(Chest. 2001;119:1533-1546.)
© 2001
American College of Chest Physicians
The Anti-inflammatory Effects of Leukotriene-Modifying Drugs and Their Use in Asthma*
Sundeep S. Salvi, MD, PhD;
Mamudipudi T. Krishna, MBChB, PhD;
Anthony P. Sampson, PhD and
Stephen T. Holgate, MD, DSc
*
From the Respiratory Cell and Molecular Biology Division, Department of University Medicine, Southampton General Hospital, Southampton, UK.
Correspondence to: Sundeep S. Salvi, MD, PhD, Department of University Medicine, Level D Centre Block, Southampton General Hospital, Southampton SO16 6YD, UK; e-mail: sss{at}soton.ac.uk
 |
Abstract
|
|---|
Asthma is a chronic inflammatory disease of the airways.
Anti-inflammatory drug therapy, primarily using corticosteroids, is now
considered the first-line treatment in the management of all grades of
asthma severity. Although corticosteroids are believed to be the most
potent anti-inflammatory agents available, they do not suppress all
inflammatory mediators involved in the asthmatic response.
Leukotrienes, which are lipid mediators generated from the metabolism
of arachidonic acid, play an important role in the pathogenesis of
asthma. They produce bronchospasm, increase bronchial
hyperresponsiveness, mucus production, and mucosal edema, and enhance
airway smooth muscle cell proliferation and eosinophil recruitment into
the airways, and their synthesis or release is unaffected by
corticosteroid administration. The use of leukotriene synthesis
inhibitors or leukotriene receptor antagonists as anti-inflammatory
therapies in asthma has therefore been investigated. Beneficial effects
of leukotriene-modifying drugs have been demonstrated in the management
of all grades of asthma severity, and there is evidence that certain
patient groups (such as those with exercise-induced asthma or
aspirin-induced asthma) may be particularly suitable for such
therapy.
Key Words: anti-inflammatory • antileukotrienes • aspirin-induced asthma • asthma • corticosteroids • eosinophil • inflammation
|
Introduction
|
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Asthma
is one of the most common respiratory diseases encountered in clinical
practice, affecting approximately 10% of children and 5% of adults
worldwide. It is one of the few chronic diseases in the developed world
that is increasing in prevalence, despite better understanding of its
pathogenesis and improved treatments. This paradox necessitates
continuing efforts to review current knowledge and to
search for new insights into the pathogenesis and treatment of this
complex disorder. For many years, asthma was regarded as a
bronchospastic disease of airway smooth muscles, leading to treatment
with oral and inhaled bronchodilators. However, with the institution
and use of fiberoptic bronchoscopy with lavage and biopsy along with
rapid advances in the fields of cellular and molecular biology, airway
inflammation has been found to be an integral component in the
pathogenesis of asthma. Even in patients with mild-to-moderate disease,
a strong inflammatory component has been noted and is believed to be
the driving force responsible for airway hyperresponsiveness and the
propensity to airflow obstruction.1
A report by the Global Initiative for Asthma2
has
defined asthma as
a chronic inflammatory disorder of the airways in which many
cells play a role, in particular mast cells, eosinophils, and T
lymphocytes. In susceptible individuals this inflammation causes
recurrent episodes of wheezing, breathlessness, chest tightness, and
cough particularly at night and/or in the early morning. These symptoms
are usually associated with widespread but variable airflow limitation
that is at least partially reversible either spontaneously or with
treatment. The inflammation also causes an associated increase in
airway responsiveness to a variety of stimuli.
|
Inflammation in Asthma
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The histopathologic characteristics of asthma include shedding of
airway epithelium, sub-basement membrane fibrosis, hypertrophy of
airway smooth muscle, excessive secretion of mucus, and a multicellular
inflammation involving activated mast cells, eosinophils, neutrophils,
macrophages, basophils, and lymphocytes. Each of these cells has an
important contribution and a specific relation to the development of
airway inflammation and airway narrowing.
Activation of mast cells by specific antigens through
cell-bound IgE releases histamine and causes synthesis of
cysteinyl leukotrienes (CysLTs); these acute-phase mediators cause
airflow obstruction by directly increasing airway smooth muscle tone.
Mast cells also release proteases (eg, tryptase,
stromolysin, and chymase) and many pro-inflammatory cytokines
(eg, tumor necrosis factor-
[TNF-],
granulocyte-macrophage colony-stimulating factor [GM-CSF],
interleukin [IL]-3, IL-4, IL-5, IL-13), and chemokines, which
contribute to airway inflammation and airway
hyperresponsiveness.3
Eosinophils are considered to be one of the major cells that mediate
much of the pathology and disordered airway function that characterizes
atopic and nonatopic asthma. Upon activation, these cells release
several toxic mediators (major basic protein, eosinophil cationic
protein, eosinophil peroxidase, and eosinophil-derived neurotoxin),
reactive oxygen, and leukotrienes, as well as several proinflammatory
cytokines including GM-CSF, IL-3, IL-4, and IL-5, all of which
contribute to increased airway hyperresponsiveness and damage to the
airway epithelium. Eosinophil numbers are found to be increased in the
peripheral blood, sputum, BAL fluid, and bronchial tissues of patients
with active asthma,4
and their numbers correlate
positively with asthma severity.5
T lymphocytes, through their capacity to recognize foreign proteins
processed by antigen-presenting cells, generate a wide range of
cytokines relevant to asthma pathogenesis and play a central role in
the initiation and persistence of the inflammatory response. On
activation, CD4+ T-helper cells differentiate along two broad pathways,
termed Th1 and Th2, based on their pattern of cytokine secretion.
Th1-like cells secrete IL-2, interferon-
, and TNF-, which
mediate delayed-type hypersensitivity reactions, while the Th2-like
cells secrete IL-4, IL-5, and IL-13 and mediate allergic inflammatory
responses.6
A clear differentiation between Th1 and Th2
does not occur in humans (rather there occurs a biased cytokine
repertoire toward Th1 or Th2), and it is also important to realize that
there are other cell sources of these cytokines in addition to CD4+ T
cells. Asthma is characterized by selective recruitment of Th2-like
cells, with a resultant increase in cytokines encoded in a
cluster on chromosome 5q31–33. IL-4 and IL-13 induce and enhance IgE
synthesis, while IL-13 also causes mucus hypersecretion,
subepithelial fibrosis, and increases the levels of the
eosinophil chemoattractant, eotaxin.7
IL-5 and GM-CSF
induce eosinophil chemotaxis, differentiation, and activation, and
enhance eosinophil survival.8
9
10
Macrophages contribute to asthma pathogenesis by secreting a range of
inflammatory mediators, including cytokines (TNF-, IL-1ß, IL-6,
IL-8, IL-12), chemokines, and leukotrienes; neutrophils, which are
found in large numbers in the airways of patients with severe asthma,
are believed to produce a wide range of inflammatory mediators,
including IL-8 and other chemokines, leukotrienes, and reactive
oxygen,11
which further perpetuate the inflammatory
response.
Epithelial cells, which until recently were considered to act mainly as
a physical barrier participating in mucociliary clearance and the
removal of noxious agents, have been shown to participate actively in
the asthmatic airway inflammatory response by releasing eicosanoids,
peptidases, matrix proteins, proinflammatory cytokines, chemokines, and
nitric oxide, as well as performing an antigen presenting function by
their capacity to express major histocompatibility complex class II
(human leukocyte antigen-DR) antigens.12
More recently,
airway smooth muscle cells13
14
and
fibroblasts15
have also been shown to contribute to asthma
pathogenesis by acting as a cellular source for proinflammatory
cytokines involved in asthma pathogenesis.
Thus, on activation, epithelial cells, mast cells, eosinophils,
neutrophils, macrophages, and fibroblasts release a wide range of
inflammatory mediators, including histamine, proteases, growth factors,
platelet-activating factor, cytokines, and leukotrienes, which
lead to bronchospasm, airway hyperresponsiveness, airway smooth muscle
hypertrophy, denudation of airway epithelium, subepithelial fibrosis,
thickening of basement membrane, mucus hypersecretion, and activation
of sensory nerves, all of which contribute to the pathophysiology of
asthma (Fig 1
).
|
The Role of Leukotrienes in Asthma Pathogenesis
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|---|
Leukotrienes are lipid mediators synthesized from the ubiquitous
precursor arachidonic acid, a normal constituent of the phospholipid
bilayer that is present in many biological membranes, particularly the
nuclear membrane. These molecules have received renewed interest as one
of the major inflammatory mediators involved in asthma pathogenesis.
They fall into two classes: the dihydroxy acids such as leukotriene
B4 (LTB4), which are
neutrophil chemoattractants, and the cysteinyl conjugates leukotriene
C4 (LTC4), leukotriene
D4 (LTD4), and leukotriene
E4 (LTE4), which are potent
smooth muscle contractants (constituting the slow reacting substance of
anaphylaxis) and eosinophil chemoattractants.
|
Leukotriene Synthesis
|
|---|
A variety of biological signals activates cytosolic phospholipase
A2 to liberate arachidonic acid from membrane
phospholipid, including receptor activation, antigen-antibody
interaction, physical stimuli such as cold or altered ionic
environment, or stimuli that directly increase intracellular
Ca++.16
Once released, metabolism of
arachidonic acid gives rise to a group of pharmacologically active
compounds collectively known as eicosanoids, made up of the
prostaglandins, thromboxanes, leukotrienes, and hydroxyeicosatetraenoic
acids. Arachidonic acid cleaved from the membrane interacts with
5-lipoxygenase–activating protein (FLAP), which helps to transfer it
to the enzyme 5-lipoxygenase (5-LO). The result of this
enzyme-substrate interaction is the production of
5-hydroperoxyeicosatetraenoic acid, which is transformed into the
unstable intermediate leukotriene A4
(LTA4) by the same oxygenase.17
In
neutrophils and monocytes, LTA4 is converted
predominantly to the chemoattractant LTB4 by
LTA4 hydrolase; in human eosinophils, mast cells,
and basophils, LTA4 is conjugated with reduced
glutathione by LTC4 synthase to form the first of
the CysLTs, LTC4. After carrier-mediated cellular
export, sequential cleavage of the glutathionyl side chain of
LTC4 generates the extracellular metabolites
LTD4 and LTE4 (Fig 2
).
|
Cellular Origin of Leukotrienes
|
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Expression of 5-LO is essentially restricted to various myeloid
cells (neutrophils, eosinophils, monocytes/macrophages, mast
cells/basophils, and B lymphocytes). Eosinophils and pulmonary mast
cells, as well as fragments of human lung parenchyma in
vitro, generate essentially CysLTs and little
LTB4. Monocytes and macrophages produce both
LTB4 and LTC4, while
neutrophils secrete LTB4 as their principal 5-LO
product. Endothelial cells and platelets do not express 5-LO, but have
LTC4 synthase or LTA4
hydrolase and can therefore participate in leukotriene production via a
transcellular mechanism. Human airway epithelial cells are thought to
express 5-LO, LTA4 hydrolase, FLAP, and
15-lipoxygenase and may be an important source of
LTB4 and 15-hydroxyeicosatetraenoic acid
in the lung.18
19
However, it should be noted that
evidence for the expression of 5-LO by epithelial cells is still
limited.
|
Leukotriene Receptors
|
|---|
Leukotrienes exert their biological effects by acting on
leukotriene receptors present on cell membranes. In man, three types of
membrane leukotriene receptors have been identified, and it is likely
that several more will be identified in the future. The non-CysLT
LTB4 activates the BLT receptor, while the CysLTs
(LTC4, LTD4,
LTE4) activate CysLT receptors 1 and 2
(CysLT1 and CysLT2)
subtypes. The BLT receptor has been recently cloned and belongs to the
family of seven transmembrane G protein-coupled
receptors.20
The CysLT1 receptor has
also been recently cloned by two independent groups.21
22
It also belongs to the family of seven transmembrane G protein-coupled
receptors and has been shown to be expressed in several organs,
including the lung, where it is found mainly localized to smooth muscle
cells and macrophages. CysLT1 receptor is also
particularly strongly expressed on peripheral blood
monocytes.21
Activation of CysLT1
receptors produces most of the biological effects that are relevant to
the pathophysiology of asthma.
|
Leukotriene Production in Asthma
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Leukotriene production is increased in asthma. Blood eosinophils
from patients with asthma synthesize fivefold to 10-fold greater
amounts of CysLTs than those from normal subjects,23
and
this can be mimicked in vitro by treatment of normal
eosinophils with the Th-2 cell-derived eosinophilopoietic cytokines
IL-3, IL-5, and GM-CSF.24
This enhanced production
probably relates to the upregulation of 5-LO and FLAP messenger RNA
observed in asthmatic subjects.25
Asthmatic airways show
increased levels of IL-5,26
and we have recently
demonstrated27
that in eosinophils, IL-5 significantly
increases FLAP expression and translocates 5-LO to the nucleus, which
is accompanied by a fourfold increase in ionophore-stimulated CysLT
synthesis. A large number of studies have shown increased levels of
CysLTs in BAL and urine samples of patients with asthma28
after bronchial allergen challenge,29
30
31
32
33
or in
aspirin-intolerant patients after exposure to aspirin
challenge.34
35
36
In patients with asthma presenting with
spontaneous exacerbation, the principal urinary metabolite
LTE4 is also greatly elevated.37
|
Biological Properties of Leukotrienes Relevant to Asthma
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|---|
The biological properties of leukotrienes are summarized in Table 1
. CysLTs are the most potent bronchoconstrictor agents, being
approximately 1,000 times more potent than histamine. After aerosol
challenge, they have been shown to increase bronchial
hyperresponsiveness to methacholine or histamine, especially in
patients with asthma.38
39
40
41
More recently, CysLTs have
been shown to partly mediate eotaxin-induced bronchial
hyperresponsiveness and eosinophilia in IL-5 transgenic
mice.42
LTD4, acting via CysLT1
receptors, has been shown to induce airway smooth muscle proliferation
in vitro when combined with an appropriate growth factor
such as epidermal growth factor or insulin-like growth
factor,43
an effect that can be blocked by
CysLT1 receptor antagonists.44
CysLTs are potent inducers of mucus hypersecretion.45
46
They also increase microvascular permeability and impair ciliary
activity.47
48
49
In addition, CysLTs have been shown to
induce influx of eosinophils into the airways of guinea pigs, which can
persist for up to 4 weeks.50
51
Similar effects have been
observed in vitro as well as in vivo in patients
with asthma and probably are the result of eotaxin induction and
secretion.52
53
54
Evidence from studies in guinea pigs
suggests that these mediators can also potentiate the release of
acetylcholine from vagal nerve endings and of tachykinins from
capsaicin-sensitive afferent C fibers.55
56
57
In summary, CysLTs induce bronchoconstriction, enhance airway
hyperresponsiveness and smooth muscle hypertrophy, cause mucus
hypersecretion and mucosal edema, and induce influx of eosinophils
into the airway tissue (Fig 3
). Thus, the biological properties of leukotrienes strongly suggest that
they play a key mediator role in the pathogenesis of asthma.
LTB4 does not exhibit any contractile effect on
airway smooth muscle cells, but is one of the most potent chemotactic
agents and activators for neutrophils.58
LTB4 also induces the expression of adhesion
proteins on the surface of endothelial cells and polymorphonuclear
leukocytes, which are essential for margination and
diapedesis.59
|
The Role of Anti-inflammatory Drugs in Asthma Management
|
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Based on an understanding of the role of inflammation in the
pathogenesis of asthma, reversal of existing airway inflammation is
considered to be a primary aim of asthma treatment, and therapeutic
strategies have focused on either reducing inflammatory cell influx,
reducing the production of inflammatory mediators, or blocking their
effects. Antihistamines and platelet-activating factor antagonists have
undergone trials in asthma management; however, their efficacy is
minimal. The role of cytokines in the pathogenesis of asthma has been
recently reviewed by Chung and Barnes,60
and trials are
now underway to study the effects of blocking some of the major
cytokines involved in asthma pathogenesis. Clinical trials using
monoclonal antibody directed against IL-5 have shown reduction in
eosinophils in peripheral blood and sputum, but have demonstrated no
effect on the late asthmatic response or bronchial hyperresponsiveness
after allergen challenge.61
Similar results have been
obtained with recombinant IL-12 (S.A. Bryan, MBChB; unpublished data;
October 2000).
|
The Effects of Corticosteroid Treatment on Asthma
|
|---|
Corticosteroids are the most effective anti-inflammatory agents
currently available for the treatment of asthma. They produce a marked
reduction in the numbers of mast cells, macrophages, T lymphocytes, and
eosinophils in the bronchial epithelium and submucosa.62
Furthermore, they reverse the shedding of epithelial cells and the
goblet cell hyperplasia characteristically seen in biopsy specimens of
bronchial epithelium from patients with asthma; reduce microvascular
permeability; block the activation of inflammatory cells; suppress
mediator generation from lymphocytes; and reduce the expression of
vascular adhesion molecules.63
64
By reducing airway
inflammation, inhaled corticosteroids modify airway
hyperresponsiveness,65
downregulate production of
proinflammatory cytokines, and upregulate anti-inflammatory cytokines
such as IL-10. Several clinical studies have clearly demonstrated that
inhaled corticosteroid therapy greatly reduces asthma symptoms,
improves lung function, reduces nonspecific airway hyperreactivity, and
reduces the consumption of bronchodilating drugs.62
Validated by international consensus meetings, glucocorticoids have
become the first-line treatment for asthma management.
|
Glucocorticoids Do Not Suppress All Inflammatory Responses in
Asthma
|
|---|
Despite the well-recognized efficacy of inhaled corticosteroid
treatment in improving the symptoms of asthma, it appears that
inflammation still persists at a low level in the airways of patients
with asthma who have poor airway function, despite regular and
prolonged treatment with inhaled steroids, even at dosages up to 2,000
µg/d.66
67
68
Corticosteroids only affect certain
inflammatory mediators involved in asthma. In general, glucocorticoids
substantially reduce the eosinophil/lymphocyte driven processes, while
leaving behind or even augmenting a neutrophil-mediated
process.68
Patients with severe asthma treated with oral
glucocorticoids for 1 year have demonstrated dramatically increased
numbers of neutrophils in biopsy and lavage specimens, while
effectively eliminating eosinophils.69
Previous
reports70
71
have also suggested that glucocorticoids
enhance neutrophil function through increased leukotriene and
superoxide production, as well as inhibition of apoptosis. A recent
study by Pizzichini et al72
has demonstrated that,
although glucocorticoids reduce eosinophil numbers and eosinophil
cationic protein levels in the airways of patients with severe asthma,
they have no effect on neutrophil numbers, fibrinogen, or IL-5. In
addition, some reports73
74
suggest that glucocorticoids
can induce growth factors and/or collagen synthesis in certain
conditions.
At one time, it was thought that glucocorticoids effectively inhibit
phospholipases by inhibiting gene transcription of phospholipase
A2 through upregulation of gene transcription of
lipocortin-1, a protein exerting an inhibitory activity of
phospholipase A2, hence, decreasing prostanoid
and leukotriene production. However, this inhibition is limited only to
certain conditions and/or cells.75
Numerous in
vivo and in vitro studies have demonstrated minimal
suppression of leukotriene production by glucocorticoids, and in some
cases an enhanced production.68
The FLAP gene promoter
contains a glucocorticoid response element,76
and
glucocorticoids enhance gene transcription and protein production of
FLAP in human neutrophils, monocytes, and eosinophils in
vitro.27
77
78
Dexamethasone is ineffective in
inhibiting the LTB4/LTC4
release from human lung fragments,79
80
purified lung mast
cells,81
and purified blood neutrophils.70
In
addition to these in vitro results, oral or IV
administration of corticosteroids have similarly been reported to have
no inhibitory effect on the unstimulated or stimulated release of
leukotrienes by whole-blood leukocytes, purified neutrophils, or
monocytes,82
83
or even to increase ex vivo
leukotriene biosynthesis by blood neutrophils.84
Similarly, treatment of healthy volunteers with dexamethasone (8 mg/d
for 3.5 days) did not show any significant inhibition of the triggered
release of LTB4 as well as other arachidonic acid
metabolites from alveolar macrophages obtained by
BAL.81
85
These data suggest that glucocorticoids have
minimal or no effect on LT synthesis and that their anti-inflammatory
effects are mainly because of inhibition of the synthesis and release
of other mediators, particularly cytokines.
|
The Role of Leukotriene-Modifying Drugs as Anti-inflammatory Agents
in Asthma Treatment
|
|---|
Leukotrienes are potent inflammatory mediators that play an
important role in asthma pathogenesis. It would therefore seem logical
that drugs that modify their effects would be anti-inflammatory.
Although glucocorticosteroids are one of the most potent
anti-inflammatory agents available, they do not suppress either
leukotriene production or release into asthmatic airways. It is
therefore logical to consider that leukotriene synthesis inhibitors or
CysLT1 antagonists may have complementary
anti-inflammatory effects in asthma management, and as a result offer
additional clinical benefit. In line with this hypothesis, clinical
studies86
87
have shown that addition of leukotriene
synthesis inhibitors or CysLT1 antagonists to
inhaled glucocorticoids improves asthma control. The 5-LO inhibitors
are classified into those that inhibit 5-LO directly and those that
bind to FLAP. Zileuton is the only 5-LO inhibitor currently available
for clinical use, while three CysLT1 antagonists
are available: montelukast, zafirlukast, and pranlukast. Zileuton
inhibits leukotriene synthesis by approximately 70 to
90%,88
while montelukast, zafirlukast, and pranlukast
(available in Japan and Korea) are selective antagonists of the
CysLT1 receptor.22
Effects on Airway Responsiveness to Allergen Challenge
Hyperresponsiveness to histamine is a key feature of a variety of
pathologic conditions, including bronchial asthma. It has been
demonstrated89
that CysLTs prime histamine responses by
recruiting additional histamine-1 receptors in human peripheral
blood monocytes and umbilical smooth muscle cells in vitro.
A single dose of the 5-LO inhibitor zileuton, 400 mg,90
or
the CysLT1 receptor antagonist
zafirlukast91
have been shown to attenuate bronchial
hyperresponsiveness to histamine and distilled water in patients with
asthma who were receiving regular treatment of inhaled beclomethasone
dipropionate or budesonide. Treatment with 1.6 to 2.4 g/d of zileuton
for 7 days has been shown to produce beneficial effects on airway
responsiveness to cold, dry air.92
In patients with mild
asthma, zafirlukast and montelukast have been shown to attenuate both
the early-phase and late-phase responses to inhaled allergen, reduce
lymphocyte and basophil recruitment to the airways,93
94
and attenuate bronchial hyperresponsiveness to histamine that normally
accompanies antigen inhalation.95
96
More recently,
pranlukast has been shown to suppress the production of IL-4 (a
cytokine that affects IgE antibody production), IL-5, and GM-CSF
(cytokines that affect eosinophil activation) by peripheral blood
mononuclear cells under stimulation with specific antigens in patients
with bronchial asthma.97
Anti-Eosinophil Effects of CysLT-Modifying Drugs
Eosinophil recruitment is considered to be one of the most
characteristic processes in asthma pathogenesis. On activation,
eosinophils release a vast array of mediators, including leukotrienes
and basic proteins (eosinophil cationic protein, major basic protein)
that cause epithelial cell damage. Several studies have demonstrated
that CysLTs induce eosinophil activation and recruitment into the
airways: the 5-LO inhibitor, zileuton, has been shown to inhibit
eosinophil migration into guinea pig tracheal explants,98
while another study99
has demonstrated that
zileuton reduces circulating blood eosinophil numbers. The leukotriene
synthesis inhibitor MK-886100
and the CysLT receptor
antagonist pranlukast have shown significant attenuation of eosinophil
recruitment into the airways of rats and mice after allergen
challenge.42
52
Inhalation of LTE4
has been shown to increase eosinophil numbers in bronchial biopsies, an
effect which can be significantly attenuated by
zafirlukast.101
Studies carried out in asthmatic subjects
have demonstrated that zafirlukast94
and
montelukast73
102
103
104
significantly reduce sputum as well
as peripheral blood eosinophil counts. In addition, pranlukast caused a
significant reduction in activated eosinophils in bronchial biopsy
specimens.105
Clinical Benefits of Leukotriene-Modifying Drugs
Zafirlukast has demonstrated significant reductions in rescue
ß2-agonist use and in nighttime awakenings, and
significant improvements in daytime symptoms and lung functions in
patients with chronic mild-to-moderate asthma.106
107
Similar results have been demonstrated with the use of
montelukast108
109
and pranlukast.110
111
High-dose zafirlukast, 80 mg bid, when added to the existing
treatment regimen of 368 patients with asthma who remained symptomatic
on high-dose inhaled corticosteroid treatment for 6 weeks, demonstrated
significant improvements in asthma symptoms, a decrease in asthma
exacerbations, and reduced need for oral corticosteroids as well as
ß2-agonists.112
The beneficial
effects of antileukotrienes in patients with asthma treated with
high-dose (1,000 µg/d) inhaled corticosteroids allows reduction of
the dose of steroids to half while maintaining clinical
stability.113
Zileuton has also been reported to decrease
symptom scores and ß2-agonist use and improve
airway function in patients with mild-to-moderate asthma, not treated
with inhaled or oral steroids.114
115
116
Oral administration of CysLT1 receptor
antagonists or 5-LO inhibitors to patients with chronic persistent
asthma therefore improves airway function, decreases the need for
rescue medication with ß-adrenergic agonists, relieves the symptoms
of asthma, decreases the frequency of exacerbation of asthma requiring
oral glucocorticoid therapy, and reduces the dose of inhaled
glucocorticoid required to maintain control of asthma, thus exerting a
glucocorticoid-sparing effect.37
Leukotrienes and Aspirin-Induced Asthma
Aspirin-induced asthma is present in 3 to 8% patients with asthma
and causes profound and sometimes life-threatening bronchoconstriction
as well as naso-ocular, dermal, and GI responses. By inhibiting the
cyclo-oxygenase pathway, nonsteroidal anti-inflammatory drugs either
shunt arachidonic acid through the 5-LO pathway to produce more
LTB4, LTC4,
LTD4, and
LTE4,117
or remove the inhibitory
effect of prostaglandin E2 on the CysLT
pathway.36
After aspirin challenge, CysLTs are released
into nasal and bronchial secretions and can be collected in the urine.
LTC4 synthase, the terminal enzyme for CysLT
production, is markedly overexpressed in eosinophils and mast cells
from bronchial biopsy specimens of most patients with aspirin-induced
asthma,118
and many of these patients have elevated levels
of CysLTs even in the absence of exposure to aspirin.34
Pretreatment with the CysLT1 receptor antagonists
or 5-LO inhibitors prevents physiologic responses after oral
administration of aspirin.109
114
119
120
It has been
recently demonstrated121
that pranlukast protected against
analgesic-induced bronchoconstriction through mechanisms that were not
related to the bronchodilator property, but to improvements in
bronchial hyperresponsiveness and hypersensitivity to analgesics. These
results support the view that CysLTs are one of the most important
components in the pathogenesis of aspirin-intolerant asthma, and that
leukotriene-modifying drugs greatly relieve asthma symptoms induced by
aspirin and other nonsteroidal anti-inflammatory drugs.
Leukotrienes and Exercise-Induced Asthma
Exercise stimulates bronchoconstriction in 70 to 80% of
patients with asthma.122
CysLTs have been recovered from
urine during exercise-induced bronchospasm,123
124
while
the CysLT1 receptor antagonists
MK-571,125
zafirlukast,126
montelukast,127
and cinalukast128
all inhibit
the maximal bronchoconstrictor response after exercise by 50 to 80%,
an effect that supports an important role of the CysLTs in
exercise-induced airway obstruction. Treatment with zileuton has
demonstrated similar effects in patients in whom bronchoconstriction
was induced by either cold air, hyperventilation, or
exercise.129
In a recent randomized, double-blind,
placebo-controlled study,130
131
montelukast was found to
be more effective than salmeterol in the long-term treatment of
exercise-induced bronchospasm in patients with mild asthma, as
demonstrated by effect size, maintenance of effect, and fewer
respiratory clinical adverse events. Montelukast has also demonstrated
significant protection against exercise-induced asthma in children aged
6 to 12 years who have mild asthma.132
In addition, a
recent study133
has demonstrated that regular treatment
with zafirlukast protects against exercise-induced bronchoconstriction
for at least 8 h after dosing.
|
The Place for Antileukotrienes in the Asthma Management Guidelines
|
|---|
Antileukotrienes are the first new class of antiasthma drugs
developed in the last 20 years. Unlike most antiasthma controller
medications, the leukotriene modifiers offer a potential advantage of
ease of administration (usually as a once-daily or twice-daily oral
medication), compared with the need for careful administration of
inhaled medications. They are therefore more likely to improve patient
compliance, especially in children and adolescents. In addition,
antileukotrienes may be effective in concomitant allergic diseases,
common in patients with asthma, such as rhinitis and eczema.
Currently, available studies indicate that antileukotrienes are
highly effective in patients with aspirin-induced
asthma35
121
134
and in those with exercise-induced asthma
exacerbations.130
Leukotriene-modifying drugs
therefore merit recommendation as first-line therapy in these subgroups
of patients.
Although > 35 clinical trials with this drug class reveal efficacy in
asthma management, the issue of the positioning of the antileukotrienes
in asthma management guidelines continues to attract much attention: in
particular, whether they should be used in step 2 of the asthma
management guidelines (either as an alternative or in addition to
low-dose inhaled corticosteroids), or whether they sit more comfortably
at step 3 as an alternative to increasing the dose of inhaled steroid
or the introduction of a long-acting ß2-agonist
(Fig 4
). Clinical trials37
show efficacy across the whole
spectrum (mild, moderate, and severe). An interesting feature of most
clinical studies is that some patients appear to show better
responses than others,135
suggesting that leukotrienes may
play a more important role in some patients. This highlights the
importance of individualizing treatment to suit the patient, and
ensuring that management guidelines are flexible to allow this. Recent
studies103
135
136
that have directly compared the
clinical efficacy of antileukotrienes with inhaled corticosteroids
suggest that they are unlikely to replace these drugs in asthma
management, but provide no reason to believe that the addition of a
leukotriene modifier to a multifaceted asthma treatment program
will not have a complementary effect. In patients with
moderate-to-severe chronic persistent asthma, leukotriene-modifier
therapy can be combined with inhaled glucocorticoids to maintain
control of asthma with lower doses of the latter, or it can be added to
an existing regimen to achieve better control of asthma.37
In European Union countries, montelukast and zafirlukast have been
launched with therapeutic indications that are for the time being
mostly limited to add-on therapy in patients with mild-to-moderate
persistent asthma who are inadequately controlled on inhaled
corticosteroids, and in whom as-needed short-acting ß-agonists
provide inadequate clinical control of asthma. A subgroup of patients
in step 3 of the asthma management guidelines who do not perceive that
their symptoms, despite poor lung function measurements (poor
perceivers), are more likely to benefit from antileukotrienes, because
they are not only more likely to comply with oral antileukotriene
medications, may continue with these medications, which have a
better safety profile than long-acting theophyllines. In addition, the
rapid onset of action of the leukotrienes (often seen after the first
dose) may help to reinforce patient compliance and encourage their
continued use.137
There are no published clinical trial data directly comparing the
efficacy and safety of two or more leukotriene-modifying drugs in the
same or matched patient populations. Clinical trials of leukotriene
receptor antagonists were mostly performed in mild-to-moderate
asthmatic subjects, while many trials of the leukotriene synthesis
inhibitor zileuton were in moderate asthmatic subjects, but clinical
experience suggests that leukotriene receptor antagonists and
leukotriene synthesis inhibitors provide similar therapeutic benefit
across the spectrum of asthma severity. Relatively few trials have been
performed in patients with severe asthma, but early clinical experience
suggests that therapeutic benefits may be substantial.
|
Conclusion
|
|---|
Anti-inflammatory therapy is now considered first-line treatment
for all grades of asthma severity. Although corticosteroids are thought
to be the most potent anti-inflammatory agents available, they do not
affect all the inflammatory processes occurring in the asthmatic
airways. Leukotrienes, which are lipid mediators generated from the
metabolism of arachidonic acid, have been shown to play an important
role in the pathogenesis of asthmatic inflammation. CysLTs, acting on
CysLT1 receptors, produce bronchospasm, airway
hyperresponsiveness, airway smooth muscle proliferation, excess mucus
production, and mucosal edema and airway eosinophilia, features that
are characteristic of the inflammatory responses seen in asthma.
Because corticosteroids do not inhibit either leukotriene production or
release, it therefore seems logical to incorporate
leukotriene-modifying drugs in the management of asthma. 5-LO
inhibitors and CysLT receptor antagonists improve airway function,
decrease the need for rescue medication with ß-adrenergic agonists,
relieve asthma symptoms, decrease the frequency of exacerbations of
asthma requiring oral glucocorticoid therapy, and reduce the dose of
inhaled glucorticoid required to maintain control of asthma. Several
clinical studies37
have demonstrated beneficial
effects of leukotriene-modifying drugs in the management of all grades
of asthma severity. Patients with aspirin-induced asthma and those with
exercise-induced asthma exacerbations seem to benefit the most;
therefore, these agents should be considered as a potential
first-line therapy in these patients.
|
Footnotes
|
|---|
Abbreviations:
CysLT = cysteinyl leukotriene; FLAP = 5-lipoxygenase–activating
protein; GM-CSF = granulocyte-macrophage colony-stimulating factor;
IL = interleukin; 5-LO = 5-lipoxygenase;
LTA4 = leukotriene A4;
LTB4 = leukotriene B4;
LTC4 = leukotriene C4;
LTD4 = leukotriene D4;
LTE4 = leukotriene E4; TNF- = tumor
necrosis factor-
Received for publication March 28, 2000.
Accepted for publication October 12, 2000.
|
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Abstract
Introduction
