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.

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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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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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