann Otol Rhi-
nol Laryngol (1992); 101: 982–987.
Reimer A, Klementsson K, Ursing J, Wretlind
B. The mucociliary activity of the respira-
tory tract. I. Inhibitory effects of products
of Pseudomonas aeruginosa on rabbit tra-
chea in vitro. Acta Otolaryngol (1980); 90:
462–469.
Robinson M, Eberl S, Tomlinson C, Daviskas
E, Regnis JA, Bailey DL, Torzillo PJ,
Menache M, Bye PT. Regional mucociliary
clearance in patients with cystic fibrosis.
J Aerosol Med (2000); 13: 73–86.
Rogers DF. Mucociliary dysfunction in COPD:
effect of current pharmacotherapeutic
options. Pulm Pharmacol Ther (2005); 18: 1–8.
Rubin BK. Mucus, phlegm, and sputum in
cystic fibrosis. Respir Care (2009); 54: 726–
732; discussion 732.
Sagel SD, Davis SD, Campisi P, Dell SD.
Update of respiratory tract disease in

children with primary ciliary dyskinesia.
Proc Am Thorac Soc (2011); 8: 438–443.
Soler-Cataluna JJ, Martinez-Garcia MA, Roman
Sanchez P, Salcedo E, Navarro M, Ochando
R. Severe acute exacerbations and mortality
in patients with chronic obstructive pulmo-
nary disease. Thorax (2005); 60: 925–931.
Stenbit AE, Flume PA. Pulmonary exacerba-
tions in cystic fibrosis. Curr Opin Pulm Med
(2011); 17: 442–447.
Tarran R, Grubb BR, Gatzy JT, Davis CW,
Boucher RC. The relative roles of passive
© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 34, 3, 171–177
Mucociliary clearance: pathophysiological aspects, M. Munkholm and J. Mortensen 177
surface forces and active ion transport in
the modulation of airway surface liquid vol-
ume and composition. J Gen Physiol (2001);
118: 223–236.
Wang LF, White DR, Andreoli SM, Mulligan
RM, Discolo CM, Schlosser RJ. Cigarette
smoke inhibits dynamic ciliary beat fre-
quency in pediatric adenoid explants. Otolar-
yngol Head Neck Surg (2012); 146: 659–663.
Wanner A, Salathe M, O’Riordan TG. Muco-
ciliary clearance in the airways. Am J Respir
Crit Care Med (1996); 154: 1868–1902.
Worlitzsch D, Tarran R, Ulrich M, Schwab U,
Cekici A, Meyer KC, Birrer P, Bellon G, Ber-
ger J, Weiss T, Botzenhart K, Yankaskas JR,
Randell S, Boucher RC, Doring G. Effects of
reduced mucus oxygen concentration in
airway Pseudomonas infections of cystic
fibrosis patients. J Clin Invest (2002); 109:
317–325.
Yoo Y, Koh YY. Current treatment for pri-
mary ciliary dyskinesia conditions. Expert
Opin Pharmacother (2004); 5: 369–377.