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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 7, Number 5, May 2006
Contents
New Drug Targets for the Treatment of Asthma
Guest Editor: D. Knight
Editorial Pp.
523
Airway Smooth Muscle Phenotype and Function: Interactions
with Current Asthma Therapies Pp. 525-540
A.J. Halayko, T. Tran, S.Y. Ji, A. Yamasaki and
R. Gosens
[Abstract]
Interactions Between Airway Epithelial Cells and Dendritic
Cells: Implications for the Regulation of Airway Inflammation
Pp. 541-545
J.W. Upham and S.M. Stick
[Abstract]
TGF-β___Its
Role in Asthma and Therapeutic Potential Pp. 547-565
J.E. Howell and R.J. McAnulty
[Abstract]
Extracellular Matrix, Integrins, and Mesenchymal Cell
Function in the Airways Pp. 567-577
D.J. Fernandes, J.V. Bonacci and A.G. Stewart
[Abstract]
Role of Chemokines in Severe Asthma Pp.
579-588
L.A. Murray, F. Syed, L. Li, D.E. Griswold and A.M. Das
[Abstract]
Transcription Factors in Asthma: Are Transcription
Factors a New Target for Asthma Therapy? Pp. 589-595
M. Roth and J.L. Black
[Abstract]
Carbohydrates and Epithelial Repair – More Than Just
Post Translational Modification Pp. 597-606
S. Allahverdian, B.J. Patchell and D.R. Dorscheid
[Abstract]
Zinc and its Specific Transporters as Potential
Targets in Airway Disease Pp. 607-627
C. Murgia, C. J. Lang, A.Q. Truong-Tran, D. Grosser,
L. Jayaram, R.E. Ruffin, G. Perozzi and P.D. Zalewski
[Abstract]
Protease-Activated Receptors (PARs) are Partly Pro-Inflammatory
and Partly Anti-Inflammatory: Will PAR Agonists or Antagonists
Participate in Future Drug Therapies? Pp. 629-637
B.A. DeCampo and P.J. Henry
[Abstract]
Abstracts
[Back
to top]
EDITORIAL
Asthma is a serious international public health problem and
is a hot topic in medical research for a number of reasons.
Firstly, it is a common disease with the World Health Organization
estimating that between 100 million and 150 million people
worldwide suffer from the disease. Secondly, it remains an
enormous burden on health-care systems, with the economic
costs associated with asthma estimated to exceed those of
tuberculosis and HIV/AIDS combined. Thirdly, asthma has increased
in prevalence over the past two decades in many countries,
and this is particularly marked in children. Significant advances
in our understanding of the disease have meant several testable
hypotheses regarding its etiology and pathogenesis have emerged.
Currently, the most widely accepted paradigm is that the most
common form of asthma as a multi- phase developmental
disease, beginning in childhood as an allergen induced Th-2
mediated inflammation, followed by a consolidation phase in
which chronic inflammation induces a self sustaining cycle
of airway remodeling and heightened responsiveness that leads
to chronic asthma in adulthood. Despite this, current therapies
still only treat symptoms.
In this issue of Current Drug Targets, nine groups of researchers
provide state-of-the-art reviews of critical areas of asthma
research ranging from studies on early mechanisms in pediatric
cohorts through to adult disease. Each of the reviews relates
the state of knowledge to the identification of novel targets
that may lead to the development of better treatments for
this disease. The issue leads off with Andrew Halayko and
colleagues reviewing the current state of knowledge of factors
that regulate airway smooth muscle phenotype and function
and identifies novel cellular pathways that may serve as targets
for future therapeutic initiatives. Steve Stick and John Upham
follow on from this; they discuss the cross-talk between airway
epithelial cells and dendritic cells as a foundation for the
development of new drug targets for use in asthma prevention.
The applicability of this strategy to other diseases such
as cystic fibrosis and chronic obstructive pulmonary disease
is also discussed. The next review by Jane Howell and Robin
McAnulty reviews the current knowledge of perhaps the best
known growth factor family in wound healing and fibrosis,
the TGF-β
superfamily and their role in normal and asthmatic airways,
as well as the potential for modulating their effects as a
therapeutic approach to asthma. Following this, Darren Fernandes
and co-workers introduce the extracellular matrix and illustrate
its effects on mesenchymal cell phenotype and function. The
article also describes the expression and role of specific
receptors for extracellular matrix proteins and alludes to
their suitability as a molecular target for drug discovery.
Lynne Murray, Anuk Das and colleagues then review of the therapeutic
potential of chemokines in asthma. This review is timely since
clinical trials are currently underway with therapeutics targeting
chemokine pathways for a number of other inflammatory diseases.
Judith Black and Michael Roth evaluate specific transcription
factor abnormalities that they and others have documented
are aberrant in asthmatic airways. Since transcription factors
play a central role in tissue homeostasis, long term suppression
or activation may cause severe side effects in other organs.
Thus, cell type specific strategies for manipulating these
molecules are also discussed.
The next two reviews focus on specific co-factors that potentially
influence the expression and function of the pathways and
mediators described in the earlier reviews. Del Dorscheid
and colleagues review the role of cell surface carbohydrates
in epithelial repair. Glycosylation and carbohydrate moieties
have been shown to play important role in regulating receptor
function during wound repair in a variety of organs and as
such offer exciting therapeutic potential. In the next review,
Carla Murgia and co-workers review what is currently known
about intracellular zinc in the airways, both in the normal
and inflamed states, and then considers how developing strategies
to monitor and manipulate airway zinc levels in can be used
to treat asthma and other inflammatory airway diseases.
The final review, by Peter Henry and Ben DeCampo focuses on
a relatively newly described family of receptors uniquely
activated by protease cleavage. The Protease activated receptors
have a myriad of functions that are considered pro- and anti-inflammatory
and as such their potential as therapeutic targets either
by activation or inhibition is being actively researched around
the world.
Dr. Darryl Knight
Canada Research Chair in Airway Disease
James Hogg iCAPTURE centre for Cardiovascular and Pulmonary
Research
St. Paul's Hospital, 1081 Burrard St. Vancouver, B.C. V6Z
1Y6
Associate Professor of Pharmacology, University of British
Columbia
E-mail: dknight@mrl.ubc.ca
[Back to top]
Airway Smooth Muscle Phenotype and Function: Interactions
with Current Asthma Therapies
A.J. Halayko, T. Tran, S.Y. Ji, A. Yamasaki and
R. Gosens
Asthma incidence has climbed markedly in the past
two decades despite an increased use of medications that suppress
airway inflammation and repress contraction of smooth muscle
that encircles the airways. Asthmatics exhibit episodes of
airway inflammation that potentiates reversible airway smooth
muscle spasm. A hallmark diagnostic symptom of asthma is airway
hyperresponsiveness to inhaled non-allergic stimuli, such
as methacholine, that directly induce airway smooth muscle
contraction. Inhaled gluccocorticoids are used for first-line
prevention of airway inflammation, and are frequently combined
with inhaled β2-adrenoceptor
agonists that can effectively relax airway smooth muscle and
restore airway conductance. Leukotriene receptor antagonists
and anti-cholinergics can also be used in many patients to
ensure optimal control of symptoms. With increasing disease
duration irreversible airway restriction develops from inflammation-driven
fibro-proliferative airway remodeling that includes increased
deposition of extracellular matrix, the accumulation of airway
smooth muscle, and increased numbers of myofibroblasts. Mature
airway smooth muscle cells are phenotypically plastic, enabling
them to subserve contractile, proliferative, migratory and
secretory functional responses that contribute to airway remodeling
and persistent hyperresponsiveness. This review assesses current
understanding of acute and chronic effects of common anti-asthma
medications on the diverse phenotype and functional characteristics
of airway smooth muscle cells. Furthermore, we describe the
significance of these effects in the treatment of asthma symptoms
and pathogenesis.
[Back to top]
Interactions Between Airway Epithelial Cells and Dendritic
Cells: Implications for the Regulation of Airway Inflammation
J.W. Upham and S.M. Stick
Airway epithelial cells (AEC) and dendritic cells (DC) are
situated in close proximity within the airway epithelium,
and are the first cells to encounter inhaled pathogens, allergens
and environmental pollutants. AEC and DC interact through
the release of cytokines and other soluble mediators and through
direct cell-cell contact, and these interactions are likely
to play an important role in maintaining immune homeostasis.
Increasing evidence indicates that both AEC and DC from asthmatic
individuals exhibit distinct functional properties, compared
with AEC and DC from healthy individuals. Both animal models,
and novel co-culture models for directly studying human AEC/DC
interactions are providing new insight into the cross-talk
between these two important cells types, as a foundation for
the development of new drug targets for use in asthma, cystic
fibrosis and chronic obstructive pulmonary disease.
[Back to top]
TGF-β___Its
Role in Asthma and Therapeutic Potential .
J.E. Howell and R.J. McAnulty
Asthma is a chronic disease of the airways affecting around
10% of the population. The majority of cases are well controlled
with current therapies, however in approximately 20% of severe
asthmatics the available therapeutic strategies are inadequate.
Structural changes in the asthmatic airway, including an increase
in smooth muscle mass and an increased deposition of extracellular
matrix proteins, which correlate with airway hyperresponsivenes,
reduced lung function and an increase in fibroblast/myofibroblast
numbers, are not specifically targetted by current therapeutic
agents and therefore represent an area of unmet need. The
mechanisms involved in the development of airway remodelling
are incompletely understood but are thought to involve one
or more isoforms of transforming growth factor-β
(TGF-β).
The TGF-βs
are pleiotropic mediators which have important roles in the
regulation of inflammation, cell growth, differentiation and
wound healing. All three mammalian isoforms of TGF-β
are present in the airways and at least TGF-β1
and TGF-β2
have been shown to be increased in asthmatic airways and cells,
together with evidence of increased TGF-β
signalling. In addition, evidence from animal models suggests
that airway remodelling may be prevented or reversed using
agents which target TGF-β.Therefore
modulation of TGF-βs
or their activity represent a potential therapeutic target
for asthma. This review focuses on the current knowledge of
TGF-β1-3,
their their role in normal and asthmatic airways, as well
as the potential for modulating the TGF-βs
and their effects as a therapeutic approach to asthma.
[Back to top]
Extracellular Matrix, Integrins, and Mesenchymal Cell
Function in the Airways
D.J. Fernandes, J.V. Bonacci and A.G. Stewart
Subepithelial fibrosis is one of the characteristic features
of asthmatic airways. The fibrotic response includes an increase
in volume occupied by extracellular matrix (ECM) tissue, and
a change in the ECM composition favouring wound type collagens,
fibronectin and a number of glycoproteins and proteoglycans
normally associated with development. The altered ECM is likely
to be deposited by the mesenchymal cells (including (myo)
fibroblasts and smooth muscle) that are increased in number
in asthmatic airways. In turn, the altered asthmatic ECM is
likely to influence the function of the resident airway cells,
and may be directly responsible for increasing proliferation,
migration, ECM synthesis, inflammatory mediator release, and
survival of resident mesenchymal cells. Therefore, the deposited
ECM may perpetuate the disease phenotype. The different components
of the ECM bi-directionally communicate with cells through
a family of transmembrane recepto rs called integrins. Current
research has begun to characterize: 1) the particular ECM
components altered in airways disease; 2) the breadth of activity
of different ECM components on airway cell function; and 3)
the par-ticular integrins responsible for mediating these
effects. Further understanding of the role of integrins in
transmitting re-sponses of ECM in healthy or diseased airways
may lead to novel targets for anti-asthma therapy.
[Back to top]
Role of Chemokines in Severe Asthma
L.A. Murray, F. Syed, L. Li, D.E. Griswold and A.M. Das
The severe asthma phenotype is exhibited by a subset of
asthma patients whose asthma symptom is poorly controlled
by current therapies. Severe asthma represents a high unmet
medical need and warrants research into the mechanisms driving
the underlying pathophysiology. It is hypothesized that the
underlying pathology associated with severe asthma is driving
the symptoms experienced by these patients, which may share
common features with mild to moderate asthma or may represent
a unique pathological phenotype. For the purpose of this review,
the pathophysiology associated with asthma in general are
described and extended to incorporate severe asthma. Chemokines
may contribute towards multiple features of asthma pathophysiology
and this current review focuses on the biology of chemokines
pertaining to asthma pathophysiology. Chemokines are important
recruiters and activators of inflammatory cells and these
infiltrating cells interact with resident cells, such as fibroblasts
and it is through these pathways that chemokines appear to
exert multiple biological actions. Clinical trials are underway
with therapeutics targeting chemokine pathways for other inflammatory
diseases. It is hoped that the information generated from
these studies will contribute towards furthering our under-standing
of chemokine biology and be applied towards targeting severe
asthma.
[Back to top]
Transcription Factors in Asthma: Are Transcription
Factors a New Target for Asthma Therapy?
M. Roth and J.L. Black
The essential features of persistent severe asthma include
structural changes in the airway wall (remodelling). It is
not known whether these are the sequelae of chronic inflammation
or indeed its initiators. Several transcription factors have
been implicated in the inflammatory process in asthma, including
the glucocorticoid receptor (GR), NFκB,
Activator Protein-1 (AP-1), Nuclear Factor of Activated T-cells
(NF-AT), cyclic AMP Response Element Binding Protein and more
recently, the CCAAT/Enhancer Binding Protein (C/EBP), Peroxisome
Proliferator-activated Receptor (PPAR) and the bZIP transcription
factor, Nrf2. Could a pathological de-regulation of one of
these transcription factors explain the broad spectrum of
asthma pathology and can their modulation lead to better symptom
control?
Although some of the transcription factors seem to be valid
targets (NFκB,
Nrf2 or STAT6) or tools (PPARγ,
-α
and C/EBP-α)
for new therapeutic approaches, since many transcription factors
play a central role in tissue and organ homeostasis, a longterm
general suppression or overexpression, would cause severe
side effects in other organs.
Cell type specific application of decoy or antisense oligonucleotides
for NFκB,
Nrf2 or STAT6, or specific agonists for PPARγ
and -α
may help to control the inflammatory response in lung epithelial
cells and infiltrated immune cells, but additional, unwanted,
effects on other resident cells of the lung cannot be excluded
and a beneficial effect over known anti-asthma drugs has first
to be proven. In order to progress with such novel therapeutic
strategies, the only option seems to be to link transcription
factor inhibitors/activators to a cell type specific delivery
system.
[Back to top]
Carbohydrates and Epithelial Repair – More Than
Just Post Translational Modification
S. Allahverdian, B.J. Patchell and D.R. Dorscheid
Epithelia are the layers of cells that form barriers between
external milieu and underlying tissues and thus, are important
components of most organs of the body. Epithelial layers of
organs, such as the lung, are exposed to various challenges
resulting in frequent injury. Epithelial wound healing represents
an important process by which repair restores the physical
barrier lost as a result of cell damage and apoptosis. The
repair of epithelial layers consists of a series of ordered
events including epithelial cell spreading, migration proliferation
and, differentiation. Carbohydrates attached to cell surface
proteins and lipids can modulate the function of structures
that they are conjugated to and therefore, can affect cell
behavior. Although the basic mechanisms of epithelial repair
are not entirely understood, many studies suggest glyco-conjugates
attached to proteins on the cell surface of epithelial cells
play important roles in many of these cellular processes.
In the present review, the role of carbohydrates in epithelial
repair of different organs, including the sources of epithelial
injury and current models of epithelial repair will be discussed
with a focus on our understanding of the airway epithelium.
With a better understanding of carbohydrates and their role
in epithelial repair, new therapeutic targets for diseases
involving damage to the epithelium can be identified.
[Back to top]
Zinc and its Specific Transporters as Potential Targets
in Airway Disease
C. Murgia, C. J. Lang, A.Q. Truong-Tran, D. Grosser,
L. Jayaram, R.E. Ruffin, G. Perozzi and P.D. Zalewski
The dietary group IIb metal zinc (Zn) plays essential housekeeping
roles in cellular metabolism and gene expression. It regulates
a number of cellular processes including mitosis, apoptosis,
secretion and signal transduction as well as critical events
in physiological processes as diverse as insulin release,
T cell cytokine production, wound healing, vision and neurotransmission.
Critical to these processes are the mechanisms that regulate
Zn homeostasis in cells and tissues. The proteins that control
Zn uptake and compartmentalization are rapidly being identified
and characterized. Recently, the first images of sub-cellular
pools of Zn in airway epithelium have been obtained. This
review discusses what we currently know about Zn in the airways,
both in the normal and inflamed states, and then considers
how we might target Zn metabolism by developing strategies
to monitor and manipulate airway Zn levels in airway disease.
[Back to top]
Protease-Activated Receptors (PARs) are Partly Pro-Inflammatory
and Partly Anti-Inflammatory: Will PAR Agonists or Antagonists
Participate in Future Drug Therapies?
B.A. DeCampo and P.J. Henry
Protease-activated receptors (PARs) are characterised by
a unique mechanism of activation, which enables them to act
as cellular sensors for protease activity. PARs are expressed
throughout the cardiovascular, gastrointestinal and pulmonary
systems, where they are potential drug targets for the treatment
of disease. However, there are currently very few selective
PAR antagonists or potent PAR agonists available as effective
research tools, and moreover, there is considerable evidence
to suggest that PARs can promote both pro-inflammatory and
anti-inflammatory responses in a wide range of disease models.
These confounding issues have, to date, prevented us from
developing a clear understanding of the role of PARs in disease.
Nevertheless, this review provides an overview of the distribution
and function of PARs in the cardiovascular, gastrointestinal
and pulmonary systems, and attempts to evaluate whether PAR
agonists or antagonists have a place in future drug therapy.
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