Pathogenic 5

PART

Mechanisms in
Asthma and COPD
 Pathophysiology of Asthma
INTRODUCTION
This chapter aims to provide a brief overview
of disease mechanisms to integrate some of the
detailed information provided in earlier chap-
ters into a framework with clinical relevance.
Asthma and chronic obstructive pulmonary dis-
ease (COPD) are both highly complex condi-
tions whose pathobiology remains inadequately
defined. In both diseases there are many differ-
ent and distinct inflammatory cells and multiple
mediators with complex acute and chronic effects
on the airways and airspaces. We now appreci-
ate that these changes may vary among patients
because of genetic variance in susceptibility [1].
Although our understanding of asthma patho-
genesis has been enhanced by the application of
new molecular, cell biological, and genetic tech-
niques to the condition, and the key test of the
acquired knowledge is the success of new specifi-
cally targeted therapies. In this area the successes
have been few in asthma and are virtually absent
in COPD. Thus, even though we have made
considerable advances in understanding asthma,
there remain many fundamental questions that
need to be answered.
Our views on asthma and COPD have
continued to evolve. Although it is recognized
that chronic inflammation underlies the clinical
syndromes, it has been hard to define the precise
nature of this inflammation, much less its pri-
mary etiology. Nevertheless it is appreciated that
the final consequence of this chronic inflamma-
tory response is an abnormal control of airway
caliber in vivo in asthma. In contrast, the evolu-
tion of understanding in COPD has been much
slower; key insights are sought which will open up
the understanding of this complex disorder (see
Chapter 34).
33CHAPTER
ASTHMA AS AN INFLAMMATORY Peter J. Barnes1 and
DISEASE Jeffrey M. Drazen2
1
National Heart and Lung Institute
It had been recognized for many years that (NHLI), Clinical Studies Unit,
patients who die of asthma attacks have grossly Imperial College, London, UK
inflamed airways. The airway lumen is occluded 2
Department of Medicine, Pulmonary
by tenacious mucus plugs composed of plasma Division, Brigham and Women’s
proteins exuded from airway vessels and mucus
Hospital, Boston, MA, USA
glycoproteins secreted from surface epithelial
cells. The airway wall is edematous and infiltrated
with inflammatory cells, which are predominantly
eosinophils and T-lymphocytes [2]. The airway
epithelium is invariably shed in a patchy man-
ner and clumps of epithelial cells are found in
the airway lumen. Occasionally there have been
opportunities to examine the airways of asth-
matic patients who die in accidents thought to be
unrelated to their asthma. In this setting inflam-
matory changes have been observed but they are
less marked than those observed in patients with
active asthma [3]. These studies also reveal that
the inflammation in asthmatic airways involves
not only the trachea and bronchi, but also extends
to the terminal bronchioles [4]; some investiga-
tors using transbronchial biopsies have shown
inflammatory cells in the parenchyma [5].
It has also been possible to examine the
airways of asthmatic patients by fiberoptic and
rigid bronchoscopy, bronchial biopsy, and bron-
choalveolar lavage (BAL). Direct bronchoscopic
examination reveals that the airways of asthmatic
patients are often erythematous and swollen,
indicating acute inflammation. Lavage of the air-
ways has revealed an increase in the numbers of
lymphocytes, mast cells, and eosinophils and evi-
dence for activation of macrophages in compari-
son with nonasthmatic controls. Biopsies have
provided evidence for increased numbers and
activation of mast cells, macrophages, eosinophils,
401
 Asthma and COPD: Basic Mechanisms and Clinical Management

T-lymphocytes including regulatory T-cells, and mucin
secreting cells [6–9]. These changes are found even in patients
with mild asthma who have few symptoms [10], suggesting
that inflammation may be found in all asthmatic patients who
are symptomatic. Similar inflammatory changes have been
found in bronchial biopsies of children with asthma, even at
the onset of symptoms [11, 12].
AIRWAY HYPERRESPONSIVENESS
The relationship between inflammation and clinical symp-
toms of asthma is not clear. There is evidence that the degree
of inflammation is loosely related to airway hyperrespon-
siveness (AHR), as measured by histamine or methacholine
challenge. However, the degree of inflammation, as measured
by the number of various types of inflammatory cells in the
lesion, is not closely linked to the clinical severity of asthma or
AHR [13]. This suggests that other factors, such as structural
changes in the airway wall, are important in mediating the
clinical symptoms of asthma. The increased airway respon-
siveness in asthma is a striking physiological abnormality that
is present even when airway function is otherwise normal. It is
likely that there are several factors that underlie this increased
responsiveness to constrictor agents, particularly those that
act indirectly by releasing bronchoconstrictor mediators from
airway cells or that modify the mechanical characteristics
of the airway wall. AHR may be due to increased release of
mediators (such as histamine and leukotrienes from mast
cells), abnormal behavior of airway smooth muscle, thicken-
ing of the airway wall by reversible (edema), and irreversible
(airway smooth muscle thickening, fibrosis) elements. Airway
sensory nerves may also contribute importantly to symptoms,
such as cough and chest tightness, as the nerves become sen-
sitized by the chronic inflammation in the airways.
Although most attention has been focused on the acute
inflammatory changes seen in asthmatic airways (bronchoc-
onstriction, plasma exudation, mucus secretion), asthma is a
chronic disease, persisting over many years in most patients.
Superimposed on this chronic inflammatory state are acute
inflammatory episodes, which correspond to exacerbations
of asthma. It is clearly important to understand the mecha-
nisms of acute and chronic inflammation in asthmatic air-
ways and to investigate the long-term consequences of this
chronic inflammation on airway function.
INFLAMMATORY CELLS
Many different inflammatory cells are involved in asthma,
although the precise role of each cell type is not yet certain
(Fig. 33.1). It is evident that no single inflammatory cell is

Inhaled allergens

Epithelial cells
CCL11
Mast cell SCF

Histamine TSLP
Cys-LTs
PGD2 Dendritic cell
IL-9
CCL17
CCL22
Bronchoconstriction ↓T-reg
CCR4
IgE
Th2 cell

IL-4, IL-13 IL-5

CCR3

B-Iymphocyte
Eosinophils

FIG. 33.1 A potential schema of Inflammation in asthma. Inhaled allergens activate sensitized mast cells by crosslinking surface-bound IgE molecules to
release several bronchoconstrictor mediators, including cysteinyl-leukotrienes (cys-LT) and prostaglandin D2 (PGD2). Epithelial cells release stem-cell factor
(SCF), which is important for maintaining mucosal mast cells at the airway surface. Allergens are processed by myeloid dendritic cells, which are conditioned
by thymic stromal lymphopoietin (TSLP) secreted by epithelial cells and mast cells to release the chemokines CC-chemokine ligand 17 (CCL17) and CCL22,
which act on CC-chemokine receptor 4 (CCR4) to attract T helper 2 (Th2) cells. Th2 cells have a central role in orchestrating the inflammatory response in
allergy through the release of interleukin-4 (IL-4) and IL-13 (which stimulate B-cells to synthesize IgE), IL-5 (which is necessary for eosinophilic inflammation)
and IL-9 (which stimulates mast-cell proliferation). Epithelial cells release CCL11, which recruits eosinophils via CCR3. Patients with asthma may have a defect
in regulatory T-cells (T-reg), which may favor further Th2-cell proliferation.

402
 Pathophysiology of Asthma 33
able to account for the complex pathophysiology of asthma Macrophages
but some cells predominate in asthmatic inflammation. The
inflammation in asthmatic airways differs strikingly from that Macrophages, which are derived from blood monocytes,
observed in COPD, where there is a predominance of mac- may traffic into the airways in asthma and may be activated
rophages, cytotoxic (CD8) T-lymphocytes, and neutrophils,
although both of these common diseases may coexist in some
patients. However, although the differences in inflammation
between mild asthma and COPD are well described, it is not
recognized that patients with severe asthma have inflamma-
tory changes that are similar to those of COPD, with increased
numbers of neutrophils, CD4 Th1 and CD8 cells [14].
Mast cells
Mast cells are clearly important in initiating the acute bron-
choconstrictor responses to allergen and probably to other
indirect stimuli, such as exercise and hyperventilation (via
osmolality or thermal changes) and fog. Mast cell activation
is likely to play a key role in the symptoms of asthma and
during acute exacerbations. There is infiltration of airway
smooth muscle by mast cells in patients with asthma that
is associated with the characteristic disordered airway func-
tion of this condition [15]. Treatment of asthmatic patients
with prednisone results in a decrease in the number of tryp-
tase-only positive mast cells [16]. Furthermore, the number
of mast cells in induced sputum in patients with seasonal
allergic rhinitis is related to the degree of AHR [17].
There appears to be an infiltration of mast cells into airway
smooth muscle of asthmatic patients and this is associated
with AHR [15]. The key role of mast cells in asthma has
been the subject of comprehensive reviews [7, 18]. Mast
cells are maintained at the mucosal surface by the secre-
tion of stem cell factor, which acts on c-kit receptors, by
epithelial cells [19]. However, it is now clear that mast cells
alone cannot account for all the pathobiological changes
in asthma and that other cells, such as macrophages, eosi-
nophils, and T-lymphocytes, play key roles in the chronic
inflammatory process including induction and maintenance
of AHR.
Classically mast cells are activated by allergens
through an IgE-dependent mechanism. The importance of
IgE in the pathophysiology of asthma has been highlighted
by clinical studies with humanized anti-IgE antibodies,
which inhibit IgE-mediated effects. Although anti-IgE
antibody results in a reduction in circulating IgE to unde-
tectable levels, this treatment results in minimal clinical
improvement in patients with severe steroid-dependent
asthma [20]. Examination of the patients receiving anti-IgE
therapy with omalizumab reveals downregulated expres-
by allergen via low-affinity IgE receptors (FcRII) [23]. The
enormous immunological repertoire of macrophages allows
these cells to produce many different products, including a
large variety of cytokines that may orchestrate the inflam-
matory response. Macrophages have the capacity to initiate
a particular type of inflammatory response via the release of
a certain pattern of cytokines. Macrophages may increase
or decrease inflammation depending on the stimulus. For
example, alveolar macrophages from normal and patients
with mild asthma phagocytose apoptic cells resulting from
lipopolysaccharide (LPS) exposure in vitro and produce
the anti-inflammatory mediator PGE2. In contrast alveolar
macrophages from patients with severe asthma are impaired
with respect to apoptotic cell uptake and production of
PGE2 [24]. These observations indicate that the severity
of asthma and perhaps its chronicity can modulate the role
of macrophages in asthma. It is also possible that the oppo-
site is true, that is, patients with severe asthma are the indi-
viduals with defective macrophage function. It is established
that repeated short term exposure to ozone recruits alveolar
macrophages to the airways of patients with mild asthma
[25] and that there is an association between the amount of
carbon in alveolar macrophages, which had to be activated
to ingest this material, and lung function [26]. Thus the
role of alveolar macrophages appears to be to modulate the
expression and severity of asthma.
Dendritic cells
By contrast, dendritic cells (which are specialized macro-
phage-like cells in the airway epithelium) are very effec-
tive antigen-presenting cells and may therefore play a very
important role in the initiation of allergen-induced responses
in asthma [27, 28]. Dendritic cells take up allergens though
their long finger-like projections, which extend into the air-
way lumen, process them to peptides, and migrate to local
lymph nodes where they present the allergenic peptides to
uncommitted T-lymphocytes, to program the production of
allergen-specific T-cells. Although there is no established
ways to manipulate dendritic cells, it has been shown that
during experimental allergen challenge in humans that a sig-
nificantly greater proportion of CD33 cells expressed the
cys-LT1-receptor compared with CD123 cells. Pranlukast,
cys-LT1-receptor antagonist, decreased the allergen-induced
decrease in CD33 dendritic cells at 3 h compared with
sion of IgE receptors (FcRI) on mast cells and basophils
[21]. Biopsy studies show a profound reduction in tissue
eosinophilia, together with reductions in T-cell and B-cell
numbers in the airway submucosa [22]. These observations
suggest that treatment with anti-IgE may be more effec-
tive in early stage rather than late stage asthma; however,
no clinically directive trials with omalizumab have been
conducted in this population. Furthermore, unless the
cost of such therapy is dramatically reduced it is unlikely
that such treatment would be used in patients with mild
disease.
placebo treatment. Based on this finding it is reasonable to
speculate that anti-leukotriene treatment could modify the
initial responses to allergen exposure [29].
Eosinophils
Eosinophil infiltration is a characteristic feature of asthmatic
airways and differentiates asthma from other non-infectious
inflammatory conditions of the airway. Indeed, asthma was
described as “chronic eosinophilic bronchitis” as early as 1916.
403
 Asthma and COPD: Basic Mechanisms and Clinical Management
Allergen inhalation results in a marked increase in eosi-
nophils in BAL fluid at the time of the late reaction, and
there is a correlation between eosinophil counts in periph-
eral blood or bronchial lavage and AHR. Eosinophils are
linked to the development of AHR through the release of
basic proteins and oxygen-derived free radicals [30, 31].
An important area of research is now concerned with
the mechanisms involved in recruitment of eosinophils into
asthmatic airways. Eosinophils are derived from bone mar-
row precursors; the Th2 cytokine IL-5 is a unique mediator
of eosinophil differentiation and survival in response to aller-
gen provocation. After allergen challenge eosinophils appear
in BAL fluid during the late response, and this appearance
is associated with a decrease in peripheral eosinophil counts
and with the appearance of eosinophil progenitors in the
circulation. The signal for increased eosinophil production
is likely IL-5 derived from the inflamed airway. Eosinophil
recruitment initially involves adhesion of eosinophils to vas-
cular endothelial cells in the airway circulation, their migra-
tion into the submucosa, and their subsequent activation. The
role of individual adhesion molecules, cytokines, and media-
tors in orchestrating these responses has been extensively
investigated but since there are no pathways that are unique
to eosinophils, this aspect of eosinophil biology has not been
extensively probed. Adhesion of eosinophils involves the
expression of specific glycoprotein molecules on the surface
of eosinophils (integrins) and their expression of such mol-
ecules as intercellular adhesion molecule-1 (ICAM-1) on
vascular endothelial cells. An antibody directed at ICAM-1
markedly inhibits eosinophil accumulation in the airways
after allergen exposure and also blocks the accompanying
hyperresponsiveness [32]. However, ICAM-1 is not selective
for eosinophils and cannot account for the selective recruit-
ment of eosinophils in allergic inflammation. Eosinophil
migration may be due to the effects of lipid mediators, such
as leukotrienes [33, 34] and possibly platelet-activating factor
(PAF), to the effects of cytokines, such as GM-CSF and IL-
5 both of which are important for the survival of eosinophils
in the airways and “prime” eosinophils to exhibit enhanced
responsiveness. Eosinophils from asthmatic patients show
exaggerated responses to PAF and phorbol esters, compared
with eosinophils from atopic nonasthmatic individuals [35].
This is further increased by allergen challenge [36, 37] sug-
gesting that they may have been primed by exposure to
cytokines in the circulation.
There are several mediators involved in the migration of
eosinophils from the circulation to the surface of the airway.
There are data showing that cysteinyl leukotrienes, through
stimulation at the cys-LT1-receptor, are in part responsi-
ble for eosinophilopoiesis in human airways [38], but other
mediators such as the eotaxins, a family of chemoattractant
cytokines that promote eosinophil recruitment to tissues in
response to allergic provocation via CCR3 receptors also play
a role [39–42]. Other potent and selective eosinophil chem-
oattractants include chemokines, such as CCL5 (RANTES)
and CCL13 (MCP-4), that are expressed in epithelial cells
[40, 43, 44] but data for their involvement in intact humans
are minimal. There appears to be a co-operative interaction
between IL-5, IL-13, and chemokines, so that more than one
cytokine may be necessary for the eosinophilic response in
airways [45, 46]. Once recruited to the airways, eosinophils
404
require the presence of various growth factors, of which
GM-CSF and IL-5 appear to be the most important [47].
In the absence of these growth factors eosinophils undergo
programmed cell death (apoptosis) [48].
A humanized monoclonal antibody to IL-5 has been
administered to asthmatic patients [49]; and, as in animal
studies, there is a profound and prolonged reduction in cir-
culating eosinophils. Although the infiltration of eosinophils
into the airway after inhaled allergen challenge is completely
blocked, there is no effect on the response to inhaled aller-
gen and no reduction in AHR. Anti-CCR3, anti-integrin,
and antiselectin treatments are currently being consid-
ered as anti-eosinophil strategies for treatment of asthma;
the results of these studies should better define the role of
eosinophils as mediators of asthmatic events. Eosinophils
may play a role in airway remodeling rather than AHR in
asthma as anti-IL-5 treatment is able to reduce extracellular
matrix deposition in asthma [50].
Neutrophils
The eosinophil has been the recipient of current attention as
an effector cell in asthma, but attention has been returning
to the role of neutrophils [51, 52]. Although neutrophils are
not a predominant cell type observed in the airways of most
patients with mild-to-moderate chronic asthma, they appear
to be a more prominent cell type in airways and induced spu-
tum of patients with more severe asthma [53–57]. The mecha-
nism of neutrophilic inflammation are not yet well understood,
but several mediators, including CXCL8 (IL-8) are likely to
be involved (Fig. 33.2). Sputum analysis shows that ∼20%
of asthmatics, even with mild disease, have a predominantly
neutrophilic pattern of inflammation [58]. Also in patients
who die suddenly of asthma, large numbers of neutrophils are
found in their airways [59] although this may reflect the rapid
kinetics of neutrophil recruitment compared to eosinophil
inflammation. Rapid withdrawal of corticosteroids results in
the appearance of neutrophils in the airways of patients with
asthma [60]. There are data to suggest that monomeric IgE
may mediate the appearance of neutrophils in the airways
of asthmatics and may represent the anti-apoptic activity of
myeloid cell leukemia-1 protein, decreased caspase-3 activ-
ity, diminished availability of Smac from mitochondria, and
sequestration of the pro-apoptic protein Bax in the cytoplasm
[61]. Thus the presence of neutrophils in the airway may reflect
the inflammatory microenvironment rather than indicate a
causal role for this cell. Further research into the role of neu-
trophils especially in severe asthma is ongoing [62].
T-lymphocytes
Th2 cells
T-lymphocytes play a very important role in co-ordinating
the inflammatory response in asthma through the release of
specific patterns of cytokines, resulting in the recruitment and
survival of eosinophils and in the maintenance of mast cells
in the airways. T-lymphocytes are coded to express a distinc-
tive pattern of cytokines, which are similar to that described
 Pathophysiology of Asthma 33
Viruses Allergens Allergen

Antigen presenting cell

Dendritic cell Dendritic cell, macrophage
TCR
Epithelial cells MHC1
Allergenl B7-2
peptide
TCR CD28
IL-17 IL-23 Mast cell
Th0
TNF-α CXCL1, CXCL8 Th17
IL-12 IL-4
IL-18
Neutrophils Th1
IFN-γ Th2
Neutrophil IL-4
IgE
elastase CXCL8 T-bet IL-13
MMP-9 TGF-β
IL-10
TGF-β IL-5
Th17 IL-2
Goblet cells IFN-γ
Fibroblast
↓ Treg
Mucus hypersecretion Fibrosis
Eosinophil
FIG. 33.2 Neutrophilic inflammation in asthma. Viruses, such as rhinovirus,
stimulate the release of CXCL8 (IL-8) and CXCL1 (GRO-α) from airway FIG. 33.3 T-lymphocytes in asthma. Asthmatic inflammation is
epithelial cells. Allergens activate dendritic cells to release IL-23, which characterized by a preponderance of T helper 2 (Th2) lymphocytes over
recruits helper T-cells that secrete IL-17 (Th17 cells) to release tumor T helper 1 (Th1) cells. Regulatory T-cells (Treg) have an inhibitory effect,
necrosis factor-α (TNF-α), which amplifies inflammation and CXCL1 and whereas T helper 17 (Th17) cells have a proinflammatory effects. MHC1:
CXCL8, which recruit neutrophils into the airways. Neutrophils release Class 1 major histocompatibility complex; IL: interleukin; IFN-γ: interferon
more CXCL8 and also transforming growth factor-β (TGF-β), which gamma; TGF-β: transforming growth factor beta; IgE: immunoglobulin E,
activates fibroblasts to cause fibrosis, and neutrophil elastase and matrix Th0: uncommitted T-cell.
metalloproteinase-9 (MMP-9) which stimulate mucus hypersecretion from
goblet cells.

in the murine Th2 type of T-lymphocytes, which characteris-
tically express IL-4, IL-5, and IL-13 [6]. This programming
of T-lymphocytes is presumably due to antigen-presenting
cells such as dendritic cells, which may migrate from the epi-
thelium to regional lymph nodes or which interact with lym-
phocytes resident in the airway mucosa. The naive immune
system is skewed to express the Th2 phenotype; data now
indicate that children with atopy are more likely to retain
this skewed phenotype than are normal children [63]. There
is also evidence that chitinase, a hydrolase that cleaves envi-
ronmental chitin, an insect protein, plays a critical role in
murine Th2 differentiation and has been identified in human
tissues from patients with asthma [64, 65]. The recruitment
of Th2 cells in the airway is dependent on several chemotac-
tic mediators, including the chemokines CCL17 (TARC)
and CCL22 (MDC) which act on CCR4 that are selectively
expressed on Th2 cells. These CCR4 ligands show increased
expression in airway epithelial cells, macrophages, and mast
cells of asthmatic patients [66]. PGD2, mainly derived from
mast cells, is also an important chemoattractant of Th2 cells
through the activation of DP2-receptors (or CRTH2) [67].
There is some evidence that steroid treatment may differen-
tially affect the balance between IL-12 expression and IL-13
expression [68]. Data from murine models of asthma [69–71]
have strongly suggested that IL-13 is both necessary and suf-
ficient for induction of the asthmatic phenotype. One of the
most important areas of asthma research in the next few years
will be to establish the importance of IL-13 in the induction
of the Th2 phenotype and asthma in humans.
Regulatory T-cells
A subset of CD4 T-cells expressing CD25, termed
T-regulatory cells (Tregs), are capable of suppressing both
Th1 and Th2-mediated adaptive immune responses, and
these cells may mediate their suppressive actions through
release of TGF-β or IL-10 [72]. An imbalance between
allergen-specific Tregs and effector Th2 cells has been shown
in allergic diseases [73]. There is some evidence that early
infections or exposure to endotoxins might promote Th1-
mediated responses to predominate and that a lack of infec-
tion or a clean environment in childhood may favor Th2-cell
expression and thus atopic diseases [74, 75]. Indeed, the bal-
ance between Th1 cells and Th2 cells is thought to be deter-
mined by locally released cytokines, such as IL-12, which tip
the balance in favor of Th1 cells, or IL-4 or IL-13, which
favor the emergence of Th2 cells (Fig. 33.3).
Th17 cells
Another subset of CD4 T-cells, known as Th17 cells, has
recently been described and shown to have an important
role in inflammatory and autoimmune diseases [76]. Little is
known about the role of Th17 cells in asthma, but increased
concentrations of IL-17A (the predominant product of Th17
cells) have been reported in the sputum of asthma patients
[77]. IL-17A and the closely related cytokine IL-17F have
been linked to neutrophilic inflammation by inducing the
release of CXCL1 and CXCL8 from airway epithelial
cells [78]. As well as IL-17, Th17 cells also produce IL-21,
which is important for the differentiation of these cells and
thus acts as a positive autoregulatory mechanism, but it also

405
 Asthma and COPD: Basic Mechanisms and Clinical Management
inhibits FOXP3 expression and regulatory T-cell devel-
opment [79, 80]. Another cytokine IL-22 is also released
by these cells and stimulates the production of IL-10 and
acute-phase proteins [81]. However, more work is needed to
understand the role and regulation of Th17 cells in asthma,
as they may represent important new targets for future
therapies.
Natural killer T-cells
A subset of CD4 T-cells termed invariant natural killer
T (iNKT) cells, which secrete IL-4 and IL-13, has been
shown to account for 60% of all CD4 T-cells in bronchial
biopsies from asthmatic patients [82], but this has been dis-
puted in another study, which failed to show any increase
in iNKT-cell numbers in bronchial biopsies, BAL or spu-
tum of either asthma patients or COPD patients [83]. The
role of iNKT cells in asthma is currently uncertain as there
appears to be a discrepancy between the data from murine
models of asthma and humans with the disease [84].
CD8 cells
CD8 (cytotoxic) T-cells are present in patients with more
severe disease and irreversible airflow obstruction [85] and
these cells may be of either the TC1 or the TC2 type, releas-
ing the same patterns of cytokines as CD4 cells [86].
B-lymphocytes
B-cells have an important role in asthma through the release
Basophils
The role of basophils in asthma is uncertain, as these cells have
previously been difficult to detect by immunocytochemistry
[89]; indeed there may be multiple phenotypes of basophils
with some able to release histamine on IgE challenge and
others not able to do so [90]. Using a basophil-specific marker,
a small increase in basophils has been documented in the air-
ways of asthmatic patients, with an increased number after
allergen challenge. However, these cells are far outnumbered
by eosinophils [91].
STRUCTURAL CELLS AND AIRWAY
REMODELING
Structural cells of the airways, including epithelial cells, fibrob-
lasts, and even airway smooth muscle cells are the site of
influence of many of the cytokines, growth factors, and inflam-
matory mediators that characterize the asthmatic diathesis.
Interestingly they may also be an important source of these
same molecular entities [92, 93]. Although the concept is
poorly defined, the idea that there are long-lasting changes in
the cells that make up the airway wall and that these cells nar-
row the lumen and contribute to chronic airflow limitation has
been termed airway remodeling. Given the absence of a clean
case definition, most investigators agree that certain changes,
such as thickening of the collagen layer deposited below the
true basement membrane, is a critical component of this aspect
of allergen-specific IgE which binds to FcRI on mast cells of asthma [94–98]. Indeed, because structural cells far outnum-
and basophils and to low-affinity FcRII on other inflam-
matory cells, including B-cells, macrophages, and possibly
eosinophils [87]. The Th2-type cytokines IL-4 and IL-13
induce B-cells to undergo class switching to produce IgE.
In both atopic asthma and non-atopic asthma, IgE may be
produced locally by B-cells in the airways [88].
ber inflammatory cells they may become the major source of
mediators driving chronic inflammation in asthmatic airways.
For example, epithelial cells may have a key role in translat-
ing inhaled environmental signals into an airway inflammatory
response and are probably a target cell for inhaled glucocorti-
coids and anti-leukotrienes (Fig. 33.4) [99].

Mechanical stress Allergens Viruses

Viruses
O2, NO2
Y

Macrophage
FcεRII

TNF-α, IL-1β, IL-6

Airway
epithelial cells

GM-CSF PDGF
CCL11 CCL5 FGF
PDGF
CCL5 IL-16 IGF-1
EGF FIG. 33.4 Airway epithelial cells in asthma. Airway
CCL13 CCL17, CCL22 IL-11
TGFβ epithelial cells may play an active role in asthmatic
ET inflammation through the release of many inflammatory
mediators, cytokines, chemokines and growth factors.
TNF-α: tumor necrosis factor alpha; IL: interleukin,
Eosinophil Lymphocyte Smooth muscle Fibroblast CCL: C-C chemokine, PDGF: platelet-derived growth factor;
survival activation hyperplasia activation EGF: epidermal growth factor; FGF: fibroblast growth factor;
chemotaxis IGF: insulin-like growth factor.

406

Structural changes in the airways may account for
the accelerated decline in airway function seen in asthmatic
patients over several years [100, 101]. Structural changes in
asthmatic airways include
● increased thickness of airway smooth muscle;
● infiltration of the airway smooth muscle with mast cells
● fibrosis (which is predominantly subepithelial);
● increased mucus-secreting cells;
● increased numbers of blood vessels (angiogenesis).
It is not known if these changes are reversible with
therapy. These changes may occur in some patients to a greater
extent than others and may be increased by other factors such
as concomitant cigarette smoking. It is likely that genetic fac-
tors will influence the extent of remodeling that occurs in indi-
vidual patients.
There are good data to support the idea that mechani-
cal deformation of the airway epithelium as a result of airway
smooth muscle constriction results in the creation of a micro-
environment that promotes airway remodeling. Deformed air-
way epithelial cells activate signaling via the epidermal growth
factor receptor (EGFR) and the urokinase plasminogen acti-
vator system. Experimental data show that soluble signals
generated by airway epithelial cells can influence the pheno-
type of fibroblasts to produce collagen similar to that found in
remodeled airways [102–104]. These data could help explain
why combination treatments with inhaled steroids and long-
acting β-agonists are effective asthma therapies.
Pathophysiology of Asthma 33
other inflammatory cells. Because each mediator has many
effects in the role of individual mediators in the pathophysi-
ology of asthma is not yet clear. Although the multiplicity of
mediators makes it unlikely that preventing the synthesis or
action of a single mediator will have a major impact in clinical
asthma, recent clinical studies with anti-leukotrienes suggest
that cysteinyl leukotrienes have a clinically important effect.
Leukotrienes
The cysteinyl leukotrienes LTC4, LTD4, and LTE4 are potent
constrictors of human airways and have been reported to
increase AHR and may play an important role in asthma
[107–110] (see Chapter 24). The recent development of
potent specific leukotriene antagonists has made it possible to
evaluate the role of these mediators in asthma. Potent LTD4
antagonists protect (by about 50%) against exercise- and
allergen-induced bronchoconstriction [111–114], suggesting
that leukotrienes contribute to bronchoconstrictor responses.
Combined treatment with an anti-histamine and an anti-
leukotriene is particularly effective [115, 116] Chronic treat-
ment with anti-leukotrienes improves lung function and
symptoms in asthmatic patients, although the degree of lung
function improvement is not as great as that seen with an
inhaled corticosteroid. It is only through the use of specific
antagonists that the role of individual mediators of asthma
may be defined. In the future, pharmaceuticals with specific
targets of action will be of special value in providing patho-
biological insights into the basic mechanisms of asthma;
their potential role in the treatment of asthma remains to be
determined.

INFLAMMATORY MEDIATORS Platelet-activating factor

Many different mediators have been implicated in asthma. Platelet-activating factor (PAF) and PAF-acetylhydrolase,
They may have a variety of effects on the airways, which could the enzyme that degrades PAF, constitute a potent inflam-
account for the pathological features of asthma (Fig. 33.5) matory mediator system that mimics many of the features
[105, 106]. Mediators such as histamine, prostaglandins, and of asthma, including eosinophil recruitment and activation
leukotrienes contract airway smooth muscle, increase micro- and induction of AHR; yet even potent PAF antagonists,
vascular leakage, increase airway mucus secretion, and attract such as modipafant, do not control asthma symptoms, at
least in chronic asthma [117–120]. However, genetic stud-
ies in Japan, where there is a high frequency of a genetic
mutation which disables the PAF metabolizing enzyme,
Inflammatory cells
Mediators
PAF-acetylhydrolase, have shown that there is an association
Mast cells between the presence of the mutant form of the enzyme and
Eosinophils Histamine
Leukotrienes severe asthma [121, 122]. In addition, there are data showing
Th2 cells
Basophils Prostanoids Effects that patients with a deficiency of the enzyme that degrades
Neutrophils PAF Bronchospasm PAF is associated with enhanced asthma severity [123].
Platelets Kinins Plasma exudation These data suggest that there may be certain conditions
Adenosine Mucus secretion
Structural cells associated with a significant role for PAF in asthma.
Endothelins AHR
Epithelial cells Nitric oxide Structural changes
Sm muscle cells Cytokines
Endothelial cells
Fibroblasts
Chemokines Cytokines
Growth factors
Nerves
Cytokines are increasingly recognized to be important in
FIG. 33.5 Multiple cells, mediators and effects. Many cells and mediators chronic inflammation and play a critical role in orchestrating
are involved in asthma and lead to several effects on the airways. Th2: the type of inflammatory response (see Chapter 27) (Fig. 33.6)
T helper 2 cells; Sm: smooth; PAF: platelet-activating factor; AHR: airway [124]. Many inflammatory cells (macrophages, mast cells,
hyperresponsiveness. eosinophils, and lymphocytes) are capable of synthesizing

407
 Asthma and COPD: Basic Mechanisms and Clinical Management
Allergen
Epithelial cells
IL-1β
TNF-α
Dendritic cell
Macrophage IL-12, IL-18
Th0 cell
IL-10
CCL1 IL-4
IL-13
GM-CSF
Monocyte Th2 cell
IL-3
IL-9 IL-4
IL-13
TNF-α
IL-4
Y
IL-5 IgE
Mast cell B-Iymphocyte
and releasing these proteins, and structural cells such as epi-
thelial cells and endothelial cells may also release a variety of
cytokines and may therefore participate in the chronic inflam-
matory response [125, 126]. There are number of major classes
of cytokines. One class includes T-cell derived cytokines,
examples of which include interferon (IFN)γ and TNFα
from Th1 cells and IL-4 and IL-5 from Th2 cells. Another
class includes pro- and anti-inflammatory cytokines with IL-
1β and IL-10 being respective examples. Chemoattractant
cytokines, such as CCL11 and CXCL8 (IL-8), and growth
factors cytokines, including PDGF, TGF-β, and VEGF are
other major classes. It is now clear that cytokines play a domi-
nant role in chronic inflammation of asthma.
T-cell-derived cytokines play a key role in creating the
microenvironment that lends itself to initiating and perpet-
uating the chronic inflammatory response of asthma [127].
The key cytokines here are Th2 cytokines, IL-3, IL-4, and
IL-5. IL-3 induces eosinophilia in vivo and maintains mast
cell viability. IL-4 induces differentiation of Th2 cells and
creates the microenvironment in which IgE antibody is syn-
thesized [128] and enhances mucin expression in goblet cells
[129]. IL-5 enhances eosinophil maturation and prevents
apoptosis of inflammatory cells [130]. The recently described
IL-17 family of cytokines, produced by cells as a result of the
action of IL-15 or IL-23 on CD4 or CD8 memory cells may
be important regulators of the asthmatic response [131–133].
A lack of specific small molecule antagonists has made
cytokine related research in humans difficult. Although
important observations have been made using specific neu-
tralizing antibodies [134], interventions involving immune
function can be difficult.
There is increased gene expression of IL-5 in lym-
phocytes in bronchial biopsies of patients with sympto-
matic asthma [135, 136]. The role of IL-5 in eosinophil
recruitment in asthma has been confirmed in a study in
which administration of an anti-IL-5 antibody to asthmatic
408
GM-CSF, IL-6, IL-11, IL-16
CCL11, CCL5, CXCL8, CCL17
Smooth muscle
GM-CSF
CCL5, CCL11
IL-5
FIG. 33.6 The cytokine network in
asthma. Many inflammatory cytokines
are released from inflammatory and
IL5, GM-CSI structural cells in the airway and
orchestrate and perpetuate the
Eosinophil inflammatory response.
patients was associated with a decrease in eosinophil counts
in the blood and BAL fluid [49]. Interestingly in this study
there was no effect on the physiology of the allergen-
induced asthmatic response; although this is not the last
word on eosinophils in asthma, it provides evidence that the
eosinophil, as recruited by IL-5, is not the major pathoge-
netic cell in asthma. This has been confirmed by a study of
the same antibody in symptomatic asthmatic patients, who
showed no improvement in asthma control despite a pro-
found reduction in circulating eosinophils [137]. Another
Th2 cytokine produced by peripheral blood cells of patients
with asthma, IL-9, may play a critical role in airway remod-
eling, eosinophilopoiesis, and may interact with the IL-4
receptorα in mediating some of the pathobiological features
of asthma [138–141].
Other cytokines, such as IL-1β, IL-6, TNF-α, TGF-
β, and GM-CSF, are released from a variety of cells, includ-
ing macrophages and epithelial cells and may be important
in amplifying the inflammatory response. TNF-α may be an
amplifying mediator in asthma and is produced in increased
amounts in asthmatic airways. Inhalation of TNF-α increased
airway responsiveness in normal individuals [142]. TNF-α
and IL-1β both activate the proinflammatory transcription
factors, nuclear factor-κB (NF-κB) and activator protein-1
(AP-1) which then switch on many inflammatory genes in
the asthmatic airway [143]. TGF-β, through ligation of two
receptors, type I and II, has been linked to tissue remodeling,
and potentially to subepithelial fibrosis through the Smad-
signaling pathway which could be a site for therapeutic inter-
vention [144–146].
Thymic stromal lymphopoeitin (TSLP) is a cytokine
that shows a marked increase in expression in airway epi-
thelium and mast cells of asthmatic patients [66]. TSLP
appears to play a key role in programming airway dendritic
cells to release CCL17 and CCL22 to attract Th2 cells (Fig.
33.7) [147]. It therefore acts as an upstream cytokine which

Epithelial cells Mast cell
Y
TSLP
Myeloid dendritic cell
CCL17
CCR4
Th2 cell
IL-5 IL-4, IL-13
IgE
Eosinophil B-lymphocyte
FIG. 33.7 Thymic stromal lymphopoetin in asthma. TSLP is an upstream
cytokine produced by airway epithelial cells and mast cells in asthma that
acts on immature dendritic cells to mature and release CCL17 (TARC),
which attracts Th2 cells via CCR4. Th2: T helper 2; CCL: chemokine; CCR:
chemokine receptor.
may play a key role in orchestrating an allergic pattern of
inflammation in asthmatic airways.
Complement
A decade ago it was postulated that complement had little
role in the biology of asthma. However, studies in mice har-
boring a targeted deletion of the C5a receptor showed dimin-
ished bronchial hyperresponsiveness induced after allergen
challenge [148]. In addition, genetic linkage studies in mice
have linked regions of the mouse genome containing the
gene for C5a to the phenotype of AHR [149]. Furthermore,
the complement peptide C5a has been recovered from BAL
fluid of patients after allergen challenge [148]. Current think-
ing is that complement contributes to the airway inflam-
mation, AHR and mucus production observed in human
asthma and may also prevent the formation of a Th2-directed
immune response to allergens [150–152].
Oxidative stress
In asthma, activation of epithelial cells, and resident macro-
phages, and the recruitment and activation of neutrophils,
eosinophils, monocytes, and lymphocytes leads to the gen-
eration of reactive oxygen species (ROS) and reactive nitro-
gen species (RNS). Action of many systems but primarily
NADPH oxidase results in the microenvironmental availabil-
ity of superoxide anions (O2•), which are rapidly converted
to H2O2 through the catalytic action of superoxide dismutase
(SOD). Hydroxyl ion (•OH) is then formed nonenzymati-
cally; this damages tissues, particularly cell membranes by
Pathophysiology of Asthma 33
peroxidation of their lipid membranes. Phagocytes use heme
peroxidases (myeloperoxidase, MPO) or eosinophil peroxi-
dase (EPO) to produce ROS; these moieties can also inter-
act with nitrite (NO2) and hydrogen peroxide (H2O2)
to promote formation of RNS. Eosinophils, a key cell in
asthma, have several times greater capacity to generate O2•
and H2O2 than do neutrophils, and the content of EPO in
eosinophils is 3–10 times higher than the amount of MPO
present in neutrophils [153–155].
Evidence for increased oxidative stress in asthma is
provided by the increased concentrations of 8-isoprostane
(a product of oxidized arachidonic acid) in exhaled breath
condensates [156], and increased ethane (a product of oxi-
dative lipoid peroxidation) in exhaled breath of asthmatic
patients [156–158]. Airflow obstruction, airway hyperre-
sponsiveness and airway remodeling have been associated
with impaired SOD activity [159, 160]. Oxidative stress is
increased particularly in patients with severe asthma (perhaps
as a result of the neutrophilic infiltration in these patients)
and this may reduce the activity of histone deacetylase
(HDAC), which may account for the reduced response to
corticosteroids in these patients [161, 162].
Endothelins
Endothelins are potent peptide mediators that are vasocon-
strictors, bronchoconstrictors and promote fibrosis [163,
164]. Endothelin-1 levels are increased in the sputum, serum,
and BAL fluid of patients with asthma; these levels are mod-
ulated by allergen exposure and steroid treatment [165–167].
Endothelins also induce airway smooth muscle cell prolifera-
tion and promote a profibrotic phenotype and may therefore
play a role in the chronic inflammation of asthma [164, 168].
Nitric oxide
Nitric oxide (NO) is produced by several cells in the airway
by NO synthases [169, 170] (see Chapter 30). Although the
cellular source of NO within the lung is not known, infer-
ences based on mathematical models suggest that it is the
large airways which are the source of NO [171]. However, in
patients with severe asthma NO is also derived form periph-
eral airways [172]. Current data indicate that the level of
NO in the exhaled air of patients with asthma is higher than
the level of NO in the exhaled air of normal subjects (see
Chapter 30) [173–177]. The elevated levels of NO in asthma
are closely linked to airway pH [178–180] and thus are more
likely reflective of inflammatory mechanisms than of a direct
pathogenetic role of this gas in asthma [181, 182]. The com-
bination of increased oxidative stress and NO may lead to
the formation of the potent radical peroxynitrite that may
result in nitrosylation of proteins in the airways [183, 184].
Asthmatics managed by measurements of exhaled nitric
oxide achieved equivalent asthma control with less inhaled
corticosteroids than those managed using conventional algo-
rithms [185]; the availability of portable devices to measure
exhaled nitric oxide may allow management of asthma in
manner similar to the self management of diabetics [186].
409
 Asthma and COPD: Basic Mechanisms and Clinical Management
EFFECTS OF INFLAMMATION ON
THE AIRWAYS
The idea that the chronic inflammatory response results in
the characteristic pathophysiological changes associated
with asthma has been widely promulgated. However, biop-
sies from children with wheezing show many of the charac-
teristic features of asthma [12]. Thus it is probable that some
of the differences between the condition of the airways in
normal and asthmatic subjects reflects the genetic makeup
of the patient influenced by environmental factors such as
airway infections and allergen exposures. The descriptions
below present the observations without adequate evidence
to support whether changes are markers for or the result of a
chronic inflammatory response. The inflammatory response
has many effects on structural cells of the airways result-
ing an amplification and perpetuation of the inflammatory
response (Fig. 33.8).
Airway epithelium
Airway epithelial cells play a critical role in asthma and
link environmental influences to inflammatory responses in
the airway (Fig. 33.4). Airway epithelial shedding may be
important in contributing to AHR and may explain how
several different mechanisms, such as ozone exposure, certain
virus infections, chemical sensitizers and allergen exposure
can lead to its development, since all these stimuli may lead
to epithelial disruption. Epithelium may be shed because of
an inflammatory milieu made up of eosinophil basic pro-
teins, oxygen-derived free radicals, proteases released from
Allergen
Macrophage/
dendritic cell
Th2 cell
Mucus plug
Nerve activation
Plasma leak
Edema
Mucus
hypersecretion Vasodilatation
hyperplasia New vessels
FIG. 33.8 The complexity of asthma. The pathophysiology of asthma is complex, with participation of several interacting inflammatory cells which result in
acute and chronic inflammatory effects on the airway.
410
inflammatory cells, and activated complement. Epithelial
cells shed from the airway wall may be found in clumps in
the BAL fluid or sputum (Creola bodies) of asthmatics, sug-
gesting that there has been a loss of attachment to the basal
layer or basement membrane. The damaged epithelium may
contribute to AHR in a number of ways, including
● loss of its barrier function to allow penetration of
allergens and irritants;
● loss of enzymes (such as neutral endopeptidase) which
normally degrade inflammatory mediators such as kinins;
● loss of a relaxant factor (so-called epithelial-derived
relaxant factor);
● edema and swelling that promotes obstruction by
lumenal encroachment;
● loss of surfactant function leading to increased increased
recoil of the airway;
● exposure of sensory nerves which may lead to reflex
neural effects on the airway.
Fibrosis
The basement membrane in asthma appears on light micros-
copy to be thickened; on closer inspection by electron micro-
scopy it has been demonstrated that this apparent thickening
is due to subepithelial fibrosis with deposition of types III
and V collagen below the true basement membrane; however,
the ratio of interstitial collagen fibrils to matrix is not dif-
ferent from that found in normal subjects [187–189]. Data
from a number of investigative groups show that the thick-
ness of the deposited collagen is related to airway obstruction
Mast cell
Neutrophil
Eosinophil
Epithelial compression and loss
Subepithelial
fibrosis
Myofibroblast
Sensory nerve
activation
Cholinergic
reflex
Bronchoconstriction
Hypertrophy/hyperplasia

and airway responsiveness [190–193]. The mechanism of
the collagen deposition is not known. However, it is known
that several profibrotic cytokines, including TGF-β and
PDGF, and mediators such as endothelin-1, can be pro-
duced by epithelial cells or macrophages in the inflamed
airway [126]. Even simple mechanical manipulations can
alter the phenotype of airway epithelial cells in a profibrotic
fashion [102–104, 194]. The role of airway fibrosis in asthma
is unclear, as subepithelial fibrosis has been observed even
in mild asthmatics at the onset of disease; it is not certain
whether the collagen deposition has any functional conse-
quences. Subepitheial fibrosis is also seen in patients with
chronic eosinophilic bronchitis, who usually present with
cough and have an infiltration of eosinophils in the airways
but no AHR or airway obstruction [195]. This suggests that
the subepithelial fibrosis seen in asthmatics is likely to be
secondary to eosinophilic inflammation in the airways and
may not have important functional consequences.
Airway smooth muscle
When the concept that asthma was primarily an inflamma-
tory disease was developed in the late 1980s to early 1990s,
airway smooth muscle was thought to be predominantly a
bystander tissue. That is the inflammatory process resulted
in the availability of mediators that led to smooth muscle
constriction and expression of an asthma phenotype. There
are now substantial data to support the concept that airway
smooth muscle in asthma is phenotypically different from
normal airway smooth muscle and that these changes reflect
the impact of the inflammatory asthmatic airway microenvi-
ronment on smooth muscle [15, 196–201]. Although some
of the abnormalities identified to date in asthma impact on
the contractility of individual units of airway smooth muscle,
the more recently identified ones reflect differences in the
ability of this tissue to proliferate or to function as an endo-
crine tissue (Fig. 33.9). For example, airway smooth muscle
may increase in mass because of an increased tendency to
proliferate due to the absence of an inhibitory transcription
factor C/EBP-α [197].
Airway smooth muscle is not only influenced by
the inflammatory mediators and cytokines in which it is
immersed [202], but also recent studies suggest that airway
Inflammatory cells
Mediators
Airway smooth muscle
Contraction Proliferation
Histamine, cys -leukotrienes PDGF, EGF,
kinins, prostanoids, endothelin endothelin-1
Pathophysiology of Asthma 33
smooth muscle modulates the remodeling process by secret-
ing multiple cytokines, growth factors, or matrix proteins
and by expressing cell adhesion molecules and other poten-
tial costimulatory molecules [196]. For example, increased
numbers of mast cells have been identified in airway smooth
muscle of patients with asthma [15, 198].
The importance of airway smooth muscle in chronic
asthma was highlighted by a recent trial in which airway
smooth muscle was rendered dysfunctional by bronchial
thermoplasty. Although this intervention was limited to rel-
atively large airways there was a measurable, although not
overwhelming, clinical benefit [203]. The idea of manipu-
lating the mass or contractile capacity of airway smooth
muscle in asthma remains an important and unexplored
avenue of asthma therapeutics [199, 204].
Vascular responses
It has been known for decades that the subepithelial con-
nective tissue of the asthmatic airway has many more blood
vessels than are found in similar locations in normal subjects
[205]. It is now recognized that bronchial vessels play a key
role in the pathophysiology of asthma (Fig. 33.10). Despite
this anatomic knowledge, little is known about the role of
the bronchial circulation in asthma. This is partly because
of the difficulties involved in measuring airway blood flow.
Recent studies using an inhaled absorbable gas have dem-
onstrated increased airway mucosal blood flow in asthma
[206–208].
The bronchial circulation may also play an important
role in regulating airway caliber, since an increase in the vas-
cular volume may contribute to airway narrowing. Vascular
blanching of the skin is used to measure the potency of
topical steroids and a similar mechanism may be involved
with the effects of inhaled steroids in asthma [207, 209].
Increased airway blood flow may be important in removing
inflammatory mediators from the airway, and may play a
role in the development of exercise-induced asthma [210].
Increased shear stress due to high expiratory pressures may
lead to gene transduction and enhanced production of nitric
oxide by type III (endothelial) NO synthase [211, 212];
there are in vivo experimental data in sheep that support the
importance of this mechanism [213]. There may also be an
FIG. 33.9 Airway smooth muscle in asthma.
Inflammation has several effects on airway smooth
muscle cells, resulting in contraction, proliferation and
Secretion secretion of inflammatory mediators. Cys: Cysteinyl;
cytokines, chemokines, PDGF: platelet-derived growth factor; EGF: epidermal
prostanoids growth factor.
411
 Asthma and COPD: Basic Mechanisms and Clinical Management

increase in the number of blood vessels in asthmatic airways Mucus hypersecretion

as a result of angiogenesis in response to VEGF [214–216].
Microvascular leakage is an essential component of
the inflammatory response and many of the inflammatory
mediators implicated in asthma produce this leakage [217,
218]. There is a good evidence for microvascular leakage
in asthma, and it may have several consequences on airway
function, including increased airway secretions, impaired
mucociliary clearance, formation of new mediators from
plasma precursors (such as kinins), and mucosal edema
which may contribute to airway narrowing and increased
AHR [219–221].
Inflammatory
mediators
Vasodilatation Plasma exudation
NO, CGRP histamine, cys-leukotrienes
histamine, PGE2 kinins, PAF
Mucus hypersecretion is a common inflammatory response
in secretory tissues and is an important component of the
inflammatory response in asthma (Fig. 33.11). Increased
mucus secretion contributes to the viscid mucus plugs
which occlude asthmatic airways, particularly in fatal
asthma. There is evidence for hyperplasia of submucosal
glands which are confined to large airways, and of increased
numbers of epithelial goblet cells in patients with asthma,
especially those with severe asthma [8]. One of the major
mucin genes, MUC5AC is induced by complement factor
C3a [222], NO [223], TNF-α [224], EGF family ligands
[225], or neutrophil elastase [226]. Since both neutrophils
and enhanced expression of mucin genes have been found
in great profusion in the airways of patients with severe
asthma [52], it is tempting to speculate that the neutrophils
may have led to the enhanced mucin gene expression. Thus
enhanced mucin expression in epithelial cells can be viewed
as an indicator of the inflammatory state of the airways.
These findings are not limited to cell culture, since in intact
humans with asthma, exercise-induced bronchospasm is
associated with enhanced expression of MUC5AC [227].
It is highly likely that methods to manipulate mucin gene
expression in response to inflammatory stimuli will be iden-
tified and could be of value in the treatment of asthma as
Angiogenesis well as COPD.
VEGF, TNF-α

FIG. 33.10 Vascular abnormalities in asthma. Allergic inflammation has

several vascular effects, including vasodilatation, plasma exudation from
post-capillary venules and new vessel formation (angiogenesis). NO: Nitric
oxide; CGRP: calcitonin gene-related peptide; PGE2: prostaglandin E2; PAF:
platelet-activating factor; VEGF: vascular-endothelial growth factor; TNF-α:
tumor necrosis factor-alpha.
Neural effects
Neural mechanisms play an important role in the patho-
genesis in asthma as discussed in Chapter 32 [228].
Autonomic nervous control of the airways is complex; in
addition to classical cholinergic and adrenergic mechanisms,

Neutrophil Th2 cell

Oxidative stress
IL-4, IL-13, IL-9

Neutrophil
elastase

EGFR

↑ MUC5AC

Goblet cells

Goblet cells Mucus hyperplasia

Mucus hypersecretion
Submucosal gland

FIG. 33.11 Mucus hypersecretion in asthma. Increased mucus secretion in asthma may be stimulated by neutrophils through the release of neutrophil
elastase, T helper 2 (Th2) cytokines and oxidative stress. This may be mediated via epidermal growth factor receptors (EGFR) which may result in mucus
hyperplasia and increased expression of the mucin gene MUC5AC. Mucus hypersecretion is also enhanced by neural mechanisms through the release of
acetylcholine (ACh) and substance P (SP).

412

nonadrenergic noncholinergic (NANC) nerves and several
neuropeptides have been identified in the respiratory tract
[229–231]. Many studies have investigated the possibility
that defects in autonomic control may contribute to AHR
in asthma, and abnormalities of autonomic function, such as
enhanced cholinergic and α-adrenergic responses or reduced
β-adrenergic responses, have been proposed. Current think-
ing suggests that these abnormalities are likely to be second-
ary to the disease, rather than primary defects [228]. It is
possible that airway inflammation may interact with auto-
nomic control by several mechanisms.
There is a close interaction between airway inflamma-
tion and airway nerves (Fig. 33.12). Inflammatory media-
tors may act on various prejunctional receptors on
airway nerves to modulate the release of neurotransmitters
[232, 233]. Thus thromboxane and PGD2 facilitate the
release of acetylcholine from cholinergic nerves in canine
airways, whereas histamine inhibits cholinergic neurotrans-
mission at both parasympathetic ganglia and postganglionic
nerves via histamine H3-receptors. Inflammatory media-
tors may also activate sensory nerves, resulting in reflex
cholinergic bronchoconstriction or release of inflammatory
neuropeptides. Inflammatory products may also sensitize
sensory nerve endings in the airway epithelium, so that the
nerves become hyperalgesic. Hyperalgesia and pain (dolor)
are cardinal signs of inflammation, and in the asthmatic air-
way may mediate cough and chest tightness, which are such
characteristic symptoms of asthma. The precise mechanisms
of hyperalgesia are not yet certain, but mediators such as
prostaglandins, certain cytokines, and neurotrophins may
be important. Neurotrophins, which may be released from
various cell types in peripheral tissues, may cause prolifera-
tion and sensitization of airway sensory nerves [234].
Bronchodilator nerves which are nonadrenergic are
prominent in human airways and may be dysfunctional in
asthma [235]. In human airways, the bronchodilator neuro-
transmitter appears to be NO [236].
Airway nerves may also release neurotransmitters
which have proinflammatory effects. Thus neuropeptides
such as substance P (SP), neurokinin A, and calcitonin-gene
Pathophysiology of Asthma 33
related peptide may be released from sensitized inflamma-
tory nerves in the airways which increase and extend the
ongoing inflammatory response [237]. There is evidence
for an increase in SP-immunoreactive nerves in airways
of patients with severe asthma [238], which may be due
to proliferation of sensory nerves and increased synthesis
of sensory neuropeptides as a result of nerve growth fac-
tors released during chronic inflammation – although this
has not been confirmed in milder asthmatic patients [239].
There may also be a reduction in the activity of enzymes,
such as neutral endopeptidase, which degrade neuropeptides
such as SP [240]. Thus chronic asthma may be associated
with increased neurogenic inflammation, which may provide
a mechanism for perpetuating the inflammatory response
even in the absence of initiating inflammatory stimuli.
TRANSCRIPTION FACTORS
The chronic inflammation of asthma is due to increased
expression of multiple inflammatory proteins (cytokines,
enzymes, receptors, adhesion molecules). In many cases
these inflammatory proteins are induced by transcription
factors, DNA-binding factors that increase the transcrip-
tion of selected target genes (Fig. 33.13) [143].
A proinflammatory transcription factor that may play
a critical role in asthma is nuclear factor-kappa B (NF-κB)
which can be activated by multiple stimuli, including protein
kinase C activators, oxidants, and proinflammatory cytokines
(such as IL-1β and TNF-α) [241–243]. There is evidence
for increased activation of NF-κB in asthmatic airways, par-
ticularly in epithelial cells and macrophages [244]. Although
many aspects of the asthmatic airway are influenced by the
expression of transcription factors, there are data linking
the mechanical deformation of the airway to expression of
proinflammatory transcription factors; these findings have
direct implications for the mechanism of exercise-induced
asthma and may explain how this physical stimulus could

Inflammatory mediators
Neutrotrophins

Airway nerves
Inflammatory
cells

Neurotransmitters
Neuropeptides

Neurogenic inflammation

FIG. 33.12 Neural mechanism in asthma. There is a close interaction between asthmatic inflammation and neural mechanisms.

413
 Asthma and COPD: Basic Mechanisms and Clinical Management

Inflammatory Inflammatory
stimuli proteins
allergens, viruses, cytokines, enzymes, receptors,
cytokines adhesion molecules

Receptor

Kinases Inactive
transcription
factor
mRNA

Activated
transcription factor
P (NF-κB, AP-1, STATs)
Nucleus

Inflammatory Promoter Coding region

gene

FIG. 33.13 Proinflammatory transcription factors in asthma. Transcription factors play a key role in amplifying and perpetuating the inflammatory response
in asthma. Transcription factors, including nuclear factor kappa-B (NF-κB), activator protein-1 (AP-1), and signal transduction-activated transcription factors
(STATs), are activated by inflammatory stimuli and increase the expression of multiple inflammatory genes.

IL-27 IL-12 IL-4 IL-33 naive T-cells into Th2 cells and it regulates the secretion
of TH2-type cytokines [248]. There is an increase in the
number of GATA-3 T-cells in the airways of asthmatic
subjects compared with normal subjects [249]. Following
STAT1 STAT4 STAT6
simultaneous ligation of the T-cell receptor (TCR) and
co-receptor CD28 by antigen-presenting cells, GATA-3
is phosphorylated and activated by p38 mitogen-activated
Th1 cells T-bet GATA-3 Th2 cells
protein kinase. Activated GATA-3 then translocates from
the cytoplasm to the nucleus, where it activates gene tran-
scription [250]. GATA-3 expression in T-cells is regulated
by the transcription factor STAT-6 (signal transducer and
Th1 cytokines Th2 cytokines
activator of transcription 6) via IL-4 receptor activation.
(IL-2, IFN-γ) (IL-4, IL-5, IL-9, IL-13) Another transcription factor T-bet has the opposite
effect and promotes Th1 cells and suppresses Th2 cells.
Allergic inflammation T-bet expression is reduced in T-cells from the airways of
asthmatic patients compared with nonasthmatic patients
FIG. 33.14 GATA-3 in asthma. The transcription factor GATA-3 (GATA- [251]. When phosphorylated, T-bet can associate with
binding protein-3) is regulated by interleukin-4 (IL-4) via STAT-6 (signal and inhibit the function of GATA-3, by preventing it
transducer and activator of transcription 6) and regulates the expression from binding to its DNA target sequences [252]. GATA-
of IL-4, IL-5, IL-9, and IL-13 from T helper 2 (Th2) cells and inhibits the 3 inhibits the production of Th1-type cytokines by inhibit-
expression of T-bet via inhibition of STAT4. IL-33 enhances the actions of ing STAT-4, the major transcription factor activated by the
GATA-3. T-bet regulates TH1-cell secretion of IL-2 and interferon-γ (IFN-γ) T-bet-inducing cytokine IL-12 [253] (Fig. 33.14). Nuclear
and has an inhibitory action on GATA-3. T-bet is regulated by IL-12 via
factor of activated T-cells (NFAT) is a T-cell-specific tran-
STAT4 and by IL-27 via STAT1. This demonstrates the complex interplay of
cytokines and transcription factors in asthma.
scription factor and appears to enhance the transcriptional
activation of GATA-3 at the IL-4 promoter [254]. FOXP3
is a transcription factor that is expressed in Tregs, whereas
modify the inflammatory microenvironment of the airway the equivalent transcription factor in Th17 cells is RORγt.
[104, 245–247]. There appears to be a negative interaction between these
The transcription factor GATA-3 (GATA-binding transcription factors so that a reduction of Tregs in asthma
protein 3) is crucial for the differentiation of uncommitted may be a factor increasing Th17 cells [255].

414

Anti-
inflammatory
mediators
IL-10, IL-1ra
IFN-γ, IL-12, IL-18
Lipoxins, resolvins
Inflammatory Protectins
mediators PGE2
Lipid mediators
Cytokines
Peptides
Oxidants
FIG. 33.15 Anti-inflammatory mediators in asthma. There may be an
imbalance between increased proinflammatory mediators and a deficiency
in anti-inflammatory mediators. IL: interleukin; IL-1ra: interleukin-1 receptor
antagonist; IFN-γ: interferon gamma; PGE2: prostaglandin E2.
ANTI-INFLAMMATORY MECHANISMS IN
ASTHMA
Although most emphasis has been placed on inflammatory
mechanisms, there may be important anti-inflammatory
mechanisms that may be defective in asthma, resulting in
increased inflammatory responses in the airways (Fig. 33.15).
Lipid anti-inflammatory mediators
Several lipid mediators appear to have anti-inflammatory
effects, including PGE2, lipoxins, resolvins, and protectins
[256, 257]. There is a strong evidence supporting the role of
signaling through the lipoxin A receptor as being deficient
in severe asthma in general and aspirin-sensitive asthma in
particular [258–263]. In addition it has now been estab-
lished that presqualene diphosphate (PSDP) is an endog-
enous regulator of phosphatidylinositol 3-kinase (PI3K).
PSDP, but not presqualene monophosphate (PSMP),
directly inhibits recombinant human PI3K-γ activity and
a new PSDP structural mimetic blocks human neutrophil
activation and murine lung PI3K activity and inflamma-
tion [264]. Resolvin E1 (RvE1: 5S,12R,18R-trihydroxyei
cosapentaenoic acid) is an anti-inflammatory lipid media-
tor derived from the ω-3 fatty acid eicosapentaenoic acid.
RvE1 is involved in the resolution of inflammation and
reduces allergic inflammation in mice exposed to inhaled
allergen [265].
Another important anti-inflammatory mediator is
protectin D1, a natural lipid based chemical mediator that
counters leukocyte activation. PD1 has been recovered from
Pathophysiology of Asthma 33
exhaled breath condensates from healthy subjects but levels
were significantly lower in condensates from patients with
asthma exacerbations [266]. PD1 when administered before
inhaled allergen challenge, in mice led to decreased airway
eosinophil and T-lymphocyte recruitment, decreased airway
mucus, and less of an increment in AHR than without the
PD1. These data suggest that endogenous PD1 is a novel
and important counterregulatory signal in allergic airway
inflammation.
IL-10
Airway and alveolar macrophages have a predominantly
suppressive effect in asthma and inhibit T-cell proliferation.
The mechanism of macrophage-induced immunosuppression
is not yet certain, but PGE2 and IL-10 secretion may con-
tribute [267]. IL-10 inhibits many of the inflammatory
mechanisms in asthma and its secretion is defective from
macrophages of asthmatic patients [268]. IL-10 is secreted
by a subset of Tregs and this is enhanced by specific allergen
immunotherapy [267]. Interestingly treatment of asthmatic
children with an inhaled corticosteroid or with montelukast
increases serum levels of IL-10 [269]; these findings sug-
gest that increasing IL-10 may be an important therapeutic
approach in asthma.
GENETIC INFLUENCES
Over the past 15 years there have been multiple studies on
the genetics of asthma (see Chapter 4). A number of poten-
tial asthma genes have been identified [270], but very few
have been replicated in multiple populations [271]. However
all the data suggest that there is not a single major asthma
susceptibility gene, but rather there are multiple genes each
explaining only a small proportion of the total variance in
the asthma phenotype. The keys to find the most important
asthma genes will be to use comprehensive methods and to
replicate the findings in an individual population in multiple
distinct populations.
ADAM33 is an asthma gene, discovered by positional
cloning, that has been replicated in many but not all popu-
lations tested [272]. It was initially identified in Caucasian
families from the United States and United Kingdom and
was associated with asthma characterized by bronchial hyper-
responsiveness. There were many variants within ADAM33
that were significantly associated with these phenotypes.
Subsequently, there have been a large number of case-control
and family-based association studies focused on ADAM33,
with the majority but not all, confirming the original finding
[273]. Current data suggest that ADAM33 may be involved
in lung development and remodeling.
In genome wide-association studies microarrays capa-
ble of typing 500,000 to 1 million single nucleotide poly-
morphisms are used to identify associations between a given
phenotype and genotype. This technology has been applied
to childhood asthma [274]. These investigators identi-
fied a strong statistical association between the diagnosis of
415
 Asthma and COPD: Basic Mechanisms and Clinical Management
asthma in childhood in families from the United Kingdom
and markers located on chromosome 17q21. The results were
replicated in two European populations. They then used the
genetic data to examine transcript levels in immortalized lym-
phocytes from children harboring the implicated variants and
showed a strong association between variants in ORMDL3
and asthma. ORMDL3 is a member of a family of genes that
encode endoplasmic reticulum proteins of unknown function.
If these studies are replicated, then the community of asthma
researchers will need to determine how variants in the func-
tion of this gene could lead to childhood asthma.
An area of importance is the relationship between
clinical responses to anti-asthma treatments and genotype
at various drug targets [275]. For example, there are known
to be a number of SNPs in the β2-adrenoceptor gene that
result in structural changes in the β2-receptor structure asso-
ciated with functional changes in isolated cell systems [276].
These are related to the acute response to bronchodilator
aerosols acting via this receptor [277, 278] and with del-
eterious effects of chronic use of albuterol [279, 280]. In a
double blind randomized controlled trial, the first in a non-
malignant condition where genotype at a specific locus was
an entry criterion, those patients harboring the alleles encod-
ing for homozygous expression of arginine rather than gly-
cine at the 16th amino acid in the β2-adrenergic receptor
had diminished morning and evening peak flow and lower
FEV1 after the regularly scheduled use of albuterol than
when albuterol was used on an “as needed only ” basis [281].
In a retrospective analysis of two other randomized clinical
trials similar changes have been observed by some groups
[282] but not by others [283]. However, other retrospective
analyses of long-acting β2-agonists have not demonstrated
a functional effect of these SNPs [284]. Similarly, there are
genetically based functional variants in the regulation of the
ALOX-5 gene [285]. Although these variants were originally
associated with the response to anti-leukotriene treatment
[286], current studies suggest that it is not these variants per
se, but variants in the ALOX-5 gene in general that may
confer differences in treatment response [287].
UNANSWERED QUESTIONS
As a syndrome much about asthma remains an enigma.
Although we have reasonably effective treatments and a
general idea of it pathophysiology, there are still many unan-
swered questions about its pathobiology.
Why is the prevalence of asthma increasing throughout the
world as a consequence of Westernization?
It is clear that allergic diseases appear as societies become
more Westernized, but what environmental factors are
responsible is not known. It is likely that several factors are
operating together [288]. Among the factors identified to
date are diet (reduced intake of antioxidants, reduced unsatu-
rated fats), lack of early childhood infections (with conse-
quent tendency to develop Th2-driven responses), greater
exposure to allergens in the home (tight housing, mattresses,
416
central heating providing more favorable environment), cig-
arette smoking (pregnancy and early childhood exposure),
and possibly air pollution due to road traffic. The role of
exposures to pets in early childhood remains unresolved and
because of confounding will be difficult to ascertain using an
epidemiological approach.
Why does asthma once established become chronic in some indi-
viduals but remain intermittent and episodic in others?
Is there a genetic difference among people or an environ-
mental difference among stimuli that results in full resolu-
tion of airway obstruction in some patients and the failure
for this to occur in others? For example, occupational asthma
due to chemical sensitizers, such as toluene diisocyanate,
may remit if the patient is removed from exposure to the
sensitizer within 6 months of development of asthma symp-
toms, whereas longer exposure is often associated with per-
sistent asthma even when avoidance of exposure is complete
[289, 290]. This suggests that once inflammation is estab-
lished it may continue independently of a causal mechanism,
whereas in others this self perpetuation does not occur.
Are there different types of asthma, each characterized by a com-
mon genetic background with its attendant immunological and
inflammatory response?
Asthma remains a syndromic diagnosis. How can we get
beyond a physiological and descriptive definition to one in
which the primary disease pathobiology, for each of the many
asthma syndromes, can be developed?
How does inflammation of the airways translate into clinical
symptoms of asthma?
Airway thickening, as a consequence of the inflammatory
response, may contribute to increased responsiveness to spas-
mogens [193, 291]. However, there is no obvious relationship
between the inflammatory response in airways and asthma
severity; patients with mild asthma may have a similar eosi-
nophil response to patients with severe asthma, suggesting
that there are other factors that determine clinical severity.
The nature of these “factors” remains elusive, but we must
identify them if we are to make true scientific progress.
How important are genetic factors (genetic polymorphisms) in
determining the phenotype of asthma?
Asthma is a complex genetic disease but likely one in which
there is both differences among individuals in the genes that
pre-dispose to asthma and a requirement for more than one
genetic variant in a given person for asthma to be manifest.
Since each “asthma gene” may account for such a small pro-
portion of the total genetic variance in asthma, how can we
use genetics to develop better asthma diagnostics? How can
we use genetics to help stratify patients to achieve uniform
cohorts for clinical trials?
Are asthma and atopy causally related or just closely linked?
Much of our understanding of asthma derives from study of
models of allergy. Although these models are of great value
in defining the pathobiology of asthma, how closely will they
relate to the human disease?

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