Role of airway epithelial cells in development
of asthma and allergic rhinitis
YaoLi Wanga, Chunxue Baia,?, Ka Lia, Kenneth B. Adlerb, Xiangdong Wanga,?
aDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 20032, China
bMolecular Biomedical Sciences, NC State University, Raleigh, NC 27606, USA
Received 18 October 2007; accepted 21 January 2008
Available online 12 March 2008
Asthma and allergic rhinitis frequently coexist in the same patient. There is a similarity
and variation as well as potential relationship between asthma and allergic rhinitis. There
is an increasing evidence to suggest a major involvement of airway epithelial cells in
the pathogenesis of asthma and allergic rhinitis. The present review describes the
importance of the airway epithelial cell in the development of allergic airway diseases, its
role as the primary airway defense against exposure of the airway and lung to
inflammatory stimuli and antigens and as an important player through activation of
epithelial Toll-like receptors (TLRs) to provide an important link between innate immunity
and allergic disease. Additionally, airway epithelial cells can act as inflammatory
promoters capable of directing dendritic cells (DCs) towards a T helper 2 (Th2) response,
and as active producers of several inflammatory/anti-inflammatory mediators. It is
hypothesized that airway epithelial cells may play as both inflammatory initiator and
immuno-pathological feedback regulation between allergic rhinitis and asthma via release
of systemic inflammatory mediators. Thus, airway epithelial cells may be valuable
therapeutic targets for discovery and development of new drugs and/or new therapeutic
strategies to treat asthma and allergic rhinitis.
& 2008 Elsevier Ltd. All rights reserved.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
Role in viral infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
Role in innate immune responses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
Role in adaptive immune responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951
Role in allergic reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951
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0954-6111/$-see front matter & 2008 Elsevier Ltd. All rights reserved.
?Corresponding authors at: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 20032, China.
E-mail address: email@example.com (X. Wang).
Respiratory Medicine (2008) 102, 949–955
Role in airway hyper-responsiveness (AHR). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 952
Role in mucus overproduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 952
Role in allergic cascade. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953
TLR-involved mediators. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953
Role in allergic inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953
Role in airway remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953
Epithelial feedback regulation via systemic inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954
Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954
Asthma is a chronic, inflammatory condition of the lower
airways characterized by largely reversible airflow obstruc-
tion, airway hyper-responsiveness, and episodic respiratory
symptoms.1Allergic rhinitis (AR) is a disorder of the upper
airways resulting from IgE-mediated inflammation of the nose
upon contact of the nasal mucosa with allergens.1AR is a
common ailment, affecting 10–25% of the world’s population2
and has an impact on asthma as a public health initiative of
the World Health Organization based on the concept of ‘‘one
airway, one disease’’. Asthma and AR frequently coexist in the
same patient and are thought to share common predisposing
genetic factors which interact with environmental influ-
ences,3increasing in prevalence over recent decades.
The links between the upper and lower airways were
clinically noted and first envisaged in the early 1800s4and then
gradually elucidated and confirmed as the pathogenic unity of
the upper and lower respiratory tract in allergy. The relationship
between asthma and AR is also supported by epidemiological
studies, by histological, physiological, and immunopathological
characteristics, and by the positive effect of various therapies
on asthma symptoms in patients with rhinitis.5
Airway epithelial cells are the first line of defense against
exposure of the airway and lung to inflammatory stimuli and
antigens, and epithelial activation is one of characteristics
of asthma and AR, significantly associated with allergic
sensitization.6The association between two diseases is
believed to be primarily due to a common allergic trigger.
Thymic stromal lymphopoietin (TSLP) is a cytokine produced
by airway epithelium, orientating dendritic cells (DCs)
towards a T helper 2 (Th2) response and acting as an
essential link between epithelial cell activation and allergic
The present review describes current
evidence that airway epithelial cells are involved in the
pathogenesis of asthma and AR, by reviewing the impor-
tance and central role of airway epithelial cells in the
development of diseases. The potential role of nasal
epithelial cells in the pathogenesis of rhinitis is also
explored separately, although the number of works on nasal
epithelial pathophysiology is limited. It should also be kept
in mind that the results from bronchial epithelial studies
cannot be extrapolated into nasal epithelia, even though
there is a similarity between two.
Role in viral infections
Upper airway viral infections (URI), caused by different
types of the virus, are associated with the development of
airway inflammation. In particular, human rhinovirus (HRV)
infections could increase numbers of neutrophils and
lymphocytes in the upper airways,9and induce neutrophil
recruitment to the lower airways in subjects with asthma.
Cold, dry air (CDA) can cause symptoms of rhinitis and
obstructive airway responses. Epithelial cell shedding mostly
accompanies with clinical responses to CDA in the nose.10
Although the pathophysiology of these reactions is not fully
understood, it is possible that the respiratory mucosa of
individuals with CDA hypersensitivity cannot compensate for
the loss of water that occurs on exposure to the stimulus,
leading to epithelial damage. In addition to allergen and air
pollutants, the asthmatic airway is particularly susceptible
to respiratory virus infection, which can contribute to
40–80% of asthma exacerbations in both children and adults.
Of particular significance is the finding in asthma that
viruses usually caused only upper respiratory tract symptoms
also cause exacerbations in patients, especially in certain
The mechanisms by which viral infections can enhance
upper and lower airway inflammation are not fully defined,
but the growing evidence supports the concept that viral
modulation of epithelial function may initiate the inflam-
matory response (Figure 1). Infection of epithelial cells by
HRV has been shown to provoke the generation of a wide
variety of proinflammatory chemokines and cytokines,12
including interleukin (IL)-8(CXCL8), ENA-78(CXCL5), IP-
10(CXCL10), RANTES (CCL5), IL-1, IL-6 and IL-11. Once viral
infection of the epithelium initiates a proinflammatory
process, subsequent production of other mediators may
further contribute to the inflammation of the airway.
Role in innate immune responses
The lung is the largest surface in the body contacting with
the outside environment, and presents an estimated area of
100m2that comes into contact with approximately 10,000L
of inhaled air each day. The airway epithelium is the direct
interface with inhaled air and others and forms the initial
defense barrier against inhaled exogenous substances.
Epithelial cells play important roles in host defense,
inflammation, and regulation of immune responses.13A role
for epithelial roles in innate immunity has been described by
the fact that lysozyme and other mucosal substances could
prevent the growth of bacteria and other microorganisms
in the lung and airways.13Airway epithelium is emerging
as a regulator of innate immune responses to a variety
of insults. The maintenance of mucosal barrier function
integrity is another important component of the epithelial
ARTICLE IN PRESS
Y. Wang et al.950
armamentarium in innate immunity. Epithelial cells are
involved in killing or neutralizing microorganisms through
the production of several families of molecules, including
enzymes, permeabilizing peptides, collectins, protease
inhibitors, and others. The production of these substances
is initiated by pathogen-recognition receptors, such as Toll-
like receptors (TLRs).
In order to explore the effects of antigens in TLR
expression and activation, we studied the density of antigen
with a human bronchial epithelial cell line for 24h, and
found that antigen increased TLR4 expression and nuclear
factor-kappa B (NF-kB) and ErK1/2 activation, and further
increased IL-8 release and chemotactic activity toward
neutrophils. Accumulation of neutrophils within the airways
in response to antigen appeared to increase the expression
of TLR4 and preferentially orients TLR4 activation toward
subsequent activation of ERK and IL-8 production.
Role in adaptive immune responses
Epithelial cells act as an initiator, mediator, and regulator in
innate and adaptive immune responses, as well as the
transition from innate immunity to adaptive immunity. DCs
and airway macrophages collaborate as sentinels against
foreign particulate antigens by building a transepithelial
interacting cellular network.14,15During inflammatory and
immune responses,13epithelial cellsexpresspattern-recognition
receptors to trigger a host defense response, interact with
DC to regulate antigen sensitization, and release cytokines
to recruit effector cells. Epithelial cells also regulate
adaptive immune cells by expression of soluble and cell-
surface molecules that alter the function of DCs, T and B
cells in the airways.15
Role in allergic reactions
Although asthma is an inflammatory disorder of the
conducting airways involving Th2-type T cells, the epithe-
lium also plays an important role in orchestrating the
inflammatory response by interacting with multiple environ-
mental factors to produce a chronic wound scenario
involving tissue injury and aberrant repair.14,15Part of this
is a primary disruption of epithelial tight junctions that
allows inhaled substances to pass more easily into the
airway wall to interact with immune and inflammatory cells.
Aberrant communication between the damaged and stressed
epithelia leads to the generation of growth factors that
interact with the underlying mesenchyme to promote airway
remodeling responses and a more chronic and persistent
inflammatory phenotype. Disordered epithelial function
with reduced antioxidant defense and impaired capacity
to produce primary interferon-gamma may also account
for asthmatic susceptibility to air pollution and respiratory
virus infection, respectively.11
AR is characterized by an initial sensitization phase where
allergen exposure results in IgE formation as well as
induction of the humoral response, and subsequent clinical
disease after repeated antigen exposure. Mucosal epithelial
cells may play critical roles in initiating and/or maintaining
local inflammation.16It is accepted that mast cells involve
the early phase inflammatory response within minutes of
allergen exposure by the release of mediators, but the
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and functional barrier against inhaled and deposited particulate antigens. Dendritic cells and airway macrophages collaborate as
sentinels against foreign particulate antigens by building a transepithelial interacting cellular network. Once viral infection of the
epithelium initiates a proinflammatory process, subsequent production of other mediators that are not of epithelial origin may
further contribute to the inflammatory status of the airway. The direction of the inflammatory reaction is mainly from the epithelial
cells to dendritic cells, as indicated by arrows.
Viral modulation of epithelial function may initiate the inflammatory response. Airway epithelium serves as a structural
Role of airway epithelial cells in development of asthma and allergic rhinitis951
question is that how can the mast cells contact and
communicate with the antigens without the involvement
of epithelial cells and whether epithelial cells pass the
message or signal to other cells. Cytokine secretion is a
major feature of the inflammatory process in AR, playing an
important role in cellular adhesion, e.g. intercellular
adhesion molecule-1, vascular cell adhesion molecule-1,
and E-selectin on the vascular endothelium. It would be
important to understand the role of epithelial cells in
the recruitment of leukocytes from the circulation to the
Role in airway hyper-responsiveness (AHR)
AHR is considered to be related to chronic airway inflamma-
tion, including leukocyte infiltration, hypersecretion of
mucus, bronchial smooth muscle spasm, and airway wall
remodeling, one of the main clinical features in asthma.17
Non-asthmatic subjects with AR can present with AHR when
exposed to an allergen to which they are sensitized.18It has
been proposed that the nasal mucosa may process allergens
into a form more capable of inducing nasal and bronchial
reactions. AHR often occurs in patients with AR, even if they
have no asthma symptoms, associated with an increased risk
for developing asthma.19About 40% of patients with AR were
found to have AHR, with a potential to develop asthma over
the subsequent 4–5 years.20Among patients with exacerba-
tion of asthma symptoms and the onset of seasonal AR, nasal
allergen challenge resulted in an increased nonspecific
bronchial responsiveness. Segmental bronchial provocation
in patients with AR rather than asthma results in allergic
inflammatory changes in the nose.21
Epithelial cell barrier dysfunction has recently been
considered to be an important mechanism in the develop-
ment of AHR. Current theories concerning its pathogenesis,
apart from the classic allergic theory, include the neuro-
genic airway inflammation hypothesis and epithelial defect
hypothesis.22Bronchial epithelial cells play a critical role in
maintenance of homeostasis in the airway microenviron-
ment through a wide range of biological functions including
anti-oxidative activity, exocrine/endocrine secretion, mu-
cus production, and antigen presentation.23,34It is reason-
able to hypothesize that disruption of these functional
processes or defects in airway epithelial integrity may be an
initial step leading to AHR. TLR stimulation could induce
AHR, by JNK and NF-kB signaling pathways, supported by the
finding that LPS and poly-I-C-induced translocation of NF-kB
p65 to the nucleus and up-regulation of kinin B(1) and B(2)
receptor mRNA and TLRs were expressed in the tracheal
smooth muscle.70It is also possible that hypertrophy
and hyperplasia of goblet cells may also contribute to the
formation of AHR.24
Role in mucus overproduction
Mucus overproduction is a prominent pathological change in
the exacerbation of asthma and AR. Epithelial cells are
downstream targets of molecules that activate IL-13R and
epidermal growth factor receptor (EGFR) and are respon-
sible for mucus production in both protective immune
responses and allergic airway inflammatory diseases.23
Multiple stimuli induce mucin production in airway epithe-
lium via effects of EGFR activation24(Figure 2). Autocrine
activation of EGFR in response to stimuli appears to be an
important mechanism of EGFR activation. EGFR expression
and activation induce goblet cell hyperplasia and metaplasia
and increase mucin production, resulting in epithelial
proliferation, differentiation, migration, and wound repair.
On the other hand, IL-4 affects differentiation of epithelial
cells towards a phenotype that releases more IL-8 and
expresses more mucins.
The g-aminobutyric acid (GABA) system, aquaporin (AQPs)
water channels and LPS-induced over-expression of MUC5AC
seem to play a major role in over-production of mucus.
Mucin over-production can be induced via a GABA system in
airway epithelium,25and IL-13 appears as a critical role in
regulating airway epithelial GABA signaling. GABAergic
blockade could prevent antigen-induced airway goblet cell
hyperplasia and mucus over-production. The AQPs, a family
of homologous water channels expressed in many epithelial
ARTICLE IN PRESS
stimuli induce mucin production in airway epithelium via the effects of epidermal growth factor (EGFR) activation. The direction of
the inflammatory reaction in mainly from stimulus to EGFR, as indicated by arrows.
Mucus overproduction is prominent pathological change in the exacerbation of asthma and allergic rhinitis. Multiple
Y. Wang et al. 952
cells, may regulate airway mucin secretion and transmem-
brane water transport.26Although LPS-induced over-expression
of MUC5AC in the airway might be the activation of the
TLR-4 pathway and mediated by the release of tumor
necrosis factor (TNF)-a, IL-1b, and IL-8, evidenced by the
fact that the inhibition of TLR-4 expression could prevent
mucus hypersecretion and AHR.70
Role in allergic cascade
Th2-type inflammation has a prominent role in epithelial
disorders during asthma and AR.27TSLP is capable of
directing DCs towards a Th2 response, providing an essential
link between epithelial cell activation and allergic-type
inflammation28,29and between epithelial injury and gen-
eration of an allergic-type inflammatory response.30,31In
addition, TSLP can interact directly with mast cells to
initiate Th2 cytokine production, providing a non-T cell
route to mediate its pro-allergic effects. TSLP interacts with
DCs to upregulate the co-stimulatory molecules OX40, CD40
and CD80 that facilitate polarization of helper T lympho-
cytes to a Th2 phenotype.32,33Induction of TSLP production
occurs through the activation of epithelial TLRs, an
important link between innate immunity and allergic
disease. It is possible that airway epithelial cells may
contribute to asthma and AR through the activation of
The pattern recognition receptors, including TLRs in the
epithelium and on DCs, are important in the origins of
allergy. Their differential activation is associated with the
prevalence of allergic diseases.34–36The activation of TLRs
in the airways and nose by viral, bacterial, and fungal
ligands has revealed a profound effect in shaping the
subsequent adaptive immune response in favor of Th1,
Th2, or Treg cells. TSLP production can be induced in airway
epithelial cells by ligands that activate TLR2 and TLR3 to
release TSLP protein, and TLR8 and TLR9 to stimulate TLSP
gene transcription through NF-kB activation. Ligands cap-
able of activating these TLRs include bacterial lipoteichoic
acid and peptidoglycans from bacteria (TLR2), single-
stranded (TLR8) and double-stranded (TLR3) viral RNA, and
CpG DNA motifs in both viruses and bacteria (TLR9).37–41The
proinflammatory cytokines e.g. TNFa, IL-1a, IL-4 and IL-13
can also induce TSLP production to drive TSLP-dependent
maturation of blood CD11c+ dendritic cells. TLR activation
can also be initiated by other factors, such as viruses, dusts,
Role in allergic inflammation
Airway epithelial cells play a critical and important role in
the development of airway inflammation,43involved in the
polarization of allergen-driven Th2 lymphocyte and in the
production of IL-3, IL-4, IL-5, IL-9, granulocyte-macrophage
colony-stimulating factor and IL-13, which are encoded in a
gene cluster on chromosome 5q.31–34These cytokines drive
the allergic inflammatory response through the recruitment
and activation of leukocytes. IL-4, IL-9 and IL-13, in the
presence of MHC-II-restricted allergen presentation by T
cells and CD40 or OX40 co-stimulation, cause an increased
IgE production with subsequent sensitization of mast cells
and basophils through the binding of allergen-specific IgE to
high affinity receptors (Fc R1).44–49Cholinergic stimulation
seems to promote a proinflammatory response in epithelial
cells by producing chemokines and TSLP. After allergen
challenge and other types of epithelial injury, both CCL17
and CCL22 could drive TH2 chemotaxis by interacting with
the common CCR4 receptor,50a basis for therapeutic effects
of corticosteroids and calcineurin inhibitors.51–54
Role in airway remodeling
Even though the inflammatory reaction in AR and asthma is
similar, the nasal remodeling in patients with rhinitis seems
to be far less extensive than the bronchial in asthmatic
patients.59The cytokine production from smooth muscle
cells might partly explain differences of remodeling be-
tween them, or genes related to embryologic differentiation
might persist between the nose and bronchi or might be re-
expressed in asthma and rhinitis. A better understanding of
nasal and bronchial remodeling might help to identify new
pathways and new therapeutic strategies to reduce long-
term remodeling in asthma. Structural alterations of bronchi
in mild asthma include epithelial fragility and thickening of
its reticular basement membrane.1The increasing severity
of asthma is accompanied by increases in airway smooth
muscle mass, vascularity, interstitial collagen, and mucus-
Airway remodeling is a major contributing factor to the
pathogenesis of asthma, especially the development of
airflow obstruction and the progressive decline in lung
function associated with the duration and severity.55Airway
epithelial cells play an important role in development of
both airway inflammation and remodeling in asthma. The
remodeling with epithelial shedding, collagen deposition
basement membrane thickening, smooth muscle hyperplasia
is a distinctive feature of bronchial asthma.
Th2 cytokines not only affect airway inflammation and
innate immunity in the lung, but also epithelial differentia-
tion and airway remodeling.56–60Oxidative stress is capable
of increasing production of Tn and Ln b2chain by bronchial
epithelial cells, contributing to remodeling in chronic
inflammatory airway diseases.60
Remodeling of the airway wall is considered as a direct
result of the inflammatory environment present in the
asthmatic airway, but in many cases the epithelium is the
primary target of mechanical forces in the lung due to
the high loads and deformations.61Mechanical activation of
the epithelium can lead to profound changes in signaling and
gene expression, and alter epithelial release of cytokines,
nucleotides, and growth factors. The mechanical forces
developed during constriction of intact airways could lead to
EGFR signaling in cultured cells.61
important questions about the biochemical links between
mechanical transduction and downstream biochemical acti-
vation in airway epithelial cells. Specific immunotherapy has
been suggested to affect the natural course of allergic
disease and be effective in the treatment of asthma and AR
These data raise
ARTICLE IN PRESS
Role of airway epithelial cells in development of asthma and allergic rhinitis953
in several double-blind randomized clinical studies.62It is
possible that epithelial cells are involved in the efficacy as
Epithelial feedback regulation via systemic
Recent studies have suggested that other pathways may be
involved in asthma.63–70Epithelial cells in different organs/
tissues have similarities and variations dependent upon the
organ, function, location, and challenge,68and can commu-
nicate with each other and play a central role in systemic
reactions and multiple organ dysfunction.69Airway epithe-
lial cells act not only as a defensive line against inflamma-
tory stimuli and antigens, but also may be initiators of
secondary inflammatory responses and systemic reactions.
It is suggested that ‘‘feedback regulation’’ between the
upper and lower airway takes place at initiation of the
possibly through a systemic
pathway, or via cytokine release of airway cells, which are
abundantly present throughout the respiratory mucosa.65,66
Possible mechanisms for the influence of AR on lower
airways include systemic propagation of nasal inflammation
to the bronchial mucosa via effects of mediators and
inflammatory cells on bone marrow.67
In conclusion, there is a clear indication that epithelial
cells are involved in the pathogenesis of asthma and AR, as
the first line of defense facing local and primary challenges.
Airway epithelial cells are important players in the devel-
opment of airway inflammation and remodeling, which act
as an inflammatory promoter for initiating both local and
systemic inflammation. Structural and functional abnormal-
ities of the epithelium can be both primer and promoter of
airway and distant organ dysfucntion. Airway epithelial cells
may be a valuable therapeutic target for discovering and
developing new drugs and/or new therapeutic strategies for
the treatment of allergic diseases.
Conflict of interest statement
None of the authors have a conflict of interest to declare in
relation to this work.
This research is supported by China Postdoctoral Science
Foundation, NO 20070420596 and by grants from the National
Natural Scientific Foundation of China, NSFC 30200120 and by
Shanghai Leading Academic Discipline Project, NO B115.
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ARTICLE IN PRESS
Role of airway epithelial cells in development of asthma and allergic rhinitis955