Asthma

Jeffrey S. Fedan NIOSH, Morgantown, USA

2007 Elsevier Inc. All rights reserved.

Introduction
Asthma is a disorder that affects the airways of the lungs and causes difficulty in
breathing. It is increasing in prevalence. The exact cause of asthma is not known. While
there are a large number of drugs available for treating asthma, they are primarily
palliative therapies. There is no cure for asthma. A combination of drugs may be needed
to manage symptoms in most patients.

Definition
The definition of asthma has evolved from several consensus documents. The most recent
definition is that of the Global Initiative for Asthma GINA (2003) (http://www.ginasthma.
com/). Asthma is a chronic inflammatory disorder of the airways in which many cells and
cellular elements play a role. The chronic inflammation causes an associated increase in
airway responsiveness (hyperreactivity) that leads to recurrent episodes of wheezing,
breathlessness, chest tightness, and coughing, particularly at night or in the early morning.
These episodes are usually associated with widespread, but variable airflow obstruction
that is often reversible either spontaneously or with treatment.
Airflow decrements arise from bronchoconstriction, swelling of the airway wall, alteration in the quality and quantity of mucus, including formation of mucus plugs and
remodeling Holgate and Davies (2000) of the airways. Abnormally high levels of IgE
antibodies in response to common allergens are seen in many, but not all, asthmatic
patients.
Status asthmaticus (near-fatal asthma) is a very severe form of asthma attack that may
lead to death. Mucus plugging, airway edema, and bronchoconstriction severely limit
airflow, and restrict airway mechanics and gas exchange.
Exercise-induced asthma, a misnomer for exercise-induced airway obstruction, may
occur in asthmatic patients. Exercise does not cause asthma, but a decrement in airflow
may occur in asthmatic patients who exercise.
Asthma may be caused or exacerbated by substances inhaled in the environment.
Terms used to describe this condition are occupational asthma or work-related asthma.
Steroid-resistant asthma and difficult asthma represent more severe manifestations of
the disease.

Classification
Asthma is a chronic obstructive lung disease. Other chronic obstructive pulmonary
diseases (COPD) include emphysema and chronic bronchitis.
Asthma, left untreated, may progress in severity. Classification of asthma by steps is
based on the severity of the disease. A given patient may move between steps. The most
accepted classification of asthma is that promulgated by the Global Initiative for Asthma
GINA (2003) (http://www.ginasthma.com/). Therapeutic choices are based on the
1

Asthma

identification of the step described by the symptoms. Therapy is directed at preventing

increases in severity. The classification follows in modified form:
Step 1: Mild intermittent
Symptoms less than once a week
Brief exacerbations
Nocturnal symptoms not more than twice a month
FEV1* or PEF* > 80% predicted
PEF or FEV1 variability < 20%
Step 2: Mild persistent
Symptoms more than once a week, but less than once a day
Exacerbations may affect activity and sleep
Nocturnal symptoms more than twice a month
FEV1 or PEF > 80% predicted
PEF or FEV1 variability 20-30%
Step 3: Moderate persistent
Symptoms daily
Exacerbations may affect activity and sleep
Nocturnal symptoms more than once a week
Daily use of inhaled short-acting beta-2 adrenoceptor agonist
FEV1 or PEF 60-80% of predicted
PEF or FEV1 variability > 30%
Step 4: Severe persistent
Symptoms daily
Frequent exacerbations
Frequent nocturnal asthma symptoms
Limitation of physical activities
FEV1 or PEF < 60% of predicted
PEF or FEV1 variability > 30%
*FEV1 is forced expiratory volume in 1 sec. PEF is peak expiratory flow.
Asthma acquired or exacerbated because of workplace exposures is classified as occupational asthma or work-related asthma.

Consequences
Some children outgrow their childhood asthma after adolescence. However, approximately 50% of the population carries asthma into adulthood. Periods of remission occur
in children and adults.
While asthma causes substantial morbidity, it does not cause significant mortality. Most
of the deaths are considered preventable and require identification of a worsening clinical
condition with subsequent use of efficacious drugs. Left untreated, status asthmaticus
places a patient at high risk of death by asphyxiation.

Associated Disorders
Asthma is often associated with atopy, which may give rise to conjunctivitis, eczema,
allergy, and rhinitis. Allergic rhinitis accompanies asthma in many children. Often,
treatment of the associated disorder improves the asthmatic condition.

Asthma

Etiology
Asthma attacks, including those that can lead to status asthmaticus, may be provoked by
allergen exposure and challenge, for example to indoor allergens such house dust mites
and outdoor allergens such as pollen; respiratory infections; air pollutants; chemicals;
aspirin; weather (cold and dry air); menstruation; emotional stress; and exercise. Asthma
is a complex condition involving many pathophysiological changes. The greatest risk
factor for the development of asthma is atopy, with increased levels of circulating Ig
E. However, asthma may exist in nonatopic individuals. Asthma tends to be familial,
suggesting a genetic predisposition Barnes (2000a) exists for the development of the
disease. Atopy, airway responsiveness, and IgE are thought to have heritable components.
Recently, a gene (ADAM33) for metalloproteases found on chromosome 20p13 was linked
to asthma and airway hyperreactivity Van eerdewegh et al (2002). Environmental factors
may predispose individuals toward establishment of asthma Anderson and Cookson
(1999), Cookson (1999). Near fatal attacks of asthma (status asthmaticus) may be precipitated by a variety of causes, including exposure to allergen, air pollutants, respiratory
tract infections, emotional stress, weather, noncompliance with medications, and aspirin
or other nonsteroidal anti-inflammatory drugs. The cause of exercise-induced asthma
(obstruction) is not understood. However, it is hypothesized that drying of the airway
surface during hyperventilation, and the subsequent increase in osmolarity, may trigger
hyperemia in the airway wall and the release of mast cell mediators, such as histamine and
leukotrienes, which cause bronchoconstriction. Cool, dry air inhalation is a greater
stimulus to exercise-induced obstruction than warm, humid air.

Epidemiology
In 2001, 14 million adults and 6.3 million children were considered asthmatic. Approximately 4.3 million children (5.7%) had an asthma attack. There were 4,269 deaths from
asthma (1.5 per 100,000) in 2001 and 1.8 million visits to the emergency room for asthma
in 2000.
Exercise-induced asthma (obstruction) occurring during or after exercise is experienced by approximately 90% of asthmatic patients and 12% of the general population.
The prevalence of asthma is increasing. The frequency of asthma among children in
developed countries is being referred to as a pediatric epidemic. In children younger than
10 years, males have increased incidence compared to females. However, more adult
women are affected by asthma than men. The prevalence of acute asthma in AfricanAmerican and Hispanic populations in the United States exceeds that of Caucasians
Rhodes et al (2004).
Asthma outcomes are worse in underserved minority groups.
It has been hypothesized (hygiene hypothesis) that in Western countries atopy is
correlated with a decline in common infections and an improvement in hygiene. This
favors differentiation of the Th2 cell lymphocyte subtype (the asthma phenotype) over
the Th1 cell type.

Pathophysiology
A predominant feature of asthma is inflammation of the airways. The effects of asthma
result from complex and self-sustaining interactions between several inflammatory cell
types and their released mediators, including epithelial cells, dendritic cells, mast cells,

Asthma

Th2 cells, neutrophils, myofibroblasts Holgate and Davis (2000), and neuropeptidecontaining sensory nerves.
Eosinophils are implicated in the disease process because of the toxicity of proteins
contained in their large, dense core granules, e.g., major basic protein. Major basic protein
may be primarily responsible for the damage to and sloughing of airway epithelium
throughout the asthmatic airway. Eosinophils are elevated in the airway wall during
late-phase asthmatic responses.
Inflammatory cells and their mediators bring about a number of changes in the airway
wall, including:
(1) Nonspecific airway hyperreactivity to bronchoconstrictors (greater than normal
bronchoconstrictive response to inhaled drugs such as methacholine and histamine)
(2) Airway smooth muscle contraction (bronchoconstriction)
(3) Microvascular leakage and submucosal edema
(4) Thickening of the reticular basement membrane
(5) Smooth muscle hypertrophy (along with basement membrane thickening, this results
in thickening of the airway wall)
(6) Increased vascularization of the lamina propria (increase in the number and size of
blood vessels)
(7) Damage to and sloughing of airway epithelium
(8) Squamous and goblet cell proliferation
(9) Hypersecretion of a thick, tenacious mucus
(10) Mucus plugging
(11) Increased sputum production
The principle mediators Barnes et al (1998), Toews (2001), Riffo-Vasquez and Spina
(2002) involved in the inflammation include lipid products (leukotriene B4, leukotriene
C3, leukotriene D4 and leukotriene E4); prostaglandins (E2, F2a, D2); platelet activating
factor, peptides (bradykinin, endothelin, neuropeptides), a multitude of TH2 cytokines
(IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13) and other potent chemotactic peptides
(RANTES, eotaxin) Wenzel (2003), Riffo-Vasquez and Spina (2002), Toews (2001),
Barnes et al (1998).
Inhaled adenosine, cyclic AMP (cAMP), and hypertonic solutions (NaCl or Dmannitol) elicit bronchoconstriction in asthmatic patients but not nonasthmatic individuals. The mechanisms and significance of the response to inhaled adenosine and cyclic
AMP is not clear, but the effects of hypertonic solutions may bear some relationship to the
changes in airway surface liquid osmolarity that may stimulate exercise-induced obstruction. Interestingly, asthmatic patients may also experience obstruction upon inhalation of
hypotonic solutions.
Inhalation of an allergen to which the asthmatic patient is already sensitized leads to an
early phase and a late phase bronchoconstriction. These may vary in their intensities. The
early phase is immediate in onset and resolves within a few hours. The late phase develops
3 to 12 hours later and is accompanied by an inflammatory response in the airway wall and
airway hyperreactivity. The early phase is IgE-dependent and is thought to result from
degranulation of mast cells and the liberation of histamine, leukotrienes, and other
mediators, which then stimulate the inflammatory response associated with the late
phase. In an acute attack, therapy is directed at control of the late phase response. Therapy
for chronic asthma is directed toward prevention of both phases. Because both phases
involve contraction of airway smooth muscle, bronchodilator agonists that cause relaxation of the muscle are effective for treating bronchoconstriction in either phase, but they
are ineffective at stemming the inflammatory response of the second phase.

Asthma

Signs and Symptoms

Airway smooth muscle contraction, airway edema, and mucus plugging restrict the
passage of air in the airways, making it difficult to breathe. The patient experiences
coughing, wheezing, and dyspnea. Typically the forced expiratory volume in 1 sec (FEV1)
and the peak expiratory flow (PEF) are decreased.
Asthmatic patients exhibit nonspecific airway hyperreactivity to a number of agents
such as inhaled histamine, methacholine, adenosine, and 5AM P. Obstruction may also be
evoked after inhalation of hypertonic and hypotonic solutions.
During an attack, breathing becomes difficult and the lungs become over-inflated.
Patients may experience tachypnea and tachycardia.
Although asthmatic patients who have reversible disease may be free of symptoms
during exacerbations, airway remodeling that occurs in advanced stages of the disease
results in a fixed airflow limitation with a greater degree of irreversibility.

Standard Therapies
Goals of asthma therapy
The intensity and plan of therapy, and the ability to reverse the pathophysiological
changes in the asthmatic patient, are related to the severity of the disease. Generally,
the goals are to: 1) normalize lung function, 2) decrease airway hyperresponsiveness, 3)
prevent exacerbation of symptoms and, 4) minimize drug side effects.

Prevention and treatment of asthma

With the realization that asthma is an inflammatory disease of the lungs, and not a disease
instigated solely by airway smooth muscle contraction, modern therapy is designed to
prevent the development or worsening of the inflammatory process. Therefore, inhaled
anti-inflammatory drugs (glucocorticoids) are used for the treatment of the mildest form
of the disease. Bronchodilator drugs, while providing palliative relief, do not interfere to
an appreciable degree with the progression of the inflammatory process.
The selection of agents for treatment of asthma depends on the severity of the disease
and, to some degree, on the response and other considerations. A step-therapy approach
is used because significant side effects limit the utility of some agents. In severe asthma,
where substantial remodeling of the lung has occurred and the airway wall is thickened,
reversibility of obstruction is more difficult to achieve.
The agents used for the treatment of asthma are broadly classified into bronchodilators
and anti-inflammatory drugs. Bronchodilator is a misnomer when used to describe
collectively all agents of this class because not all cause relaxation of airway smooth
muscle.
Some agents are suited for inhalation delivery, whereas others are administered
parenterally. The advantage of inhalation is that a high dose of the agent may be delivered
to the site where it is needed while minimizing systemic side effects.
With progression of the patient through the four steps of asthma, daily control and
prophylaxis can be attained by the introduction of drugs in the following order (steptherapy):
(1) Inhaled low dose glucocorticoid (begun at the onset of mild persistent asthma)
(2) Oral anti-leukotriene drug
(3) Inhaled beta-2 adrenoceptor agonist (short- or long-acting)
(4) Inhaled cromone

Asthma

(5) Oral glucocorticoid

(6) Oral theophylline (the use of theophylline is now debated)
This step approach is subject to alteration depending on the needs of the individual,
responsiveness, and side effects. Often, drugs of different classes are co-administered. The
glucocorticoids used for inhalation, on the one hand, and for parenteral administration, on
the other, are not interchangeable.
Status asthmaticus
The therapeutic management of status asthmaticus requires more aggressive use of drugs
than those employed on an outpatient basis McFadden (2003). Inhaled beta-2 adrenoceptor agonist is a mainstay of therapy, as is administration of a systemic glucocorticoid.
Theophylline and ipratropium may provide additional benefit in some patients. In some
cases, mechanical ventilatory support is required as part of the management. In those
instances, sedative and paralyzing medications may be needed.
Agent Name

Discussion

Beta-2 adrenoceptor
agonists

Beta-2 adrenoceptor agonists activate adenylate cyclase to in cyclic AMP

(cAMP). In airway smooth muscle cells an elevation in cyclic AMP causes
relaxation. Therefore, these drugs are bronchodilators. A bronchodilatory
response may be produced during the early and late phases of an acute
exacerbation. Beta-2 adrenoceptor agonists also inhibit the release of
mast cell mediators, but this effect does not inhibit the development of
the late phase response. These drugs do not generally produce an antiinflammatory effect.
Beta-2 adrenoceptor agonists are indicated for symptomatic relief of
bronchospasm, for severe bronchospasm such as that which occurs
during status asthmaticus, and for prophylaxis of obstruction that occurs
during exercise.
While nonselective beta-adrenoceptor agonists, such as isoproterenol
and metaproterenol are efficacious bronchodilators, they also stimulate
cardiac beta-1 receptors, causing tachycardia and, potentially, cardiac
arrythmias. Beta-2 selective agonists are therefore preferred as they are
selective for the airway smooth muscle. Beta-2 adrenoceptor agonists
are useful for treating asthma include terbutaline, albuterol (racemic;
also known as salbutamol), levo-albuterol, pirbuterol, and bitolterol.
Some of these agents may be administered orally, subcutaneously, or by
inhalation.Salmeterol and formoterol are long-acting beta2 adrenoceptor-selective agonists. Their onset of action is slower than
other beta-2 selective agonists, and they are used for prophylaxis rather
than for treatment of bronchospasm in an acute attack. Long-acting beta2 agonists are often administered in conjunction with glucocorticoids.
Some beta-2 adrenoceptor-selective agonists induce muscle tremors.
Epinephrine, a catecholamine, is a non-selective agonist at both alpha and
beta adrenoceptors. It is used for the treatment of severe
bronchospasm and status asthmaticus.
The methylxanthines, theophylline and aminophylline (the
ethylenediamine salt of theophylline), are airway smooth muscle relaxants
with unclear mechanisms of action. It is likely that relaxation results from
inhibition of cyclic nucleotide phosphodiesterases. Theophylline also
inhibits adenosine receptors, which may block stimulation of mast cell
mediator release by adenosine. A release of epinephrine from the adrenal
medulla has been attributed to theophylline. Lastly, by preventing
mediator release and trafficking of inflammatory cells, theophylline may
exert an anti-inflammatory effect.
Once a prominent drug in asthma therapy, the use of theophylline has
diminished with the advent of beta-2 adrenoceptor-selective agonists for
achieving bronchodilation and the realization that glucocorticoids are

Epinephrine

Methyl xanthines

Asthma

Anticholinergics

Glucocorticoids

Cromones

superior anti-inflammatory agents. Generally, its use is restricted to

management of status asthmaticus and to those who have not
responded to front-line therapies. This is because of its side effects which
include nausea, headache, arrhythmias, and seizures. In addition, plasma
levels of theophylline are unpredictable from dose, and are affected by
hepatic, cardiac, and viral diseases. Theophylline plays a more prominent
role in the treatment of chronic obstructive pulmonary disease, and may
one day be replaced with more selective phosphodiesterase 4 inhibitors.
The release of acetylcholine from parasympathetic postganglionic
neurons stimulates contraction of airway smooth muscle through M3muscarinic receptors and secretion of mucus by way of M1-muscarinic
receptors. In asthma, reflex pathways are thought to be activated, which
increase vagal outflow that leads to cholinergically-mediated
bronchoconstriction.
Ipratropium is a non-selective muscarinic receptor antagonist and
quaternary amine (i.e., positively-charged) derivative of atropine.
Ipratropium causes fewer systemic side effects than atropine because it
is not as readily absorbed. By blocking muscarinic receptors, ipratropium
inhibits vagal activation of smooth muscle and causes bronchodilation
indirectly, although it is not a bronchodilator per se. Glandular secretion is
also inhibited by ipratropium
Ipratropium is administered by inhalation, and may cause dry mouth. Its
effects are slow in onset (hour) but relatively long-lived (6 hours). It is
much less effective in causing bronchodilation than beta-2 adrenoceptorselective agonists. It has no anti-inflammatory effect, and is not effective
in every patient, but may provide relief in asthmatics suffering from
psychogenic asthma.
The powerful anti-inflammatory effect of glucocorticoids reverses many of
the pathophysiological changes that occur in the airway wall of the
asthmatic patient, but the drugs do not relax airway smooth muscle. An
anti-inflammatory effect is accomplished with a group of drugs used by
and a group that is taken systemically. The inhalation agents include
fluticasone, budesonide, flunisolide, and triamcinolone, whereas the
systemic agents include hydrocortisone, prednisone, prednisolone,
and methylprednisolone. The inhalation agents are used for prophylaxis
in milder forms of asthma, whereas the systemic agents are indicated for
management of severe asthma and status asthmaticus.
Histone acetyltransferase activity is increased in biopsies of asthmatic
airways and is associated with enhanced inflammatory gene expression
Ito et al (2002). The glucocorticoids inhibit gene transcription of
inflammatory cytokines by enhancing histone deacetylase activity, which
allows winding of DNA around histone. In addition to this antiinflammatory effect, glucocorticoids may also prevent down-regulation of
beta adrenoceptors, which has been reported to occur in the smooth
muscle of asthmatic airways.
Hours are required for the onset of the anti-inflammatory response to
glucocorticoids. Their administration at the beginning of the early phase
of an asthma attack is targeted at ameliorating the magnitude of the
inflammatory response and bronchoconstriction that occurs during the
late phase response. When the drugs are used chronically, both the early
and the late phase responses are inhibited.
Little inhaled glucocorticoid is absorbed into the systemic circulation, and
the drugs are relatively free of side effects when administered by this
route. Some slight growth retardation may occur in children The
Childhood Asthma Management Program Research Group (2000), and
oral candidiasis may occur. Systemic delivery of glucocorticoids gives
rise to their side effects, which include osteoporosis, weight gain,
hypertension, diabetes, myopathy, psychiatric disturbances, skin
fragility, and cataracts.
The cromones, sodium cromoglycate and nedocromil, produce antiinflammatory effects in select (60-70%) asthmatic patients. They do not
relax airway smooth muscle. While the precise mechanism of action of

Asthma

Leukotriene receptor
antagonists

5-Lipoxygenase
inhibitors

Omalizumab

these agents is not defined, they are thought to produce a stabilization of

mast cells, macrophages, and eosinophils, thereby reducing the ability of
these cells to release inflammatory mediators. These drugs can block
chloride channels, which could interfere with C-fiber sensory nerve
reflexes in the airway wall.
The cromones are administered chronically by inhalation only, and
prevent the early and late asthmatic responses in mild to moderate
asthma. These drugs are not as potent as anti-inflammatory agents as are
the inhaled glucocorticoids. Side effects associated with cromones are
rare, and the drugs alleviate steroid-induced side effects when they are
administered to children. The cromones are less effective in older
patients than in children.
Leukotriene receptor antagonists Drazen et al (1999), Wenzel (2003) are
used for treating mild to moderate asthma and for preventing exerciseinduced obstruction. This class of drugs includes zafirlukast,
montelukast, and pranlukast.
These drugs inhibit stimulation of the CysLT1 receptor by the proinflammatory cysteinyl leukotrienes LTC3, LTD4 and, to a lesser extent,
LTE4, formed by inflammatory cells. Leukotrienes are potent airway
smooth muscle contractile agonists, and blockade of the leukotriene
receptors attenuates bronchoconstriction mediated by them..
The leukotriene receptor antagonists are an alternative to inhaled steroids
for asthma prophylaxis. Effectively orally on a chronic basis, they are not
used to treat acute exacerbations.
5-Lipoxygenase is the enzyme that converts arachidonic acid, through
intermediates, to leukotriene A4 (LTA4). LTA4 is converted spontaneously
to LTB4, a chemotactic mediator. LTA4 is converted to LTC4 through the
action of LTC4 synthase, and LTD4 and LTE4 are derived sequentially
from LTC4 through the actions of peptidases. The orally-active antiinflammatory drug, zileuton, is a selective inhibitor of the enzyme, 5lipoxygenase. Inhibition of LTB4 results in an anti-inflammatory effect,
and inhibition of the formation of LTC4 and LTD4 abrogates their
bronchoconstrictor and pro-inflammatory effects Drazen et al (1999),
Wenzel (2003).
Zileuton is administered chronically, and is not indicated for treatment of
acute asthma attacks.
When oral zileuton is used to reduce patient dependence on steroids,
symptoms suppressed by the steroids may reappear. One such disease
is Churg-Strauss syndrome, which consists of skin rash, pulmonary
inflammation, eosinophilia, and heart failure.
>Omalizumab, also known as rhuMAB-E25, Milgrom et al (1999), Barnes
(2000b), Chang (2000) is a monoclonal antibody directed against IgE that
was is approved for use in children with moderate to severe allergic
asthma who are not controlled adequately with inhaled glucocorticoids. It
binds to the high-affinity Fc receptor of circulating IgE in the blood, and
inhibits the binding of IgE to mast cells. Thus, the release of mast cell and
other mediators is inhibited. It also binds to low-affinity Fc receptors on
antigen-processing cells and decreases the release of pro-inflammatory
mediators. The drug causes a substantial decrease in circulating IgE
levels.
Omalizumab must be given by injection and is very expensive.

Experimental Therapies
The search for new anti-asthma medications is stimulated by the inadequacies of the
current agents. The etiology of asthma is complex, and involves a large number of pathways
and mechanisms. Ideally, an asthma cure will be discovered. Until that time, new
therapies will provide flexibility in therapeutic approaches while decreasing side effects.

Asthma

Agent Name

Discussion

Phosphodiesterase 4
inhibitors

Many of the inflammatory cells involved in asthma contain the subtype 4

cyclic nucleotide phosphodiesterase (PDE4) Giembycz (2000). Increasing
cyclic AMP concentrations in inflammatory cells decreases mediator
release. The anti-inflammatory effect of theophylline may involve
inhibition of PDE4. Thus, PDE4 represents a reasonable target for
producing cell-specific anti-inflammatory effects while limiting the side
effects characteristic of theophylline. A large number of compounds are
currently under consideration Campillo and Paez (2002).
Some asthma patients respond poorly to standard therapies, necessitating
the development of alternative agents for these individuals Niven and
Argyros (2003). Some of these agents have anti-inflammatory and
immunomodulatory effects and/or are useful for treating other disorders.
They include methotrexate, troleandomycin, auranofin (gold),
cyclosporine, immune globulin IV, and inhaled furosemide, which have
been examined in clinical trials, and hydroxychloroquine,
azathioprine, inhaled heparin and dapsone, which have not undergone
clinical study for this application. Other approaches to drug development
may be targeted at preventing the synthesis or effects of inflammatory
mediators and adhesion molecules, which are involved in the trafficking
of inflammatory cells from the blood into the airway wall Bryan et al
(2000), Pahl and Szelenyi (2002), Holtzman (2003).

Alternative therapies

Animal Models
No animal model has been developed that recapitulates all the hallmarks of human
asthma. Invariably, the many models that have been developed in several species involve
sensitization with a foreign antigen and re-challenge later with inhaled antigen. The
inhaled antigen generally provokes an immediate and a late phase response, and the
mediators involved in both phases resemble those involved in the human disease, as
judged by the effects of pharmacological blockers. Inflammation of the airways is usually,
but not always, produced, but the relationship between inflammation and airway hyperreactivity is not unequivocally established. The subject of asthma animal models has been
reviewed Vargaftig (1999), Abraham (2000), Bice and Seagrave (2000), Szelenyi (2000). As
examples, investigators have noted altered mucin gene expression in guinea pigs Li et al
(2001), lung remodeling in mice Tanaka et al (2001), and smooth muscle hypertrophy in
rats Moir et al (2003).

Other Information Web Sites

This is the web site at which the Global Strategy for Asthma Management and Prevention
document may be viewed. This is a comprehensive and contemporary consensus document describing asthma and its treatment: www.ginasthma.com
At this website from the British Thoracic Society, the BTS/SIGN British Guideline on
the Management of Asthma, another comprehensive consensus document describing
asthma treatment may be viewed: www.brit-thoracic.org.uk/sign/
Basic and clinical information about asthma and its treatment may be found at the
following web sites:
www.emedicine.com/
www.merck.com/mrkshared/mmanual/section6/chapter68/68b.jsp

10

Asthma

www.harrison.accessmedicine.com/
www.search.nlm.nih.gov/medlineplus/ (search using term: asthma)
www.intelihealth.com/IH/ihtIH/WSIHW000/408/408.html (search using term:
asthma; this is a site for lay audiences)
www.fpnotebook.com/LUNCh4.htm (This site is very comprehensive and allows efficient
searching.)
This site from the American College of Chest Physicians contains material presented at
the postgraduate level: www.chestnet.org/cgi-bin/search/x/search.pl?Realm=All&Match
=1&Terms=asthma&nocpp=1&Rank=41

Journal Citations
Anderson, G.G., Cookson, W.O.C.M., 1999. Recent advances in the genetics of allergy and asthma. Mol.
Med. Today, 5, 264273.
Barnes, K.C., 2000a. Atopy and asthma genes-where do we stand. Allergy, 55, 803817.
Barnes, P.J., Chung, K.F., Page, C.P., 1998. Inflammatory mediators of asthma: An update. J. Pharmacol.
Exp. Therap., 50(4), 515596.
Barnes, P.J., 2000b. Anti-IgE therapy in asthma: Rationale and therapeutic potential. Internat. Arch. Allergy
Immunol., 123, 196204.
Bice, D.E., Seagrave, J., 2000. Animal models of asthma: Potential usefulness for studying health effects of
inhaled particles. Inhal. Tox., 12, 829862.
Bryan, S.A., Leckie, M.J., Hansel, T.T., Barnes, P.J., 2000. Novel therapy for asthma. Expert Opinion on
Investigational Drugs, 9(1), 2542.
Campillo, N., Paez, J.A., 2002. Novel bronchodilators in the treatment of asthma and COPD. Expert Opinion
on Therapeutic Patents, 12(1), 5362.
Cookson, W., 1999. The alliance of genes and environment in asthma and allergy. Nature, 402(suppl. 25),
B5B11.
Chang, T.W., 2000. The pharmacological basis of anti-IgE therapy. Nature Biotech., 18(2), 157162.
Childhood Asthma Management Program Research Group (CAMP) Long-term effects of budesonide or
nedocromil in children with asthma 2000 N. Eng. J.Med., 343, 10541062.
Van eerdewegh, P., Little, R.D., Dupuis, J., et al., 2002. Association of the ADAM33 gene with asthma and
bronchial hyperresponsiveness. Nature, 418, 426430.
Giembycz, M.A., 2000. Phosphodiesterase 4 inhibitors and the treatment of asthma: Where are we now and
where do we go from here. Drugs, 59(2), 193212.
Holgate, S.T., Davies, D.E., 2000. Airway inflammatory and remodelling in asthma-cause and effect.
Immunologist, 8(6), 131135.
Holtzman, M.J., 2003. Drug development for asthma. Amer. J.Resp. Cell and Mol. Biol., 29, 163171.
Ito, K., Caramori, G., Lim, S., Oates, T., Chung, K.F., Barnes, P.J., Adcock, I.M., 2002. Expression and
activity of histone deacetylases in human asthmatic airways. Amer. J. Resp. Critical Care Med., 166,
392396.
Li, Y., Martin, L.D., Minnicozzi, M., Greenfeder, S., Fine, J., Pettersen, C.A., Chorley, B., Adler, K.B., 2001.
Enhanced expression of mucin genes in guinea pig model of allergic asthma. Amer. J.Resp. Cell and Mol.
Biol., 25, 644651.
McFadden, E. R. Jr, 2003. Acute severe asthma. Amer. J. Resp. Critical Care Med., 168, 740759.
Milgrom, H., Fick, R.B. Jr, Su, J.Q., Reimann, J.D., Bush, R.K., Watrous, M.L., Metzger, W.J., 1999.
Treatment of allergic asthma with monoclonal anti-IgE antibody. N. Eng. J. Med., 341(26), 19662008.
Moir, L.M., Leung, S.Y., Eynott, P.R., McVicker, C.G., Ward, J.P., Chung, K.F., Hirst, S.J., 2003. Repeated
allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats.
Amer. J. Physiol.. Lung Cellular and Molec. Physiol., 284, L148L159.
Niven, A.S., Argyros, G., 2003. Alternate treatments in asthma. Chest, 123, 12541265.
Pahl, A., Szelenyi, I., 2002. Asthma therapy in the new millennium. Inflam. Res., 51, 273282.
Rhodes, L., Bailey, C.M., Moorman, J.E., 2004. Asthma prevalence and control characteristics by race/
ethnicity-United States, 2002. Morbid. Mortal. Weekly Rep., 53(7), 145148.
Riffo-Vasquez, Y., Spina, D., 2002. Role of cytokines and chemokines in bronchial hyperresponsiveness
and airway inflammation. Pharmacol. Therap., 94, 185211.
Szelenyi, I., 2000. Animal Models of bronchial asthma. Inflam. Res., 49, 639654.
Tanaka, H., Masuda, T., Tokuoka, S., Komai, M., Nagao, K., Takahashi, Y., Nagai, H., 2001. The effect of
allergen-induced airway inflammation on the airway remodeling in a murine model of allergic asthma.
Inflam. Res., 50, 616624.
Toews, G.B., 2001. Cytokines and the lung. Euro. Res. J., 18, 3S17.
Vargaftig, B.B., 1999. What can we learn from murine models of asthma. Clin. Exper. Allergy, 29(suppl. 1),
S9S13.

Asthma
Wenzel, S.E., 2003. The role of leukotrienes in asthma. Prostaglandins, Leukotrienes and Essential Fatty
Acids, 69, 145155.
Drazen, J.M., Israel, E., OBryne, P.M., 1999. Treatment of asthma with drugs modifying the leukotrine
pathway. N. Eng. J. Med., 340, 197206.

Book Citations
Abraham, W.M., 2000. Animal Models of Asthma. Busse, W.W., Holgate, S.T. (Ed.), Asthma and Rhinitis,
Edition 2, pp. 12051227, Blackwell Science Ltd, Oxford.
GINA 2003 Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH
Publication No 02-3659.

Further Reading
Anon., British guidelines on the management of asthma, Thorax, 58(Suppl 1) (1996) S1S92
Barnes, P.J., Grunstein, M.M., Leff, A. R. and Woolcock, A.J., Asthma, Lippincott-Raven, Philadelphia,
1997
Busse W. W. and Holgate, S.T., Asthma and Rhinitis, Blackwell Science, Oxford, 2000
Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH Publication No
023659, 2003. (This volume is also available at www.ginasthma.com).
Textbook of Respiratory Medicine, J. F. Murray, J. A. Nadel, R. J. Mason and H. A. Boushey (Eds.),
W. B. Saunders, Philadelphia, 2000

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