SCIENCE IN MEDICINE
New insights into the pathogenesis of asthma
Jack A. Elias, Chun Geun Lee, Tao Zheng, Bing Ma, Robert J. Homer, and Zhou Zhu
Yale University School of Medicine, New Haven, Connecticut, USA
J. Clin. Invest. 111:291–297 (2003). doi:10.1172/JCI200317748.
Historical perspective
Asthma is a disease whose ability to cause episodic
symptomatology has been appreciated since antiquity. Although the fine points of the definition can be
debated, it is reasonable to think of asthma as a pulmonary disorder characterized by the generalized
reversible obstruction of airflow and to define
reversibility as a greater than 12% increase in the
patient’s forced expiratory volume in 1 second (FEV1)
that occurs either spontaneously or with therapy. Airway hyperresponsiveness, an exaggerated bronchospastic response to nonspecific agents such as
methacholine and histamine or specific antigens, is
the physiologic cornerstone of this disorder. A diagnosis of asthma is established based on a history of
recurrent wheeze, cough, or shortness of breath,
reversible airway obstruction demonstrated by pulmonary-function testing, and, in cases where questions exist, a methacholine challenge demonstrating
airway hyperresponsiveness. It has long been assumed
that patients with asthma experience intermittent
attacks and have relatively normal lung function during intervening periods. More recent studies have
demonstrated that asthma can cause progressive lung
impairment and, in some patients, eventuate in partially reversible or irreversible airway obstruction.
Any discussion of asthma must take into account the
recent increase in its prevalence. Since approximately
1980, the frequency of this disorder has almost doubled. As a result of this “epidemic,” asthma now affects
approximately 8–10% of the population in the US, is
the leading cause of hospitalization among children
less than 15 years of age, and costs society billions of
dollars annually. This increase in prevalence is not simply due to diagnostic transference or increased diagnostic awareness, since asthma mortality rates have
also increased during this interval.
The Science in Medicine series is supported in part by a generous grant
from the Doris Duke Charitable Foundation.
Address correspondence to: Jack A. Elias, Yale University School
of Medicine, Section of Pulmonary and Critical Care Medicine,
333 Cedar Street/105 LCI, PO Box 208057, New Haven,
Connecticut 06520-8057, USA. Phone: (203) 785-4163;
Fax: (203) 785-3826; E-mail: Jack.Elias@yale.edu.
Conflict of interest: The authors have declared that no conflict of
interest exists.
Nonstandard abbreviations used: T regulatory [cell] (Tr); signal
transducer and activator of transcription (STAT); chemokine
receptor 2 (CCR2); histone deacetylase (HDAC).
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An aerosol antigen challenge of an appropriately sensitized asthmatic patient can induce two types of airway
responses. The early response is an acute bronchospastic event that occurs 15–30 minutes after exposure and
resolves over time. The late-phase response peaks 4–6
hours after exposure and can cause prolonged symptomatology. Over the years, a variety of concepts of pathogenesis have been put forth in an attempt to explain one
or both of these responses (Table 1). Early investigators
postulated that there was an intrinsic airway smooth
muscle abnormality at the root of the asthmatic diathesis. However, many studies with airway myocytes in culture have not corroborated this contention. This was
followed by the contention that asthma is an autonomic dysfunction syndrome characterized by excess cholinergic and/or tachykinin pathway activity. This was never
proven or disproven. Instead, IgE-mediated mast cell
and/or basophil degranulation with the release of
leukotrienes, histamine, prostaglandins, tryptase,
cytokines (such as IL-4 and IL-5), and other mediators
was appreciated to be a key event in the acute response.
The prominent eosinophil-, macrophage-, and lymphocyte-rich inflammatory response in the airways of
patients with asthma (Figure 1) and the efficacy of
steroids in the majority of patients with asthma then led
to the present-day concept that asthma is a chronic
inflammatory disorder of the airway and that T cells are
pivotal initiators and regulators of this response. Structural alterations including airway wall thickening, fibrosis in the lamina reticularis and adventitia of the airway,
mucus metaplasia, myocyte hypertrophy and hyperplasia, and neovascularization are all readily appreciated in
the asthmatic airway (Figure 1). This led to the hypothesis that the inflammatory response in the asthmatic
airway causes these remodeling events, and to the belief
that these events contribute to disease pathogenesis.
Studies using new immunologic and molecular
approaches have provided impressive insights into the
nature of this inflammatory response and the relationship between this response and the remodeling and
physiologic alterations characteristic of the disorder.
The Th1/Th2 paradigm
It has been known for over 50 years that people tend to
mount antibody- or cell-mediated immune responses
to specific antigens. A major advance in our knowledge
of the mechanisms responsible for these divergent
effects was achieved when it was discovered, initially in
studies in mice, that the type of response that is seen is
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Table 1
Evolving concepts of asthma pathogenesis
1. A primary abnormality of airway-myocyte hyperresponsiveness
2. Autonomic dysfunction with exaggerated activity of cholinergic or
tachykinin pathways
3. IgE-mediated mast cell/basophil degranulation
4. Complex T lymphocyte–mediated airway inflammation
5. Airway remodeling
influenced greatly by the type of T cells that accumulate at the site of local antigen deposition. In the
mouse, a number of functionally distinct CD4+ T cells
have been defined based on the profile of cytokines
that they elaborate. Although the differentiation is not
as clear in humans, similarly differentiated cells in
humans have been described. Th1 and Th2 cells have
been the topic of the most intense study, with the former elaborating IFN-γ, IL-2, and lymphotoxin, and the
latter elaborating IL-4, IL-5, IL-9, IL-13, and IL-10. Significantly, less is known about T regulatory (Tr) cells
and Th3 cells, which produce IL-10 and TGF-β1, respectively (1, 2). As shown in Figure 2, Th1 and Th2 cells are
formed from a common naive precursor T cell and differentiate into polarized populations based on signals
from the local microenvironment. In the presence of
CD8α+ DCs and/or IL-12, IL-18, or IFN-γ, they differentiate into Th1 cells. This evolution is mediated by a
mechanism that is dependent on signal transducer and
activator of transcription-1 (STAT-1) and the T-bet
transcription factor (1, 3). In the presence of CD8α–
DCs and/or IL-4 (which can come from IgE-activated
mast cells or DCs), Th2 cells are formed. This is a complex process that involves STAT-6–mediated signal
transduction and the activation of a variety of transcription factors, including GATA-3, nuclear factor of
activated T cells-c (NFATc), and c-maf (2, 4). Interestingly, Th1/Th2 counter-regulation has also been
described, with each cell population able to inhibit
and/or regulate the development and/or phenotype
induced by the other. Th1 polarized responses play a
key role in macrophage activation in delayed-type
hypersensitivity reactions. They are a key feature in the
pathogenesis of diseases like rheumatoid arthritis, sarcoidosis, and tuberculosis. In contrast, Th2-dominant
responses stimulate antibody-mediated responses, activate mast cells, and elicit tissue eosinophilia. They play
a key role in allergy and antiparasite responses. They
are also the predominant responses in the asthmatic
airway, where elevated levels of IL-4, IL-5, IL-13, and
IL-9 have been detected by a variety of investigators (5).
Characterization of the chronic effector functions
of Th2 cytokines
In contrast to the vast majority of injury and repair
responses in the lung and other organs, asthmatic
inflammation frequently starts in childhood and persists throughout the life of the afflicted individual. In
addition, physicians treating asthmatics invariably find
themselves attempting to deal with manifestations of
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established disease, often in the setting of a disease
exacerbation. Surprisingly, the model systems that have
been used most frequently in studies designed to
understand asthma pathogenesis have not appropriately taken these issues into account. Instead, the most
commonly employed modeling systems evaluate the
acute responses that are elicited in the lung after normal animals are sensitized to and then challenged with
an aeroallergen. The asthma-like inflammation and
physiologic dysregulation that are seen in these models are an end result of the cellular and molecular
events involved in sensitization, Th2 cell development,
Th2 cytokine elaboration, and the activation of Th2
cytokine effector pathways. Interventions that inhibit
any of these steps can appear to have a beneficial effect
on the asthma-relevant readouts that are employed.
However, since it is likely that antigen sensitization,
Th2 cell development, and Th2 cytokine elaboration
have already occurred in patients with established disease and/or a disease exacerbation, interventions at
these sites will likely be less than useful therapeutically. In contrast, interventions that regulate Th2 cytokine
effector pathways are attractive as therapies. Until
recently, modeling systems that allowed the inflammatory and remodeling effects of chronically elaborated Th2 cytokines to be selectively evaluated did not
exist. Overexpression-transgenic methodology has,
however, powerfully addressed this issue.
The standard approaches used to generate overexpression-transgenic mice are illustrated in Figure 3.
First, a DNA construct is prepared that contains the
gene that the investigator wishes to express and a promoter to drive the expression of this gene in the
desired organ and/or tissue (Figure 3a). If temporally
regulated gene expression is desired, recent advances
in transgenic methodology that involve the generation of double- and triple-transgenic animals allow
the transgene to be selectively turned on or off at any
time during the life of the animal (6, 7). When asthma-relevant questions are being asked, the Clara cell
10-kDa protein (CC10) promoter is used to target
gene expression, because it is selectively expressed by
Figure 1
Inflammation and remodeling in the asthmatic airway. There is impressive inflammation (I), mucus plugging (MP), subepithelial fibrosis (SF),
myocyte hypertrophy and hyperplasia (MH), and neovascularization (N)
in this autopsy lung section from a teenage asthmatic individual.
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Figure 2
Development of Th1 and Th2 lymphocytes. Antigens enter through the endobronchial tree, cross the epithelial surface, and interact with naive Th
cells and DCs. As a result of signals from the surrounding microenvironment, they differentiate into Th1 cells, which produce IFN-γ, IL-2, and lymphotoxin (LT), or Th2 cells, which produce IL-4, IL-5, IL-9, IL-13, and IL-10. Polarization into Th1 cells occurs via a STAT-1– and T-bet–dependent
pathway under the influence of CD8α+ DCs and macrophage-derived cytokines such as IFN-γ, IL-12, and IL-18. Differentiation into Th2 cells occurs
via a pathway that involves STAT-6, GATA-3, nuclear factor of activated T cells-c (NFATc), and c-maf under the influence of CD8α– DCs and IL-4,
which may come from mast cells.
the Clara cells that make up 40% of the epithelium of
the murine airway. To generate transgenic mice, male
and female mice are allowed to mate, and the fertilized eggs are washed out of the female’s oviduct. The
desired DNA construct is then directly microinjected
into the pronuclei of these eggs, and the eggs are
placed in the uterus of a pseudopregnant mouse. A
pseudopregnant mouse is a female that has been
mated with a vasectomized male. She is behaving,
from a hormonal perspective, as if she is pregnant and
becomes pregnant when the fertilized eggs are
deposited in her uterus. She subsequently carries to
term, delivering a litter of pups, some of which have
the transgene randomly integrated into their genome,
others of which do not (Figure 3b). Transgene-positive and -negative mice can be differentiated by
extracting DNA from tail biopsies from the pups and
determining whether the transgene is present by
Southern or PCR analysis. Thus, an outstanding
experimental system is established where one can
compare the phenotypes of mice born to the same
mother, on the same day, that are exposed to the same
environment and differ only in the one gene that was
inserted. The power of this approach can be easily
appreciated in studies designed to define the effects
of IL-13 in the asthmatic airway (8).
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IL-13 is the product of a gene on chromosome 5 at
q31, a site that has been repeatedly implicated in
genetic studies looking for the genes involved in the
asthmatic diathesis. It was originally discovered as an
IL-4–like molecule and was presumed to have an effector profile identical to that of IL-4. It has since become
clear that IL-13 and IL-4 differ in their effector properties, with IL-4 and IL-13 playing more prominent
roles in the initiation and the effector phases of Th2
inflammation, respectively.
The effector functions of IL-13 were defined and
clarified using overexpression-transgenic modeling
systems. These studies demonstrated that IL-13 is a
potent inducer of an eosinophil-, macrophage-, and
lymphocyte-rich inflammatory response, airway
fibrosis, mucus metaplasia, and airway hyperresponsiveness (8) (Figure 4). These studies also demonstrated that other Th2 cytokines, such as IL-9, mediate their effects in the lung via their ability to induce
IL-13 (9), suggesting that IL-13 may be a final common pathway for Th2-mediated inflammatory
responses. Importantly, these transgenic systems were
also manipulated to define the mechanisms by which
IL-13 generates these critical tissue responses. This
was done using standard methods of quantitating
mRNA and gene chip methodology to define the
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They also highlight target genes against which therapies can be directed to control selected aspects of the
IL-13–induced tissue response.
Figure 3
Generation of transgenic mice. To express a transgene in vivo, the
investigator first makes a construct containing the transgene being
evaluated. A typical construct is illustrated in a. It contains a promoter that targets the transgene to the desired organ, the transgene being
expressed, and intronic and polyadenylation sequences that ensure the
proper processing of the mRNA transcripts that are produced. The
methodology for generating transgenic mice is illustrated in b. Fertilized eggs are washed out of the oviducts of female mice. They are then
microinjected under direct visualization and implanted into the uterus
of pseudopregnant female mice. The genotype of the pups that are
produced is evaluated in tail biopsy–derived DNA using PCR reactions
or Southern blot evaluations.
genes that are regulated by IL-13 in lungs from transgenic mice. This was followed by a variety of manipulations that characterized the contributions of specific genes to the pathogenesis of the IL-13 phenotype.
One such manipulation was the use of neutralizing
antibodies against the gene products in question.
Another was the breeding of the IL-13 transgenic mice
with mice with null mutations of selected downstream genes, followed by characterization of the
effects of the transgene in mice that were sufficient or
deficient in the downstream gene in question (Figure
5). As can be seen in Figure 6, these studies have provided impressive insights into the mechanisms of
IL-13–induced inflammation and tissue fibrosis. The
inflammatory response is mediated by the ability of
IL-13 to stimulate the elaboration of chemotactic
cytokines called chemokines and proteolytic enzymes
called matrix metalloproteinases (MMPs) (10, 11).
These studies demonstrate that chemokine receptor
2 (CCR2), MMP-9, and MMP-12 play key roles in
these responses (10, 11). They also demonstrate that
the fibrotic response results from the ability of IL-13
to stimulate the production and activation of the
fibrogenic cytokine TGF-β1, and that TGF-β1 is activated via an MMP-9– and plasmin-dependent pathway in this setting (12). These studies provide a road
map that defines the pathways that IL-13 uses to generate tissue inflammatory and remodeling responses.
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Contributions of new pathogenic insights
to the therapy of asthma
For decades, the overt bronchospasm and impressive
benefit that patients experienced with bronchodilators led physicians and patients to rely heavily on
these agents to control asthmatic symptomatology.
Although steroids were also well known for their ability to control asthmatic symptoms, their side effect
profile caused them to be used only in the most severe
cases. The appreciation that asthma is an inflammatory disorder, the availability of effective aerosol
steroid preparations, and the belief that chronic
unchecked inflammation leads to airway remodeling
all contributed to a change in this pattern of practice.
This change is reflected in the treatment guidelines
for asthma that have been promulgated in recent
years by the NIH and other organizations (13). These
guidelines stress the need for anti-inflammatory therapy for all but the mildest patients with infrequent
symptoms. At present, steroids are the cornerstone of
this anti-inflammatory intervention. However, recent
advances in our understanding of asthma pathogenesis have provided insights into the mechanisms by
which some of our present therapies alter airway
inflammation and have provided the rationale for
Figure 4
Demonstration of the effects of transgenic IL-13 on airway fibrosis and
mucus metaplasia. (a) Trichrome stains are used to compare the amount
of blue-staining collagen around airways from transgene-negative mice
(left) and transgene-positive mice (right). (b) Alcian blue stains are used to
demonstrate mucus accumulation in airways from transgene-negative mice
(left) and transgene-positive mice (right). Mucus is blue in this evaluation.
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Figure 5
Use of null mutant (knockout) mice to define the pathways that transgenes use to generate disease-relevant phenotypes. In these experiments,
transgenic mice with a disease-relevant phenotype (for example, fibrosis
or inflammation) are mated with mice that have a null mutation of a
downstream gene that is believed to play an important role in the generation of this phenotype. Transgene-positive (TG[+]) and transgene-negative (TG[–]) mice are generated that have normal downstream genes
(+/+), are heterozygote knockout at the downstream gene in question
(+/–), or are null-mutant for the downstream gene in question (–/–). The
presence and intensity of the phenotypes of these mice are then compared. These comparisons allow an investigator to define the role(s) that
this downstream gene plays in the generation of the pathologic response.
therapies directed against new selective inflammation-regulating targets that may have better side effect
profiles than the current therapies. Lastly, our new
insights raise the possibility of interventions that
might actually prevent asthma in at-risk individuals.
Each is reviewed below.
Inflammation regulating the effects
of standard therapies
Over sixty years ago, slow-reacting substance of anaphylaxis (SRSA) was appreciated as a spasmogenic
activity in lung effluent. Subsequent studies demonstrated that SRSA was mediated by leukotriene products of arachidonic acid metabolism and defined the
pathways responsible for the generation of LTB4 and
the cystinyl leukotrienes (LTC4, LTD4, and LTE4). They
also demonstrated the striking accumulation of
cystinyl leukotrienes in biologic fluids from patients
with asthma, and the bronchospasm and inflammation generating effects of these agents. As a result of
these efforts, we now have cystinyl leukotriene receptor
antagonists and inhibitors of 5-lipoxygenase, the
enzyme that initiates the breakdown of membrane
arachidonic acid. These agents have received regulatory approval for asthma therapy and are the first new
therapies to be licensed for asthma in over thirty years.
Their ability to improve lung function and ameliorate
aspects of asthmatic inflammation is well documented. Recent studies have also demonstrated that these
agents may also control tissue fibrotic responses such
as that in asthmatic airway remodeling (14).
Although theophyllines have been used to treat asthma for over seventy years, their use has declined in
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recent decades because of their low therapeutic index
and the appreciation that their anti-inflammatory
effects are modest compared with those of corticosteroids. However, theophyllines can diminish airway
hyperresponsiveness. In addition, the administration
of low-dose theophylline to patients on steroids gives
a greater improvement in asthma control than can be
achieved by a doubling of the steroid dose itself.
Recent studies have demonstrated that these effects
may be mediated by a novel mechanism relating to
chromatin remodeling. In a quiescent state, the chromatin in genes is tightly wound around core histone
proteins. During gene activation, histones are acetylated, which unwinds the chromatin, allowing transcription factors and RNA polymerase II to bind and
increase gene transcription (15, 16). This process is
mediated by histone acetyl transferase (HAT). Corticosteroids inhibit this process by recruiting histone
deacetylase (HDAC), which suppresses the activity of
HAT. This suppression leaves the chromatin densely
wound and, as a result, decreases target gene transcription. Patients with asthma have decreased levels
of HDAC at base line (15). In addition, although
steroids increase the levels of HDAC in asthmatic
patients, those levels remain well below those induced
by steroids in normal individuals (15). This suggests
that therapies that increase HDAC activity will prove
useful in the pharmacologic management of asthma.
Interestingly, low-dose theophylline has recently been
shown to augment the activation of HDAC by steroids
(16). This highlights a mechanism by which low-dose
theophylline can be used to augment anti-inflammatory effects of steroids in asthmatic tissues.
Figure 6
Mechanisms of IL-13–induced phenotype generation. IL-13 binds to the
IL-13 receptor complex made up of IL-4 receptor α (IL-4Rα) and IL-13
receptor α1 (IL-13Rα1). IL-13 also binds to IL-13Rα2, which is a decoy
receptor that inhibits IL-13 responses. After binding to the IL-13 receptor complex, IL-13 activates STAT-6 signal transduction pathways. Pathways that involve chemokines, the chemokine receptor CCR2, MMPs, urinary plasminogen activator (UPA), TGF-β1, VEGF, and/or adenosine are
then activated, and inflammation, fibrosis, blood vessel alterations, and
mucus responses are generated. Each of these pathways is a site against
which therapeutic agents can be directed.
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Site-specific interventions
Advances in our understanding of the pathogenesis of
asthma have opened the door to a variety of new targets
against which novel therapies can be directed. It is
beyond the scope of the present article to describe all of
the targets that are being studied. It is, however, convenient to categorize them as interventions that alter
the development of Th2 immune responses and interventions that alter the effector functions of Th2
cytokines that have been elaborated. The generation of
a Th2 response requires antigen presentation by APCs
such as DCs, and T cell proliferation and Th2 differentiation. These events can be inhibited by blockade of
APC function (e.g., of costimulatory molecules like
B7.2 or the inducible costimulator ICOS) and by blockade of T cell proliferation and/or differentiation (e.g.,
blockade of IL-4 or GATA-3, or the administration of
IFN-γ or IL-12). Examples of interventions that block
Th2 effector pathways include therapies that block IL-5,
IL-13, or IL-9, decrease eosinophil influx and effector
function, and/or alter the production and/or effector
pathways of inflammation-inducing chemokines.
Treatment with a humanized antibody against IgE also
alters effector pathways and has shown promise in preliminary investigations (17). Since IL-13 may be a final
common pathway for Th2 cytokines (9), approaches
that control IL-13 are particularly appealing (18). As
illustrated in Figure 6, this includes therapies directed
at the STAT-6 signal transducer that mediates the
effects of IL-13, therapies directed against the multimeric IL-13 receptor system (IL-4 receptor α and IL-13
receptor α1), and the administration of IL-13 receptor
α2, a decoy receptor protein that binds IL-13 but does
not transduce a signal. It also includes therapies directed against the genes that are downstream of IL-13 and
mediate its effects, for example, CCR2 (11).
Preventing asthma
Our present therapeutic approach to asthma focuses
exclusively on symptom amelioration. However, our
knowledge of the processes that regulate Th1 and Th2
immune responses has raised the possibility of designing interventions that can prevent asthma in at-risk
individuals. Many of these approaches are based on in
vitro studies demonstrating that Th1 cytokines (such
as IFN-γ) can inhibit Th2 cell development, and in vivo
observations demonstrating that Th1 responses can
feed back to diminish Th2 tissue responses. A variety of
approaches have been proposed to accomplish this,
including the administration of IFN-γ or IFN-γ–inducing cytokines such as IL-12, and the administration of
infectious agents or vaccinations that induce Th1
immunity, such as Mycobacterium bovis bacilli CalmetteGuérin (BCG). In addition, therapies have been proposed that entail the administration of oligodeoxynucleotides that contain unmethylated CpG motifs.
Unmethylated CpG DNA motifs are more common in
bacterial than in mammalian DNA. The administration of these agents mimics infections and induces Th1
inflammation via a Toll-like receptor 9–dependent
mechanism. The ultimate utility of each of these
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approaches is unclear. This is due, in part, to safety
concerns because it is now known that Th1 responses
can contribute to the initiation of Th2 responses, that
exaggerated Th1 responses contribute to autoimmunity and pulmonary pathology, and that Th1-like signal transduction pathway activation may also contribute to the pathogenesis of asthma (19).
The lung is unique among mucosal compartments in
that it is constantly exposed to airborne antigens. As a
consequence, the respiratory immune system must differentiate harmless antigens and potentially harmful
infectious agents. This is done, in part, by a system of
barriers that ensures that harmless antigens induce tolerance and do not elicit sensitization while potentially
harmful exposures illicit sensitization and immune system activation. These tolerogenic pathways are altered
in patients with asthma. As a result, asthmatics manifest a heightened ability to sensitize and to mount Th2
immune responses to antigens (for example, ragweed)
that would not elicit similar responses in normal individuals. The details of the tolerogenic pathways in normal people and their defects in asthmatics are poorly
understood. There is evidence that tolerance is mediated by special regulatory T cell populations (Tr cells) that
produce IL-10 or TGF-β1 (2). Treatments that induce
tolerance in asthmatics or people at risk for asthma are
therefore of potential benefit in preventing and/or ameliorating asthmatic responses. Oral allergen immunotherapy and conventional allergen immunotherapy
appear to work, in part, via the induction of tolerance.
It is hoped that, over time, more effective toleranceinducing therapies will be developed.
Major issues and future directions
Disorders such as asthma are believed to be the result
of a dysregulated mucosal immune system and pathologic T cell responses in genetically susceptible individuals (1). Over the next five to ten years we will need
to define the relationships between the inflammatory
response, the structural alterations noted in the remodeled asthmatic airway, and asthmatic symptomatology,
physiologic dysregulation, and disease progression.
These investigations will allow us to determine which
inflammatory and structural changes contribute to
disease pathogenesis (and thus need to be suppressed)
and which are more reasonably thought of as aspects
of an appropriate healing response in the injured airway (and thus should not be inhibited). It will also be
essential to define the genetic alterations that contribute to asthmatic susceptibility, the genetic alterations responsible for the person-to-person variability
in asthma presentation and severity, the processes regulating tolerance in the asthmatic and normal lung,
and the mechanisms responsible for the lifelong nature
of asthmatic inflammation. It is conceivable that, at
some time in the future, DNA samples from patients
with asthma or people at risk for asthma will be
assessed for the presence or absence of polymorphisms
of specific genes. Based on these assays, physicians
would know whether the patient would develop asthma and, if so, what the natural history of the disease
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would be and what therapies the patient would optimally respond to. From this perspective, it is easy to see
how our knowledge of asthma pathogenesis can have
impressive ramifications for our practice of medicine.
It is important to point out, however, that it has taken
us over a century to get where we are. One is humbled
by the appreciation that in 1892 Sir William Osler, in
The Principles and Practice of Medicine, said that
Asthma is a term which has been applied to various conditions associated with dyspnea . . . Of
the numerous theories the following are most
important:
1. It is due to spasm of bronchial muscles.
2. The attack is due to swelling of the bronchial
mucous membrane.
3. In many cases it is a special form of inflammation of the smaller bronchioles.
Hopefully, it will not take us another century to go
from our understanding of the inflammatory nature
of the asthmatic diathesis to effective interventions
that control and even prevent this common and
debilitating disorder.
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February 2003
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Volume 111
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Number 3
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