Asthma advances in pathophysiology

Recent Advances in the Pathophysiology of
Asthma
Desmond M. Murphy and Paul M. O'Byrne

Chest 2010;137;1417-1426
DOI 10.1378/chest.09-1895
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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

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

www.chestpubs.org CHEST / 137 / 6 / JUNE, 2010 1417


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

1418 Recent Advances in Chest Medicine


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



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 Figure 1. Kaplan-Meier analysis of patients without an asthma
has been shown to illicit a Th17-mediated airway neu- exacerbation during a study by Nair et al47 examining the effect of
the monoclonal antibody to interleukin-5, mepolizumab, in
trophilic response following antigen challenge.16,33 patients with steroid-dependant asthma The median time to first
Treg cells play roles in the determination of self- exacerbation was 20 weeks in the mepolizumab group vs 12 weeks
tolerance and the regulation of immune responses. in the placebo group (P 5 .003).
Th17 and Treg cells have opposing actions, being in
the main proinflammatory and antiinflammatory, phenotype or the clinical manifestations of asthma.
respectively. Experimental data suggest that retinoic Despite this, therapies that reduce sputum eosino-
acid suppresses Th17 cell differentiation while pro- philia are effective in both forms of asthma.42
moting Treg expansion.34,35 Further studies have IL-5 has a key role in the modulation of eosinophil
brought this a step further and demonstrated recip- differentiation and the promotion of eosinophil sur-
rocal generation of Treg and Th17 cells, with the vival. Hence, targeting IL-5 would seem a logical
presence of transforming growth factor (TGF)-b in therapeutic strategy for allergic asthma. Indeed, anti-
isolation favoring a Treg response, while TGF-b in IL-5 therapy has demonstrated clinical efficacy in
combination with IL-6 favored a Th17 response.35,36 hypereosinophilic syndromes.43 In patients with asthma,
A similar reciprocal relationship between Th17 and a monoclonal IL-5 antibody, while markedly reduc-
Treg cells, dependant on the relative levels of RORgt ing blood eosinophils, only partially abrogated the
and Foxp3, with Foxp3 attenuating the function of pulmonary eosinophilic response and, subsequently,
RORgt, has also been shown.37 had minimal impact on clinical outcomes.44,45 More
Invariant natural killer (NK) T cells produce both recent studies in patients with refractory, eosinophilic
Th1 and Th2 cytokines in large quantities and therefore asthma have demonstrated the ability of an anti-IL-5
enhance the function of dendritic cells, NK-T cells, monoclonal antibody (mepolizumab) to reduce both
B cells, and conventional T-cell subsets. Initial studies blood and sputum eosinophil levels, reduce exacer-
suggested a potential role for invariant NK-T cells in bations, and facilitate a reduction in oral corticosteroid
the pathophysiologic development of asthma.38 Later dose (Fig 1).46,47 These results indicate that, at least in
studies have, however, disputed this.39,40 Furthermore, a subset of patients with asthma, eosinophils are
it has also been reported that NK-T cells alone or in critical effector cells in persistent asthma and severe
combination with memory CD81 T cells are insuffi- exacerbations.
cient to induce allergic airway inflammation in mice
and their presence is not a prerequisite for its develop- Neutrophils
ment.41 The nature of the part played by invariant NK-T
cells has therefore yet to be conclusively illustrated. In acute, severe exacerbations of asthma, there are
increased eosinophils and neutrophils within the air-
Eosinophils way, with the increase in neutrophils proportionately
higher than that of eosinophils.48 Inhaled corticoster-
The precise role eosinophils play in the pathophys- oids reduce airway eosinophils, but increase airway
iologic causes of asthma remains controversial. Asthma neutrophils and increase the expression of the neu-
can be divided into eosinophilic and noneosinophilic trophil chemoattractant IL-8, which is associated
asthma depending on the presence or absence of air- with loss of asthma control.49 There has been long-
way eosinophils. The inference from this is that standing interest in the observed differences and
eosinophils are not a prerequisite for the asthmatic similarities between the asthmatic airway and that



described in COPD. A recently published study has ticular in patients with steroid-resistant asthma.64
described elevated levels of granulocyte-macrophage Particulate matter has also been shown to induce the
colony-stimulating factor in the sputum of patients release of proinflammatory mediators and induce
with moderate to severe asthma and also in patients cycloxygenase-2 expression in human airway epithe-
with COPD, regardless of its severity.50 Therefore, it lial cells.65 In addition to acting as a potent source of
appears likely that an increase in airway neutrophils proinflammatory cytokines, epithelial cells possess
has important clinical implications in asthma.51 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-
The Regulation of Inflammatory moting immune tolerance.66
Cell Production in Asthma The process of airway remodeling involves altera-
tions to the various components of airway structure,
The bone marrow represents a vast source of
with fibroproliferation, influx of myofibroblasts, col-
potential effector cells with the ability to affect
lagen deposition, hypertrophy of airway smooth mus-
inflammation.52 While the bone marrow may act as a
cle, and reticular basement membrane thickening
reservoir for mature granulocytes, it is increasingly
typical. Remodeling occurs in asthma, and indeed,
recognized that hemopoietic progenitor stem cells
parameters associated with remodeling are increased
may be released from the bone marrow and recruited
in severe disease, with the airway mucosa of patients
to sites of injury, including the lung, and participate
with severe asthma displaying evidence of increased
in the inflammatory and the reparative processes.53
proliferation of epithelium and increased thickening
Allergen inhalation challenge experiments impli-
of the epithelium and lamina reticularis.60 The para-
cate upregulation of the chemokine receptor (CCR) 3
digm of remodeling as a chronic, dysfunctional, repair
in facilitating the egress of these progenitors from the
response to ongoing inflammation has, however,
bone marrow. Eotaxin-1 up-regulates CCR3 on
recently been challenged. While studies demonstrate
CD341 cells, with the resultant increased release of
a progressive loss of lung function associated with
these cells into the circulation, while pharmacologic
severe asthma exacerbations,67,68 it has been recognized
down-regulation of CCR3 attenuates sputum eosino-
that remodeling may occur very early in asthma and
philia in response to allergen inhalation in patients
may in some cases even predate clinical symptoms.
with mild to moderate asthma.54,55 Down-regulation
Airway biopsy studies in children suggest that patho-
of CXCR4 on bone marrow CD341 cells and reduced
logic changes such as epithelial loss, basement mem-
stromal-cell-derived factor 1a may further promote
brane thickening, and angiogenesis occur early in the
progenitor cell efflux from the bone marrow following
asthmatic airway.59,69 Although there exist progenitor
allergen challenge, while attenuation of expression of
cell types within the bronchial epithelium with the
the adhesion molecule b1-integrin on progenitor cells
capacity for renewal following injury, repair pathways
may aid their release into the circulation.56,57
are likely dysfunctional in asthma.70
In the asthmatic airway, there are increased num-
Airway Structural Cells in Asthma bers of subepithelial myofibroblasts, and allergen
challenge in people with asthma leads to increased
Traditionally viewed as a passive defensive barrier accumulation of myofibroblasts in the airway
to pathogenic insult, the airway epithelium is now mucosa.58,71 The precise source of these fibroblasts in
accorded a pivotal position in orchestrating the host airway disease remains a topical source of debate.
inflammatory response in airway remodeling and Fibroblastic infiltration of the lung may plausibly be
fibroproliferation.58 Multiple asthma biopsy studies secondary to the recruitment of circulating bone-
have demonstrated airway epithelial abnormality, marrow-derived progenitors termed fibrocytes to the
and the epithelium, placed at the interface between airway and to the proliferation and expansion of resi-
the external environment and the host, appears to be dent fibroblasts, or possibly, epithelial cells may
both a site of action and of reaction within the asth- undergo phenotypic change to effector fibroblasts
matic inflammatory cascade.58-60 through a process termed epithelial-mesenchymal
The airway epithelium is known to be a major transition. Airway biopsies have demonstrated the
source of proinflammatory mediators. Recent examples increased presence of fibrocytes in the airway smooth
include thymic stromal lymphopoietin, an epithelial- muscle bundle of patients with asthma of varying
derived cytokine expressed in the asthmatic airway, severity compared with control subjects. Further-
which has been shown to activate dendritic cells, more, in an ex vivo model, airway smooth muscle
promote Th2 responses, and activate mast cells.61-63 cells promoted fibrocyte migration.72 A murine model
Endothelin-1 is also increased in airway epithelial of chronic allergenic-stimulated airway remodeling
biopsies in patients with severe asthma and in par- has revealed a crucial role for stem cell factor and



IL-31 in promoting the influx of bone-marrow-derived kinase, with further experiments in rat models sug-
fibroblast progenitors to the lung.73 Recently, primary gesting that this may be associated with the potential
airway epithelial cells derived from subjects with to increase maximal flow and thereby contribute to the
asthma demonstrated increased susceptibility to TGF- airway hyperresponsiveness seen in asthma.82 Airway
b-induced epithelial mesenchymal transition than smooth muscle cells can also be induced to secrete
those derived from normal subjects.74 mediators that may promote mast cell chemotaxis,
Fibroblast culture, animal, and human studies sup- proliferation, and survival, while cell-cell interaction
port the ability of leukotrienes to promote airway between airway smooth muscle cells and mast cells
remodeling.75-77 Bronchial epithelial cell experiments enhances activated complement-induced mast cell
have demonstrated a role for TLR signaling in the degranulation.83-85 Interestingly, human lung mast cells
activation of epidermal growth factor receptor, sug- will migrate toward Th2 cytokine-stimulated airway
gesting a role for TLRs in potentiating remodeling.78 smooth muscle cells from subjects with asthma,
Histamine is capable of inducing the transition from but not subjects without asthma, while supernatants
fibroblasts to myofibroblasts, as measured by a-smooth obtained from airway smooth muscle cell cultures of
muscle actin expression, and can, in addition, induce subjects without asthma inhibit the chemotactic
connective-tissue-growth-factor expression in fibro- action of asthmatic airway smooth muscle cells.86
blasts, suggesting the ability to participate in the pro- In a recent study examining differences between
cess of remodeling.79,80 chronic persistent and intermittent persistent
Airway smooth muscle mass is increased in the asthma, endobronchial biopsy specimens showed
asthmatic airway.81 Asthmatic airway smooth muscle increased a-smooth muscle actin immunoperoxidase
shows increased expression of the fast myosin heavy staining in samples obtained from subjects with
chain isoform transgelin, as well as myosin light chain 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.



proportion of both neutrophils and eosinophils in manifestations of the disease, particularly in the devel-
sputum obtained from this group.87 opment of severe exacerbations. The epithelium,
The angiogenic changes associated with asthma smooth muscle, and vascular and neuronal elements of
may also occur early in the pathophysiologic develop- the asthmatic lung also show evidence of dysfunction.
ment of the disease (Fig 2).59 Airway smooth muscle While these structural components undergo consider-
cells from subjects with asthma but not healthy sub- able architectural disturbance through remodeling,
jects can promote in vitro angiogenesis.88 BAL fluid they additionally act as a potent source of critical effec-
obtained from patients with asthma has been shown tor cells within the asthmatic airway.
to possess a proangiogenic effect, which appears to
be mediated through the actions of vascular endothe-
lial growth factor (VEGF), while further studies of Acknowledgments
the asthmatic airway demonstrate increased vascular- Financial/nonfinancial disclosures: The authors have reported
ity and higher levels of VEGF, and potentially impli- to CHEST the following conflicts of interest: Dr Murphy is a past
recipient of an European Respiratory Society fellowship. Dr O’Byrne
cate mast cells as a significant source of VEGF.89-92 is on advisory boards for AstraZeneca, GlaxoSmithKline, Topigen,
However, increased vascularity and higher VEGF Wyeth, and Schering-Plough. He has received speakers honoria
levels exist both in patients with asthma and patients from AstraZeneca and GlaxoSmithKline, and has received
research support from AstraZeneca, GlaxoSmithKline, Merck,
with eosinophilic bronchitis but without asthma, Wyeth, Schering-Plough, and Alexion.
implying that vascular remodeling may not directly
influence airway hyperresponsiveness.93
Studies point to an interactive process between the References
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Recent Advances in the Pathophysiology of Asthma
Desmond M. Murphy and Paul M. O'Byrne
Chest 2010;137; 1417-1426
DOI 10.1378/chest.09-1895
This information is current as of July 22, 2011
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