CHEST Recent Advances in Chest Medicine

Recent Advances in the Pathophysiology

of Asthma
Desmond M. Murphy, MB, PhD; and Paul M. O’Byrne, MB, FCCP

There has been an increased understanding, over the past 2 decades, that asthma is a chronic,
immunologically mediated condition with a disturbance of the normal airway repair mechanism,
which results in inflammatory changes and airway remodeling. The airway inflammation and
remodeling together likely explain the clinical manifestations of asthma. The mechanisms by
which the external environmental cues, together with the complex genetic actions, propagate the
inflammatory process that characterize asthma are beginning to be understood. There is also an
evolving awareness of the active participation of structural elements, such as the airway epithe-
lium, airway smooth muscle, and endothelium, in this process. In tandem with this has come the
realization that inflammatory cells respond in a coordinated, albeit dysfunctional manner, via an
array of complex signaling pathways that facilitate communication between these cells; these
structural elements within the lung and the bone marrow serve as reservoirs for and the source
of inflammatory cells and their precursors. Although often viewed as separate mechanistic enti-
ties, so-called innate and acquired immunity often overlap in the propagation of the asthmatic
response. This review examines the newer information on the pathophysiologic characteristics of
asthma and focuses on papers published over the past 3 years that have helped to improve current
levels of understanding. CHEST 2010; 137(6):1417–1426

Abbreviations: CCR 5 chemokine receptor; IL 5 interleukin; NK 5 natural killer; TGF 5 transforming growth factor;
Th 5 T-helper; TLR 5 toll-like receptor; TNF 5 tumor necrosis factor; Treg 5 T-regulatory; VEGF 5 vascular endothe-
lial growth factor

Asthma remains a major health-care issue. It mani-

fests clinically with repeated, variable, episodic
attacks of breathlessness, cough, and wheeze occur-
ring secondary to bronchoconstriction in the setting
of airway hyperresponsiveness and mucous hyperse-
cretion. Clinically, the disease may be divided into
allergic and nonallergic asthma, distinguished by the
presence or absence of IgE antibodies to common
environmental allergens. However, in both forms
of the disease, the airway is infiltrated by T-helper
(Th) cells, which predominantly secrete characteristic
Manuscript received August 10, 2009; revision accepted November
16, 2009.
Affiliations: From the Firestone Institute for Respiratory Health,
St Joseph’s Healthcare; and the Department of Medicine,
McMaster University, Hamilton, ON, Canada.
Correspondence to: Paul O’Byrne, MB, FCCP, HSC 3W10,
McMaster University, 1200 Main St W, Hamilton, ON, Canada,
L8N 3Z5; e-mail: obyrnep@mcmaster.ca
© 2010 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (www.chestpubs.org/
site/misc/reprints.xhtml).
DOI: 10.1378/chest.09-1895
cytokines such as interleukin (IL)-4, IL-5, and IL-13,
the so-called Th2 cytokine milieu. These cytokines
stimulate mast cells, cause eosinophilia, promote leu-
kocytosis, and enhance B-cell IgE production, and
may also participate in the characteristic airway
remodeling of asthma. However, for an individual to
develop an asthmatic phenotype appears to require
the combination of both exposure to appropriate
stimuli and a genetic predisposition.1,2
The last 3 decades have provided vast quantities
of research affording significant insights into the
pathophysiologic characteristics of this complex entity.
In this article, we review progress, over the past 3 years,
that has augmented the level of understanding of the
pathophysiologic characteristics of asthma.
Innate and Acquired Immune
Mechanisms in Asthma
The trigger factors precipitating acute asthmatic exa-
cerbations are, for the most part, either environmen-
tal allergens or viruses, suggesting that immunologic

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responses viewed traditionally as either innate or and the host immune response. Airway inflammation
acquired are in fact intertwined. The “hygiene in asthma reflects a distortion of this balance and
hypothesis” for asthma pathogenesis contends that is orchestrated through complex interplay between
microbiologic factors may also be inherently involved multiple effector and target components.
in the suppression of the asthmatic phenotype, with
childhood exposure to microbiologic stimuli confer- Mast Cells
ring a protective effect against the development of
Mast cells are critical in mediating the acute
atopy.3 The proposed explanation for this effect is that
response in asthma. While classically, mast cell acti-
infection early in life stimulates a Th1 immunologic
vation occurs following the binding of antigens to
response (characterized by the release of cytokines
FcεR1-bound, antigen-specific IgE, they may also be
such as interferon-g), rather than the Th2 response
activated through other mechanisms, including stim-
(characterized by cytokines such as IL-4, IL-5, IL-13,
ulation of complement receptors, FcgR1, and via
and tumor necrosis factor [TNF]-a) associated with
TLRs.10 Other novel mechanisms of mast cell activa-
allergy and asthma. A person’s initial exposure to
tion, independent of IgE, are via the protein S100A12
microorganisms occurs in the birth canal during normal
and the receptors CD200R3/CD200R, whereas
vaginal delivery. A Dutch birth cohort study suggests
IL-33, a member of the IL-1 cytokine family, has
an increased risk of asthma at 8 years of age in chil-
demonstrated the ability to activate mast cells, even
dren delivered by caesarean section and therefore
in the absence of FcεR1 stimulation.11-15
lends further credence to this hypothesis.4 Further
TNF-a is preformed in mast cells and released as
studies suggest that a rural upbringing has a protective
part of the asthmatic airway response. In animal and
effect on later development of allergy.3,5 It has been
ex vivo models, mast-cell-derived TNF-a promotes
suggested that the consumption of farm milk may be
antigen- and Th17 cell-dependant neutrophilia after
protective against subsequent atopy, with this protec-
allergenic stimulation and induces dendritic cell
tive effect linked to CD14, thereby implicating toll-
migration.16,17 In murine culture experiments, mast cells
like receptor (TLR) recognition and innate immune
induce CD41 T-cell migration, but down-regulate
involvement in the evolution of an atopic phenotype.6
FcεR1 expression only in Treg cells, while activated
The main function of TLRs is in the recognition of
Treg cells suppress mast cell FcεR1 expression. This
infectious agents to facilitate an appropriate host
suggests bidirectional communication between mast
immunologic response. Advocates of the hygiene
cells and Treg cells in modulating IgE-mediated
hypothesis originally believed that microbiologic
responses.18 A role for mast cells in antigen presenta-
stimulation of TLRs modified an individual’s suscep-
tion is also suggested by the recent observation that
tibility to asthma by promoting a Th1 rather than a
mast cells stimulated by IgE-specific antigen undergo
Th2 lymphocytic response to an allergen.3 However,
FcεR1 cross-linking that enhances apoptosis. These
with the discovery of other T-cell subtypes and
dead mast cells become ingested by dendritic cells,
increasing evidence supporting pivotal roles for
and this incorporated antigen helps propagate ongoing
T-regulatory (Treg) and Th17 cells, the Th1/Th2
CD41 response.19
paradigm of infection/atopy appears to oversimplify
Whereas mast cells are generally considered proin-
the complex mechanisms involved.
flammatory and mediators of tissue destruction,
Recent studies may help explain the similarity in
they may conversely help limit airway damage.20
response evoked by allergens and microbes in the
Mast-cell-derived tryptase can cleave IgE, thereby
asthmatic airway. The house mite allergen Der p 2 has
preventing further mast cell activation and plau-
been shown to have similar structural characteristics
sibly helping to contain the allergic response.21,22
to MD-2, an integral component of the TLR4/CD14/
Disappointingly, a recent human study examining
MD-2 transmembrane receptor and TLR signaling.7,8
a potential role for therapeutic intervention with
Also, Trompette et al9 have provided in vitro and
the monoclonal antibody to TNF-a, golimumab, in
in vivo evidence of functional similarity between Der
severe, persistent asthma was abandoned because of
p 2 and MD-2. These results place TLRs in an ideal
an unfavorable risk-benefit profile.23
position to coordinate responses traditionally viewed
separately, as either innate or adaptive immunologic Basophils
reactions that typify the asthmatic response.
Basophils have a crucial role in initiating allergic
Effector Cells of Inflammation inflammation through the binding of antigen-specific
and Remodeling in Asthma IgE antibodies at the FcεR1.24 Basophils also drive Th2
cell differentiation of activated naive CD41 T cells via
In the healthy human airway there is normally a production of IL-4 and direct cell-cell contact.25 Murine
fine balance between immune cells, the epithelium, studies show that following activation, basophils migrate

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© 2010 American College of Chest Physicians
in small numbers to adjacent lymph nodes. Using a
basophil FcεR1-specific monoclonal antibody, it has
been demonstrated that the presence of basophils but
not mast cells is an absolute requirement for Th2 cell
differentiation.26 Basophils also increase humoral
immune responses on repeat antigenic exposure in the
presence of activated CD41 cells through the release of
IL-4 and IL-6, which provide support for B-cell prolif-
eration and antibody generation.27
Mice lacking the Fc receptor for IgG FcgR res-
pond to IL-3 in terms of normal development and
proliferation but have defective IL-4 (and also IL-6)
production and impaired ability to stimulate Th2
differentiation.28 In culture, basophils themselves
possess the ability to release IL-3 following FcεR1
activation, and this IL-3 promotes IL-13 release, sug-
gesting an autocrine function of IL-3 in upregulating
the basophilic response.29
Dendritic Cells
Pulmonary dendritic cells are potent antigen-
presenting cells with the capability to rapidly migrate
to draining lymph nodes, suggesting an innate role in
initiating immune response against airborne antigen.
Hence, dendritic cells may dictate the subsequent
T-cell response. Two major subsets of dendritic cells
have been described, based on CD11c expression.
Myeloid (CD11c1) dendritic cells are proinflamma-
tory, critical to both Th2 sensitization and the second-
ary immune response, and typically produce IL-12.
In contrast, plasmacytoid (CD11c2) dendritic cells
play a role in the induction of tolerance, preventing
inflammatory responses to harmless antigen, and
mainly produce interferon-g (Table 1). Plasmacytoid
dendritic cells turn over peptide-major histocompat-
ibility complex class 2 complexes when activated, with
the result that they are inefficient at presenting exog-
enous antigen but useful at presenting self-antigen
and viral antigen in a continuous manner following
activation.30 Therefore, in the regulation of allergy
and asthma, plasmacytoid and myeloid dendritic cells
would appear to have opposing/balancing roles.
T Lymphocytes
A paradigm emerged whereby the fundamental
problem in asthma was believed to be disturbance of

Table 1—Summary of the Key Mediators of Asthmatic Inflammatory Response

Mediator Potential Sources Potential Key Actions

IL-4 Mast cells, basophils Immunoglobulin class switching of B cells from IgG to IgE;
differentiation of Th2 cells; maturation of dendritic cells
IL-5 Mast cells Differentiation and enhanced survival of eosinophils
IL-13 Mast cells, basophils Immunoglobulin class switching of B cells from IgG to IgE; induction
of inflammatory cytokine release from epithelial and other structural
cells
TNF-a Mast cells, alveolar macrophages, T cells, Induction of proinflammatory cytokine release from structural cells;
epithelial cells, airway smooth muscle promotion of Th17-induced neutrophilia; enhancement of
dendritic cell migration; induction of CD4 T-cell migration;
antigen presentation; modulation of Treg cells
IL-6 “Structural” cells, dendritic cells, basophils Aids Th17 expansion and development
IL-17A Th17 cells Promote neutrophilia via induction of proinflammatory cytokine and
chemokine release from structural cells
IL-33 Structural cells such as epithelial cells Promote differentiation to Th2 cells; chemoattractant for Th2 cells;
enhance survival of, and cytokine production by, mast cells
SCF Structural cells, mast cells, and eosinophils Growth factor and chemoattractant for mast cells
TGF-b Eosinophils, mast cells, and macrophages Proliferation of fibroblasts; possibly induction of EMT; development
of immune tolerance via promotion of a Treg response; in
combination with IL-6, may promote a Th17 response
VEGF Structural cells, eosinophils Angiogenic promotion of vascular remodeling
TSLP Epithelial cells Promotion of a Th2 response; activation of dendritic cells and mast cells
Neurotrophin Epithelial cells, fibroblasts, airway smooth Enhanced airway eosinophilia; mast cell recruitment and activation;
(NGF and BDNF) muscle cells, macrophages, mast cells, increased airway hyperresponsiveness; promotion of airway
eosinophils, and lymphocytes inflammatory response
Lipoxins Derived at mucosal surface from interaction Attenuate bronchial hyperresponsiveness and promote resolution
between neutrophils and primarily epithelial of inflammation
cells, but also platelets, endothelial cells,
leukocytes, and fibroblasts
Resolvins Interaction between neutrophils and Enhance resolution of airway inflammation and attenuate bronchial
structural cells hyperresponsiveness
Protectins Interaction between neutrophils and Decrease allergic airway inflammation and airway hyperresponsiveness
structural cells
BDNF 5 brain derived neurotrophic factor; EMT 5 epithelial mysenchymal transition; IL 5 interleukin; NGF 5 nerve growth factor; SCF 5 stem
cell factor; TGF 5 transforming growth factor; Th 5 T-helper; TNF 5 tumor necrosis factor; Treg 5 T-regulatory; TSLP 5 thymic stromal lymphopoietin;
VEGF 5 vascular endothelial growth factor.

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the normal Th1/Th2 balance. Although elements of
this hypothesis remain useful, the emerging roles for
other T-cell subtypes in asthma suggest that it is too
simplistic. Th17 cells are a distinct population of
CD41 cells that produce IL-17A, IL-17F, IL-22,
TNF-a, and IL-21, and express the transcription fac-
tor RORgt.31 Recently, Th17 cells were isolated from
biopsy samples obtained from patients with asthma.32
IL-17 induces the release of a range of proinflam-
matory cytokines and chemokines from a variety of
cell types.31 It is linked to the development of airway
neutrophilia, and its presence in the asthmatic airway
correlates with increased disease severity. In murine
models of asthma, IL-23 and Th17 cells enhance
antigen-induced airway recruitment of both eosino-
phils and neutrophils, while mast-cell-derived TNF
has been shown to illicit a Th17-mediated airway neu-
trophilic response following antigen challenge.16,33
Treg cells play roles in the determination of self-
tolerance and the regulation of immune responses.
Th17 and Treg cells have opposing actions, being in
the main proinflammatory and antiinflammatory,
respectively. Experimental data suggest that retinoic
acid suppresses Th17 cell differentiation while pro-
moting Treg expansion.34,35 Further studies have
brought this a step further and demonstrated recip-
rocal generation of Treg and Th17 cells, with the
presence of transforming growth factor (TGF)-b in
isolation favoring a Treg response, while TGF-b in
combination with IL-6 favored a Th17 response.35,36
A similar reciprocal relationship between Th17 and
Treg cells, dependant on the relative levels of RORgt
and Foxp3, with Foxp3 attenuating the function of
RORgt, has also been shown.37
Invariant natural killer (NK) T cells produce both
Th1 and Th2 cytokines in large quantities and therefore
enhance the function of dendritic cells, NK-T cells,
B cells, and conventional T-cell subsets. Initial studies
suggested a potential role for invariant NK-T cells in
the pathophysiologic development of asthma.38 Later
studies have, however, disputed this.39,40 Furthermore,
it has also been reported that NK-T cells alone or in
combination with memory CD81 T cells are insuffi-
cient to induce allergic airway inflammation in mice
and their presence is not a prerequisite for its develop-
ment.41 The nature of the part played by invariant NK-T
cells has therefore yet to be conclusively illustrated.
Eosinophils
The precise role eosinophils play in the pathophys-
iologic causes of asthma remains controversial. Asthma
can be divided into eosinophilic and noneosinophilic
asthma depending on the presence or absence of air-
way eosinophils. The inference from this is that
eosinophils are not a prerequisite for the asthmatic
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Figure 1. Kaplan-Meier analysis of patients without an asthma
exacerbation during a study by Nair et al47 examining the effect of
the monoclonal antibody to interleukin-5, mepolizumab, in
patients with steroid-dependant asthma The median time to first
exacerbation was 20 weeks in the mepolizumab group vs 12 weeks
in the placebo group (P 5 .003).
phenotype or the clinical manifestations of asthma.
Despite this, therapies that reduce sputum eosino-
philia are effective in both forms of asthma.42
IL-5 has a key role in the modulation of eosinophil
differentiation and the promotion of eosinophil sur-
vival. Hence, targeting IL-5 would seem a logical
therapeutic strategy for allergic asthma. Indeed, anti-
IL-5 therapy has demonstrated clinical efficacy in
hypereosinophilic syndromes.43 In patients with asthma,
a monoclonal IL-5 antibody, while markedly reduc-
ing blood eosinophils, only partially abrogated the
pulmonary eosinophilic response and, subsequently,
had minimal impact on clinical outcomes.44,45 More
recent studies in patients with refractory, eosinophilic
asthma have demonstrated the ability of an anti-IL-5
monoclonal antibody (mepolizumab) to reduce both
blood and sputum eosinophil levels, reduce exacer-
bations, and facilitate a reduction in oral corticosteroid
dose (Fig 1).46,47 These results indicate that, at least in
a subset of patients with asthma, eosinophils are
critical effector cells in persistent asthma and severe
exacerbations.
Neutrophils
In acute, severe exacerbations of asthma, there are
increased eosinophils and neutrophils within the air-
way, with the increase in neutrophils proportionately
higher than that of eosinophils.48 Inhaled corticoster-
oids reduce airway eosinophils, but increase airway
neutrophils and increase the expression of the neu-
trophil chemoattractant IL-8, which is associated
with loss of asthma control.49 There has been long-
standing interest in the observed differences and
similarities between the asthmatic airway and that
Recent Advances in Chest Medicine
described in COPD. A recently published study has
described elevated levels of granulocyte-macrophage
colony-stimulating factor in the sputum of patients
with moderate to severe asthma and also in patients
with COPD, regardless of its severity.50 Therefore, it
appears likely that an increase in airway neutrophils
has important clinical implications in asthma.51
The Regulation of Inflammatory
Cell Production in Asthma
The bone marrow represents a vast source of
potential effector cells with the ability to affect
inflammation.52 While the bone marrow may act as a
reservoir for mature granulocytes, it is increasingly
recognized that hemopoietic progenitor stem cells
may be released from the bone marrow and recruited
to sites of injury, including the lung, and participate
in the inflammatory and the reparative processes.53
Allergen inhalation challenge experiments impli-
cate upregulation of the chemokine receptor (CCR) 3
in facilitating the egress of these progenitors from the
bone marrow. Eotaxin-1 up-regulates CCR3 on
CD341 cells, with the resultant increased release of
these cells into the circulation, while pharmacologic
down-regulation of CCR3 attenuates sputum eosino-
philia in response to allergen inhalation in patients
with mild to moderate asthma.54,55 Down-regulation
of CXCR4 on bone marrow CD341 cells and reduced
stromal-cell-derived factor 1a may further promote
progenitor cell efflux from the bone marrow following
allergen challenge, while attenuation of expression of
the adhesion molecule b1-integrin on progenitor cells
may aid their release into the circulation.56,57
Airway Structural Cells in Asthma
Traditionally viewed as a passive defensive barrier
to pathogenic insult, the airway epithelium is now
accorded a pivotal position in orchestrating the host
inflammatory response in airway remodeling and
fibroproliferation.58 Multiple asthma biopsy studies
have demonstrated airway epithelial abnormality,
and the epithelium, placed at the interface between
the external environment and the host, appears to be
both a site of action and of reaction within the asth-
matic inflammatory cascade.58-60
The airway epithelium is known to be a major
source of proinflammatory mediators. Recent examples
include thymic stromal lymphopoietin, an epithelial-
derived cytokine expressed in the asthmatic airway,
which has been shown to activate dendritic cells,
promote Th2 responses, and activate mast cells.61-63
Endothelin-1 is also increased in airway epithelial
biopsies in patients with severe asthma and in par-
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ticular in patients with steroid-resistant asthma.64
Particulate matter has also been shown to induce the
release of proinflammatory mediators and induce
cycloxygenase-2 expression in human airway epithe-
lial cells.65 In addition to acting as a potent source of
proinflammatory cytokines, epithelial cells possess
the ability to present self-antigen, with resultant
effects on the regulation of CD41 T-cell function,
including the induction of Foxp3 Treg cells, thus pro-
moting immune tolerance.66
The process of airway remodeling involves altera-
tions to the various components of airway structure,
with fibroproliferation, influx of myofibroblasts, col-
lagen deposition, hypertrophy of airway smooth mus-
cle, and reticular basement membrane thickening
typical. Remodeling occurs in asthma, and indeed,
parameters associated with remodeling are increased
in severe disease, with the airway mucosa of patients
with severe asthma displaying evidence of increased
proliferation of epithelium and increased thickening
of the epithelium and lamina reticularis.60 The para-
digm of remodeling as a chronic, dysfunctional, repair
response to ongoing inflammation has, however,
recently been challenged. While studies demonstrate
a progressive loss of lung function associated with
severe asthma exacerbations,67,68 it has been recognized
that remodeling may occur very early in asthma and
may in some cases even predate clinical symptoms.
Airway biopsy studies in children suggest that patho-
logic changes such as epithelial loss, basement mem-
brane thickening, and angiogenesis occur early in the
asthmatic airway.59,69 Although there exist progenitor
cell types within the bronchial epithelium with the
capacity for renewal following injury, repair pathways
are likely dysfunctional in asthma.70
In the asthmatic airway, there are increased num-
bers of subepithelial myofibroblasts, and allergen
challenge in people with asthma leads to increased
accumulation of myofibroblasts in the airway
mucosa.58,71 The precise source of these fibroblasts in
airway disease remains a topical source of debate.
Fibroblastic infiltration of the lung may plausibly be
secondary to the recruitment of circulating bone-
marrow-derived progenitors termed fibrocytes to the
airway and to the proliferation and expansion of resi-
dent fibroblasts, or possibly, epithelial cells may
undergo phenotypic change to effector fibroblasts
through a process termed epithelial-mesenchymal
transition. Airway biopsies have demonstrated the
increased presence of fibrocytes in the airway smooth
muscle bundle of patients with asthma of varying
severity compared with control subjects. Further-
more, in an ex vivo model, airway smooth muscle
cells promoted fibrocyte migration.72 A murine model
of chronic allergenic-stimulated airway remodeling
has revealed a crucial role for stem cell factor and
CHEST / 137 / 6 / JUNE, 2010 1421
IL-31 in promoting the influx of bone-marrow-derived
fibroblast progenitors to the lung.73 Recently, primary
airway epithelial cells derived from subjects with
asthma demonstrated increased susceptibility to TGF-
b-induced epithelial mesenchymal transition than
those derived from normal subjects.74
Fibroblast culture, animal, and human studies sup-
port the ability of leukotrienes to promote airway
remodeling.75-77 Bronchial epithelial cell experiments
have demonstrated a role for TLR signaling in the
activation of epidermal growth factor receptor, sug-
gesting a role for TLRs in potentiating remodeling.78
Histamine is capable of inducing the transition from
fibroblasts to myofibroblasts, as measured by a-smooth
muscle actin expression, and can, in addition, induce
connective-tissue-growth-factor expression in fibro-
blasts, suggesting the ability to participate in the pro-
cess of remodeling.79,80
Airway smooth muscle mass is increased in the
asthmatic airway.81 Asthmatic airway smooth muscle
shows increased expression of the fast myosin heavy
chain isoform transgelin, as well as myosin light chain
kinase, with further experiments in rat models sug-
gesting that this may be associated with the potential
to increase maximal flow and thereby contribute to the
airway hyperresponsiveness seen in asthma.82 Airway
smooth muscle cells can also be induced to secrete
mediators that may promote mast cell chemotaxis,
proliferation, and survival, while cell-cell interaction
between airway smooth muscle cells and mast cells
enhances activated complement-induced mast cell
degranulation.83-85 Interestingly, human lung mast cells
will migrate toward Th2 cytokine-stimulated airway
smooth muscle cells from subjects with asthma,
but not subjects without asthma, while supernatants
obtained from airway smooth muscle cell cultures of
subjects without asthma inhibit the chemotactic
action of asthmatic airway smooth muscle cells.86
In a recent study examining differences between
chronic persistent and intermittent persistent
asthma, endobronchial biopsy specimens showed
increased a-smooth muscle actin immunoperoxidase
staining in samples obtained from subjects with
chronic persistent asthma. There was also an increased

Figure 2. The pathophysiologic mechanism of asthma involves a coordinated, albeit dysfunctional,

multisystem response to airway stimulation, involving the airway epithelium, airway smooth muscle,
circulatory system, regional lymph nodes, and the bone marrow, with these elements in tandem with
effector inflammatory cells such as dendritic cells, mast cells, T cells, and eosinophils, as well as cytok-
ines and chemokines propagating the host inflammatory response. The airway epithelium appears to be
inherently abnormal. Over time, the epithelium, smooth muscle, and vasculature undergo structural
changes termed remodeling. The regional lymph nodes serve as stations to facilitate a specific immune
response, while the bone marrow serves as a source of both effector inflammatory cells and fibrocytes,
which contribute to airway inflammation and remodeling, respectively. DC 5 dendritic cell; MC 5 mast
cell; Th 5 T helper; TLR 5 toll-like receptor.

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proportion of both neutrophils and eosinophils in
sputum obtained from this group.87
The angiogenic changes associated with asthma
may also occur early in the pathophysiologic develop-
ment of the disease (Fig 2).59 Airway smooth muscle
cells from subjects with asthma but not healthy sub-
jects can promote in vitro angiogenesis.88 BAL fluid
obtained from patients with asthma has been shown
to possess a proangiogenic effect, which appears to
be mediated through the actions of vascular endothe-
lial growth factor (VEGF), while further studies of
the asthmatic airway demonstrate increased vascular-
ity and higher levels of VEGF, and potentially impli-
cate mast cells as a significant source of VEGF.89-92
However, increased vascularity and higher VEGF
levels exist both in patients with asthma and patients
with eosinophilic bronchitis but without asthma,
implying that vascular remodeling may not directly
influence airway hyperresponsiveness.93
Studies point to an interactive process between the
immunologic and neuronal systems in the propaga-
tion of asthmatic response. Murine models of asthma
have shown that the communicative process between
the two systems may be linked via the ion channel
TRPA1.94 In human studies, increased levels of brain-
derived neurotrophic factor have been associated with
loss of control in patients with mild allergic asthma.95
Endogenous Antiinflammatory Mediators
Much of this article and indeed research to date has
focused on proinflammation, fibroproliferation, and
the propagation of the remodeling response in asthma.
There has, however, been recent interest in the poten-
tial role of endogenous antiinflammatory compounds
in attenuating the asthmatic response. Culture models
have suggested a role for lipoxins, antiinflammatory
eicosanoids synthesized at a local level in response to
inflammation, in possibly inhibiting the actions of
eosinophils.96 Recent studies point to roles for addi-
tional, novel, endogenous, lipid-derived, antiinflam-
matory compounds such as the protectins and resolvins
in resolution of human airway inflammation.97,98 While
preliminary, animal models have demonstrated plau-
sible roles in asthma, but these results have yet to be
fully translated into human studies.98
Conclusions
Asthma is a complex, coordinated, multisystem, mul-
ticellular, inflammatory disorder. The development of
asthma requires an interaction between the environ-
ment and genetic susceptibility. Recent studies have
highlighted important interactions between the innate
and acquired immune system in some of the clinical
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© 2010 American College of Chest Physicians
manifestations of the disease, particularly in the devel-
opment of severe exacerbations. The epithelium,
smooth muscle, and vascular and neuronal elements of
the asthmatic lung also show evidence of dysfunction.
While these structural components undergo consider-
able architectural disturbance through remodeling,
they additionally act as a potent source of critical effec-
tor cells within the asthmatic airway.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST the following conflicts of interest: Dr Murphy is a past
recipient of an European Respiratory Society fellowship. Dr O’Byrne
is on advisory boards for AstraZeneca, GlaxoSmithKline, Topigen,
Wyeth, and Schering-Plough. He has received speakers honoria
from AstraZeneca and GlaxoSmithKline, and has received
research support from AstraZeneca, GlaxoSmithKline, Merck,
Wyeth, Schering-Plough, and Alexion.
References
1. Kabesch M, Schedel M, Carr D, et al. IL-4/IL-13 pathway
genetics strongly influence serum IgE levels and childhood
asthma. J Allergy Clin Immunol. 2006;117(2):269-274.
2. Loza MJ, Chang BL. Association between Q551R IL4R
genetic variants and atopic asthma risk demonstrated by
meta-analysis. J Allergy Clin Immunol. 2007;120(3):578-585.
3. von Hertzen L, Haahtela T. Disconnection of man and the
soil: reason for the asthma and atopy epidemic? J Allergy Clin
Immunol. 2006;117(2):334-344.
4. Roduit C, Scholtens S, de Jongste JC, et al. Asthma at 8 years
of age in children born by caesarean section. Thorax. 2009;
64(2):107-113.
5. Debarry J, Garn H, Hanuszkiewicz A, et al. Acinetobacter
lwoffii and Lactococcus lactis strains isolated from farm
cowsheds possess strong allergy-protective properties. J Allergy
Clin Immunol. 2007;119(6):1514-1521.
6. Bieli C, Eder W, Frei R, et al; PARSIFAL study group. A poly-
morphism in CD14 modifies the effect of farm milk consump-
tion on allergic diseases and CD14 gene expression. J Allergy
Clin Immunol. 2007;120(6):1308-1315.
7. Kim HM, Park BS, Kim JI, et al. Crystal structure of the
TLR4-MD-2 complex with bound endotoxin antagonist
Eritoran. Cell. 2007;130(5):906-917.
8. Ohto U, Fukase K, Miyake K, Satow Y. Crystal structures of
human MD-2 and its complex with antiendotoxic lipid IVa.
Science. 2007;316(5831):1632-1634.
9. Trompette A, Divanovic S, Visintin A, et al. Allergenicity
resulting from functional mimicry of a toll-like receptor com-
plex protein. Nature. 2009;457(7229):585-588.
10. Nigo YI, Yamashita M, Hirahara K, et al. Regulation of aller-
gic airway inflammation through toll-like receptor 4-mediated
modification of mast cell function. Proc Natl Acad Sci
U S A. 2006;103(7):2286-2291.
11. Yang Z, Yan WX, Cai H, et al. S100A12 provokes mast cell acti-
vation: a potential amplification pathway in asthma and innate
immunity. J Allergy Clin Immunol. 2007;119(1):106-114.
12. Kojima T, Obata K, Mukai K, et al. Mast cells and basophils are
selectively activated in vitro and in vivo through CD200R3
in an IgE-independent manner. J Immunol. 2007;179(10):
7093-7100.
13. Ho LH, Ohno T, Oboki K, et al. IL-33 induces IL-13 produc-
tion by mouse mast cells independently of IgE-FcepsilonRI
signals. J Leukoc Biol. 2007;82(6):1481-1490.
CHEST / 137 / 6 / JUNE, 2010 1423
14. Iikura M, Suto H, Kajiwara N, et al. IL-33 can promote sur-
vival, adhesion and cytokine production in human mast cells.
Lab Invest. 2007;87(10):971-978.
15. Allakhverdi Z, Smith DE, Comeau MR, Delespesse G. Cutting
edge: the ST2 ligand IL-33 potently activates and drives
maturation of human mast cells. J Immunol. 2007;179(4):
2051-2054.
16. Nakae S, Suto H, Berry GJ, Galli SJ. Mast cell-derived TNF
can promote Th17 cell-dependent neutrophil recruitment in
ovalbumin-challenged OTII mice. Blood. 2007;109(9):3640-3648.
17. Suto H, Nakae S, Kakurai M, Sedgwick JD, Tsai M, Galli SJ.
Mast cell-associated TNF promotes dendritic cell migration.
J Immunol. 2006;176(7):4102-4112.
18. Kashyap M, Thornton AM, Norton SK, et al. Cutting edge:
CD4 T cell-mast cell interactions alter IgE receptor expres-
sion and signaling. J Immunol. 2008;180(4):2039-2043.
19. Kambayashi T, Baranski JD, Baker RG, et al. Indirect involve-
ment of allergen-captured mast cells in antigen presentation.
Blood. 2008;111(3):1489-1496.
20. Kalesnikoff J, Galli SJ. New developments in mast cell biol-
ogy. Nat Immunol. 2008;9(11):1215-1223.
21. Schneider LA, Schlenner SM, Feyerabend TB, Wunderlin M,
Rodewald HR. Molecular mechanism of mast cell mediated
innate defense against endothelin and snake venom sarafo-
toxin. J Exp Med. 2007;204(11):2629-2639.
22. Rauter I, Krauth MT, Westritschnig K, et al. Mast cell-derived
proteases control allergic inflammation through cleavage of
IgE. J Allergy Clin Immunol. 2008;121(1):197-202.
23. Wenzel SE, Barnes PJ, Bleecker ER, et al; T03 Asthma
Investigators. A randomized, double-blind, placebo-controlled
study of tumor necrosis factor-alpha blockade in severe persis-
tent asthma. Am J Respir Crit Care Med. 2009;179(7):549-558.
24. Obata K, Mukai K, Tsujimura Y, et al. Basophils are essen-
tial initiators of a novel type of chronic allergic inflammation.
Blood. 2007;110(3):913-920.
25. Oh K, Shen T, Le Gros G, Min B. Induction of Th2 type
immunity in a mouse system reveals a novel immunoregula-
tory role of basophils. Blood. 2007;109(7):2921-2927.
26. Sokol CL, Barton GM, Farr AG, Medzhitov R. A mecha-
nism for the initiation of allergen-induced T helper type 2
responses. Nat Immunol. 2008;9(3):310-318.
27. Denzel A, Maus UA, Rodriguez Gomez M, et al. Basophils
enhance immunological memory responses. Nat Immunol.
2008;9(7):733-742.
28. Hida S, Yamasaki S, Sakamoto Y, et al. Fc receptor gamma-chain,
a constitutive component of the IL-3 receptor, is required for
IL-3-induced IL-4 production in basophils. Nat Immunol. 2009;
10(2):214-222.
29. Schroeder JT, Chichester KL, Bieneman AP. Human baso-
phils secrete IL-3: evidence of autocrine priming for pheno-
typic and functional responses in allergic disease. J Immunol.
2009;182(4):2432-2438.
30. Young LJ, Wilson NS, Schnorrer P, et al. Differential MHC
class II synthesis and ubiquitination confers distinct antigen-
presenting properties on conventional and plasmacytoid den-
dritic cells. Nat Immunol. 2008;9(11):1244-1252.
31. Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17
helper T cells. N Engl J Med. 2009;361(9):888-898.
32. Pène J, Chevalier S, Preisser L, et al. Chronically inflamed
human tissues are infiltrated by highly differentiated Th17
lymphocytes. J Immunol. 2008;180(11):7423-7430.
33. Wakashin H, Hirose K, Maezawa Y, et al. IL-23 and Th17 cells
enhance Th2-cell-mediated eosinophilic airway inflammation
in mice. Am J Respir Crit Care Med. 2008;178(10):1023-1032.
34. Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regula-
tory T cell differentiation mediated by retinoic acid. Science.
2007;317(5835):256-260.
1424
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on June 7, 2010
© 2010 American College of Chest Physicians
35. Xiao S, Jin H, Korn T, et al. Retinoic acid increases Foxp3+
regulatory T cells and inhibits development of Th17 cells by
enhancing TGF-beta-driven Smad3 signaling and inhibiting
IL-6 and IL-23 receptor expression. J Immunol. 2008;181(4):
2277-2284.
36. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental
pathways for the generation of pathogenic effector TH17 and
regulatory T cells. Nature. 2006;441(7090):235-238.
37. Zhou L, Lopes JE, Chong MM, et al. TGF-beta-induced
Foxp3 inhibits T(H)17 cell differentiation by antagonizing
RORgammat function. Nature. 2008;453(7192):236-240.
38. Akbari O, Faul JL, Hoyte EG, et al. CD41 invariant T-cell-
receptor1 natural killer T cells in bronchial asthma. N Engl J
Med. 2006;354(11):1117-1129.
39. Thomas SY, Lilly CM, Luster AD. Invariant natural killer
T cells in bronchial asthma. N Engl J Med. 2006;354(24):
2613-2616.
40. Vijayanand P, Seumois G, Pickard C, et al. Invariant natural
killer T cells in asthma and chronic obstructive pulmonary
disease. N Engl J Med. 2007;356(14):1410-1422.
41. Das J, Eynott P, Jupp R, et al. Natural killer T cells and CD81
T cells are dispensable for T cell-dependent allergic airway
inflammation. Nat Med. 2006;12(12):1345-1346.
42. Jayaram L, Pizzichini MM, Cook RJ, et al. Determining
asthma treatment by monitoring sputum cell counts: effect on
exacerbations. Eur Respir J. 2006;27(3):483-494.
43. Rothenberg ME, Klion AD, Roufosse FE, et al; Mepolizumab
HES Study Group. Treatment of patients with the hypere-
osinophilic syndrome with mepolizumab. N Engl J Med.
2008;358(12):1215-1228.
44. Flood-Page P, Swenson C, Faiferman I, et al; International
Mepolizumab Study Group. A study to evaluate safety and
efficacy of mepolizumab in patients with moderate per-
sistent asthma. Am J Respir Crit Care Med. 2007;176(11):
1062-1071.
45. Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS.
Eosinophil’s role remains uncertain as anti-interleukin-5 only
partially depletes numbers in asthmatic airway. Am J Respir
Crit Care Med. 2003;167(2):199-204.
46. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab
and exacerbations of refractory eosinophilic asthma. N Engl J
Med. 2009;360(10):973-984.
47. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for
prednisone-dependent asthma with sputum eosinophilia.
N Engl J Med. 2009;360(10):985-993.
48. Qiu Y, Zhu J, Bandi V, Guntupalli KK, Jeffery PK. Bronchial
mucosal inflammation and upregulation of CXC chemoattrac-
tants and receptors in severe exacerbations of asthma. Thorax.
2007;62(6):475-482.
49. Maneechotesuwan K, Essilfie-Quaye S, Kharitonov SA,
Adcock IM, Barnes PJ. Loss of control of asthma following
inhaled corticosteroid withdrawal is associated with increased
sputum interleukin-8 and neutrophils. Chest. 2007;132(1):
98-105.
50. Saha S, Doe C, Mistry V, et al. Granulocyte-macrophage
colony-stimulating factor expression in induced sputum and
bronchial mucosa in asthma and COPD. Thorax. 2009;64(8):
671-676.
51. Pallan S, Mahony JB, O’Byrne PM, Nair P. Asthma man-
agement by monitoring sputum neutrophil count. Chest.
2008;134(3):628-630.
52. Rankin SM. Impact of bone marrow on respiratory disease.
Curr Opin Pharmacol. 2008;8(3):236-241.
53. Denburg JA, Keith PK. Eosinophil progenitors in airway
diseases: clinical implications. Chest. 2008;134(5):1037-1043.
54. Sehmi R, Dorman S, Baatjes A, et al. Allergen-induced
fluctuation in CC chemokine receptor 3 expression on bone
Recent Advances in Chest Medicine
 marrow CD34+ cells from asthmatic subjects: significance
for mobilization of haemopoietic progenitor cells in allergic
inflammation. Immunology. 2003;109(4):536-546.
55. Gauvreau GM, Boulet LP, Cockcroft DW, et al. Antisense
therapy against CCR3 and the common beta chain attenuates
allergen-induced eosinophilic responses. Am J Respir Crit
Care Med. 2008;177(9):952-958.
56. Dorman SC, Babirad I, Post J, et al. Progenitor egress from
the bone marrow after allergen challenge: role of stromal cell-
derived factor 1alpha and eotaxin. J Allergy Clin Immunol.
2005;115(3):501-507.
57. Catalli AE, Thomson JV, Babirad IM, et al. Modulation of
beta1-integrins on hemopoietic progenitor cells after aller-
gen challenge in asthmatic subjects. J Allergy Clin Immunol.
2008;122(4):803-810.
58. Holgate ST. Epithelium dysfunction in asthma. J Allergy Clin
Immunol. 2007;120(6):1233-1244.
59. Barbato A, Turato G, Baraldo S, et al. Epithelial damage
and angiogenesis in the airways of children with asthma.
Am J Respir Crit Care Med. 2006;174(9):975-981.
60. Cohen L, E X, Tarsi J, et al; and the NHLBI Severe Asthma
Research Program (SARP). Epithelial cell proliferation con-
tributes to airway remodeling in severe asthma. Am J Respir
Crit Care Med. 2007;176(2):138-145.
61. Ziegler SF, Liu YJ. Thymic stromal lymphopoietin in nor-
mal and pathogenic T cell development and function. Nat
Immunol. 2006;7(7):709-714.
62. Allakhverdi Z, Comeau MR, Jessup HK, et al. Thymic
stromal lymphopoietin is released by human epithelial cells
in response to microbes, trauma, or inflammation and
potently activates mast cells. J Exp Med. 2007;204(2):253-258.
63. Ying S, O’Connor B, Ratoff J, et al. Thymic stromal lym-
phopoietin expression is increased in asthmatic airways and
correlates with expression of Th2-attracting chemokines and
disease severity. J Immunol. 2005;174(12):8183-8190.
64. Pégorier S, Arouche N, Dombret MC, Aubier M, Pretolani
M. Augmented epithelial endothelin-1 expression in refrac-
tory asthma. J Allergy Clin Immunol. 2007;120(6):1301-1307.
65. Zhao Y, Usatyuk PV, Gorshkova IA, et al. Regulation of COX-2
expression and IL-6 release by particulate matter in airway
epithelial cells. Am J Respir Cell Mol Biol. 2009;40(1):19-30.
66. Gereke M, Jung S, Buer J, Bruder D. Alveolar type II epi-
thelial cells present antigen to CD4(1) T cells and induce
Foxp3(1) regulatory T cells. Am J Respir Crit Care Med. 2009;
179(5):344-355.
67. Bai TR, Vonk JM, Postma DS, Boezen HM. Severe exacer-
bations predict excess lung function decline in asthma. Eur
Respir J. 2007;30(3):452-456.
68. O’Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW;
START Investigators Group. Severe exacerbations and
decline in lung function in asthma. Am J Respir Crit Care Med.
2009;179(1):19-24.
69. Turato G, Barbato A, Baraldo S, et al. Nonatopic children
with multitrigger wheezing have airway pathology comparable
to atopic asthma. Am J Respir Crit Care Med. 2008;178(5):
476-482.
70. Rawlins EL. Lung epithelial progenitor cells: lessons from
development. Proc Am Thorac Soc. 2008;5(6):675-681.
71. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification
of circulating fibrocytes as precursors of bronchial myofibro-
blasts in asthma. J Immunol. 2003;171(1):380-389.
72. Saunders R, Siddiqui S, Kaur D, et al. Fibrocyte localization
to the airway smooth muscle is a feature of asthma. J Allergy
Clin Immunol. 2009;123(2):376-384.
73. Dolgachev VA, Ullenbruch MR, Lukacs NW, Phan SH. Role
of stem cell factor and bone marrow-derived fibroblasts in
airway remodeling. Am J Pathol. 2009;174(2):390-400.
www.chestpubs.org
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on June 7, 2010
© 2010 American College of Chest Physicians
74. Hackett TL, Warner SM, Stefanowicz D, et al. Induction of
epithelial-mesenchymal transition in primary airway epithelial
cells from patients with asthma by transforming growth factor-
beta1. Am J Respir Crit Care Med. 2009;180(2):122-133.
75. Yoshisue H, Kirkham-Brown J, Healy E, Holgate ST, Sampson
AP, Davies DE. Cysteinyl leukotrienes synergize with growth
factors to induce proliferation of human bronchial fibroblasts.
J Allergy Clin Immunol. 2007;119(1):132-140.
76. Henderson WR Jr, Chiang GK, Tien YT, Chi EY. Reversal
of allergen-induced airway remodeling by CysLT1 receptor
blockade. Am J Respir Crit Care Med. 2006;173(7):718-728.
77. Kelly MM, Chakir J, Vethanayagam D, et al. Montelukast
treatment attenuates the increase in myofibroblasts following
low-dose allergen challenge. Chest. 2006;130(3):741-753.
78. Koff JL, Shao MX, Ueki IF, Nadel JA. Multiple TLRs acti-
vate EGFR via a signaling cascade to produce innate immune
responses in airway epithelium. Am J Physiol Lung Cell Mol
Physiol. 2008;294(6):L1068-L1075.
79. Vancheri C, Gili E, Failla M, et al. Bradykinin differenti-
ates human lung fibroblasts to a myofibroblast phenotype
via the B2 receptor. J Allergy Clin Immunol. 2005;116(6):
1242-1248.
80. Kunzmann S, Schmidt-Weber C, Zingg JM, et al. Connective
tissue growth factor expression is regulated by histamine in
lung fibroblasts: potential role of histamine in airway remod-
eling. J Allergy Clin Immunol. 2007;119(6):1398-1407.
81. Panettieri RA Jr, Kotlikoff MI, Gerthoffer WT, et al; National
Heart, Lung, and Blood Institute. Airway smooth muscle in
bronchial tone, inflammation, and remodeling: basic knowl-
edge to clinical relevance. Am J Respir Crit Care Med. 2008;
177(3):248-252.
82. Léguillette R, Laviolette M, Bergeron C, et al. Myosin, trans-
gelin, and myosin light chain kinase: expression and function
in asthma. Am J Respir Crit Care Med. 2009;179(3):194-204.
83. El-Shazly A, Berger P, Girodet PO, et al. Fraktalkine
produced by airway smooth muscle cells contributes to
mast cell recruitment in asthma. J Immunol. 2006;176(3):
1860-1868.
84. Hollins F, Kaur D, Yang W, et al. Human airway smooth mus-
cle promotes human lung mast cell survival, proliferation, and
constitutive activation: cooperative roles for CADM1, stem
cell factor, and IL-6. J Immunol. 2008;181(4):2772-2780.
85. Thangam EB, Venkatesha RT, Zaidi AK, et al. Airway smooth
muscle cells enhance C3a-induced mast cell degranulation
following cell-cell contact. FASEB J. 2005;19(7):798-800.
86. Sutcliffe A, Kaur D, Page S, et al. Mast cell migration to Th2
stimulated airway smooth muscle from asthmatics. Thorax.
2006;61(8):657-662.
87. Kaminska M, Foley S, Maghni K, et al. Airway remodeling in
subjects with severe asthma with or without chronic persis-
tent airflow obstruction. J Allergy Clin Immunol. 2009;124(1):
45-51.
88. Simcock DE, Kanabar V, Clarke GW, et al. Induction of
angiogenesis by airway smooth muscle from patients with
asthma. Am J Respir Crit Care Med. 2008;178(5):460-468.
89. Simcock DE, Kanabar V, Clarke GW, O’Connor BJ, Lee TH,
Hirst SJ. Proangiogenic activity in bronchoalveolar lavage
fluid from patients with asthma. Am J Respir Crit Care Med.
2007;176(2):146-153.
90. Hoshino M, Takahashi M, Aoike N. Expression of vascular
endothelial growth factor, basic fibroblast growth factor,
and angiogenin immunoreactivity in asthmatic airways and
its relationship to angiogenesis. J Allergy Clin Immunol.
2001;107(2):295-301.
91. Chetta A, Zanini A, Foresi A, et al. Vascular endothelial
growth factor up-regulation and bronchial wall remodelling
in asthma. Clin Exp Allergy. 2005;35(11):1437-1442.
CHEST / 137 / 6 / JUNE, 2010 1425
92. Zanini A, Chetta A, Saetta M, et al. Chymase-positive mast
cells play a role in the vascular component of airway remod-
eling in asthma . J Allergy Clin Immunol. 2007;120(2):
329-333.
93. Siddiqui S, Sutcliffe A, Shikotra A, et al. Vascular remodeling
is a feature of asthma and nonasthmatic eosinophilic bronchitis.
J Allergy Clin Immunol. 2007;120(4):813-819.
94. Caceres AI, Brackmann M, Elia MD, et al. A sensory neuronal
ion channel essential for airway inflammation and hyperre-
activity in asthma. Proc Natl Acad Sci U S A. 2009;106(22):
9099-9104.
95. Lommatzsch M, Lindner Y, Edner A, Bratke K, Kuepper
M , Virchow JC . Adverse effects of salmeterol in asthma:
a neuronal perspective. Thorax. 2009;64(9):763-769.
96. Starosta V, Pazdrak K, Boldogh I, Svider T, Kurosky A.
Lipoxin A4 counterregulates GM-CSF signaling in eosino-
philic granulocytes. J Immunol. 2008;181(12):8688-8699.
97. Kohli P, Levy BD. Resolvins and protectins: mediating solu-
tions to inflammation. Br J Pharmacol. 2009;158(4):960-971.
98. Levy BD, Kohli P, Gotlinger K, et al. Protectin D1 is gener-
ated in asthma and dampens airway inflammation and hyper-
responsiveness. J Immunol. 2007;178(1):496-502.

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