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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4473_Библиотеки_им_академика_М_И_Перельмана
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T. Shimizu
and goblet cell products, mucus contains various
defensive components such as glycoproteins
(mucins), antibodies, defensin, lysozyme, and
lactoferrin.
The mucous blanket is subdivided into two
layers: the outer mucous layer and the periciliary
uid layer. The outer mucous layer is a gel layer,
produced mainly by secretions of epithelial goblet cells and submucosal glands. The periciliary
uid or sol layer is produced by ion transport
through the epithelium (Fig.1.1). Ciliary beating
takes place at 10–14Hz in this periciliary layer,
propelling the outer mucous layer toward the
pharynx. Healthy mucociliary transport requires
maintenance of a balance among volume and
composition of mucus, adequate periciliary uid,
and ciliary beating [1]. Mucus is essential for
mucociliary transport. If the mucus is replaced
with saline, particles do not move even while
cilia beat actively [2].
Hypersecretion of mucus is an important characteristic of sinonasal inammation that occurs in conditions such as acute rhinitis, chronic rhinosinusitis
(CRS), and allergic rhinitis (AR). Hypertrophic,
hyperplastic, and metaplastic changes in goblet cells
of the surface epithelium and in submucosal gland
cells are frequently observed in association with pronounced rhinorrhea. In pathological conditions,
mucus hypersecretion and damaged epithelium
impair mucociliary clearance, resulting in stagnant
pathological mucus containing pathogenic microbes,
various inammatory mediators, and inammatory
cells, a situation that facilitates bacterial colonization
and local inammation, leading to infection and tissue damage.
The major components of mucus are glycoproteins called mucins, which are secreted by
epithelial goblet cells and submucosal glands.
Mucins are large heterogeneous macromolecules,
containing oligosaccharide chains attached to
peptide backbones, which are encoded by several
MUC genes. Secreted mucins are stored in secretory granules and are released by regulated
exocytosis.
This chapter will focus on mucus, goblet cells,
and submucosal glands of the nasal mucosa and
Fig. 1.1 Mucous
blanket is subdivided
into two layers: the outer
mucous layer and the
periciliary uid layer.
(a) Normal mucous
blanket. (b) Pathological
mucous blanket with
hypersecretion of
mucus. Mucus
hypersecretion increases
the viscoelasticity of the
mucus, and mucus
strands connect the outer
mucous layer with the
epithelial goblet cells,
causing the disruption of
the periciliary uid
layer. These changes in
mucus impair
mucociliary interaction
a
b
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will summarize the mechanisms regulating
mucus secretion and pathological mucus hypersecretion in sinonasal inammation. Therapeutic
strategies to inhibit mucus hypersecretion will be
also discussed.
1.2 Mucus Composition
The nasal epithelium is covered by a mucous gel
layer. Ciliary beating within the periciliary uid
layer propels the gel layer to the pharynx and is
then swallowed together with entrapped particles and pathogens. Mucus is a heterogeneous
mixture of water, glucose, various ionic solutes,
antimicrobial proteins, cells, and cellular debris.
Mucins are major glycoprotein components of
mucus that contribute greatly to the viscoelastic
and gel-forming properties of the mucous layer
[3–5].
Mucins are complex glycoproteins with oligosaccharide chains attached to peptide backbones,
which are encoded by MUC genes. Mucins can
be divided into two structurally and functionally
distinct subfamilies: membrane-bound mucins
and secreted mucins. Membrane-bound mucins
have transmembrane and cytoplasmic domains
that anchor the molecules to the apical cell membrane, where they participate in functions such as
structural barrier formation, cellular adhesion,
pathogen binding, and signal transduction [6, 7].
Extracellular subunits of membrane-bound
mucins can be released from the plasma membrane into the mucus layer by proteolytic cleavage or by shearing forces. Some membrane-bound
mucin genes are alternatively spliced to form
transcripts that lack a transmembrane domain;
these are present in airway secretion [8]. Secreted
mucins are stored in secretory granules located in
the apical cytoplasm and are released by regulated exocytosis.
Secreted mucins have high molecular weights
(more than 1000kDa) and are heavily glycosylated proteins (composed of 70–90% carbohydrate
moieties) with tandemly repeated amino acid
sequences that are rich in serine and threonine.
Different mucin genes contain various sizes and
numbers of tandem repeats, and there are genetic
polymorphisms within single mucin genes [9].
Tandem repeats are sites of O-glycosylation, and
hundreds of oligosaccharide chains are attached to
a single core peptide (Fig.1.2). Mucin glycosylation is determined by tissue-specic glycosyltransferase expression and by host and
environmental factors that inuence transferase
expression. Mucin carbohydrate chains are highly
heterogeneous, and this structural diversity may
allow mucins to interact with many microorganisms [10]. These carbohydrate moieties are possible sites of attachment for pathogenic bacteria and
Fig. 1.2 A schematic model of a secreted mucin.
Hundreds of O-glycans are attached to serine or threonine
residues of tandem repeat domains in the MUC protein
backbone. Secreted, gel-forming mucins contain cysteine-
rich domains that permit oligomerization through the formation of disulde bonds; they also aggregate through
ionic and hydrophobic interactions with proteins and with
other mucins
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viruses. Several recognition sites for respiratory
pathogens have been identied; these promote
their entrapment and removal by mucociliary
clearance [11–14].
Secreted mucins contain cysteine-rich
domains that permit oligomerization through the
formation of disulde bond; they also aggregate
through ionic and hydrophobic interactions with
proteins and with other mucins. These complex
macromolecules provide the viscoelastic and
space-occupying properties of the mucus gel
layer [15]. Secreted mucins are negatively
charged by sulfated and sialylated oligosaccharide chains. Mucins, the most plentiful highmolecular- weight polyanions of the nasal
mucosa, interact with and inhibit the effects of
cationic inammatory proteins such as leukocyte
elastase and lysozyme [16, 17]. The negatively
charged carbohydrates of mucins may protect
against proteolysis caused by cationic inammatory proteins and bacterial enzymes.
1.3 Mucin Genes
The mucin protein backbones are encoded by
MUC genes. More than 20 human mucin genes
have been identied throughout the respiratory,
gastrointestinal, and reproductive tracts [9]. In
respiratory epithelium, mainly MUC1, MUC2,
MUC4, MUC5AC, MUC5B, MUC7, and MUC8
are expressed, and similar expressions of mucin
genes are observed in normal nasal mucosa [18,
19] (Table1.1). MUC2, MUC5AC, MUC5B, and
MUC8 are secreted, gel-forming mucins that
contain cysteine-rich domains for oligomerization and are responsible for the viscoelastic property of mucus. They are encoded by a cluster of
highly related genes on chromosome 11 and by a
similar gene on chromosome 12 [15]. MUC7 is a
secreted, non-gel-forming mucin that exists as a
monomer and so is not thought to contribute signicantly to mucus viscoelasticity.
In the airways, MUC1 and MUC4 are the predominant membrane-bound mucins present on
the apical membranes of epithelial cells.
Membrane-bound mucins contain a highly glycosylated extracellular domain, a transmembrane
domain, and a short cytoplasmic tail. Extracellular
units can be released from cells under certain
conditions and then potentially contribute to the
mucus layer. Some MUC4 mucins secreted into
airways are encoded by alternatively spliced transcripts that lack a transmembrane domain [8].
The cytoplasmic tail domain participates in signal transduction and regulates a variety of biological functions [20]. In airway epithelial cells,
MUC1 is a receptor for Pseudomonas aerugi-
nosa agellin [21]; MUC1 inhibits agellin-
activated Toll-like receptor (TLR)-5-mediated
signaling and interleukin (IL)-8 release [22].
Both MUC1 and MUC4 dimerize with and regulate the epidermal growth factor receptor [23].
Their roles in inammation and cancer biology
have been studied in detail [24–26]. However,
their function in nasal mucosa remains to be
elucidated.
Recent studies revealed the specic localization of mucins in nasal epithelial cells and submucosal glands. The membrane-bound mucins
MUC1 and MUC4 are diffusely expressed at the
apical surface of epithelial cells. The secreted,
gel-forming mucin MUC5AC is mainly expressed
in epithelial goblet cells, while MUC5B is the
predominant mucin expressed in mucous cells of
the submucosal glands. MUC2 is mainly
expressed in epithelial goblet cells, but its expression is much lower than that of MUC5AC.MUC
Table 1.1 Major mucin genes in human nasal mucosa
MUC gene Mucin subfamily Chromosome locus Main tissue localization
MUC1 Membrane-bound 1q21–q24 Epithelial cells
MUC2 Secreted, gel-forming 11p15.5 Goblet cells
MUC4 Membrane-bound 3q29 Epithelial cells
MUC5AC Secreted, gel-forming 11p15.5 Goblet cells
MUC5B Secreted, gel-forming 11p15.5 Mucous cells of submucosal glands
MUC7 Secreted, non-gel-forming 4q13.3 Serous cells of submucosal glands
MUC8 Secreted, gel-forming 12q24.3 Goblet cells, mucous cells of submucosal glands
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8 is expressed in both epithelial goblet cells and
mucous cells of the submucosal glands. The
secreted, non-gel-forming mucin MUC7 is
expressed in serous cells of the submucosal
gland. Similar distributions of MUC genes seem
to be found in nasal polyps [27, 28]. MUC2,
MUC5AC, and MUC5B expressions are reported
to be upregulated during airway inammation in
humans and in animals, and MUC5AC expression is the highest of the three [29, 30]. Therefore,
MUC5AC has been the most intensively studied
MUC gene with regard to airway mucus
secretion.
1.4 Goblet Cells andSubmucosal
Glands
Mucous cells in the surface epithelium (called
goblet cells) and in submucosal glands are the
major sources of gel-forming mucins. Epithelial
goblet cells contain numerous electron-lucent
granules that ll most of the cytoplasm and fuse
with the apical cell membrane before secretion
(Fig.1.3). The nucleus, numerous mitochondria,
Fig. 1.3 Goblet cells of rat nasal epithelium induced by
intranasal instillation of lipopolysaccharides. Numerous
electron-lucent granules ll most of the cytoplasm and
fuse with the apical cell membrane before secretion
and the rough endoplasmic reticulum are
restricted to a small volume in the basal aspect of
the cells. Submucosal glands comprise a mixture
of mucous cells and serous cells, and the mucous
cells, the important source of gel-forming mucin,
resemble epithelial goblet cells. These mucous
cells can be detected histochemically by Alcian
blue and periodic acid Schiff’s stains.
Serous cells of submucosal glands contain
discrete electron-dense granules containing
secretory products including immunoglobulins,
lysozyme, lactoferrin, and other antimicrobial
enzymes, all of which are important for normal
function of the airway innate immune system
[31]. Thus, serous cells are an important source
of antimicrobial peptides essential for host
defense mechanisms, while mucous cells contribute to the viscoelastic property of airway
mucus by producing gel-forming mucins. Human
submucosal glands are innervated by parasympathetic and sensory efferent nerves, and the glands
express muscarinic receptors. The parasympathetic (cholinergic) nervous system is the neural
pathway most active in airway submucosal
glands, and stimulation of cholinergic nerves or
use of muscarinic receptor agonists induces
marked mucus secretion [32, 33].
Mucus hypersecretion is a major characteristic of airway inammation; it is associated with
hypertrophy, hyperplasia, and metaplasia of epithelial goblet and submucosal gland cells. An
increased number of hypertrophic goblet cells are
commonly observed in the nasal epithelium during experimental inammation caused by inhalation of irritant gases or allergens or by viral or
bacterial infection. In the human nose, the goblet
cell density of the inferior turbinate ranges from
5000 to 10,000 cells/mm2, similar to that of maxillary sinus mucosa [18, 34]. However, changes
of goblet cell numbers in patients with allergic
rhinitis (AR) and chronic rhinosinusitis (CRS)
are controversial.
Submucosal glands contribute to mucus
hypersecretion in airway inflammation by
secreting mucins, ions, and water; the submucosal gland cell density ranges from 1000 to
2000 cells/mm2 in human inferior turbinate
and maxillary sinus mucosa. In CRS patients,
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the number of submucosal gland cells
increases to 2000–4000 cells/mm2, and the
area occupied by acini of the lamina propria
also increases [34].
1.5 Regulation ofMucin
Secretion
Mucin secretion is regulated by a multi-step
process that includes synthesis and exocytosis.
Mucin synthesis includes gene transcription in
the nucleus, posttranscriptional modification
and transport of mRNA, and translation in the
endoplasmic reticulum. In the Golgi apparatus, oligosaccharides chains are then attached
to the peptide backbone by glycosylation. The
synthesized mucins are stored in secretory
granules located in the apical cytoplasm until
stimulated for subsequent release by
exocytosis.
1.5.1 Mucin Production
Mucin gene expression is induced in response to
a wide variety of inammatory stimuli. MUC5AC
is the predominant gel-forming mucin in the
human airways and has been extensively studied
for evaluation of mucin gene regulation and
mucin glycoprotein secretion. A variety of epithelial stimuli (including bacterial products, viral
infection, environmental pollutants and chemicals, proteases, inammatory cytokines, and
growth factors) upregulate mucin gene expressions during sinonasal inammation (Fig.1.4).
Many bacteria and bacterial products induce
mucus hypersecretion in vivo and in vitro.
Lipopolysaccharide/TLR-4, peptidoglycan/
TLR-2 or TLR-6, and agellin/TLR-5 signaling
induce MUC5AC expression in airway epithelial
cells through activation of transcription factors
such as nuclear factor-κB (NF-κB), cAMP
response element-binding protein (CREB), and
Fig. 1.4 A variety of environmental stimuli, inammatory mediators, growth factors, and parasympathetic and sensory
nerves are involved in mucus production and secretion in nasal mucosa
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activated protein-1 (AP-1) [29, 35]. Respiratory
viral infections (including inuenza virus and
respiratory syncytial virus) induce mucin gene
expression in mice [36, 37], and rhinovirus stimulates MUC5AC expression in human airway
epithelial cells [38]. Environmental pollutants
and oxidants (such as cigarette smoke, acrolein,
ozone, SO2, and hydrogen peroxide) stimulate
MUC5AC expression and mucin production [39–
42]. Airway proteases (including neutrophil elas-
tase, matrix metalloproteases, airway trypsin,
and thrombin) stimulate MUC5AC expression
and mucin secretion [43–47].
The proinammatory cytokines IL-1β and
tumor necrosis factor (TNF)-α and the Th2 cytokines IL-4, IL-9, and IL-13 stimulate mucin production invivo [48, 49]. Epithelial cell-derived
cytokine IL-33 also induces mucin production in
the mouse airway [50]. IL-13 is an important and
essential mediator of mucin production in Th2mediated airway inammation through direct
stimulation of epithelial cells [51]. IL-13 activates signal transducer and activator of transcription 6 (STAT6), and then STAT6-dependent
downregulation of the transcription factor
Forkhead box a2 (Foxa2) stimulates MUC5AC
expression [52, 53]. Foxa2 is a negative regulator
of MUC5AC expression, and its deletion induces
mucous metaplasia in the mouse lung [54].
Retinoic acid (RA) and its related analogs
play an important role in cell growth and cell differentiation. In the airway epithelium, RA is
essential for induction and maintenance of mucociliary differentiation [55, 56]. Expression of the
gel-forming mucins MUC2 and MUC5AC is RA
dependent in cultured airway epithelial cells [57].
Epidermal growth factor receptor (EGFR) signaling is also important for mucin production in a
variety of animal models and in human airway
epithelial cells. The EGFR ligands EGF, transforming growth factor (TGF)-α, and amphiregulin stimulate MUC5AC expression [58].
Activation of EGFR is critical for invivo and
invitro induction of mucin production in response
to stimulation of airway epithelial cells by allergens, viruses, neutrophil elastase, and cigarette
smoke [15, 29, 59–61].
1.5.2 Mucin Exocytosis
Mucin exocytosis from epithelial goblet cells is
stimulated by many inammatory mediators
including cholinergic agonists, neuropeptides,
prostaglandins, leukotrienes, bacterial products,
neutrophil elastase, inhaled pollutants, and nucleosides [62]. The nucleoside ATP is released in
response to mechanical, irritant, and inammatory stimulation of epithelial cells. Extracellular
release of ATP activates P2Y2 purinergic receptors on the apical surface of airway epithelial
cells, resulting in induction of calcium release
and regulated exocytosis [63]. Exocytosis is a
complex process controlled by many regulatory
molecules, including myristoylated alanine-rich
C kinase substrate (MARCKS), which is essential for mucin release invivo and invitro [6, 7,
64, 65].
Mucus secretion from submucosal glands is
regulated mainly by parasympathetic and sensory
nerves. Neurotransmitters and neuropeptides
released by these nerves directly stimulate gland
secretion [32]. In airway inammation, parasympathetic activity is stimulated by sensory nerves
and histamine. Inammatory mediators, such as
prostaglandins, leukotrienes, and neutrophil elastase, also stimulate gland secretion.
1.5.3 Mucin Glycosylation
In addition to factors that regulate synthesis and
release, mucin activity is also regulated by glycosylation [10]. Th2 cytokines and TNF-α alter the
glycosylation and sialylation of secreted mucins
[66, 67]. The carbohydrate moieties of mucins
are potential adhesion sites for bacteria and
viruses [68]. Inammation-associated glycosylation of secreted mucin facilitates the interaction
between mucus and microorganisms, leading to
entrapment and removal by mucociliary clearance [69, 70].
Increased modication of secreted mucin by
sialylation and sulfation is commonly observed
in airway inammation [71–73]. Resulting carbohydrate moieties are negatively charged and
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have inhibitory effects against cationic inammatory proteins and bacterial enzymes [16, 17].
Such alterations may be important mechanisms
involved in host defense, as they lead to neutralization of these proteolytic enzymes and removal
of pathogenic microbes. However, the precise
biological function of mucin carbohydrate chains
remains to be elucidated.
1.6 Pathophysiological Mucus
Hypersecretion
Mucus hypersecretion is a common characteristic
of the sinonasal inammation seen in disorders
like chronic rhinosinusitis (CRS) and allergic rhinitis (AR) and is the cause of rhinorrhea. A variety of inammatory mediators and inltrating
cells are capable of stimulating mucus hypersecretion. Many inammatory stimuli such as
inhaled irritants, neutrophil products, lipopolysaccharide, viral and bacterial infections, and
antigen challenge have been used to study mechanisms of mucus hypersecretion in animal
models.
a
b
Fig. 1.5 Immunohistochemical staining of MUC5AC in
nasal polyp of patient with chronic rhinosinusitis. Mucous
granules of epithelial goblet cells (a) and the mucus layer
of epithelial surface (b) are strongly stained. Mucus
strands connect the mucous blanket with the epithelial
goblet cells (b)
1.6.1 Chronic Rhinosinusitis (CRS)
CRS is a common nasal infectious disease with
or without nasal polyps, characterized by the following symptoms: anterior and posterior nasal
discharge, nasal obstruction, olfactory disturbance, headache, and facial pain. Hypersecretion
of mucus in CRS patients may be induced by
various inammatory mediators such as the proinammatory cytokines IL-1β and TNF-α, bacterial products, and neutrophil products. Mucin
gene expression in nasal and sinus mucosa is
similar to that in other respiratory epithelia.
MUC5AC, MUC5B, and MUC2 are major
secreted, gel-forming mucins, and the production
of these is upregulated in nasal mucosa and nasal
polyps of CRS patients [18, 28] (Fig.1.5).
Excessive mucin production increases the vis-
coelasticity of the mucus, and mucus strands con-
nect the mucous blanket with epithelial goblet
cells [74] (Figs.1.1 and 1.5). These changes of the
mucus and the damaged epithelium impair mucociliary interaction. Obstruction of the nasal passages caused by inamed mucosa or nasal polyps
and mucociliary dysfunction lead to “mucostasis,”
an accumulation of stagnant, pathological mucus
that contains various inammatory mediators,
inammatory cells, and pathogenic microbes.
Mucostasis triggers mediators, normally host protective, but which in this setting become host invasive, further exacerbating mucus hypersecretion,
tissue damage, mucociliary dysfunction, and bacterial infection (Fig.1.6). Successful treatment of
CRS patients involves stopping the self-mediated
inammation caused by stagnant mucus. Nasal
blowing, suction and irrigation, antral lavage, and
endoscopic sinus surgery are useful treatments to
remove stagnant mucus and restore mucociliary
clearance.
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arachidonic acid metabolites, growth factors, etc.
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Infection and inflammation
Inflammatiory mediators
Bacterial products, proteases, cytokines,
Mucus
hypersecretion
Mucociliary dysfunction
Fig. 1.6 A vicious cycle of self-mediated inammation
caused by the stagnant mucus in the pathogenesis of
chronic rhinosinusitis. Mucus hypersecretion and damaged epithelium impair mucociliary function, resulting in
“mucostasis,” an accumulation of stagnant, pathological
mucus that contains various inammatory mediators and
Tissue
damage
Stagnation of mucus and mediactors
Obsrtuction of
nasal passages
1.6.2 Allergic Rhinitis (AR)
AR is caused by IgE-mediated Th2 immune
responses and is characterized by the following
symptoms: sneezing, nasal obstruction, itching,
and rhinorrhea. Histamine is a key mediator for
allergic rhinitis, and histamine-induced cholinergic nerve stimulation is important for antigeninduced mucus hypersecretion. MUC5AC is a
main secreted mucin, and it is found to be upregulated in AR patients [75, 76].
Ovalbumin (OVA)-sensitized animals are
commonly used to study the pathophysiologic
changes of allergic inammation. When hypertrophic and metaplastic changes in epithelial
goblet cells are induced in a rat model of nasal
allergy, intraepithelial mucus production is signicantly inhibited by a Th2 cytokine inhibitor
and by a cysteinyl leukotrienes (cysLTs) antagonist, indicating that Th2 cytokines and cysLTs
(LTs C4, D4, and E4) are important for mucus syn-
Bacterial
colonization
pathogenic microbes. These mediators and microbes
exacerbate the local inammation and further bacterial
colonization. For treatment of patients with chronic rhinosinusitis, surgical removal the stagnant mucus is very
important to stop the self-mediated inammation
thesis in AR [77, 78]. Mucus secretion (goblet
cell exocytosis) can be evaluated by measuring
the transient decrease of intraepithelial mucus.
Histamine stimulates early-phase (1h after challenge) secretion through H1 receptor on cholinergic nerve terminals, and inltrating inammatory
cells (eosinophils and/or neutrophils) play a role
in late-phase (6h) secretion. CysLTs are important for both early-phase secretion and late-phase
secretion [79].
1.7 Therapeutic Strategies
toInhibit Mucus
Hypersecretion
Mucus and mucociliary clearance serve important functions in the host defense system by
removing irritants, allergens, pathogens, and
dead cells from the airway. However, hypersecretion of mucus impairs mucociliary function and
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thus becomes part of the pathogenic process,
causing symptoms such as nasal obstruction and
anterior and posterior nasal discharge. Inhibition
of mucus hypersecretion restores mucociliary
clearance and improves symptoms. Selection of
an appropriate therapeutic strategy is important
because mechanisms of mucus synthesis and
secretion differ among the diseases, stimuli, and
types of inammation.
1.7.1 Surgical Managements
Hypersecretion of mucus and obstruction of nasal
passages impair mucociliary clearance, resulting
in stagnation of mucus that contains host- invasive
mediators and pathogenic microbes. Stagnation
of mucus causes a vicious cycle of self-mediated
inammation in the pathogenesis of CRS
(Fig.1.6). For treatment of CRS patients, surgical
removal of the stagnant mucus is very important.
Nasal blowing and irrigations are useful for
improving the symptoms [80]. Antral puncture
and lavage decrease mucus viscoelasticity and
improve mucociliary activity [81]. Endoscopic
sinus surgery to remove the obstructed mucosa
and polyps is very effective for restoring mucociliary clearance [82, 83].
1.7.2 Mucolytic andMucokinetic
Agents
The formation of disulde bonds to oligomerize
gel-forming mucins contributes to the viscoelastic property of mucus. Increased viscoelasticity
impairs mucociliary function. Mucolytic agents
such as L-cysteine and N-acetylcysteine have free
sulfhydryl groups that dissolve disulde bonds
and therefore decrease the viscoelasticity of nasal
discharge and sputum [84, 85]. Mucokinetic
agents such as carbocysteine cannot break mucin
disulde bonds, but they improve mucociliary
function and suppress goblet cell hyperplasia.
These mucolytic and mucokinetic agents are
reported to be effective as treatments for CRS
patients [86–88].
The release of large amounts of DNA from
dead neutrophils contributes to increased mucus
viscoelasticity. By decreasing the amount of
DNA in sputum, inhaled DNase has become an
important treatment for patients with cystic brosis (CF) [89]. Inhaled hypertonic saline is also
used to improve mucociliary clearance in CF
patients [90]; this stimulates water secretion into
the airway by creating a temporary osmotic gradient. Hypertonic saline nasal irrigations are
reported to be effective as treatment for CRS
patients [91].
1.7.3 Macrolide Antibiotics
The 14-member macrolides clarithromycin
(CAM), erythromycin (EM), and roxithromycin
and the 15-member macrolide azithromycin
(AZM) are widely used to treat airway inammation. Low-dose, long-term macrolide therapy has
been reported to be very effective for patients
with chronic airway diseases such as diffuse panbronchiolitis, chronic bronchitis, chronic obstructive pulmonary disease, CF, and CRS [92–96].
The effects of these agents depend on antiinammatory and immunomodulatory rather
than antibacterial actions.
CAM, EM, and AZM inhibit mucus hypersecretion and metaplastic and hypertrophic changes
of nasal epithelial goblet cells invivo and invitro
[97, 98]. They inhibit inammatory responses of
neutrophils, lymphocytes, macrophages, and epithelial cells and suppress gene expression and
production of inammatory cytokines and chemokines [99, 100]. In CRS patients, macrolide
therapy reduces anterior and posterior nasal discharge and is effective for treating neutrophilic
and lymphocytic inammation. However, macrolide therapy is not effective for patients with
eosinophilic inammation, characterized by
serum and tissue eosinophilia, high serum IgE,
multiple polyposis, severe CT ndings, and bronchial asthma [96, 100–103].
1.7.4 Anti-inammatory Agents
Systemic and topical steroids are very effective
for reducing mucus hypersecretion in patients
with CRS and AR [104, 105]. Glucocorticoids
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are potent anti-inammatory agents that inhibit
functions of a variety of inammatory cells.
Mucus hypersecretion is suppressed mainly by
reductions in the release of secretagogue
mediators such as histamine, leukotrienes, neutrophil elastase, and Th2 cytokines.
Anti-inammatory agents such as antihistamines, cysLTs antagonist, Th2 cytokines inhibitor, and anticholinergic agents are clinically
useful for reducing nasal AR symptoms, including anterior and posterior discharge [80, 106]. All
have been conrmed in animal model of allergic
inammation as inhibitors of nasal or tracheal
mucus hypersecretion.
1.8 Conclusions
Mucin secretion is regulated by a multi-step process that includes synthesis and exocytosis. A
wide variety of inammatory stimuli upregulate
mucin gene expression and induce mucus overproduction. During the past decades, there have
been signicant advances in our understanding of
the biological roles of mucus and of mechanisms
which regulate mucus hypersecretion, including
(1) the structural biology of mucins and mucus,
(2) regulation of mucin gene expression, (3)
mechanisms of mucin synthesis and exocytosis,
(4) epithelial cell differentiation and goblet cell
metaplasia, and (5) development of animal models for studying mucus hypersecretion in sinonasal inammation. Further understanding will
provide the best possible therapeutic strategies
for the treatment of various causes of mucus
hypersecretion in sinonasal inammation.
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