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Airway Mucus and Mucociliary System

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 44 
Airway Mucus and Mucociliary System
Samriddha Ray, Jeffrey A. Whitsett
CONTENTS
Introduction, 702
Epithelial Cells Lining Conducting Airways and
Submucosal Glands, 702
Nasal Passages and Submucosal Glands, 704
Ciliated Cell Differentiation and Function, 705
Goblet Cell Differentiation, 706
SUMMARY OF IMPORTANT CONCEPTS
• Defects in mucociliary clearance related to mucus hypersecretion, ciliary
protein dysfunction, or disruption of respiratory tract epithelial cells underlie
pathogenesis of chronic pulmonary disorders including asthma, chronic
obstructive pulmonary disease (COPD), and cystic fibrosis (CF).
• Abundant submucosal glands within nasal passages, sinuses, and conducting
airways secrete mucus, fluids, and host defense proteins.
• Goblet cell differentiation and mucus production by submucosal and airway
epithelial cells are regulated by Notch and SPDEF.
• Mutations in the CFTR (cystic fibrosis transmembrane conductance regulator)
gene (ABCC7) compromise periciliary fluid flow, leading to airway dehydra­
tion, mucus hyper production, and recurrent microbial colonization and
infection.
• Therapy for asthma includes antiinflammatory agents, glucocorticoids, theo­
phylline, macrolides, anticholinergics, PDE4 inhibitors, antileukotrienes, and
targeted therapeutics (e.g., anti-IgE, anti-IL5, anti-TSLP/AMG-157 monoclonal
blocking antibodies).
• Therapy for CF includes ivacaftor, a CFTR potentiator, in combination with
CFTR correctors tezacaftor and lumacaftor, which restore CFTR function,
useful for treatment of CF.
INTRODUCTION
The respiratory tract, from the nares to the peripheral alveoli, is con­
tinuously exposed to particles, toxicants, and microbial pathogens that
are cleared by combinatorial actions of the mechanical, innate, and
acquired immune systems that protect the lung and the organism from
the environment. Mucociliary clearance, mediated by the actions of
diverse conducting airway and submucosal gland epithelial cells, plays
a critical role in this multilayer defense system by secreting fluids, elec­
trolytes, host defense proteins, and mucus onto airway surfaces that
are removed from the lung by the mechanical activities of cilia and
cough. Abnormalities in mucociliary clearance, related to aberrations
in fluid secretion, ciliary protein functions, cough, or to the disruption
of epithelial cells lining the respiratory tract, underlie the pathogenesis
702
Role of Submucosal Glands in Mucociliary Clearance, 706
Mucus and Mucins, 706
Therapeutic Approaches (Asthma/Chronic Obstructive Pulmonary
Disease), 707
Therapeutic Approaches (Cystic Fibrosis), 709
Summary, 710
of common chronic pulmonary disorders. Chronic mucus hyperpro­
duction or dehydration cause airway obstruction and infections, which
contribute to the pathogenesis of many pulmonary disorders, including
chronic obstructive pulmonary disease (COPD), asthma, idiopathic
pulmonary fibrosis (IPF), cystic fibrosis (CF), bronchiectasis, and
primary ciliary dyskinesia (PCD). In this chapter, the molecular and
cellular mechanisms mediating airway mucociliary clearance and the
role of disrupted mucociliary clearance in the pathogenesis of chronic
respiratory diseases are considered. Therapeutic approaches useful for
the treatment of disorders in mucociliary clearance will be discussed.
EPITHELIAL CELLS LINING CONDUCTING AIRWAYS
AND SUBMUCOSAL GLANDS
Human conducting airways are lined primarily by a pseudostratified
epithelium consisting primarily of ciliated cells and lesser numbers of
secretory (club), goblet, and far fewer numbers of “brush” and neuro­
endocrine cells. Cartilaginous airways also contain numerous submu­
cosal glands, consisting of a diversity of serous, secretory, goblet, and
myoepithelial cells (Fig. 44.1). Under steady state, basal cells are located
adjacent to the basement membrane and their apical surfaces are not
directly exposed to toxicants or pathogens on the airway surfaces. Basal
cells serve as the primary progenitors from which ciliated, secretory,
and goblet cells differentiate during development and during repair
after injury.1
Airway columnar cells are indirectly attached to the basement mem­
brane via desmosomal interactions between basal and columnar cells.
Hemidesmosome structures maintain the connection of basal cells to
basement membranes. Ultrastructural analyses of epithelium of bron­
chial biopsies or nasal polyps from patients with asthma demonstrate
weakened desmosomes and reduced attachment of epithelial cells to
the basal lamina impairing barrier function and aggravating inflam­
matory cell infiltration.2
The diversity of epithelial cells lining the airways are derived from
foregut endodermal progenitors that are specified early in embryonic
development as the trachea and esophagus separate and the epithelial
cells lining each structure differentiate. Conducting airway epithelial
cell progenitors are distinguished from those that form the peripheral,
 CHAPTER 44  Airway Mucus and Mucociliary System 703

alveolar regions of the lung in the embryonic period. Expression of
SOX2, a transcription factor required for airway epithelial cell differ­
entiation, regulates differentiation of epithelial cells lining conducting
airway and submucosal glands, while SOX9 and ID2 mark progenitors
that form the alveoli.3 In conducting airways, basal cells express TP63
and SOX2 and serve as primary progenitors of goblet, ciliated, and
other secretory cells.4 Ciliated, goblet, club, and neuroendocrine cells
are derived from basal cells or other embryonic progenitors via tran­
scriptional networks that are strongly regulated by Notch signaling.
Intercellular signaling between airway epithelial cells via Notch ligands
such as JAG1 and JAG2 activate Notch receptors that determine epithelial
cell differentiation. In the absence of Notch activity, basal or club cell

KRT14

MUC5B

TUBA4A

TP63

NKX2.1

KRT5 9 Months
4 Years
B C
Fig. 44.1  Representative hematoxylin and eosin (A) or immunofluorescence (B and C) images show human
submucosal glands and conducting airways. Sections were immunostained with alpha tubulin (TUBA4A),
keratin14 (KRT14), and mucin (MUC5B) identifying ciliated, basal and goblet cells. (B) Submucosal glands
and ducts are identified by the preferential distribution of MUC5B. Ciliated cells (white) line most of the
airway surface. (C) Immunofluorescence confocal images of human lung sections were stained with basal
cell markers TP63 and KRT5 identifying conducting airways that do not stain strongly with NKX2.1.
Continued
704 SECTION E  Respiratory Tract

Mucin
layer Mucin

Conducting
airway

Basement
membrane

Vagus
nerves Submucosal
gland

Cell type Cell type specific marker

Goblet SPDEF, MUC5AC, MUC5B

Secretory (club) SCGB1A1

Ciliated FoxJ1, Alpha tubulin (TUBA4A)

Serous Lysozyme

Basal KRT14, KRT5, TP63 (P63)

Myoepithelial KRT5, TP63

Neuroendocrine CGRP (CALCA)

D
Fig. 44.1, cont’d (D) The organization of diverse epithelial cell types that line conducting airways and sub-
mucosal glands in the human lung. Conducting airways are lined by basal, ciliated, secretory, club, brush,
neuroendocrine, and goblet cells that protect the airway and mediate mucociliary clearance. Basal and secre-
tory or club cells serve as epithelial progenitors that generate diverse differentiated epithelial cell types.
Extensive submucosal glands (SMG) secrete mucus, fluid, electrolytes, and host defense proteins onto
airway surfaces. Goblet and serous cells secrete diverse innate immune proteins into submucosal gland
ducts lined by primarily ciliated and basal cells. SMGs are highly innervated and respond to irritants and
neurochemical mediators. Glands are lined by myoepithelial cells whose contractions release mucus into the
ducts and onto the airway surfaces.

progenitors differentiate into ciliated cells; increasing levels of Notch
causes secretory cell differentiation, and high levels of Notch cause
goblet cell differentiation.5,6 In contrast, suppression of Notch favors
neuroendocrine cell differentiation in the embryonic lung.
Each epithelial cell type is readily identified by their morphology
and protein expression profiles that have evolved for unique functions
that maintain tissue homeostasis under steady state and during repair.
The epithelial lining of nasal passages and sinuses share cellular char­
acteristics and functions with conducting airways; both are lined pri­
marily by a pseudostratified epithelium with an abundance of complex
submucosal glands that, together, mediate mucociliary clearance. Dis­
ruption of normal repair processes and loss of normal differentiation
program of the airway and nasal epithelia causes goblet cell metaplasia
and hyperplasia, which impairs mucociliary clearance associated with
chronic lung diseases and rhinosinusitis.
NASAL PASSAGES AND SUBMUCOSAL GLANDS
Nasal passages and sinuses play critical roles in hydration of inhaled gases
and protecting the peripheral respiratory tract from particles, microbes,
and toxicants. At homeostasis, epithelial surfaces of nasal passages and
sinuses are lined primarily by ciliated cells and contain a plethora of
submucosal glands that are lined primarily by serous and goblet cells.
Nasal passages contain Bowman glands, which are predominantly serous
 CHAPTER 44  Airway Mucus and Mucociliary System 705

and actively secrete liquids. Anterior nasal glands are composed of exten­
sive ducts and acini, lined predominately by serous cells secreting fluids.
Submucosal glands produce both serous fluid and mucus onto nasal
surfaces. As in the airways, these glands secrete a variety of host defense
molecules, including lactoferrin, lysozyme, and fluid and electrolytes that
are highly responsive to adrenergic, cholinergic, and irritant stimulation.
In the airways, the nasal turbinates are highly innervated and respond
to neurosensory stimulation causing nasal gland secretion. Similar to
the processes in conducting airways, abnormalities in ciliary function,
defects in mucus hydration and production, as seen in CF, and mucus
hyperproduction contribute to rhinosinusitis and associated chronic
bacterial infection. There is a high prevalence of chronic rhinosinusitis
in the setting of asthma wherein Th2 inflammation activates goblet
cell metaplasia and mucus hypersecretion.7-9 Consistent with findings
in allergic airway disease, Th2 signaling, activated by production of
TSLP and IL-33 by airway epithelial cells, recruits eosinophils and Th2
immune cells to the nasal epithelium.10,11
CILIATED CELL DIFFERENTIATION AND FUNCTION
Ciliated cells are readily identified by their multiple apical, motile cilia
that are composed of unique motor proteins (e.g., axonemal dynein
that drive their coordinated beating, critical for mucociliary clearance).
In the absence of Notch signaling, airway TP63+(p63), p73+ progenitors
differentiate into ciliated cells under direction of GMNC, a master
regulator of ciliated cell fate. GMNC activates multicilin (MCIDAS),
E2F4/5, and DEUPI, causing centriole amplification, and organization
of apical microtubules that contribute to function of the cilia. Activa­
tion of a transcriptional network regulated by FOXJ1, RFX, and MYB
activates the transcription and assembly of ciliary proteins. IL-13 cytokine
response also inhibits multicilin ciliated cell differentiation independently
of Notch signaling. Fig. 44.2A represents a schematic of the hierarchy
of transcription factors and associated regulators of multiciliogenesis
that drives ciliated cell differentiation. Functional significance of regula­
tors of ciliogenesis is underscored in presentation of clinical symptoms

(Basal / Club progenitor cells) (Basal/Club progenitor cells)

Sox2+/Tp63+/Krt5+/14+/Tp73+ Sox2+/Tp63+/Krt5+/14+
Il-13 Ciliated cell Il-13/virus
lineage Stat signaling
Notch
signaling Jak-Stat Notch Ras
signaling Runx2
Erk1/2
Gmnc FoxM1
Nkx2-1
FoxA2 Spdef

Mcidas, E2F4/5, Deup1

FoxA3 Cell
Muc5ac Cycle
FoxJ1, FoxN4, Rfx, Myb Muc5b Tslp, Il-33, Il-25
(Goblet Cells) (Th2 response)
A (Ciliated cells) B
KRT14 KRT14
MUC5B
MUC5B
TUBA4A
TUBA4A

D
3 Years
C
Fig. 44.2  (A) Multiciliated cells are derived from basal and secretory progenitor cells. TP73 and Gmnc act
as master transcriptional regulators of ciliated cell differentiation. Notch signaling and IL13-JAK/STAT pathways
inhibit ciliated cell differentiation. (B) Regulators of goblet cell differentiation from basal and club progenitor
cells are shown. SPDEF is required for differentiation into airway and submucosal gland goblet cells. Mucus
production is enhanced upon stimulation by environmental exposure and infection. SPDEF enhances Th2
cytokine responses by the goblet cells, contributing to mucus hyperproduction. (C and D) Low and high
magnification immunofluorescence confocal images of 3-year-old human lung sections that were stained
with KRT14 (basal cells), MUC5B (goblet cells) and TUBA4A (ciliated cells) in small airways.
706 SECTION E  Respiratory Tract
for mucociliary clearance defects such as those manifested by individuals
with biallelic nonsense mutations in the MCIDAS.12-18
Ciliated cells are linked via calcium currents that synchronize ciliary
beating required for the directional cephalad movement of the muco­
ciliary layer up the airway. Mutations in more than 35 genes encoding
the structural proteins forming cilia (e.g., outer dynein arm proteins
and microtubular motor proteins) cause severe chronic lung disorders
termed primary ciliary dyskinesias (PCD). These disorders are diagnosed
by genetic testing or testings of clinical symptoms of chronic otitis,
sinusitis, and pulmonary infection bronchiectasis together with iden­
tification of causal gene mutations, decreased nasal nitric oxide (NO),
by videomicroscopy of airway brushings or biopsies, and by ultrastruc­
tural changes in ciliary structures. PCD is variably associated with
abnormalities in organ situs (e.g., situs inversus, as seen in Kartagener
syndrome). The severity of sinus and pulmonary disease caused by
mutations in the ciliary proteins in PCD highlights the critical role of
ciliated cell function and mucociliary clearance in innate defense of
the respiratory tract. Although not associated with genetic mutations,
disruption of ciliated cell functions as commonly seen in many chronic
lung diseases (e.g., COPD, IPF, and asthma) contributes to infection,
morbidity, and mortality in these disorders.19-21
GOBLET CELL DIFFERENTIATION
Although the tracheal basal and airway luminal secretory cells serve as
common progenitors of both ciliated and goblet cells, the genetic and
signaling networks controlling goblet cell differentiation are highly
distinct from those regulating ciliated cell identity. Goblet cell fate is
favored by activated Sam-pointed domain Ets-like factor (SPDEF),
FOXA3, and increased Notch signaling, which inhibit differentiation
of ciliated cells. SPDEF regulates a transcriptional network that includes
upregulation of FOXA3 and inhibition of FOXM1, NKX2-1, and FOXA2.
SPDEF activates synthesis of mucins (MUC5AC and MUC5B) in sub­
mucosal glands and in airway epithelial cells. Although goblet cells are
found throughout the normal airway and submucosal glands, their
differentiation and role in mucus secretion is strongly induced by expo­
sure to allergens and toxicants—for example, signaling pathways and
inflammatory cytokines such as IL13 and JAK/STAT activated after
exposure to environmental toxicants, microorganisms, and virus infec­
tion induce SPDEF.22-29 A schematic of the hierarchical model of key
transcription factors and signaling pathways that regulate goblet cell
differentiation and mucin gene expression is shown in Fig. 44.2B. Goblet
cell metaplasia or “hyperplasia” accompanies and contributes to both
chronic lung disease and rhinosinusitis. The hyperproduction and secre­
tion of mucins by goblet cells causes airway narrowing obstruction and
often accompanies infection, as seen in COPD, CF, PCD, and asthma.
Similarly, these disorders are associated with mucus hyperproduction
or hyperplasia of submucosal glands. Fig. 44.2C-D show low- and high-
magnification views which illustrate the distribution of basal progenitor,
luminal differentiated goblet, and ciliated cells in representative confocal
images of human lung sections immunostained with KRT14 (basal),
MUC5B (goblet), and TUBA4A (ciliated) cells.
In light of its role in the pathogenesis of goblet cell metaplasia,
mucus hyperproduction, and airway inflammation, therapies to modulate
SPDEF activity present a potential approach in treatment of chronic
airway diseases. Elucidation of the mechanisms involved in expression
and function of SPDEF represent potential therapeutic targets of dis­
orders complicated by mucus hyperproduction and inflammation. For
example, SPDEF is regulated via STAT-6 signaling downstream of IL-4
and IL-13 and is inhibited by miRNA 125b. Regulatory regions of the
SPDEF gene are controlled via methylation of CpG sites near the
promoter.30,31
ROLE OF SUBMUCOSAL GLANDS IN
MUCOCILIARY CLEARANCE
The combined surface area of nasal and airway submucosal glands is
vastly greater than that of the conducting airway surface per se. The
duct of each submucosal gland is lined primarily by serous and ciliated
cells. Glandular structures in submucosal glands are lined by goblet
cells and serous cells that produce a variety of innate immune proteins,
mucins, electrolytes, and water. Myoepithelial cells encircling the acini
are innervated and mediate mucus secretion in response to neural inputs.
Massive secretory responses can be elicited from submucosal glands
after stimulation by irritants and toxicants.32 Submucosal glands secrete
mucins, predominantly MUC5B, and lesser amounts of MUC5AC, and
a variety of innate host defense proteins, antimicrobial peptides, includ­
ing lysozyme, lactoferrin, β-defensins, and surfactant proteins SP-D
and SP-A. The proteinaceous products of submucosal glands are precisely
balanced with fluid and electrolyte secretion that enables their rapid
dispersal onto the airway surfaces, creating the periciliary layer that
moves the mucous gel up the airway by ciliary activity. The critical role
of fluid and electrolyte secretion in submucosal glands and airway epi­
thelial cells in airway homeostasis is highlighted by the severe pulmonary
disease and rhinosinusitis caused by mutations in cystic fibrosis trans­
membrane conductance regulator (CFTR). Recurrent sinusitis and airway
infections, bronchiectasis, and pulmonary tissue remodeling in cystic
fibrosis are caused in large part by the lack of chloride, bicarbonate,
and water secretion onto the epithelial surfaces disrupting mucociliary
clearance.33
MUCUS AND MUCINS
Mucus is a complex mixture of mucins, diverse innate defense proteins,
metabolites, fluids, and electrolytes whose abundance and composition
varies along the cephalocaudal axis of the lung and nasal epithelium,
during environmental exposures and in the setting of acute and chronic
lung diseases. Airway mucins represent a family of polymeric, highly
glycosylated proteins produced by airway epithelial cells and submucosal
glands and can be subdivided into nonpolymerizing, secreted mucins
and tethered mucins that are anchored at cell surfaces and gel-forming
mucins, the most abundant of the latter are MUC5B and MUC5AC.
There are at least 21 genes encoding human mucins, of which 14 are
expressed in airway epithelial cells.7,34 MUC1, 4, 16, 20, 21, and 22 are
cell-surface associated. MUC5B and MUC5AC are variably expressed
by both serous (club cells) and goblet cells in conducting airways and
are stored in goblet cells. MUC5B is most highly expressed in the goblet
cells of submucosal glands, while MUC5AC is more highly expressed
in airway goblet cells. MUC2, widely expressed at high levels in the
gastrointestinal tract, is not normally expressed in the upper airways but
is variably detected in patients with CF and COPD. MUC7, a monomeric
mucin, and MUC19, a polymeric secreted mucin, are expressed primar­
ily in salivary glands but are also expressed in airway epithelial cells.
At baseline, serous and airway goblet cells produce and secrete mucins
that are rapidly hydrated and undergo quaternary structural changes as
the mucociliary gel layer is formed. Fluid, secreted proteins, electrolytes,
calcium, and metabolites interact to create the periciliary fluid layer
upon which the gel-forming mucins, MUC5B and MUC5AC, ride by
ciliary activity up the airway in clearance. Submucosal glands are capable
of rapid, massive secretory activity in response to irritants and neural
stimulation, cyclic adenosine monophosphate (cAMP), muscarinic activ­
ity, and substance P. Mucus hydration is strongly influenced by CFTR
that regulates chloride and bicarbonate secretion, critical for mucus
and airway hydration and for the quaternary organization of mucus
strands. ENAC, the amiloride-sensitive sodium channel that serves to
 CHAPTER 44  Airway Mucus and Mucociliary System
reduce airway liquid, is highly active in CF. Increased ENAC activity
causes surface liquid resorption by airway epithelial cells dehydrating
mucus. Airway fluid and electrolyte homeostasis is regulated by P2Y2
purinergic receptor activity that responds to ATP release after cell injury.
Recent studies demonstrated that submucosal goblet cells release
MUC5B as mucin bundles or extended strands that are coated by lesser
amounts of MUC5AC, as mucus is released from the submucosal glands.
MUC5AC coats the strands of MUC5B and provides anchoring activ­
ity that slows the transport of the mucus gel up the airway surface
liquids.33-36 Recent insights into the role of MUC5B and MUC5AC
are derived from studies in transgenic mice in which each gene was
deleted. Gene targeting of MUC5B caused severe rhinosinusitis and lung
pathology associated with failed mucociliary clearance, the accumula­
tion of particles in airways, airway obstruction, and chronic infection
demonstrating its critical role in innate defense of the lung. In contrast,
deletion of MUC5AC in mice did not cause overt airway disease, but
ameliorated allergy-induced AHR without influencing Th2 inflam­
mation, suggesting its potential role in airway plugging and asthma-
like inflammation. MUC5AC is required for the clearance of parasitic
nematodes and inhibits neutrophilic inflammation during viral infec­
tion, supporting its importance in innate immunity. Similarly, MUC1
is immunomodulatory, suppressing responses to bacterial infection,
perhaps the inhibition of TLR signaling.
THERAPEUTIC APPROACHES (ASTHMA/CHRONIC
OBSTRUCTIVE PULMONARY DISEASE)
Glucocorticoids
Glucocorticoids (GCs) are effective in management of asthma, aller­
gic rhinitis, and COPD. GCs are administered by inhalation (inhaled
corticosteroids, ICS) or systemically (SC); both act by inhibiting mucus
gene expression and inflammation. Patients with mild, persistent
asthma are typically treated with a low dose of ICS, whereas those
with moderate asthma are treated with low doses of ICS in combina­
tion with bronchodilators, for example, LABA (long-acting β2-agonists).
Fig. 44.3 and Table 44.1 outline the range of GCs and their mechanisms
of action, along with other therapeutics that are currently used for
patients with asthma and COPD. Despite their effectiveness in improv­
ing lung function and ameliorating asthma symptoms, chronic use
of ICS and SC is associated with significant effects, including loss of
bone mineral density, development of cataract and glaucoma, high
blood pressure, and suppression of hypothalamus-pituitary adrenal axis
Budesonide, Beclomethasone dipropionate,
Fluticasone propionate, Ciclesonide (CIC)
Omalizumab
Theophylline
Azithromycin,
Clarithromycin,
Erythromycin
Mepolizumab Asthma
COPD
Tiotropium bromides,
Aclidinium bromides.
Tezepelumab Roflumilast
(AMG157) Cilomilast
Montelukast,
Pranlukast,
Zafirlukast,
Zileuton.
Fig. 44.3  Schematic representation of currently used therapeutics for
asthma and chronic obstructive pulmonary disease.
707
(HPA), skin thinning, and bruising. In children, long-term treatment with
ICS results in growth retardation that could be driven by loss in bone
mineral density and HPA suppression. Eosinophilic asthma generally
responds well to ICS and CS, whereas patients with noneosinophilic
asthma generally respond poorly to ICS treatment. Alternative GCs, for
example the nonhalogenated ICS ciclesonide (CIC), alleviates asthma-
related symptoms and may alleviate systemic side effects of ICS. CIC is
administered using an effectively designed inhaler device (CIC-HFA-
pMDI). At the time of administration, CIC is in a prodrug form and is
activated inside the respiratory tract. This mechanism of delivery and
activation facilitates increased lung deposition and reduced oropharyn­
geal deposition of the drug, which leads to reduced local and systemic
side effects.37-39
Theophylline
Theophylline is a xanthine derivative used in the treatment of asthma
and COPD for many decades. Theophylline in combination with inhaled
glucocorticoids improves lung function of COPD and asthma patients
based on improvement in forced expiratory volume (FEV1) after short-
term treatment. Theophylline acts as an antiinflammatory agent and
bronchodilator. Antiinflammatory effects are associated with reduced
eosinophilic and neutrophilic inflammation, likely mediated by inhi­
bition of phosphodiesterase activity. Side effects, including headache,
dizziness, insomnia, nausea, and vomiting and reports of increased
mortality among COPD patients has limited the use of theophylline.40,41
IgE Inhibitors
Omalizumab is a humanized anti-IgE antibody, which is US Food and
Drug Administration (FDA) approved for treatment of asthma. Omali­
zumab binds to serum IgE and inhibits its binding to the principal IgE
receptors.42,43 In combination with inhaled corticosteroids, subcutaneous
omalizumab resulted in decreased asthma symptoms and improved
lung function. Omalizumab reduced use of β-agonists and inhaled
corticosteroids in patients with persistent severe asthma. Complications
including anaphylaxis and cardiovascular diseases are reported by treat­
ment with omalizumab.44,45
IL5 Inhibitors
Mepolizumab is an FDA-approved monoclonal antibody that blocks
binding of IL-5 to its receptor on eosinophil surfaces, inhibiting inflam­
mation. Anti-IL5 antibody reduced eosinophil numbers in the bone
marrow, eosinophil myelocytes, and metamyelocytes without altering
CD34+, CD34+/IL5R alpha+ cells supporting its role in maturation of
eosinophil progenitors in the bone marrow. Additionally, there was a
decrease in bronchial mucosal CD34+/IL5R alpha mRNA (+) cell numbers
after anti-IL5 therapy, suggesting a potential role of IL-5 in local tissue
eosinophilopoiesis.46,47 Subcutaneous or intravenous administration of the
drug resulted in reduction of eosinophilic counts, improved lung function,
and reduced exacerbation of asthma and COPD-related phenotypes in
patients over a treatment course of 1 year. No major side effects were
reported for the majority of patients who were treated with the drug.48,49
TSLP Inhibitors
Tezepelumab (AMG-157) is a human IgG2 monoclonal antibody against
TSLP being tested at present. AMG-157 blocks TSLP binding to its
receptor encoded by the type 1 cytokine receptor-like factor 2 (CRLF2)
inhibiting pro-inflammatory signaling. Tezepelumab reduced exacerba­
tions in eosinophilic asthma patients, decreased blood eosinophils, IgE,
periostin, and reduced FeNO (fraction of exhaled nitric oxide) levels and
showed improved FEV1. Because TSLP regulates both eosinophilic and
noneosinophilic inflammatory responses, its blockade was effective in
patients who were relatively unresponsive to high doses of ICS and
708 SECTION E  Respiratory Tract

TABLE 44.1  Asthma and Chronic Obstructive Pulmonary Disease Therapeutics

Drugs
Budesonide, beclomethasone
dipropionate, fluticasone
propionate, Ciclesonide
(CIC)
Theophylline
Omalizumab
Mepolizumab
Tezepelumab (AMG-157)
Clarithromycin, azithromycin,
erythromycin
Tiotropium bromides,
aclidinium bromides
Roflumilast, cilomilast
Montelukast, pranlukast,
zafirlukast, zileuton
Drug Category Mechanisms
Glucocorticoids Inhibition of mucus gene expression,
antiinflammatory
Xanthine Antiinflammatory
Anti-IgE monoclonal Blocks IgE binding to receptor and
antibody downstream inflammatory signaling
Anti-IL-5 IL-5 blocking antibody, inhibition of
eosinophil inflammation, reduction
in blood eosinophils
Anti-TSLP monoclonal Inhibits TSLP binding to TSLPR and
antibody inflammatory signaling
Macrolide antibiotics Inhibit antimicrobial neutrophil
infiltration
Anticholinergics Inhibit airway obstruction by
antagonizing cholinergic signaling
Inhibit mucus production but no
effect on rheologic properties
PDE4 inhibitors Inhibit PDE4 activity, reduced
recruitment of neutrophils and
eosinophils
Anti-leukotrienes Antiinflammatory, inhibit eosinophil,
neutrophil, and macrophage activity
Findings
• Improved FEV137-39
• Improved FEV140,41
• Improved FEV1
• Reduced use of β-agonist and inhaled corticosteroids (ICS)42-45
• Improved FEV1
• Reduced symptoms of asthma and COPD exacerbations46-49
• Improved FEV1
• Reduced exacerbations50,51
• Reduced airway hyper responsiveness, IL-8, neutrophils and
elastase, asthma-related emergency visits and hospitalization
• Decreased use of ICS for patients with noneosinophilic
asthma52-54
• Reduced exacerbations of COPD
• Increased exercise capacity and improved quality of life55-57
• Improvement in FEV1
• Improved health-related quality of life58
• Improved FEV1
• Reduced use of bronchodilators and ICS59,60

FEV1, Forced expiratory volume in 1 second.

Summary of currently used drugs and their mechanisms of action to produce significant improvement in lung function in multiple clinical studies
with patients with asthma or chronic obstructive pulmonary disease (see text for details).

long-acting β-agonists. Because TSLP may mediate diverse aspects
of innate immunity, chronic use of anti-TSLP therapeutics warrants
further study.50,51
Macrolide Antibiotics
Macrolides act as antiinflammatory, immunomodulatory, and antibac­
terial agents that are used in the treatment of asthma. These agents act
by inhibiting chemotaxis and infiltration of neutrophils, are generally
well tolerated, and are used primarily for treatment of noneosinophilic
asthma. Chronic macrolide treatment is associated with hearing defects,
cardiovascular complications, and bacterial resistance to the antibiotics.
Oral macrolides are generally used in combination with inhaled gluco­
corticoids and bronchodilators in treatments of refractory asthma and
COPD. Macrolide therapy reduced airway hyperresponsiveness, neutro­
philic inflammation as well as Il-8 and neutrophil elastase levels in non-
eosinophilic asthmatics. Improved quality of life, reduced asthma-related
hospitalization, and lowered use of inhaled corticosteroids were reported
in noneosinophilic asthma patients when treated with macrolide. Their use
in treatment of eosinophilic asthma has not been supported at present.52-54
patients with COPD or severe, persistent asthma. Tiotropium bromide
has a longer duration of action and is given once daily, while activity
of ipratropium is of much shorter duration. In long-term studies in
COPD, tiotropium treatment did not significantly improve FEV1 but
reduced clinical exacerbations. Aclidinium bromide, recently FDA
approved, decreased COPD exacerbations and improved lung function
with fewer cardiovascular side effects than tiotropium and may be an
alternative for long-term treatment of COPD patients.55-57
PDE4 Inhibitors
Roflumilast, an FDA-approved drug used in treatment of COPD,
improved FEV1 and peak expiratory flow rate (PEFR) after broncho­
dilation, and improved quality of life in patients treated with the drug.
Its antiinflammatory effects are mediated by inhibition of PDE4 (the
predominant phosphodiesterase isoform in inflammatory cells) reducing
recruitment of neutrophils and eosinophils. Roflumilast was recom­
mended for use in patients with severe to very severe COPD in com­
bination with LABA, SABA, or inhaled corticosteroids. Data regarding
rehospitalization, morbidity, and mortality are pending at present.58

Anticholinergics
Cholinergic activity mediated by M1, M2, and M3 cholinergic receptors
in the setting of asthma and COPD increases airway smooth muscle
constriction and mucus secretion. Anticholinergic drugs, generally
administered by inhaler, enhance bronchodilation in asthma and COPD.
Tiotropium is used as monotherapy or in combination with LABA in
Antileukotrienes
Leukotrienes are expressed primarily in mast cells and basophils after
exposure to allergen. Most of the pathologic effects of cysteinyl leuko­
trienes (CysLTs) are mediated by activation of the CysLT receptors
expressed on immune/inflammatory cells, airway smooth muscle cells,
bronchial fibroblasts, and vascular endothelial cells. Leukotrienes promote
 CHAPTER 44  Airway Mucus and Mucociliary System
eosinophilic inflammatory responses, airway bronchoconstriction, mucus
secretion, and plasma exudation in asthma. LTRA reduces asthma
exacerbations by reducing LT signaling pathway–induced eosinophilic
responses. Zileuton is an FDA-approved drug that inhibits synthesis of
bioactive CysLT by inhibiting lipoxygenase (5-LO), the catalytic enzyme
involved in biosynthesis of CysLTs. Zileuton improved FEV1 and reduced
asthma exacerbations based on decreased hospitalization and emergency
department visits during a 12-month study period. One of the common
side effects of using this drug is hepatic injury manifested by increased
accumulation of alanine aminotransferase (ALT).
Montelukast, pranlukast, and zafirlukast are commonly used CysLT1
receptor antagonists (LTRA) with antiinflammatory effects and are
shown to improve lung function based on FEV1 and reduce use of
bronchodilators and inhaled corticosteroids. The drugs were adminis­
tered orally as monotherapy for mild to moderate asthma or in com­
bination with inhaled ICS and LABA for severe, persistent asthma.59,60
THERAPEUTIC APPROACHES (CYSTIC FIBROSIS)
Cystic Fibrosis
Cystic fibrosis is an autosomal recessive disease caused by mutations
in the ABCC7 gene encoding the cystic fibrosis transmembrane con­
ductance regulator (CFTR). The CFTR protein is located at the apical
membranes of epithelial cells in many organs where it transports chloride
and bicarbonate onto luminal surfaces, including those of sinuses and
airways. Mutations in the CFTR compromise the periciliary fluid leading
to airway dehydration, recurrent microbial colonization, and infection.
Mutations in the CFTR impair mucociliary clearance, causing recurrent
pulmonary and sinus infections, frequently caused by Pseudomonas
aeruginosa, Staphylococcus aureus, and Haemophilus influenzae in estab­
lished disease.61,62 Dehydration and inspissation of mucus, the accu­
mulation of DNA derived from microbial pathogens, and inflammatory
cells contribute to airway obstruction.63
Until recently, pharmacologic treatments for CF-related respiratory
disorders included mucolytics, antibiotics, the inhalation of hypertonic
solutions, and antiinflammatory agents. The recent development of
drugs that enhance the stability, routing, and/or function of CFTR
mutant proteins results in restoration of chloride secretion that will likely
transform the treatment of CF. Fig. 44.4 is a schematic of currently used
therapeutics for CF. Both corticosteroids and antiinflammatory agents
(e.g., NSAIDs) have been used to modify symptoms and progression
of lung disease. Use of both drugs are associated with complications
that have limited their widespread use in CF patients.64
Aztreonam, Azithromycin,
Tobramycin, Colistin, Levofloxacin.
Dornase alfa
Ibuprofen
CF
Hypertonic saline,
Mannitol
Ivacaftor Sodium bicarbonate
Tezacaftor
Lumacaftor
Fig. 44.4  Schematic representation of currently used therapeutics for
cystic fibrosis.
709
Antimicrobial Treatment of Cystic Fibrosis
While the choice of antibiotic treatments is best guided by the suscep­
tibility of the microbial pathogens and the safety of the antibiotic for
a specific indication, the bacterial flora in CF consists of multiple organ­
isms that persist despite the antibiotic treatments used for exacerbations
or for prevention of pulmonary decline. Prevention and treatment are
often guided by routine sputum culture or bronchoscopic samples used
for surveillance and diagnosis of the microbial flora in CF patients.
Inhaled antibiotics are routinely used both to prevent or to treat exac­
erbation and to minimize the systemic toxicity as related to antibiotics.
Levofloxacin, tobramycin, colistin, aztreonam, and azithromycin are
commonly used in the treatment of CF. Table 44.2 provides a list of
the antibiotics, mechanisms of action, and their effects in treatment of
CF. These drugs are generally well tolerated when administered via
nebulizer or by liposomal formulations that allow for efficient delivery
of drugs to the airway, thus reducing systemic side effects from antibiotic
treatment. Azithromycin may have both antimicrobial and antiinflam­
matory effects.65-68
Antiinflammatory Therapies
Ibuprofen, a widely used analgesic and antipyretic, acts as an antiin­
flammatory agent and has been used in the treatment of CF. Clinical
studies support its role in improving FEV1 and the rate of decline of
FEF25-75 and is frequently used in therapy of CF. Complications related
to use of ibuprofen and glucocorticoids have limited their use in CF.
High doses of ibuprofen were associated with gastrointestinal and renal
side effects that limit its use in some patients.69
Dornase Alfa
Dornase alfa is recombinant human DNase that cleaves to extracellular
DNA to enhance mucociliary clearance and improve lung function and
may reduce inflammatory responses to bacterial and cellular debris in
CF. Dornase alfa is administered by inhalation and remains widely used
in the treatment of cystic fibrosis.70,71
Hypertonic Solutions
Hypertonic solutions, including hypertonic saline, sodium bicarbonate,
and mannitol, have been used to increase airway hydration by increasing
surface liquid through osmotic forces to enhance mucus clearance and
lung function. Hypertonic solutions are generally well tolerated by
inhalation and are presently widely used by CF patients. Although clini­
cal studies are limited, improved FEV1 and FEF25-75 and declines in
exacerbations were observed.72-74
CFTR Correctors and Potentiators
Identification of CFTR as a chloride-bicarbonate conductance channel
led to high-throughput screening and identification of drugs effective
in enhancing the activity of the mutant CFTR at surface membranes
or enhancing stability and trafficking of CFTR through the epithelial
cell to improve its function.75 Ivacaftor was approved for treatment of
patients with the G551D mutation. It acts by increasing the time for
which the CFTR channel is open and thereby enhances residual func­
tion of the ion channel to potentially improve electrolyte balance of
the mucus. Ivacaftor improves lung function in patients with G551D
and other similar mutations, increasing FEV1 and weight gain, and has
been approved for use in patients 6 years of age and older.76 Although
ivacaftor was not effective in treatment of patients with CFTR phenyl­
alanine deletion (FΔ508) mutation (the most common CFTR mutation
in Caucasians), tezacaftor was approved in combination with ivacaftor.
The combination therapy reduced pulmonary exacerbations and
improved pancreatic function. Similarly, the combination of lumacaftor
710 SECTION E  Respiratory Tract

TABLE 44.2  Cystic Fibrosis Therapeutics

Drugs Category Mechanisms Findings
Tobramycin, colistin, Antibiotics • Tobramycin inhibits mRNA transition • Improved FEV165-68,83-90
levofloxacin, • Colistin and aztreonam interfere with bacterial cell
aztreonam (AZLI), membrane integrity, increase permeability
azithromycin • Levofloxacin interferes with DNA type II
topoisomerases and creates DNA double strand breaks
• AZLI inhibits neutrophil infiltration and chemotaxis
Ibuprofen Nonsteroidal • Inhibition of neutrophil migration, adherence, • Improved FEV1, FVC, and FEF69,91
antiinflammatory aggregation
drug
Dornase alfa Mucolytic agent • DNase cleaves extracellular DNA • Improved FEV1, reduced infection70,92-95
Hypertonic saline (HS) Airway surface • Increased mucociliary clearance • Improved lung function based on FEV1,
Mannitol hydration FVC, and FEF72-74,96,97
Sodium bicarbonate
Ivacaftor (P), tezacaftor CFTR potentiator (P), • CFTR trafficking, stability, open state • Improved lung function based on FEV1,
(C), lumacaftor (C) CFTR corrector (C) FVC, and FEF76-79,98-100

CFTR, Cystic fibrosis transmembrane conductance regulator; FEF, forced expiratory flow; FEV1, forced expiratory volume in 1 second;
FVC, forced vital capacity.
Summary of currently used drugs and their mechanisms of action shown to produce significant improvement in lung function in multiple clinical
studies with CFTR patients (see text for details).

and ivacaftor improved lung function and restored chloride function
in CF patients homozygous for the CFTR FΔ508 mutation. New CFTR-
related drugs are being developed in hopes of creating mutation-specific
therapies that will be effective against the more than 2000 disease-
associated mutations.77-79
SUMMARY
In the previous edition of this chapter (Airway Mucus and the Muco­
ciliary System, 2013), Dr. Duncan Rogers highlighted the discovery of
SPDEF as a central regulator of mucin secretion, antiviral, and Th2
immunity related to chronic airway disorders of mucociliary clearance.
The first part of this chapter is an update of our current understand­
ing of airway epithelial and submucosal gland biology. The chapter
updates the range of therapeutics in management of asthma, COPD and
CF. Asthma and COPD therapeutics include antiinflammatory agents,
such as glucocorticoids, xanthines, PDE4 inhibitors, and antileukotri­
enes. One of the challenges of these therapeutics is the broad range of
side effects from their long-term use, highlighting the need for target-
specific drugs. Discoveries in identification of biomarkers specific to
distinct types of asthma-related inflammation will enable development
of endotype-specific treatments. New biologicals, for example mepo­
lizumab (IL-5 blocking antibody, Table 44.1), that specifically target
eosinophilic inflammation represent effective targeted therapy for asthma
pathogenesis.
Advances regarding molecular and cellular processes involved in the
pathogenesis of chronic airway disorders are providing a diversity of
promising approaches for prevention and treatment of lung diseases.
Careful clinical, pathologic endotyping of patient subgroups will provide
the framework to optimize patient-specific therapies. Knowledge of
molecular mediators of innate and acquired immunity, which underlie
the pathogenesis of chronic lung diseases will be useful in developing
molecular biomarkers to diagnose and identify therapies directed at
specific molecular targets.
Modifications in drug design and innovations in drug delivery systems
are improving quality of life in patients with chronic pulmonary disorders.
Future discoveries targeting molecular and cellular pathways specific to
chronic lung diseases and the development of cell-specific and efficient
drug delivery systems are expected to improve treatments for asthma,
COPD and CF.80,81 Precision and personalized medicine, as developed
for CF, may synergize treatments and minimize toxicity of therapeutics
for chronic pulmonary disorders like COPD, asthma, and CF.82
Acknowledgments
We would like to thank Mr. Joseph Kitzmiller (https://research.cchmc.org/
lungimage/) for the confocal images and Ms. Ann Maher for help with
manuscript preparation.
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 CHAPTER 44  Airway Mucus and Mucociliary System 712.e1

SELF-ASSESSMENT QUESTIONS
1. What treatment will increase the activity of CFTR FΔ508 mutation? c. Omalizumab
a. Hypertonic saline inhalation d. Ivacaftor and tezacaftor combination therapy
b. AMG-157 e. Tiotropium bromide
c. Ivacaftor 3. The recommended treatment for a 14-year-old with noneosinophilic
d. Tezacaftor and ivacaftor combination asthma is:
e. Inhaled corticosteroid a. Dornase alfa
2. What treatment is appropriate for a patient with clinical symptoms b. Hypertonic saline
of persistent asthma with a history of hepatic injury, high blood c. Mepolizumab
pressure, and family history of heart disease. d. Azithromycin (macrolide)
a. Zileuton e. Lumacaftor
b. Mepolizumab

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