Auris Nasus Larynx 38 (2011) 555–563

www.elsevier.com/locate/anl

Pathogenesis of airway inflammation in bronchial asthma

Kazuyuki Nakagome a,b, Makoto Nagata a,b,*
a
Department of Respiratory Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama 350-0495, Japan
b
Allergy Center, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama 350-0495, Japan
Received 21 September 2010; accepted 5 January 2011
Available online 19 February 2011

Abstract

Bronchial asthma is a chronic disorder characterized by airway inflammation, reversible airway obstruction, and airway hyperrespon-
siveness. Eosinophils are believed to play important roles in the pathogenesis of asthma through the release of inflammatory mediators. In
refractory eosinophilic asthma, anti-IL-5 mAb reduces exacerbations and steroid dose, indicating roles of eosinophils and IL-5 in the
development of severe eosinophilic asthma. Even in the absence of IL-5, it is likely that the ‘‘Th2 network’’, including a cascade of vascular
cell adhesion molecule-1/CC chemokines/GM-CSF, can sufficiently maintain eosinophilic infiltration and degranulation. Cysteinyl
leukotrienes can also directly provoke eosinophilic infiltration and activation in the airways of asthma. Therefore, various mechanisms
would be involved in the eosinophilic airway inflammation of asthma.
In the pathogenesis of severe asthma, not only eosinophils but also mast cells or neutrophils play important roles. Mast cells are much
infiltrated to smooth muscle in severe asthma and induce airway remodeling by release of inflammatory mediators such as amphiregulin.
Treatment with anti-IgE Ab, which neutralizes circulating IgE and suppresses mast cell functions, reduces asthma exacerbations in severe
asthmatic patients. Furthermore, infiltration of neutrophils in the airway is also increased in severe asthma. IL-8 plays an important role in the
accumulation of neutrophils and is indeed upregulated in severe asthma. In the absence of chemoattractant for eosinophils, neutrophils
stimulated by IL-8 augment the trans-basement membrane migration of eosinophils, suggesting that IL-8-stimulated neutrophils could lead
eosinophils to accumulate in the airways of asthma. In view of these mechanisms, an effective strategy for controlling asthma, especially
severe asthma, should be considered.
# 2011 Elsevier Ireland Ltd. All rights reserved.

Keywords: Bronchial asthma; Eosinophils; IL-5; Cysteinyl leukotrienes; Mast cells; Neutrophils

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556
2. Eosinophilic airway inflammation in bronchial asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556
3. Role of CD4+ T cells in the pathogenesis of asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
4. Role of mast cells in the pathogenesis of severe asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
5. Neutrophilic inflammation in severe asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
6. Role of DCs in the pathogenesis of bronchial asthma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
7. Impact of allergic rhinitis on bronchial asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560

* Corresponding author at: Department of Respiratory Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama 350-
0495, Japan. Tel.: +81 49 276 1319; fax: +81 49 276 1319.
E-mail address: favre4mn@saitama-med.ac.jp (M. Nagata).

0385-8146/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.anl.2011.01.011
556 K. Nakagome, M. Nagata / Auris Nasus Larynx 38 (2011) 555–563
1. Introduction
Bronchial asthma is a chronic disorder characterized by
airway inflammation, reversible airway obstruction, mucus
hypersecretion, and airway hyperresponsiveness (AHR) [1].
In the process of airway inflammation of asthma, a variety of
cells, such as eosinophils, T lymphocytes, mast cells,
neutrophils, and dendritic cells (DCs), are involved. In this
review, recent advances in the pathogenesis of airway
inflammation in asthma are discussed.
2. Eosinophilic airway inflammation in bronchial
asthma
Eosinophils preferentially accumulate at sites of allergic
inflammation and are believed to play important roles in the
pathophysiology of asthma through the release of a variety
of inflammatory mediators, including major basic protein
(MBP), cysteinyl leukotrienes (CysLTs), radical oxygen
species, and cytokines [2,3]. However, earlier studies
involving anti-IL-5 mAb treatment of asthmatic patients
raised the possibility that eosinophils may play only a
limited role in asthma [4–6]. For example, Leckie et al.
reported that anti-IL-5 treatment significantly reduced
eosinophils in sputum or serum, but the Ab did not modify
AHR to histamine or the magnitude of the late asthmatic
response observed with allergen provocation [4], suggesting
Fig. 1. Mechanisms of eosinophilic airway inflammation in bronchial asthma.
that eosinophils have no role in the development of AHR or
airflow limitation in response to specific allergens.
A follow-up study with anti-IL-5 mAb revealed that the
treatment only partly eliminated tissue eosinophilia and did
not modify the deposition of MBP in the airways of
asthmatic patients [7]. Although the interpretation of this
study remains controversial, these findings suggest that IL-5
has a limited role in the development of eosinophilic
infiltration and is not responsible for the release of specific
granule proteins from eosinophils in mild asthma.
On the other hand, in asthmatic patients with persistent
sputum eosinophilia, treatment with anti-IL-5 mAb reduced
asthma exacerbations and the requirement for systemic
corticosteroids, and improved asthma-related quality of life
(QOL) [8,9]. These results strongly suggest essential role of
eosinophils in the development of asthma exacerbation.
Furthermore, antagonizing IL-5 could be an effective
strategy for controlling refractory eosinophilic asthma,
as well as controlling hypereosinophilic syndrome (HES)
[10–12].
Accumulating evidence established that eosinophils
largely contribute to the development of airway remodeling
of asthma [13–15]. For example, Flood-Page et al. reported
that anti-IL-5 mAb significantly reduced eosinophils
expressing mRNA for transforming growth factor (TGF)-
b and the concentration of TGF-b protein in bronchoalveo-
lar lavage (BAL) fluid [13]. In their study, they also
demonstrated that anti-IL-5 treatment reduced the deposi-
 K. Nakagome, M. Nagata / Auris Nasus Larynx 38 (2011) 555–563
tion of extracellular matrix proteins in bronchial tissue [13].
Humbles et al. reported that mice with selective ablation of
the eosinophil lineage do not develop collagen deposition or
increases in airway smooth muscle cells in response to
allergen, indicating a critical role of eosinophils in the
development of airway remodeling [14]. Similar findings
were also reported by Lee et al. [15].
The other possible mechanism by which eosinophils
contribute to the airway disease of asthma may be through
generation of CysLTs, since eosinophils are capable of
generating tremendous amounts of CysLTs in vitro [16].
There is evidence that the magnitude of eosinophilic
inflammation is positively correlated with the concentration
of CysLTs in sputum. In typical allergic asthma due to
pollen, only few inflammatory cells express LTC4 synthase
before pollen season. During the season for pollen exposure,
however, only eosinophils, but not mast cells or macro-
phages, express LTC4 synthase in the bronchial tissue [17].
Similarly, in the bronchial mucosa of aspirin-intolerant
asthma, eosinophils, but not mast cells, are the predominant
inflammatory cells expressing LTC4 synthase [18]. Collec-
tively, it is theoretically conceivable that eosinophils are a
major cellular source of CysLTs in asthma.
The mechanism by which eosinophils can still be
accumulated and activated in the airways of asthma in the
presence of anti-IL-5 remains to be established. For
circulating eosinophils to accumulate in asthmatic airways,
they must adhere to and then migrate across vascular
endothelial cells. These processes are largely regulated by
cytokines/chemokines produced by a variety of cells,
including Th2 cells (Fig. 1). Accumulating evidence has
suggested that eosinophil interaction with endothelial cells
via the a4 integrin/vascular cell adhesion molecule
(VCAM)-1 pathway is likely a key step for selective
eosinophil recruitment [19–21]. Th2 cytokines IL-4 and IL-
13 have potent activity for endothelial cells to express
VCAM-1, and blood eosinophils spontaneously adhere to
VCAM-1 [22,23]. The interaction of eosinophils and
VCAM-1 results in the respiratory burst and enhancement
of granule protein release from eosinophils and, therefore,
may be an initial step of the activation of these cells [22–24].
Following adhesive interaction with endothelial adhesion
molecules such as VCAM-1, chemoattractants that can induce
effective migration of eosinophils are required (Fig. 1). CC
chemokines, including regulated upon activation, normal T
cell expressed and secreted (RANTES), eotaxin, eotaxin-2,
monocyte chemotactic protein (MCP)-3, and MCP-4, selec-
tively augment eosinophil transmigration across endothelial
cells expressing VCAM-1 [25]. The cellular sources of CC
chemokines are likely to be epithelial cells, fibroblasts, and
mononuclear cells [25–28]. There is enough evidence that
these CC chemokines are increased in the airways of asthma.
Following migration across endothelial cells, eosinophils
can be effectively activated and degranulated by GM-CSF,
even in the absence of IL-5 (Fig. 1). For example, GM-CSF
is able to induce both degranulation and respiratory burst of
557
eosinophils in the presence of VCAM-1 or intercellular cell
adhesion molecule (ICAM)-1 in vitro [22]. Interestingly,
airway eosinophils obtained following segmental antigen-
challenge can be activated by GM-CSF, but not IL-5 [29,30].
Taken together, the main pathway of eosinophilic inflam-
mation in asthma in the absence of IL-5, the ‘‘Th2 network’’,
including a cascade of VCAM-1/CC chemokines/GM-CSF,
can sufficiently maintain eosinophilic infiltration and
activation (Fig. 1). This pathway of eosinophilic inflamma-
tion can be effectively treated with corticosteroid [31,32].
Increasing evidence has suggested that CysLTs con-
tribute to the accumulation of eosinophils in the tissues of
asthmatic airways. For example, LTE4 inhalation increases
the accumulation of eosinophils, and to a lesser extent,
neutrophils in asthmatic patients [33]. Similarly, LTD4
inhalation increases the number of eosinophils in sputum
from asthmatic patients. We have reported that LTD4
upregulates the expression of b2 integrins on human
eosinophils in vitro and augments eosinophil adhesion to
tissue culture plates or to rh-ICAM-1 [34]. Interaction
between eosinophil b2 integrin and ICAM-1 might play a
crucial role in the transendothelial migration of eosinophils.
Furthermore, adhesion enhanced via b2 integrin augments
eosinophil effector functions including respiratory burst,
degranulation, and further generation of CysLTs, suggesting
that the effect of CysLTs on the activation of b2 integrins is
an important step in cell activation in asthma [22].
Moreover, we observed that LTD4 directly induces
transendothelial migration, respiratory burst, and degranula-
tion, mainly via the cysLT1 receptor and b2 integrin [35].
Finally, there is increasing evidence that addition of cysLT1
receptor antagonists, but not long-acting beta agonists
(LABA), to inhaled corticosteroid (ICS) further reduces the
number of eosinophils in sputum or blood from asthma
patients [36,37]. Thus, in addition to the ‘‘Th2 network’’,
CysLTs can also directly provoke eosinophilic infiltration
and activation in the airways of asthma. Importantly, this
pathway is insensitive to corticosteroid therapy [37,38].
3. Role of CD4+ T cells in the pathogenesis of asthma
Allergic airway inflammation is generally considered as a
Th2-type response-mediated process [1]. Activated CD4+
Th2 cells produce a large amount of cytokines such as IL-4,
IL-5, and IL-13, which induce IgE production, eosinophilic
inflammation, mucus secretion, and AHR. In patients with
asthma, activated T cells, especially CD4+ Th2 cells,
infiltrate into the airway, which is associated with disease
severity [39–41]. In a mouse model, administration of
blocking Ab to CD4 suppressed AHR and eosinophilic
airway inflammation [42,43]. Moreover, transfer of CD4+
Th2 cells into naive mice and subsequent allergen-inhalation
induced AHR and eosinophilic airway inflammation
[44,45]. These findings suggest that CD4+ Th2 cells are
essential for the induction of asthma.
558 K. Nakagome, M. Nagata / Auris Nasus Larynx 38 (2011) 555–563
Recently, the role of the Th1-type response in the
pathogenesis of asthma has been highlighted. For example,
expression of the Th1 cytokine IFN-g in airway tissues was
upregulated in severe asthma [46]. Passive transfer of antigen-
specific Th1 cells exacerbated antigen-induced airway eosino-
philia [47,48]. IL-18-generated Th1 cells could produce a
Th2-type cytokine, thus increasing allergic airway inflamma-
tion [49]. Th1 cells promoted recruitment of Th2 cells and
eosinophils into the airway after viral infection in an antigen-
independent manner [50]. We observed that IFN-g augments
eosinophil adhesion-inducing activity of endothelial cells
[51], which might be one mechanism for Th1-mediated
accumulation of eosinophils into the airway. Although
Th1-type responses are generally considered to antagonize
Th2-type responses [52], these findings suggested that, in
some situations in asthma, Th1 responses could aggravate
Th2 responses and eosinophilic inflammation in the airway.
There are two distinct populations of memory CD4+ T cells
that are distinguished by the expression of CCR7 [53]:
CCR7high central memory T cells, which home preferentially
to lymph nodes, and CCR7low effector memory cells, which
traffic more efficiently to non-lymphoid tissues and acquire
effector function more rapidly [53,54]. CD62Llow memory T
cells are a subset of effector memory T cells [53,55]. It appears
that effector memory T cells, such as CD4+CD62Llow T cells,
contribute to the development of eosinophilic airway
inflammation [56] and AHR [57] in the airways of animal
models of asthma. The role of CD4+CD62Llow T cells in
asthmatic patients remains to be established.
Fig. 2. Neutrophil-dependent mechanism of eosinophilic inflammation.
4. Role of mast cells in the pathogenesis of severe
asthma
Increasing evidence has suggested the important role of
mast cells in severe asthma. For example, infiltration of mast
cells into smooth muscle is one of the characteristics of severe
asthma [58]. The mechanism of mast cell recruitment into
asthmatic airway muscle involves the CXCL10/CXCR3 axis,
and several mast cell mediators have profound effects on
airway smooth muscle cell functions [59]. Mast cells release
amphiregulin, which induces mucus secretion and tissue
remodeling following aggregation of FceRI [60], and
expression of this molecule is not inhibited by corticosteroid,
thus suggesting that mast cells play roles in corticosteroid-
resistant asthma.
IgE activates mast cells via aggregation of FceRI. Anti-
IgE Ab neutralizes circulating IgE and reduces FceRI
expression on mast cells, and thus suppresses functions of
mast cells. In the clinical setting, anti-IgE Ab reduced acute
exacerbations and emergency visits in severe allergic
asthmatic patients [61,62]. Although other mechanisms
might also be involved in the clinical effectiveness provided
by anti-IgE, these findings suggest clinical implications of
mast cell/IgE axis in the development of severe asthma.
5. Neutrophilic inflammation in severe asthma
Not only eosinophilic inflammation but also neutrophilic
inflammation may play roles in severe asthma. Wenzel et al.
 K. Nakagome, M. Nagata / Auris Nasus Larynx 38 (2011) 555–563
suggested that severe asthma could be divided into two
inflammatory subtypes: one is the eosinophil(+) neutro-
phil(+) group, and the other is the eosinophil( ) neutro-
phil(+) group [63]. The European Network For
Understanding Mechanisms of Severe Asthma (ENFU-
MOSA) study reported that patients with severe asthma
have both greater sputum neutrophil counts and release
of eosinophil-derived mediators than mild to moderate
asthma [64], suggesting the persistence of neutrophilic,
as well as eosinophilic, inflammation in the airways of
severe asthma. We previously reported a positive correla-
tion between the concentrations of neutrophils and
eosinophils in induced sputum from patients with severe,
corticosteroid-dependent asthma [65]. IL-8 plays an
important role in the accumulation of neutrophils in
sites of inflammation (Fig. 2), and expression of IL-8 in the
airway is upregulated in severe asthmatic patients [46,66].
We also confirmed that IL-8 protein in induced sputa
is higher in severe asthmatics than in mild asthmatics
[67]. Furthermore, we reported that, even in the absence
of chemoattractant for eosinophils, neutrophils stimulated
by IL-8 are capable of inducing the trans-basement
membrane migration of eosinophils [68], suggesting that
IL-8-stimulated neutrophils lead eosinophils to accumulate
in the airways of asthmatic patients (Fig. 2). The enhanced
migration of eosinophils by IL-8-stimulated neutrophils
was inhibited by matrix metalloproteinase-9 inhibitor or
LTB4 receptor antagonist [68].
The mechanisms of upregulation of IL-8 in severe
asthma have not been well understood. Goleva et al.
reported that LPS and genes associated with activation
of the LPS signaling are higher in BAL fluid of
corticosteroid-resistant asthma than in corticosteroid-
sensitive asthma [69]. They also reported that IL-8
mRNA expression by BAL cells positively correlates
with the amount of LPS in BAL fluid [69]. The other
candidate for upregulation of IL-8 expression is chitinase.
Chitinases are present in a wide range of organisms, and
chitinase production is important for the life-cycle of
chitin-containing fungi. The expression of acidic mam-
malian chitinase by airway epithelium and pulmonary
macrophages is upregulated in asthmatic patients [70].
Chitinase has been shown to enhance IL-8 production by
airway epithelial cells through protease-activated recep-
tor-2 [71]. Finally, IL-17A or IL-17F may play a role
in the increase of IL-8 seen with severe asthma.
IL-17A and IL-17F, which are mainly produced by
Th17 cells, induces neutrophilic inflammation via the
production of IL-8 [72]. Barczyk et al. reported that an
elevated sputum IL-17A concentration correlates with
clinical severity of asthma [73]. Al-Ramli et al. reported
that the expression of IL-17A and IL-17F in the airway
increased only in severe asthmatics [74]. Thus, increased
IL-17A or IL-17F levels might be one mechanism
responsible for neutrophilic inflammation in severe
asthma.
559
6. Role of DCs in the pathogenesis of bronchial
asthma
The initiation of the antigen-induced immune response is
mainly controlled by DCs, the most potent antigen-
presenting cells (APCs) [75]. Antigen presentation from
APCs to naı̈ve T cells induced the expression of selective
sets of cytokines, thus affecting Th differentiation [76]. In
patients with asthma, the numbers of DCs in the epithelium
and in the subepithelial lamina propria were increased
[77,78]. Moreover, transfer of antigen-pulsed DCs into naive
mice and subsequent allergen inhalation induced eosino-
philic airway inflammation [79,80]. Furthermore, van Rijt
et al. reported that in vivo depletion of lung CD11c+ DCs
during allergen challenge attenuated eosinophilic airway
inflammation [81,82], suggesting that DCs play an essential
role not only in the development but also in the maintenance
of the antigen-induced immune response in the airway.
Therefore, modulation of DC functions could be a reason-
able strategy for controlling and inducing remission of
asthma.
Recent reports suggested that immunological adjuvants
such as monophosphoryl lipid A (MPL) effectively facilitate
the action of allergen immunotherapy [83]. MPL is Th1
adjuvant that increases IL-12 production by DCs [84].
Drachenberg et al. reported that, after only four preseasonal
injections, tyrosine-absorbed glutaraldehyde-modified grass
pollen extract containing MPL adjuvant reduced nasal
symptoms, ocular symptoms, and combined symptom and
medication scores [83]. So, modulation of DC function by
adjuvants could be an effective strategy for controlling
allergic disease using this form of therapy.
Delivery of Th1 cytokine or immunomodulative cyto-
kines such as IL-10 can also be a novel therapeutic approach
for controlling allergic inflammatory diseases. From this
perspective, we reported that gene delivery of cytokines such
as IL-10 or IFN-g suppressed DC functions and attenuates
allergic airway inflammation [80,85]. Therefore, if delivered
selectively in the lung, IL-10 or IFN-g could have the
potential to become useful therapies for allergic disease such
as bronchial asthma.
7. Impact of allergic rhinitis on bronchial asthma
Coexistence of asthma and allergic rhinitis is frequent.
For example, allergic rhinitis is presented in 50–80% of
asthmatic patients [86]. Further, in patients with allergic
rhinitis, AHR and infiltration of eoinophils into the lower
airways are observed regardless of the presence of asthma
[87]. Nasal provocation with allergen induced AHR and
eosinophilic airway inflammation [88]. On the other hand, in
patients with asthma, infiltration of eosinophils into the
upper airways is observed regardless of the presence of
rhinitis [89]. Segmental bronchial provocation with allergen
induced nasal symptoms as well as reductions in nasal
560 K. Nakagome, M. Nagata / Auris Nasus Larynx 38 (2011) 555–563
function in patients with allergic rhinitis [90]. These findings
supported the concept of ‘‘one airway, one disease’’ that
allergic rhinitis could affect the development of bronchial
asthma, and vice versa [91].
In patients with allergic rhinitis and asthma, treatment of
allergic rhinitis such as nasal corticosteroid or histamine H1
receptor antagonist improves asthma symptoms and AHR,
and reduces the frequency of acute exacerbation [92–95].
We recently reported that the influence of changes in nasal
symptoms on asthma symptoms was stronger in patients
lacking good asthma control [96]. Therefore, nasal treatment
is considered to be important for asthma control especially in
patients with asthma symptoms.
Several guidelines on allergic rhinitis or bronchial asthma
indicated that LTRA, allergen immunotherapy, anti-IgE Ab
and prednisone are all effective for controlling allergic
rhinitis as well as bronchial asthma. For example, LTRA is
therapeutic agents for bronchial asthma characterized as
anti-inflammatory and anti-fibrotic property. It is also
beneficial in controlling allergic rhinitis, especially symp-
toms of nasal congestion. In asthmatic patients with allergic
rhinitis, ICS plus LTRA provided significantly greater
efficacy in reducing airflow obstruction compared with
doubling the dose of ICS, although the effect was not
confirmed in total asthmatic patients [97]. Therefore, LTRA
is more useful for controlling asthma with allergic rhinitis
than that without rhinitis. Allergen immunotherapy is a
guideline-recommended treatment for allergic rhinitis. It
also improves clinical symptoms of asthma and AHR [98].
Further, recent report suggested that allergen immunother-
apy suppressed the subsequent onset of asthma in patients
with pollen allergy rhinitis [99]. Therefore, allergen
immunotherapy is effective for not only controlling allergic
rhinitis and asthma but also suppressing the development of
new allergic disease. Patients with Japanese cedar pollinosis,
for example, may be candidates for immunotherapy in terms
of preventing development of asthma. Moreover, anti-IgE
Ab is effective for controlling allergic rhinitis [100] as well
as severe asthma. Therefore, effective treatment to both
rhinitis and asthma such as LTRA, allergen immunotherapy
or anti-IgE Ab should be considered in controlling bronchial
asthma with allergic rhinitis.
8. Conclusion
It is likely that eosinophils contribute to airway
remodeling and generation of cysLTs in asthma. The exact
role of eosinophil specific granule proteins in asthma
remains to be elucidated. Longer-term studies that
effectively and selectively eliminate either tissue eosinophils
or deposition of eosinophil specific granule proteins will be
required to establish the exact role in asthma. Increasing
evidence suggests that other cell types, including both mast
cells and neutrophils, play important roles in the pathogen-
esis of severe asthma. Further work will be needed to
sufficiently establish this area of asthma/allergy research in
the near future.
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