Aimah af Otology, Rhinohsy & Larynnology ll5l9lSuppl l%;2(l-26.

© 2006 Annals [\iblishitig Cotnpany. All rights reserved.

Sinonasal Mucociliary Clearance in Health and Disease

Noam A. Cohen, MD. PhD

Although much has beeti elucidated in the past 170 years concerning the precise mechanism of ciliary function in the
healthy or diseased human respiratory system, significant questions remain. The first description of ciliary action is cred-
ited toSharpey in 1835. However, the importance of mucosal function was not apparent until Hilding's investigations of
the postsurgical canine sinus demonstrated scar formation and disruption of mucociliary clearance. Subsequently, several
techniques for mucosal coverage of exposed bone, most notably by Sewall and Boyden. were reported. The underlying
physiology explaining the importance of the mucosa and the concept of mucosal preservation became apparent with the
description of the sinonasal mucociliary flow patterns by Messerklinger: and thus the restoration of natural sinus physiol-
ogy, ie. mucociliary clearance, became the goal of both medical and surgical treatment of sinonasal inflammatory disease.
Clearance of benign and pathological substances in the mucus is governed by the propulsive force of the beating cilia and
the physical characteristics of the overlying mucus. The respiratory cilia continually beat in a coordinated fashion, and in
times of stress (eg. exercise. infecti(>n. or fever) ciliary beat frequency increases to accelerate mucus clearance. Thus, up-
per airway ciliary motility is under dynamic modulation. Multiple investigations incontrovertibly demonstrate a marked
decrease in sinonasal mucociliary clearance in patients with chronic rhinosinusitis. Possible explanations for this finding
are 1) a reduced basal ciliary beat frequency. 2) an alteration of the viscoelastic properties of airway secretions, and/or 3)
a blunted dynamic response of sinonasal cilia to environmental stimuli. Studies of the first two explanations yield con-
flicting results.and to date, the third possibility remains uninvestigated. A review of the current understanding of the cel-
lular regulation of respiratory ciliary activity and its contribution to chronic rhinosinusitis is presented.

Key Words: cilia, mucociliary clearance.

INTRODUCTION in the sinuses while also demonstrating that the re-

Although multiple causes cotitribute to the devel-
opment of chronic rhinosinusitis (CRS), the ultimate
underlying pathophysiology is stasis of sinonasal se-
cretions due to ineffective sinonasal mucociliary
clearance (MCC) followed by subsequent bacterial
overgrowth, frank infection, and/or inflatnmation.
It is important to emphasize that the upper airway
paranasal sinuses are almost completely dependent
on the activity of cilia for removal of debris-lad-
en mucus, whereas in the lower airways deficient
MCC may be cornpcnsated for by coughing.' Thus,
the goal of treating CRS is restoration of sinonasal
MCC. and this is the central dogma of functional
endoscopic sinus surgery, which celebrates a long-
term high rate of success (approximately 90%) for
symptomatic improvement in patients with medical-
ly refractory CRS.-
Although ciliary action was first described by
Sharpey-^ in 1835, the concepts of active mucocili-
ary drainage and the physiologic beneftt to the nose
and paranasal sinuses were largely forgotten for
nearly a century. In 1932, Hilding-* studied MCC
From the Division of Rhinology, Department of Otorhinolaryngology-Head and Neck Surgery. University of Pennsylvania Medical
Center. Philadelpliia, Pennsylvania.
Correspondence: Noam A. Cohen, MD, PhD. Division of Rhinology. Dept of Otorhinolaryngology-Head and Neck Surgery. 5 Silver-
stein/Ravdin. 3400 Spruce St, Philadelphia. PA I9I04.
20
moval of mucosa from the frontal sinus in dogs re-
sulted in raised scars and significant interference
with mucociliary transport. Subsequently. Sewall.'^
Boyden.^ and others devised flaps to try to piovide
mucosal coverage for exposed bone. Messerklinger
introduced the Hopkins rod to nasal endoscopy and
is credited as being the first to develop a systematic
approach to diagnosing and treating sinus inflatnma-
tory disease. More than 40 years ago. he dcmotistrat-
ed. through the use of fresh cadavers and time-lapse
cinematography, thai each of the large sinus cavities
has distinct mucosal flow pattertis.'' He also noted
that some regions possessed higher flow velocity
than other regions.^ It has since been demonstrated
that mucosal flow is accotnplished through the beat-
itig of cilia, located at the tip of epithelial cells.
MUCOCILIARY CLEARANCE
Mucociliary clearance is an essential compo-
nent of the mammalian respiratory system, and is
designed to remove both healthy and pathological
secretions frotii the airway. Tlie mucociliary esca-
lator is the pritnary defense mechanism against in-
 Cohen. MucociUarv Clearance
haled parlictilate matter. Essentially. 2 processes
contribute to MCC: mucus production and mucus
transport, in which the mucus is secreted into the
airways, traps inhaled particulate matter, and then
transports the trapped matter either from the lower
airways up to the glotti.s or from the upper airways
posteriorly to the pharynx, where it is swallowed.
This defense respiratory epithelium comprises pre-
dominantly 2 cell types: goblet cells (approximately
20%). which produce mucus, and ciliated cells (ap-
proximately 80%). which beat and sweep the mucus
for elimination by the gastrointestinal tract. A small
number of basal cells are also present; these can dif-
ferentiate into either goblet or ciliated cells.**
Mucociliary clearance is controlled by physiolog-
ical, anatomic, and biochemical variables. The phys-
iological variables include the amount of mucus
produced, as well as the effectiveness of the ciliary
beat. Nasal airflow and patency of the sinus ostia
in the prechambers arc anatomic considerations, and
the lone biochemical factor is mucus composition.^
CILIA AND REDUCED BASAL CILIARY BEAT
FREQUENCY
The propulsion of mucus is accomplished through
the beating of cilia, located at the tip of epithelial
cells. In the forward-powered stroke, the cilia are
erect with the tips touching the viscous or gel mucus
layer. As the cilia recover from this beat, they be-
come tiaccid and bend as they return to their start-
ing position, traveling in the sol phase of the mucus.
Ciliary movement is coordinated, resulting in orga-
nized ciliary waves propelling particulate matter out
of the sinonasal eavity.
There are approximately 50 to 200 cilia per epi-
thelial cell; each measures from .S
' to 7 |.im in length.
The basal, or spontaneous, beating ranges from ap-
proximately 9 to 15 Hz for humans, with variations
among other mammals. The tip velocity is approxi-
mately 600 to 1.000 \imts. which yields a dynamic
range of mucus velocity of 50 to 450 |im/s or 3 to
25 /i'**'i
Cilia are composed of tubulin. Alpha and beta tu-
bulin dimers form to create protofilaments or micro-
tubules, with the B-tubule an ineomplete circle in
contrast to the circular A-tubule. Nine dimers. linked
by the protein nexin. encircle a core composed of 2
singlet microtubules surrounded by a central sheath,
to which the doublets are rigidly attached by means
of a radial protein spoke (Fig 1). Stimulation by aden-
osine triphosphate (ATP) causes the dynein arms
along the doublet microtubules to move, so that one
niicrottibule dimer is pushed against the other. The
net icsuli i.s ciliary movement.'""
21
The origins of the cilia are the basal bodies found
below the plasma membrane, which are oriented
identically. This orientation causes the cilia to beat
in the same direction, rather than to exhibit random
movement. This metachronous beating effectively
transports mucus. Dyskinesia. or unorganized beat-
ing cau.sed by abnormal cilia, fails to completely
transport mucus, permitting accumulation of debris
over time.
MUCUS VISCOSITY
Respiratory secretions transported by the cilia are
composed of periciliaiy tluid. surfactant, and mu-
cus, which serve to protect, hydrate, and lubricate
the respiratory system. Mucus is approximately 1%
sodium chloride. 0.5% to I % free protein, and 0.5%
to 1% mucins. which are carbohydrate-rich glyco-
proteins. and the remaining mass is water (approxi-
mately 95%).I" An intriguing substance, mucus is
viscoeiastic. as it is marked by both liquid and .solid
rheological properties. It is characterized by viscos-
ity (a liquid property) becau.se of its resistance to
How and its capacity to absorb energy when in mo-
tion, and by elasticity (a solid property) because of
its capacity to store energy that is used to move or
deform a mass. The physical properties of mucus
include spinnability. ie. its thread-forming capac-
ity and its internal cohesive force; adhesivity. ie. its
ability to bind to a solid surface; and wettabiiity. ie.
its ability to spread on a surface. All of these rheo-
logical and physical properties are influenced by the
degree of hydration and the glycoprotein composi-
tion — factors that are host-regulated.'"i-
It is important to note that the viscosity of mu-
cus decreases as more force is applied to it. That is.
as the cilia beat faster, the mucus absorbs more en-
ergy, so that its viseosity is reduced and it becomes
easier to move. A small change in ciliary beat fre-
quency (CBF) can cau.se a dramatic increase in mu-
cus velocity. Studies have shown that if the CBF is
increased by 16%. the mucus velocity can increase
by as much as 56%.'-'i-^
Sinus health in any patient depends on 3 interre-
lated factors: secretion of mucus with normal viscos-
ity, volume, and composition; normal mucociliary
flow, to prevent mucus stasis and subsequent inlec-
tion; and open sinus ostia. to allow adequate drain-
age and aeration.'"^There is overwhelming evidence
in the literature that MCC is decreased in patients
with CRS, as demt>nstrated by the u.se of saccharin
transit time and radionuclide tracer clearance stud-
ies."'-*^ However. 6 months after functit>nal endo-
scopic sinus surgery. MCC has been demonstrated to
be restored to normal values.-'' It remains to be pre-
ci.seiy defined whether the decrease of MCC in these
22 Cohen. Mucociliary Clearance

Outer
dynein ami

Inner
Radial spoke dynein arm

Spoke head

Nexin

F i g 1. M o l e c u l a r aiKitmny (if cilia.

Plasma
nmnbrane

patients is due to the cilia, mucus, or both. A number
of studies have reported that decreased CBF is re-
sponsible'"'''*---^"-*^; these studies have been coun-
tered by others."***-^' Likewise, although evidence ex-
ists for increased viscosity in patients with CRS."^
other studies have shown no difference in viscosity
between these patients and normal patients.'"^-^^ As a
clinically relevant aside, it should be noted that CBF
is reduced by benzalkonium chloride,'^ a preserva-
tive used in many intranasal drug formulations.
REGULATION OF CILIARY BEAT FREQUENCY
Despite almost a century of investigation, the
mechanisms underlying CBF regulation still are
not fully defined. Several caveats must be noted in
regard to CBF measurement, however. One of the
methods most commonly used to measure CBF has
relied on cinematography, which captures images at
a maximum of 30 frames per second, so that the mea-
surable frequency is limited to 15 Hz. This rate is
explained by the Nyquist theorem, which postulates
that the sampling interval must be equal to or less
than half the period of the waveform that is being re-
corded. A second method is the use of a photo diode,
which can estimate the CBF indirectly by detecting
changes in light intensity passing through the field
of beating cilia followed by a mathematical trans-
formation. Sampling methods also have varied, with
some investigations relying on nasal brushings and
others using either blind nasal biopsy or nasal biop-
sy under direct vision. Likewise, locations of tissue
acquisition have varied, with the inferior turhinate,
middle turbinate, and adenoids being some of the
most commonly used sampling sites. In addition,
there has been inconsistency concerning the temper-
ature at which CBF has been measured, with some
 Cohen, Mucociliarv Clearance
studies using room temperature and others using
body temperature. Finally. CBF analysis has only
focused on spontaneous beating; to date, no studies
have examined the dynamic aspect of CBF.
The dynamic regulation of cilia is an important
consideration, because both environmental and host
cues can increase or decrease CBF. Mechanostimu-
lation and chemical stimulation from the environ-
ment, as well as hormonal, thermal, and ncurotrans-
mitter stimulation from the host, can all be involved,
whether singly or in combination.•''*-'^
Mechanical stimulation was demonstrated by San-
derson and Dirksen-^"^ almost 2 decades ago in stud-
ies using cultured ciliated epithelial cells from rabbit
tracheal mucosa. They elegantly demonstrated that
mechanical stimulation of the cell surface or cilia re-
sulted in a transitory CBF increase of 20% or more.
This response was composed of a short lag, a rise,
and a recovery phase. The response duration, but not
the maximal frequency, was increased by stronger
stimulation. These ciliary responses failed to occur
when extracellular calcium was removed. Their re-
sults suggested that the frequency response was de-
pendent on calcium influx and that MCC is poten-
tially a localized self-regulating process.-'''^
Ma et al.**^ using whole cell configuration, in-
vestigated pharmacologic stimulation of rabbit tra-
cheal epithelial cells, and concluded that ATP alone
was sufficient to support spontaneous ciliary beat-
ing and that Ca-"^ was not required. Simultaneous re-
cording of Ca-"^ and ciliary activity under nonstim-
ulated basal conditions revealed no correlation be-
tween the two. Neither Ca-+nor Ca-+-caimodulin, at
concentrations as high as 1 |imol/L. altered ciliary
beating. The stimulated stage, however, requires not
only ATP, but al.so calcium and cyclic nucleotides.
Cyclic nucleotides, in the absence of Ca-+. produced
only a moderate increase in CBF, although robust en-
hancement was seen in the presence of Ca-"*". These
results suggest that the axonemal machinery may be
able to function in at least 2 different modes: a low
beating rate requiring only ATP and most likely in-
volving only the axonemal motor, and a higher beat-
ing rate involving not only ATP but an acceleratory
modification regulated by second messengers. The
role and endogenous source of extracellular ATP in
modulating respiratory cilia activity remains to be
defined."^''
Zhang and Sanderson.*"* using high-speed phase-
contrast and fluorescence imaging, further investi-
gated the changes induced by ATP on CBF and in-
tracellular calcium concentration in rabbit tracheal
epithelial cells. Their results suggest that transient
Ca-"^-coupled CBF changes are directly mediated by
23
a Ca2+-de pen dent mechanism, such as phosphoryla-
tion of axonemal proteins."*^
From these and numerous other .studies, it can be
concluded that basal CBF is dependent on intracel-
lular ATP in addition to being Ca-"^-independent.
Both basal CBF and stimulated CBF are voltage-
insensitive. Furthermore, .stimulated CBF requires
Ca^+, cyclic adenosine monophosphate, and cyclic
guanosine monophosphate in addition to ATP. and.
finally. Ca-+ oscillations maintain elevated CBF.
This last process remains to be fully defined.
The contribution ofdysfunctional respiratory cilia
in the development of CRS is presumed. To date,
no investigations have addressed the dynamic regu-
lation of ciliary beating as a potential pathologic
mechanism contributing to the development of CRS.
ANALYSIS OF CILIARY BEAT FREQUENCY
Recently, a direct method for CBF analysis was
reponed using high-speed digital video recording
(250 frames per second) and differential interference
contrast microscopy.'*'' The CBF variation within the
sinonasal cavity was addressed. This information is
paramount if comparisons ot biopsy specimens from
multiple patients from different regions of the sino-
na.sal cavity are to be performed. As stated above,
studies correlating baseline CBF with CRS have led
to conflicting evidence. Furthermore, these Investi-
gations used various sampling techniques of differ-
ent sinonasal anatomic locations to obtain the exper-
imental material, the most common being brushings
from the inferior turbinate. Whether CBF is uniform
throughout the sinonasal cavity has only been ad-
dressed in I study.-^*^ which neglected analysis of the
inferior turbinate. To assess CBF variation within
the sinonasal cavity, we analyzed regional CBF in
3 functionally distinct regions (inferior turbinate-in-
ferior meatus: uncinate proces.s-middle meatus; and
sphenoid bone-superior meatus) of the sinonasal
cavity from 9 patients without sinusitis.The average
CBF for each patient, including all subsites. ranged
from9.I to 17.1 Hz. with an overall average of 12.6
± 2.9 Hz (Fig 2). An analysis of variance for multi-
ple-group comparisons demonstrated no statistically
significant regional variation of the sites sampled (p
> .05). indicating that random biopsy locations gen-
erate a representative CBF for that individual.'''^
To determine whether the basal CBF is altered in
CRS patients, we studied mucosal explants obtained
from patients undergoing sinonasal procedures (for
CRS and non-CRS indications). Although a slightly
higher percentage of CRS patients had no detectable
beating cilia (23%) as compared with control speci-
mens (18%), no significant difference was demon-
24 Cohen. Mucociliarv Clearance

interior lurbinale
LJ uncinate piocess,
20 sphenoid recess I
N
I 9

CD 6

Patient
Fig 2. Regional sinonasal ciliary beat frequency (CBF)
analysis. Endoscopically guided biopsies of lateral in-
ferior aspect of inferior tiirbinale. uncinate process, and
sphenoid bone recess were obtained, CBF determina-
tion from these 3 regions within sinonasal cavity demon-
strates no statistically significant regional variation,
strated in basal CBF between the 2 groups (Fig 3).
A fundamental characteristic of the MCC defense
system is the acceleration of ciliary motion in re-
sponse to various stimuli. A reasonable explanation
for the well-characterized impaired MCC noted in
Normal CRS
n = 29
Fig i. Basal CBF in mucosal explants from patients with and
without chronic rhinosinusitis (CRS) demonstrates no signif-
icant difference between diseased and normal mucosae,
CRS is a dysfunctional acceleratory response to in-
fectious or environmental stimuli within the sinona-
sal cavity.To investigate this possibility, we perfused
human mucosai explants with 100 |amol/L ATP
while continuously recording the CBF. Adenosine
triphosphatc is a well-characterized exogenous stim-
ulus of CBF acting via the purinoreceptors/"-'^^ Pre-
liminary data demonstrated CBF tracings (repre-
sented as the fold increase in CBF. ie, the observed
frequency divided by the frequency at time ()) from
3 control patient explants and 3 CRS patient ex-

ATP-induced CBF change In control patients ATP-Induced CBF in CRS patients

Fig 4. CRS patients have altered CBF acceleration. Adenosine iriphosphate {ATP; 1 (H) ^imol/L) was added to perfusate at time 0
(black bar). Mucosal explants from A) 3 control patients and B) ."^ CRS patients were evaluated for CBF acceleration. CBF (f/fo)
is expressed as ratio of observed CBF at designated time divided by CBF at baseline (time 0), Control patients were undergoing
transsphenoidal adenohypophysectomy for pituitary tumors (Cont I and Cont 3) and isolated sphenoid fungal ball (Cont 2). C)
Representative computed tomographic scans for each patient demonstrated near-complete opacification of entire sinonasal cav-
ity in CRS patients (right), whereas control patients (left) have fully aerated sinuses, with exception of Cont 2. who had ist)lated
opacification of left sphenoid sinus.
 Cohen, Mucociliary Clearance
plants, as presented in Fig 4. The CBF from the con-
trol mucosa demonstrated a robust increase (50% to
70% above baseline) within I minute of exposure
to 100 ^moi/L ATP (Fig 4A). This effect decayed
during the ensuing 5 minutes. In stark contrast, the
CBF from the CRS muco.sa demon.strated either no
change (patient 3) or deceleration (patients I and 2;
Fig 4B). Preoperative computed tomographic scans
are represented in Fig 4C. Whether this finding is a
result of chrtmic inflammation and infection, or in-
dicative of a fundamental defect contributing to the
disease process, has yet to be determined.
CONCLUSIONS
In summary, overwhelming evidence in the liter-
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