airway epithelial cells – therapeutic targets for the treatment of copd
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THERAPEUTICSTRATEGIES
DRUG DISCOVERY
TODAY
Drug Discovery Today: Therapeutic Strategies Vol. 5, No. 2 2008
Editors-in-Chief
Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK
Eliot Ohlstein – GlaxoSmithKline, USA
Respiratory diseases
Airway epithelial cells – therapeutictargets for the treatment of COPDLaszlo Farkas1,3,*, Michael Pfeifer1,2, Christian Schulz1
1Klinik und Poliklinik fur Innere Medizin II, Universitat Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany2Klinik Donaustauf, Centre of Respirology, Ludwigstrasse 68, 93093 Donaustauf, Germany3Department of Medicine, McMaster University and Firestone Institute for Respiratory Health, St. Joseph’s Healthcare, 50 Charlton Avenue East, Hamilton,
Ontario L8N 4A6, Canada
The airway epithelium plays a central orchestrating
role in the complex pathophysiology underlying
chronic obstructive pulmonary disease (COPD).
Extensive research has provided us with increased
knowledge of a variety of new, more selective targets
for novel therapeutic agents in COPD. They range
from cytokines, chemokines and their receptors to
receptors of innate immunity, intracellular mediators
and growth factors. The current review discusses ther-
apeutic strategies that affect airway epithelial cells.
*Corresponding author: L. Farkas (laszlo.farkas@klinik.uni-regensburg.de)
1740-6773/$ � 2008 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddstr.2008.05.003
Section Editor:Martin Braddock – AstraZeneca R&D, Charnwood,Loughborough, UK
such as bronchodilators, corticosteroids and antibiotics, var-
Introduction
Chronic obstructive pulmonary disease (COPD) has been
defined by the Global initiative for Chronic Obstructive Lung
Disease (GOLD) as a progressive, not fully reversible limita-
tion of expiratory airflow associated with dysregulated
inflammation [1]. The pathological features include inflam-
mation of small airways and parenchymal destruction or
emphysema. Tobacco smoking has been implicated in the
aetiology as well as the development of the small airways
disease [2,3].
Airway epithelial cells (AEC) are the first to come into
contact with different kinds of inhaled substances and pos-
sible pathogens. They also take part in immunity, local
wound repair and airway remodelling [3]. Important evi-
dence indicates that AEC do not only participate in, but also
orchestrate immunological responses and pathological pro-
cesses in COPD [3,4]. Therefore, AEC represent an important
target for the treatment of COPD. The current article provides
an overview over new therapeutic approaches focusing on
these cells (Table 1).
Cytokines, chemokines and their receptors (key
strategies 1–5)
Beside the widespread use of classical COPD therapeutics
ious pro-inflammatory cytokines and chemokines that affect
or are produced by AEC and their receptors have emerged as
new targets. Cytokines are extracellular mediators that are
produced by different cell types and are involved in interac-
tions between different cell types. One important class of
cytokines are chemokines, which are characterized by their
abilities to chemoattract leukocytes [5]. Fig. 1 provides a
synopsis of important targets in this field.
Key strategy 1: targeting TNF-a
Tumor necrosis factor-a (TNF-a) is a pleiotropic cytokine of
the TNF superfamily with an important role in the innate
immune response. In COPD, TNF-a is produced by alveolar
macrophages, neutrophils, T cells, mast cells and epithelial
cells following contact with different pollutants including
cigarette smoke [5]. TNF-a induces a more pronounced
chemokine expression in AEC from COPD patients than
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Drug Discovery Today: Therapeutic Strategies | Respiratory diseases Vol. 5, No. 2 2008
Table 1. Overview of key strategies targeting AECa in COPDb
Pros Cons Latest developments
(including drug therapies
in progress and failures)
Who is working on
this strategy?
(including web address)
Refs
TNF-ac Inhibits induction of
pro-inflammatory
chemokines in AEC
Attenuates systemic
immune responses
Anti-TNF-a antibody infliximab
(Centocor): 2 clinical studies
failed to show significant benefit
Centocor (www.centocor.com) [7,8]
Soluble TNF-receptor etanercept
(Wyeth): decreased hospitalization
Wyeth (www.wyeth.com) [9]
CXCL-8d Inhibits complete
receptor effects of
CXCL-8
Blocks only CXCL-8
effects
Anti-CXCL-8 antibody
ABXIL8 (Abgenix, now part
of Amgen): No functional
improvement in a clinical study
Abgenix (www.abgenix.com/) [16]
CXCR-2e Blocks effects of
various CXC
chemokines
Targets only one of
two CXCL-8 receptors
CXCR-2 antagonists in clinical trials:
AZD8309 (AstraZeneca), phase I AstraZeneca
(www.astrazeneca.com)SCH527123 (Schering Plough), phase II
Schering Plough
(www.schering-plough.com)
IL-1bf Inhibits induction of
various pro-inflammatory
chemokines in cells
of the immune system
Decreases activation
of cells of the
immune system by
AEC-released mediators
Monoclonal antibody to IL-1b:
ACZ885 (Novartis), phase I
Novartis (www.novartis.com)
MCP-1g Selectively targets
MCP-1 effects on
CCR-2
No inhibition of other
CCR-2 ligands
Anti-MCP-1 antibody
ABN912 (Novartis), phase I
Novartis (www.novartis.com)
CXCR-3e/
CXCL-10d
High selectivity of
CXCL-10/CXCR-3
interaction
Limited anti-
inflammatory effect,
Anti-CXCL-10 antibody
MDX-1100 (Medarex), in
phase I clinical trial for
ulcerative colitis
Medarex (www.medarex.com)
CXCR-3 is a difficult
target (splice variants)
Anti-CXCR-3 antibody T487
(Amgen), evaluated for psoriasis
Amgen (www.amgen.com)
IKKh Selective reduction of
NF-kBi inducible genes
No cell type specific
effects
Small molecule inhibitor of IKK2: Institute of Molecular Design
(www.immd.co.jp/en/index.html)IMD1041 (Institute of Molecular
Design), phase I for
rheumatoid arthritisMillenium (www.mlnm.com)
and Sanofi-Aventis
(www.sanofi-aventis.com)MLN0415 (Millenium and
Sanofi-Aventis), phase I for
inflammatory disorders
(including COPD)
p38-MAPKj Inhibits cytokine release
and neutrophilia
Potential side effects Inhibitors of p38-MAPK: GlaxoSmithKline
(www.gsk.com/)GSK681323 (phase II) and
GSK856553 (phase I)
(both GlaxoSmithKline)
PDE-4k Intensely investigated
substances, effective
inhibition of cytokine
production
Dose-dependent adverse
effects, contradictory
results with different
compounds
PDE-4 inhibitors: Altana (www.altanapharma.com) [28,30,31]
Roflumilast (Altana), phase III GlaxoSmithKline (www.gsk.com/)
Cilomilast (GlaxoSmithKline), phase III Ono Pharmaceuticals (www.ono.co.jp)
Ono-6126 (Ono Pharmaceuticals), phase II Otsuka (www.otsuka.com)
Tetomilast (Otsuka), phase II Pfizer (www.pfizer.com)
Tofimilast (Pfizer), phase II Glenmark Pharmaceuticals
(www.glenmarkpharma.com)Oglemilast (Glenmark Pharmaceuticals),
phase I completed GlaxoSmithKline (www.gsk.com)
GSK256066, (GlaxoSmithKline),
inhalation, phase I
a Airway epithelial cells.b Chronic obstructive pulmonary disease.c Tumor necrosis factor-a.d CXC chemokine ligand.e CXC chemokine receptor.f Interleukin-1b.g Macrophage chemotactic protein-1.h IkB kinase.i Nuclear factor-kB.j p38-Mitogen-activated protein kinase.k Phosphodiesterase-4.
112 www.drugdiscoverytoday.com
Vol. 5, No. 2 2008 Drug Discovery Today: Therapeutic Strategies | Respiratory diseases
Figure 1. Important therapeutic targets of inflammation in COPD. The airway epithelium produces important cytokines and chemokines that are known
to act on macrophages, neutrophils and lymphocytes in COPD. But the airway epithelium is also a target of mediators produced by different leukocyte
populations. All substances and receptors in this synopsis are understood to be or are possible to become important therapeutic targets in COPD. CCR-2,
CC chemokine receptor-2; CXCL, CXC chemokine ligand; CXCR, CXC chemokine receptor; IL-1b, interleukin-1b; MCP-1, monocyte chemoattractant
protein-1; TNF-a, tumor necrosis factor-a; TNF-R, tumor necrosis factor receptor.
from healthy smokers via TNF receptors and thereby mod-
ulates neutrophil chemotaxis [6]. Results of clinical trials are
contradictory in their results regarding the benefit of sys-
temic anti-TNF-a therapy for COPD patients: Whereas the
anti-TNF-a antibody infliximab did not improve clinical
parameters in two randomized studies [7,8], TNF antagoni-
zation with the soluble TNF-receptor etanercept was more
successful to prevent hospitalization in an observational
study, although the trial was originally designed to inves-
tigate the use of etanercept in rheumatoid arthritis and not
COPD [9]. Statistics regarding adverse effects of TNF-a inhi-
bition have also been acquired mostly from clinical trials of
rheumatoid arthritis patients: These drugs have been shown
to be rather safe and well tolerated in general. However,
some adverse effects have been reported including exacer-
bation of opportunistic infections, reactivation of latent
tuberculosis or worsening of pre-existing cardiovascular
conditions [10]. Future randomized studies, comparing dif-
ferent interventions in the TNF-a pathway, are needed to
prove whether this therapy will be beneficial for COPD
patients or not.
Key strategy 2: targeting CXCL-8/CXCR-2
CXC chemokine ligand (CXCL)-8 belongs to a family of
chemokines with high chemotactic activity for neutrophils
and binds to the chemokine receptors CXC chemokine recep-
tor (CXCR)-1 and CXCR-2. The number of neutrophils in
sputum correlates with clinical parameters of disease severity
[11]. Different neutrophil chemoattractants have been
demonstrated to be increased in COPD [3]: The increased
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Drug Discovery Today: Therapeutic Strategies | Respiratory diseases Vol. 5, No. 2 2008
levels of CXCL-8 in sputum, which correlates with augmen-
ted neutrophil counts, have also been associated with
impaired lung function in COPD patients [12]. Although
CXCR-1 and CXCR-2 have been demonstrated to be upregu-
lated in the bronchial wall of COPD patients during severe
exacerbation, CXCR-1 and CXCR-2 expression was not
increased in AEC following various stimuli with pathophy-
siological relevance in COPD [13,14]. In addition, the pro-
duction of CXCL-8 is localized to AEC and leukocytes [13].
Therefore, therapeutic approaches targeting CXCL-8–CXCR-
1/-2 interactions are of potential advantage for COPD
patients, as has been demonstrated with a CXCR-2 inhibitor
reducing CXCL-8-mediated neutrophil chemotaxis [15].
Direct antagonization of CXCL-8 production with another
monoclonal antibody (ABXIL8) resulted in improvement of
dyspnoea but not functional parameters after three months
of treatment [16]. However, the antibody was well tolerated.
Evidence favours CXCR-2 inhibition instead of blocking
CXCL-8; therefore, the future drug developments are cur-
rently concentrating on CXCR-2 [17]. One reason for the
relative failure of blocking CXCL-8 could be the more limited
spectrum without inhibition of other CXC chemokines as
compared with blocking CXCR-2.
Key strategy 3: targeting IL-1b
Interleukin-1 (IL-1) is an important pro-inflammatory cyto-
kine that participates in a complex network of mediators in
acute and chronic inflammation. The elevated level of one of
its forms, IL-1b, in sputum of COPD patients correlates with
increased neutrophil numbers and augmented measure-
ments of CXCL-8 and TNF-a [18]. AEC are recognized as
an important source of IL-1b [5]. A monoclonal anti-IL-1b
antibody reduced pulmonary inflammation in a mouse
model following cigarette smoke exposure [19]. In addition,
IL-1 receptor knockout mice are partially protected against
cigarette-smoke-induced emphysema [17]. A monoclonal
antibody to IL-1b is currently investigated for therapy of
COPD. Although this strategy might improve pulmonary
inflammation by decreasing the activation of inflammatory
cells by AEC, this could also result in increased susceptibility
to infections, thereby having significant disadvantages on
exacerbation frequency in COPD patients.
Key strategy 4: targeting MCP-1/CCR-2
Monocyte chemoattractant protein-1 (MCP-1) belongs to the
family of CC chemokines and is involved in the recruitment
of monocytes, lymphocytes and basophiles [5]. Elevated
expression of MCP-1 in the airway epithelium (AE) of COPD
patients correlates with the expression of its receptor CC
chemokine receptor (CCR)-2 on macrophages and mast cells
[20]. Furthermore, augmented MCP-1 concentrations are
found in sputum samples of COPD patients and MCP-1 levels
correlate with increased neutrophil counts and declining
114 www.drugdiscoverytoday.com
lung function [21]. Therefore, it is not surprising that an
anti-MCP-1 antibody is investigated as a selective therapeutic
agent to suppress monocyte and lymphocyte accumulation
[17]. Although the selective inhibition of the recruitment of
leukocyte subpopulations by blocking MCP-1 could limit
possible adverse effects such as opportunistic infections
and exacerbations, it could also attenuate the therapeutic
effect, because different chemokines can bind to and activate
CCR-2 in addition to MCP-1, such as MCP-2, -3 and -4 [5].
Key strategy 5: targeting CXCL-10/CXCR-3
Two subsets of T lymphocytes are involved in airway patho-
physiology in COPD: First, TH1 CD4+ T cells that express the
chemokine receptor CXCR-3 and migrate to the lung follow-
ing a chemotactic gradient of CXCR-3 ligands, such as CXCL-
9, CXCL-10 and CXCL-12. These mediators are elevated in
COPD and are produced by AEC [4]. Second, CD8+ T cells that
represent the most common lymphocyte population in
COPD and also express CXCR-3 [4]. Although the exact role
of CD4+ and CD8+ T cells in COPD pathophysiology is not
fully understood, selective inhibition of CXCR-3 or CXCL-10
seems to be an interesting approach: A CXCR-3/CCR-5
antagonist has been shown to abolish TH1 migration effi-
ciently [22]. A therapeutic antibody against CXCL-10 is cur-
rently investigated in the inflammatory intestinal disease
ulcerative colitis and this strategy could possibly also be
evaluated for COPD therapy as recently suggested by P.
Barnes [4]. The advantage of this therapy would be a higher
selectivity with subsequent effects mainly on TH1 CD4+ and
CD8+ T cells, and epithelial cells. One prominent disadvan-
tage could be the difficulty to generate substances effecting
CXCR-3, because this receptor is expressed in different splice
variants [23].
Targeting intracellular mediators (key strategies 6–8)
Intracellular pathways and transcription factors that regulate
the expression of pro-inflammatory cytokines in epithelial
cells represent additional interesting molecular targets:
Key strategy 6: targeting IKK
The transcription factor nuclear factor-kB (NF-kB) is an
important regulator of a variety of pro-inflammatory genes,
including cytokines, chemokines, inflammatory enzymes
and adhesion molecules. NF-kB is increased in COPD [24].
I-kB kinase (IKK) is responsible for the release of NF-kB from I-
kB. Small-molecule inhibitors of IKK have been shown to
reduce the expression of different pro-inflammatory cyto-
kines such as CXCL-8 from human airway and alveolar
epithelial cells. In addition, IKK inhibition also decreases
the surface expression of intercellular adhesion molecule-1,
which is important for leukocyte recruitment to the airways,
on the surface of these cells [25]. IKK inhibitors are enrolled in
phase I trials [17]. A possible advantage of reduced NF-k
Vol. 5, No. 2 2008 Drug Discovery Today: Therapeutic Strategies | Respiratory diseases
activity is the extensive reduction of multiple pro-inflamma-
tory mediators. On the other side, the broad effects on
different cell types could lead to serious side effects due to
diminished immune responses.
Key strategy 7: targeting p38 MAPK
Four isoforms of p38-mitogen-activated protein kinase (p38
MAPK) are known. They phosphorylate transcription factors
and can thereby regulate gene transcription. Among other
effects, inhibition of p38 MAPK decreases cytokine produc-
tion of AEC following cigarette smoke exposure and inhibits
lipopolysaccharide (LPS)-induced pulmonary neutrophilia
[26,27]. p38 MAPK inhibitors are currently tested for their
therapeutic efficacy and safety in COPD patients [17]. Advan-
tages and disadvantages of these substances need to be care-
fully considered following these trials, similar to IKK
inhibitors.
Key strategy 8: targeting PDE-4
PDE-4 acts through hydrolysis of the intracellular second
messenger 30-50-cyclic adenosine monophosphate (cAMP)
to the inactive form 50-monophosphate [28]. PDE-4 has not
only been shown to be expressed in different cells of the
immune system, but recently also been identified in AEC [29].
Inhibitors of phosphodiesterase-4 (PDE-4) are understood to
have powerful anti-inflammatory activity. Therefore, block-
ing PDE-4 seems to be a valuable tool to decrease cytokine
expression in the AE during inflammation [30]. It is not
surprising that different PDE-4 inhibitors are currently devel-
oped and clinically evaluated, and the overall results are
rather promising so far, although adverse effects are still a
matter of concern [17]. For example, administration of the
PDE-4 inhibitor roflumilast significantly improved lung func-
tion results and exacerbation rate [31]. More selective inhibi-
tion of PDE-4 isozymes could solve this problem, because
some side effects are related to inhibition of the PDE-4D
isozyme, whereas anti-inflammatory action is attributed to
the inhibition of the PDE-4B isozyme [17].
Future perspectives
Beside the currently already investigated therapeutic targets,
several research areas are currently producing exciting new
aspects that could result in interesting approaches in the near
future. Some of them are mentioned here to provide a future
perspective beyond the ones that are already involved in
pharmaceutical trials:
Innate immunity
Ongoing research in basic immunology discovered a variety
of receptors of the innate immunity specialized in recogniz-
ing microbial products such as LPS. One group, the Toll-like
receptors (TLR) have been an eminent subject of investigation
during the past ten years [32]. Among them, TLR-4 is impor-
tant in the cellular response to LPS. AEC express TLR-4 and
LPS can induce high levels of chemokines in these cells [33].
Various other pattern recognition receptors are understood to
be involved in the detection of potential pathogens by AECs
[32]. Future studies will reveal potential interventional stra-
tegies in the complex system of innate immunity, also with a
focus on the epithelium.
AEC also produce various substances that are understood as
‘endogenous antibiotics’ owing to their broad antimicrobial
activity [32]: for example b-defensins, lysozyme, lactoferrin
and secretory leukocyte proteinase inhibitor. It is of interest
that polymorphisms in the human b-defensin-1 (hBD-1) gene
have been associated with COPD [34]. Although the exact
functional impact of these mutations is not clear yet, it was
hypothesized that they can lead to destabilized hBD-1,
thereby impairing local immunity [34]. In this case, topical
replacement of hBD-1 could represent a valuable tool to
improve local pathogen clearance in the airways and to
decrease the exacerbation rate.
Adaptive immunity
Granulocyte-macrophage stimulating factor (GM-CSF) is a
cytokine that primes neutrophils and macrophages and
induces the production of other pro-inflammatory cytokines
[35]. The AE produces GM-CSF following TNF-a- IL-1b-chal-
lenge, both cytokines with importance in COPD [5]. Treat-
ment with a neutralizing anti-GM-CSF antibody is able to
inhibit the accumulation of neutrophils and to reduce TNF-a
levels in bronchoalveolar lavage fluid in an animal model of
lipopolysaccharide (LPS)-induced inflammation [36].
Even more selective target might be IL-17. It has also been
implicated in immune responses in COPD as a product of the
newly described TH17 cells, a subset of CD4+ T cells. IL-17 is
thought to result in CXCL-1 and CXCL-8 production in AEC
and thereby to increase neutrophil accumulation in the air-
ways [4].
Future work is needed to define, whether GM-CSF or IL-17
might represent valuable targets for COPD therapy or not.
Repair processes
The pathophysiology of COPD leads to different pathological
changes in the structure of the airways and the lung par-
enchyma [3]. AEC also produce transforming growth factor-b
(TGF-b), a central growth factor involved in wound repair,
composition of the provisional matrix and activation of
fibroblasts and myofibroblasts. Some data provide insights
into the possible role of TGF-b in the development of airway
remodelling in the earlier phases of the disease [37]. Although
TGF-b is important for tissue homeostasis, approaches inhi-
biting the TGF-b pathway could prove beneficial in attenuat-
ing airway remodelling.
In addition, retinoic acid is involved not only in lung
development but also in repair mechanisms of epithelial cells
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Drug Discovery Today: Therapeutic Strategies | Respiratory diseases Vol. 5, No. 2 2008
in the mature lung [38]. It can reverse alterations of the AE
following cigarette smoke exposure such as squamous meta-
plasia and its serum level is decreased during acute exacer-
bations in COPD [38,39]. Therefore, substitution of retinoic
acid might have beneficial effects in these patients.
Conclusions
The pathophysiology of COPD is complex and AEC are right
in the middle of the sophisticated interplay between the
various cell types involved in the processes. The AE has an
important role in orchestrating inflammation. In addition,
structural alterations of the AE contribute to mucus hyper-
secretion and irreversible airflow obstruction. As presented,
the future years will see a variety of different, more specific
and selective substances targeting immune or repair pro-
cesses that will be available for COPD therapy in addition
to the bronchodilators, corticosteroids and anti-infective
agents currently used. Although it is clear that AEC are an
important target for future therapeutic interventions, it will
be difficult to measure the therapeutic effect selectively in
these cells. Additional assessment tools beyond the classical
clinical parameters will have to be used. In addition, anti-
inflammatory therapy, which is currently seen as the most
promising strategy, has a relevant potential for adverse
effects.
Two issues will have to be solved to find the optimal
therapeutic strategy: First, it will be important to find the
optimal combination and concentration of these selective
agents, as co-administration of two or more of them will
probably be necessary to achieve satisfying results, but could
also cause adverse effects that cannot be predicted right now.
Second, the route of administration will have to be chosen
carefully: Systemic application might also cause significant
disadvantages given the fact that many of the targets con-
tribute to tissue homeostasis and immunity. Therefore, inha-
lative application, as already done for bronchodilators, will be
a more topical approach to limit systemic effects. Other
vehicles including different kinds of viral vectors need to
be taken into consideration because they can target the air-
way epithelium directly when administered intratracheally
in animal models [40]. On the other side, these vectors could
also worsen the clinical condition of COPD patients; there-
fore, careful studies in animal models need to precede clinical
trials.
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