Review

New drugs for exacerbations of chronic obstructive

pulmonary disease
Trevor T Hansel, Peter J Barnes

Lancet 2009; 374: 744–55
National Heart and Lung
Institute, Imperial College,
London, UK
(T T Hansel FRCPath,
Prof P J Barnes FRS)
Correspondence to:
Dr Trevor T Hansel, Imperial
Clinical Respiratory Research
Unit, St Mary’s Hospital, Mint
Wing, Praed Street, Paddington,
London W2 INY, UK
t.hansel@imperial.ac.uk
Tobacco smoking is the dominant risk factor for chronic obstructive pulmonary disease (COPD), but viral and bacterial
infections are the major causes of exacerbations in later stages of disease. Reactive oxygen species (ROS), pathogen-
associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs) activate families of
pattern recognition receptors (PRRs) that include the toll-like receptors (TLRs). This understanding has led to the
hypothesis that COPD is an archetypal disease of innate immunity. COPD is characterised by abnormal response to
injury, with altered barrier function of the respiratory tract, an acute phase reaction, and excessive activation of
macrophages, neutrophils, and fibroblasts in the lung. The activated non-specific immune system then mediates the
processes of inflammation and repair, fibrosis, and proteolysis. COPD is also associated with corticosteroid resistance,
abnormal macrophage and T-cell populations in the airway, autoinflammation and autoimmunity, aberrant fibrosis,
accelerated ageing, systemic and concomitant disease, and defective regeneration. Such concepts have been used to
generate a range of molecular targets, and clinical trials are taking place to identify effective drugs for the prevention
and treatment of COPD exacerbations.

Introduction
Disease exacerbations have a profound effect on patients
with chronic obstructive pulmonary disease (COPD)
worldwide,1 resulting in poor health and high mortality.2
Although the precise definition of an exacerbation of
COPD remains controversial, according to guidelines
of the Global initiative for chronic Obstructive Lung
Disease (GOLD) it is “…an event in the natural course
of the disease characterized by a change in the patient’s
baseline dyspnea, cough, and/or sputum that is beyond
normal day-to-day variations, is acute in onset, and may
warrant a change in regular medication in a patient
with underlying COPD”.3
In a study of the natural history of COPD, Fletcher
and Peto4 showed that male smokers with the disease
have an increased loss of forced expiratory volume in
1 s (FEV1) every year.5 The Lung Health Study in the
USA and Canada subsequently noted that lower-
respiratory-tract illnesses promote FEV1 reduction in
current smokers,6 and evidence is growing that
exacerbations accelerate progressive decline in lung
function in patients with COPD (figure 1),2,5,7 but the
relation between exacerbations and natural history has
not been established conclusively.8
Extra-pulmonary factors could have a role in
exacerbations. For example, the BODE index—body-
mass index (B), obstruction (O), dyspnoea (D), and
exercise endurance from 6-min walk distance (E)—is a
better predictor of risk of death for patients with COPD
than is FEV1 alone.9 Inflammation might be responsible
for systemic manifestations and comorbidities of COPD
such as muscle dysfunction, cachexia, cardiovascular
disease, normocytic anaemia, osteoporosis, depression,
diabetes, and other endocrine disorders.10
COPD has complex genetic aspects yet contributing
environmental factors—tobacco smoke and other
inhaled irritants—are known.11 However, severe
α₁-antitrypsin deficiency is the only proven genetic risk
factor for COPD.12 Most candidate genes have not yet
been validated, but polymorphic variations in surfactant
protein B and mannose-binding lectin have been
associated with exacerbations of COPD.13,14
Hogg and colleagues15 assessed the immunopathology
of small airways in surgically resected lung tissue from
patients with different severities of COPD. They noted
that the progression into severe stages of COPD was
associated with increased thickness and inflammation
of the bronchiolar wall, resulting in obstruction of the
lumen, and raised numbers of neutrophils, macrophages,
and lymphocytes. In COPD of GOLD stages III (severe)
and IV (very severe), lymphoid follicles are prominent
in areas of respiratory bronchiolitis (figure 2). Hogg’s
group postulated that the pathology of early COPD
indicates activation of innate immunity, whereas
Search strategy and selection criteria
We searched PubMed for reports published in English using
the search term “COPD” in combination with
“exacerbations”, “new drugs”, “cigarette smoke”,
“immunity-innate”, “oxidants”, “virus”, “rhinovirus”,
“respiratory syncytial virus”, “influenza”, “bacteria”,
“inflammation”, “epithelial barrier”, “acute phase reactant”,
“biomarker”, “mucus”, “fibrosis”, “proteolysis”,
“corticosteroid”, “bronchodilator”, “TLR”, “scavenger
receptor”, “danger”, “RAGE”, “MyD88”, ”interleukin”,
“cytokine”, “GM-CSF”, “TNF”, “chemokine”, “adhesion
molecule”, ”PDE4”, “NFκB”, “signalling”, “statin”, “aging”,
“apoptosis”, “death”, “resolution”, “repair”, “resolving”
“regeneration”, “stem cell”, “blood”, “sputum”, “breath”,
“epithelial”, “fibroblast”, “T-cell”, “Treg”, “Th17”, “smooth
muscle”, “anti-oxidants”, “antibiotic”, “anti-viral”, and
“cell-signalling”. We selected reports published in the past
3 years, but we also included older papers that we deemed
relevant. The date of the last search was June, 2009.

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presence of lymphoid follicles in severe COPD might be
due to viral and bacterial infections of the lower airways,
associated with an adaptive immune response.15
Lymphoid follicles contain B cells and T cells that
overexpress the chemokine receptor CXCR3 (cysteine-
X-cysteine receptor 3), suggesting that this receptor
could be important for localisation of these cells.16
Additionally, oligoclonal B cells have been detected in
follicles without bacterial or viral nucleic acids, which
could relate to an antigen-specific process that is not
caused by microbes.17
Causes of COPD and exacerbations
The major cause of COPD in developed countries is
many years of heavy tobacco smoking during the asymp-
tomatic, initial phase of COPD. Tobacco smoke contains
reactive oxygen species (ROS)18 and many different
chemical components, both of which cause toxic effects
in the lung.19 ROS originate from oxygen (superoxide
anion) and nitrogen (nitric oxide and peroxynitrite), and
reactive aldehydes produce carbonyl adducts on proteins
and DNA (figure 3). Additionally, hydrogen sulphide is a
potent antioxidant and vasorelaxant.20 ROS cause damage
to host cells from lipid peroxidation, protein carbonylation,
and formation of DNA adducts. This damage can cause
both immunosuppression and proinflammatory effects
such as stimulation of phagocytosis.21 Additionally the
aryl hydrocarbon receptor is activated by environmental
pollutants22 such as particulate matter, which is a key
component of air pollution.23
Causes of exacerbations include infection, continued
oxidant damage, air pollution, systemic COPD,
comorbidities of COPD, pulmonary hypertension,
pulmonary embolus, and cor pulmonale, but many
patients have exacerbations where no specific cause can
be identified. Infective exacerbations occur in severe
disease, causing clinically unstable COPD. Increasingly
advanced diagnostic techniques for viruses (eg, PCR)
have shown that most COPD exacerbations are caused by
infection.24
Rhinovirus is a common cause of COPD exacerbation25
and directly infects the upper-respiratory and lower-
respiratory tract.26 Upregulation of the rhinovirus
receptor ICAM1 (intercellular adhesion molecule 1) on
epithelial cells occurs in COPD, and might predispose
patients to infection.27 A model of human rhinovirus-
induced COPD exacerbation has been developed to
improve understanding of the immunological and
inflammatory mechanisms of such exacerbations.28
Respiratory syncytial virus has been identified in adults
with COPD29 and can persist in stable COPD.30 Seasonal
influenza is an important cause of exacerbations, raising
concern that an influenza pandemic could cause high
mortality in patients with COPD.31
Bacterial colonisation is often reported in patients with
COPD,32,33 and is associated with the frequency of
exacerbations.34 Persistent colonisation can occur with
www.thelancet.com Vol 374 August 29, 2009
Review
Smoke from tobacco and biomass fuel contains ROS,
toxins, and particulate matter
Viral and bacterial infections
Signs and symptoms
100
Asymptomatic
Stage I
80
Stage II Progressive dyspnoea
FEV1 (% of predicted)
50
Stage III Systemic disease
Comorbidities
30
Stage IV Respiratory failure
Death
25 50 75
Age (years)
Figure 1: Physiology of exacerbations in a hypothetical regular smoker with chronic obstructive pulmonary
disease (COPD) by stage of severity
Natural history of COPD is characterised by an accelerated loss of forced expiratory volume in 1 s (FEV1) with
ageing; reactive oxygen species (ROS) cause lung damage throughout the natural history, whereas viral and
bacterial infections cause exacerbations that tend to occur in severe COPD. Stages of severity are defined by the
Global initiative for chronic Obstructive Lung Disease.3 Red arrows indicate onset of exacerbations.
Haemophilus influenzae, Streptococcus pneumoniae, and
Pseudomonas aeruginosa. Patients with severe COPD who
receive inappropriate antibiotic treatment are vulnerable
to multidrug-resistant infections.35
Innate immunity
Epithelial barrier and acute phase response
The innate immune system is the first line of defence in
the respiratory tract. Airways and alveolar interstitium,
including the respiratory epithelial mucociliary escalator
and alveolar surfactant, act as a barrier to infection or
damage. However, tobacco smoke increases the
permeability of respiratory epithelium, thus compromising
the barrier (figure 4). Respiratory viruses target respiratory
epithelial cells in preference to other cell types, and can
thereby initiate non-specific inflammation.
The acute phase response leads to production of
substantially raised concentrations of reactants such as
C-reactive protein, coagulation proteins (coagulation
factors, fibrinogen, and anticoagulants), complement
factors, mannose-binding lectin, and serum amyloid A,
which makes them useful biomarkers for exacerbations
(figure 4).36 C-reactive protein, mannose-binding lectin,
and serum amyloid A can bind to pathogens.
Inflammation, fibrosis, and proteolysis
The host responds to damage from ROS with cycles of
inflammation and repair; these cycles repeat after every
cigarette is smoked, but with increased concentration of
factors that participate in inflammation and repair after
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an exacerbation. Susceptible smokers eventually respond

Chronic bronchitis
by developing the features of COPD: increased mucus
production in large airways causing chronic bronchitis,
bronchiolar fibrosis and airway remodelling in small
airways causing obstructive bronchiolitis, and destruction
of third-order bronchioles (with attached alveoli) and
lung interstitium causing centrilobular emphysema that
predominantly affects the upper lobes (figure 2).
Exacerbations are indicative of an increase in the
same type of inflammation as in stable COPD, with
Increased mucus
corresponding increases in neutrophils, cytokines,
chemokines, and proteases in the airways.37 Trans-
epithelial migration of neutrophils38 and macrophage
Goblet cell hyperplasia activation39 are closely linked with dendritic and
epithelial cells.40 A range of T cells are implicated in
Inflammation with fibrosis
exacerbations: cytotoxic T cells of types 1 (Tc1)41 and 2
(Tc2),42 and T helper cells producing interleukin 17
(Th17).43 COPD has been postulated to be a disease with
Smooth muscle autoimmune components,44 such as circulating
Submucosal bronchial
gland hypertrophy
cell hypertrophy pulmonary epithelial IgG autoantibodies45 and anti-
elastin autoimmune factors.46 Inflammation in COPD
Obstructive bronchiolitis might also be regarded as autoinflammatory owing to
the production of interleukins 1 and 6.47
Although inflammation, fibrosis, and proteolysis are
closely related, these processes are able to occur
separately—for example, very little inflammation can be
present in idiopathic pulmonary fibrosis.48 Fibrosis in the
small airways causes obstructive bronchiolitis, but
Inflammation with
fibrosis excessive fibrosis can also contribute to emphysema. The
molecular basis of fibrosis is becoming understood and is
Collapsed lumen providing a range of targets for new drugs.49,50 By contrast,
Lymphoid follicle α₁-antitrypsin deficiency is a genetic disease that shows the
Increased mucus
(severe COPD only) importance of proteases in causing a subtype of COPD.51,52
Neutrophil elastase,53 and matrix metalloproteases 954
Goblet cell metaplasia and 1255 have been implicated in the pathogenesis of COPD
and are therefore targets for drug development.
Smooth muscle
cell hypertrophy Danger signals and pattern recognition
Loss of alveolar Penetration of the respiratory barrier is followed by
attachments activation of pattern recognition receptors (PRRs) by
danger signals such as ROS, pathogen-associated
Centrilobular emphysema molecular patterns (PAMPs), and damage-associated
molecular patterns (DAMPs; figure 5). Improved
Lung lobule section Bronchioles and alveoli
Destruction and understanding of molecular and cellular activation of
confluence of innate immunity56 has indicated that PRRs are able to drive
respiratory
bronchioles chronic lung inflammation,57 repair processes, fibrosis,
and proteolysis. A unified theory suggests that develop-
ment of mild-to-moderate COPD and exacerbations of
COPD is mediated by activation of the innate immune
system by interaction of PRRs with molecular patterns on
ROS, viruses, bacteria, and dead and damaged cells.58
PAMPs are present in nucleic acids of viruses infecting
Relative sparing Destruction and
confluence of the respiratory epithelium, and in a range of cell wall and
of peripheral
alveoli bronchioles cytoplasmic components of bacteria.59 Matzinger60
proposed the danger model in which the immune system
is important for recognition of entities that can do
Figure 2: Pathology of chronic obstructive pulmonary disease (COPD) damage, rather than for discrimination of self from

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 Review

Oxygen-based generation Nitrogen-based generation

L-arginine

NOS L-citrulline
O2–•
(superoxide radical)
present in smoke from •NO
tobacco and biomass (nitric oxide radical)
fuel, and generated by present in tobacco
cells smoke and generated by NOS

SOD O2–•
O2–•
Xanthine oxidase and H2O2 Fe2+ HO• NO2 RSNO NO2–(nitrite) ONOO–
other oxidases (hydrogen peroxide) (hydroxyl radical) (nitrogen (nitrosothiols) NO3–(nitrate) (peroxynitrite)
dioxide
Myeloperoxidase radical)
Eosinopil peroxidase
CI- OH Thiyl
HOCI NO2 radical
(hypochlorous acid)

Nitrotyrosine

Carbonylation

Michael
ROS Hydroperoxidation Reactive aliphatic aldehydes addition Aliphatic carbonyl adducts form on
Polyunsaturated
(addition of HO2 group) (addition of CHO group) proteins and DNA, resulting in altered
fatty acids
activity and degradation

Figure 3: Generation of reactive oxygen species (ROS) and downstream pathways

NOS=nitric oxide synthase. SOD=superoxide dismutase.

foreign material. Such DAMPs might include HMGB1 Clinical studies

(high mobility group box 1), S100 proteins, heat shock
proteins, and extracellular matrix hyaluronans.
Toll-like receptors (TLRs) were discovered in Drosophila
melanogaster, and 13 types with widespread cellular
distribution have been identified in man (figure 5). ROS
activate TLR261 and TLR4 using MyD88 (myeloid
differentiation primary response gene 88) signalling,62,63
and can also damage membrane lipids, cell proteins, and
DNA; these processes lead to activation of DAMPs.64,65
Bacterial components activate different cell surface
TLRs—for example, the cell wall of gram-negative bacteria
contains lipopolysaccharide that activates TLR4. By
contrast, viral nucleic acid motifs activate TLR3, TLR7,
and TLR9, all of which are located on the inner surface of
the endosomal membrane.
PRRs including TLRs,59 scavenger receptors,66 and
receptor for advanced glycation end-products (RAGE)
undergo extensive cross-talk (figure 5).67,68 Additionally,
TLRs within endosomes recognise viral nucleic acids, and
cytoplasmic PRRs—retinoic acid-inducible gene 1 (RIG1)-
like receptors (RLRs) and NOD-like receptors (NLRs)—
recognise viral RNA and bacterial PAMPs, respectively. In
COPD, PRRs are activated on epithelial cells, neutrophils,
macrophages, smooth muscle cells,69 fibroblasts, and
other airway cells. Tobacco smoke acutely activates
MyD88, which is an intracellular toll/interleukin-1
receptor adaptor protein.63
Challenge models
Models of smoking-induced COPD in animals have been
used to study protease–antiprotease imbalance,
inflammation and autoimmunity, remodelling and
mucus production, and emphysema.70 Animal models of
innate immunity and viral exacerbation of COPD are
needed to test novel therapies pre-clinically. Assessments
of new treatments need to establish whether the treatment
is acting on the intended target from phase 1/2 studies in
human beings, and the optimum dose and dose interval
from clinical pharmacology studies. Just as inhaled and
nasal allergen challenge have been used to assess anti-
inflammatory drugs for asthma, challenge models with
lipopolysaccharide71 and other TLR agonists should be
used to study the action of drugs for COPD in man.
Biomarkers
For clinical assessment of new treatments for COPD
exacerbations, validated biomarkers would be useful.72
Potential biomarkers have been measured in blood,
urine, sputum, and exhaled breath, and from
bronchoscopic and protein microarray techniques; non-
invasive methods will probably be most applicable.
Raised blood biomarkers in COPD include C-reactive
protein, coagulation proteins including coagulation
factors (eg, fibrinogen and anticoagulants), complement
factors, serum amyloid A, cardiac troponin, B-type

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ROS from tobacco smoke and pollution

Pathogen-associated molecular patterns (PAMPs) from viruses and bacteria
Damage-associated molecular patterns (DAMPs)

Epithelial barrier compromised: Acute phase response comprises release of:

• Abnormal mucociliary clearance • C-reactive protein, mannose-binding lectin
• Mucus and surfactant impaired • Complement factors
• Epithelial tight junctions damaged • Coagulation factors
• Serum amyloid A
• Anti-proteases

Pattern recognition receptors (PRRs)

Inflammation Fibrosis Proteolysis

• ROS activate epithelial cells and macrophages Fibroblasts and myofibroblasts are resident, Neutrophils and tissue macrophages are a
• Chemotactic factors, chemokines, cytokines, or are derived from blood-borne fibrocytes rich source of proteases:
and proteases released or epithelial–mesenchymal transition • Neutrophil elastase
• Neutrophil, macrophage, and T-cell Fibrogenic factors: • Matrix metalloproteases
populations (Th1, Th17, Tc1, Treg) increase • TGFβ • Serine proteases
• Endothelin 1, angiotensin II • Thrombin activates PAR1 and generates
• CTGF, PDGF, IGF1 active TGFβ
• TNFα, interleukins 1 and 13

Mucus hypersecretion: Fibrosis: Tissue destruction:

chronic bronchitis obstructive bronchiolitis centrilobular emphysema

Figure 4: Inflammation, fibrosis, and proteolysis in the respiratory tract

CTGF=connective tissue growth factor. IGF1=insulin-like growth factor 1. PAR1=protease-activated receptor 1. PDGF=platelet-derived growth factor. ROS=reactive
oxygen species. Tc1=cytotoxic T cell of type 1. TGFβ=transforming growth factor β. Th1=T helper lymphocyte of type 1. Th17=T helper cell producing interleukin 17.
TNFα=tumour necrosis factor α. Treg=regulatory T cell.

natriuretic peptide, and cytokines (eg, tumour necrosis
factor α [TNFα], and interleukins 6 and 1β). Plasma
leptin concentrations are increased during acute
exacerbations, possibly indicating that negative energy
balance and systemic oxidative stress is present.
Several inflammatory markers increase in sputum of
patients with COPD during acute exacerbations: leuko-
triene B4 (LTB4), interleukin 6, interleukin 8 (cysteine-X-
cysteine ligand 8 [CXCL8]), endothelin 1, CCL5
(cysteine-cysteine ligand 5), and CXCL5. Sputum proteo-
mics have been used for inflammatory lung disease and
could potentially be used for COPD exacerbations.
When exhaled nitric oxide is partitioned by the
multiple flow technique, peripheral nitric oxide
(including small airways and lung parenchyma) is
increased. This technique could be useful to detect
increased exhaled nitric oxide during exacerbations of
COPD. Use of exhaled breath condensate has several
methodological problems but is a non-invasive
measurement and is suited to serial measurements
during an exacerbation.
Studies of exacerbations
An acute exacerbation for which the patient needs hospital
admission is associated with high mortality, intensive
monitoring and treatment, and substantial health-care
costs. Clinical studies in hospital can measure a range of
acute endpoints including mortality, need for invasive
mechanical ventilation, features of respiratory failure,
vital functions, length of hospital stay, biomarkers, and
time to next exacerbation. Available treatments have little
effect on exacerbations, and therefore studies of the
effects of new drugs on exacerbations would be useful.
Such studies would need a rigorous definition of inclusion
criteria, which features to monitor, and criteria for rescue
therapy. To aid drug development, regulatory authorities
could expedite the assessment of treatments for
exacerbations.
New drugs for exacerbations
Improvements to existing drug classes
Present treatments for exacerbations are outside the
scope of this Review; we refer to guidelines from GOLD,3
and published reviews.73–75 Extensive efforts in drug
development have focused on inhibition of corticosteroid-
insensitive neutrophil inflammation76,77 and prevention of
exacerbations, rather than treatment of acute
exacerbations.78 Guidance for industry from the US Food
and Drug Administration about drug development for
COPD concentrates on stable COPD, not treatment of
acute exacerbations.79
Bronchodilators are the mainstay of management.
Development of bronchodilators has focused on
improving inhaled longacting β2 agonists and longacting
muscarinic antagonists.80 The active R,R-enantiomer of
formoterol—arformoterol—is available for COPD

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ROS PAMPs DAMPs

From tobacco smoke and Molecular patterns on Molecular patterns (alarmins) on
pollutants activate bacteria and viruses endogenous intracellular proteins
TLR2 and TLR4 • Damage to cells by ROS
• HMGB1 (nucleus to lysosome)
• S100 proteins (cytoplasm)
Danger signals • Heat shock proteins (exosomes)
Bacteria Viruses • Extracellular matrix hyaluronans
• Lipopolysaccharide: TLR4 • RNA (double-stranded): TLR3 • Uric acid
• Peptidoglycan: TLR2 • RNA (single-stranded): TLR7
• Lipoteichoic acid: TLR2, TLR6 • Cytosine-phosphoryl-guanine: TLR9
Soluble PRRs • Flagellin: TLR5
• C-reactive protein
• Mannose-binding lectin
• Surfactant proteins A and D
HMGB1
Scavenger receptors
• Scavenger receptor A
TLR2, TLR4, TLR1/2,
• MARCO RAGE
TLR6/2, TLR5, TLR11
• CD36
• Scavenger receptor B1
TLR
PRRs have extensive cross-talk:
• TLRs
• Scavenger receptors
• RAGE Inflammasome
• RLRs Caspase-1 activation causes release of
Endosome
• NLRs TLR3, TLR7, TLR9 interleukins 1β and 18, and can cause
death of host cell

RLRs NLRs
Cytoplasmic PRRs that recognise Cytoplasmic PRRs that recognise
viral RNA PAMPs and generate bacterial PAMPs and activate
type 1 interferons inflammasome

Antimicrobial or anti-inflammatory products

Cycles of inflammation,
Cell activation in macrophages, • Defensins (small antimicrobial peptides)
fibrosis, destruction,
neutrophils, epithelial cells, and fibroblasts • Resolvins or protectins
regeneration, and repair
• Eicosanoids that resolve inflammation

Figure 5: Activation of innate immunity by danger signals

DAMPs=damage-associated molecular patterns. HMGB1=high mobility group box 1. MARCO=macrophage receptor with collagenous structure. NLRs=NOD-like receptors. PAMPs=pathogen-associated
molecular patterns. PRRs=pattern recognition receptors. RAGE=receptor for advanced glycation end-products. RLRs=RIG1 (retinoic acid-inducible gene 1)-like receptors. ROS=reactive oxygen species.
TLR=toll-like receptor.

treatment in some countries, but has not been studied
for acute exacerbations.81 Longacting β2 agonists with a
duration of more than 24 h, such as indacaterol and
carmoterol, are in development for treatment of stable
COPD. Tiotropium is an effective bronchodilator for
stable COPD and reduces exacerbations, but is not suited
as a reliever for acute exacerbations because of its slow
onset of action. Aclidinium is a new anticholinergic drug
with acute onset; so far it has disappointed in trials but
might be suited to acute symptomatic relief.82 Novel
classes of bronchodilator have been difficult to develop
because they often affect vascular smooth muscle,
resulting in postural hypotension and headache.
Early treatment with antibiotics is beneficial for
exacerbations of bacterial origin.83 Non-invasive
ventilation has proven useful in selected patients with
respiratory acidosis,84 and non-pharmacological
approaches such as pulmonary rehabilitation are
recommended. Systemic corticosteroids reduce systemic
inflammation and can have some effect on acute airway
inflammation,85 but a form of corticosteroid resistance
has been reported in some patients with COPD.76 Low-
dose theophylline can increase the anti-inflammatory
effects of steroids during exacerbations of COPD,86 and
the drug can also restore reduced histone deacetylase
activity seen in macrophages in patients with COPD.87
Antioxidants and combating pathogens
The causes of COPD exacerbations—oxidative stress,
viruses, and bacteria—are rational targets for drug
development. These factors activate the innate immune
system and therefore drugs that inhibit innate immunity
could potentially treat acute exacerbations, provided that
they do not suppress the immune system and cause
immunodeficiency.
Increased oxidative stress might play a key part in
COPD exacerbations because it amplifies the
inflammatory response and might inhibit anti-

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 Review
inflammatory effects of corticosteroids, even in high
doses. Therefore treatment with antioxidants could be
useful.88 Dietary polyphenols in red wine (resveratrol),
tomatoes (stilbenes), and tumeric (curcumin) act as
antioxidants, but these are unlikely to achieve sufficient
concentrations in established COPD. Effective anti-
oxidants in development include glutathione com-
pounds with increased stability, superoxide dismutase
analogues, and radical scavengers. Nitrone spin-trap
antioxidants have increased potency and generate
stable compounds to inhibit formation of intracellular
ROS, and thioredoxin is a redox sensor inhibitor.
Hydrogen sulphide is a potent endogenous antioxidant;
the molecule GYY4137 releases hydrogen sulphide and
protects against endotoxic shock in rats.89
Despite remarkable strides in antiviral development,
resistance to viral therapy is a recurrent problem.67
Viruses that cause mild upper-respiratory-tract infection
in healthy individuals, are prone to cause lower-
respiratory-tract infection and acute severe exacerbations
of COPD,2 but improved diagnostic techniques should
help to manage such acute exacerbations. The most
common single cause of COPD exacerbations—
rhinovirus—as yet has no approved treatment, but a
potential target is airway mucin production that is
dependent on TLR3 and epidermal growth factor (EGF)
receptor.90,91 Treatment of respiratory syncytial virus
infection remains largely supportive, but the monoclonal
antibody palivizumab against the viral F protein is
licensed for specialist use in restricted circumstances.92
The present swine-origin influenza A H1N1 pandemic
could have extremely serious consequences for patients
with pre-existing lung disorders if the virus mutates. All
patients with COPD should have adequate influenza
immunisation, and be considered for early treatment
with zanamivir and oseltamivir93 in the event of an
influenza-induced exacerbation. Development of
resistance against these drugs is substantial and new
antivirals are being actively sought against influenza.94
Similarly, resistance to antibiotics is an important
barrier to effective treatment of bacterial infections.
Development of new antibiotics has become increasingly
difficult, and new types of treatment are urgently
needed. Bacteriophages have been used in Russia for
many decades, but other developed countries have not
adopted their use.95 Lytic phages are highly specific to
particular bacteria, are well tolerated with no risk of
overgrowth of intestinal flora, and they can be inhaled,
so could be effective for treatment of respiratory bacterial
infections. Antimicrobial peptides such as α-defensins,
β-defensins, and cathelicidins are produced from
epithelial and other cells in the respiratory tract and
have a key role in innate immunity and stimulating
adaptive immune responses.96 These peptides could be
useful for treatment since they are small, have a low
probability of resistance, and interact with influenza A
virus.97 Macrolide antibiotics with rings of 14 and
750
15 members have several anti-inflammatory effects, but
the molecular mechanisms for these effects are
unknown.98 Non-antibiotic macrolides could also be
useful against inflammation and could be inhaled
during an exacerbation. An erythromycin derivative
inhibits neutrophilic inflammation, release of
transforming growth factor β (TGFβ), and fibrosis in a
bleomycin model of pulmonary fibrosis.99
Another approach for treatment is to block interaction
of PRRs, especially with TLRs activated by oxidants and
pathogens. TLRs are closely associated with exacerbations:
rhinovirus causes mucin production through a pathway
mediated by TLR3 and EGF receptor,91 respiratory syncytial
virus activates TLR2100 and can interact with
lipopolysaccharide activation of TLR4,101 and severe
influenza of any type depresses systemic responses to TLR
ligands.102 Release of defensins during viral infection
promotes production of proinflammatory cytokines, and
therefore defensins could potentially be developed for
treatment.97,103 Intensive efforts are underway to develop
agonists and antagonists of TLRs to treat diseases in which
inflammation and infection occur,104 and soluble RAGE-
modulating drugs to treat vascular disorders. Improved
molecular understanding of activation of innate immunity
has also helped to identify targets. For example, PRRs
activate several signal transduction pathways (eg, nuclear
factor κB [NFκB], mitogen-activated protein kinase
[MAPK], and type 1 interferon),105 and MyD88 is a common
adapter protein that participates in signalling pathways for
several TLRs (TLR2, TLR4, TLR7, TLR8, and TLR9).63,106
Preservation of the epithelial barrier and targeting of acute
phase reactants could also be beneficial.
Anti-inflammatory treatments
Approaches to treatment of pulmonary and systemic
inflammation, and inflammation associated with co-
morbidities include statins, phosphodiesterase-4 (PDE4)
inhibitors, cytokine-directed therapy, and chemokine-
receptor antagonists (figure 6). Corticosteroids have
proven poorly effective in treating stable COPD and
exacerbations. Alternative anti-inflammatory treatments
are expected to effectively treat increased inflammation
during an exacerbation, possibly by inhalation. However,
all anti-inflammatory approaches risk increasing the
extent of infection by blunting host defence mechanisms.
COPD is associated with complex systemic symptoms,
such as inflammation associated with cachexia and skeletal
muscle weakness,10 and comorbidities like cardiovascular
disease.107 Since statins have a range of anti-inflammatory
effects, they are attractive treatments for COPD.108 Statins
increase survival in patients with COPD,109–111 including
those with coexisting peripheral arterial disease.112 Statins
could reduce COPD exacerbations,113 but prospective
studies are needed to fully assess their benefit for
prevention and treatment of exacerbations.114
PDE4 inhibitors have a broad range of anti-inflammatory
effects, but their effectiveness in human beings has been
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 Review

Improvements to existing drugs

New bronchodilators Reversal of steroid resistance

New corticosteroids Theophylline and histone deacetylase 2

Targeting causes of exacerbations and interactions with PRRs

New antibiotics and antivirals Antioxidants

Dietary polyphenols
Nitrone spin traps, iNOS inhibitors
Manipulating the innate immune system Redox sensor inhibitors: thioredoxin
Epithelial barrier preservation Enzyme mimetics: SOD-Salens
Acute phase reactants: C-reactive protein, mannose-binding Glutathione peroxidase mimetic: ebselen
lectin, serum amyloid A H2S-releasing molecule: GYY4137
PRRs: TLRs, scavenger receptors, HMGB1 and RAGE

Targeting processes in COPD

Oral anti-inflammatory treatment Mucoactive drugs Treatment of systemic and concomitant

PDE4 inhibitors Inhibitors of EGF-receptor tyrosine kinase disease, and comorbidities
Statins Calcium-activated chloride channel inhibitors Cardiovascular disease: statins
New corticosteroids Surfactant protein B Diabetes mellitus
Cachexia
Muscle disease
Cell-directed treatment Inhibition of fibrosis
Macrophage skewing (M1/M2) TGFβ (PAR1)
Th17, Treg, Tc Connective tissue growth factor, platelet-derived
CD1D-restricted natural killer T cells growth factor
Endothelin 1
Insulin-like growth factor 1
Interleukins 1 and 13
Cytokine and chemokine inhibitors
Serum amyloid P
GM-CSF, TNFα
Imatinib
Interleukins 1β, 6 and 8 (CXCL8)
Interferons, TGFβ, interleukins 10 and 17
CXCR1, CXCR2, CXCR3, CCR2, CCR5
Anti-proteases Ageing and cell death
Neutrophil elastase Damage induced by reactive oxygen species
Adhesion molecules α1-antitrypsin Sirtuins: SIRT1-specific activator
Integrins, ICAM1 Matrix metalloprotease p38 MAPK, phosphoinositide-3-kinase, histone
E selectin Serine protease deacetylase
Thrombin and other coagulation factors Vascular endothelial growth factor

Cell signalling and transcription

MyD88 Lung regeneration
p38 MAPK Retinoic acid receptor γ agonist
Phosphoinositide-3-kinase γ and δ Mesenchymal stem cells
NFκB, inhibitor of κB kinase WNT signalling family
JAK, SYK HMGB1
Histone deacetylase Hyaluronase
PPAR activators

Figure 6: Targets for drug development in exacerbations of chronic obstructive pulmonary disease (COPD)
CCR=cysteine-cysteine receptor. CXCL=cysteine-X-cysteine ligand. CXCR=cysteine-X-cysteine receptor. EGF=epidermal growth factor. H2S=hydrogen sulphide.
HMGB1=high mobility group box 1. ICAM1=intercellular adhesion molecule 1. iNOS=inducible nitric oxide synthase. JAK=janus kinase. MAPK=mitogen-activated
protein kinase. MyD88=myeloid differentiation primary response gene 88. NFκB=nuclear factor κB. PAR1=protease-activated receptor 1. PDE4=phosphodiesterase 4.
PPAR=peroxisome proliferator-activated receptors. PRR=pattern recognition receptor. RAGE=receptor for advanced glycation end-products. SOD=superoxide
dismutase. SYK=spleen tyrosine kinase. Tc=cytotoxic T cell. TGFβ=transforming growth factor β. Th17=T helper cell producing interleukin 17. TLR=toll-like receptor.
TNFα=tumour necrosis factor α. Treg=regulatory T cell. WNT=wingless.

limited by side-effects such as nausea, diarrhoea, and
headache.115,116 Such side-effects suggest that use of oral
PDE4 inhibitors for acute anti-inflammatory treatment
would not be possible. Cilomilast showed good results
for the first 6 weeks of treatment for stable COPD117 but
was less efficacious in a 6-month study.118 Roflumilast had
some efficacy in studies lasting 24 weeks119 and 1 year,120
but results for prevention of COPD exacerbations are
awaited. Future development of inhaled PDE4 inhibitors
might help to reduce side-effects.
In patients with COPD, inflammatory cells that infiltrate
the airways have a range of abnormalities. For example,
alveolar macrophages have a distinct activation state that
is induced by tobacco smoke,121 and respiratory viral
infection causes macrophage activation by CD1D-
dependent natural killer T cells, causing interleukin-13
production and chronic inflammatory lung disease.122 In
patients with stable COPD, cytotoxic T cells increase and
regulatory T-cell responses are blunted,123 and early COPD
exacerbations are accompanied by increased Tc2s.42 In

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 Review
mice, chronic tobacco smoke causes T cells to express
interferon gamma or interleukin 17, representing a Th1
(T helper lymphocyte of type 1) and Th17 subtype, and this
is associated with airspace enlargement.124
Although blocking TNFα is not effective in patients with
stable COPD,125,126 such treatment during an acute
exacerbation might be effective since TNFα concentration
increases during exacerbations. However, the TNF
antibody infliximab increased the occurrence of respiratory
cancers in patients with COPD,125 and increased other
types of cancer and infections in those with severe
asthma.127 Such safety concerns with anti-TNFα treatment
could have substantial implications for other anti-
inflammatory treatment for exacerbations of COPD.
Monoclonal antibodies against interleukins 6, 1β, and
17, TGFβ, and GM-CSF could be useful for COPD.
Tobacco smoke inhibits lipopolysaccharide-induced GM-
CSF release by bronchial epithelial cells,128 and GM-CSF
regulates alveolar macrophage responses to Pseudomonas
endotoxins.129 Hence, tobacco smoke might cause
defective anti-bacterial responses. Tocilizumab, a
monoclonal antibody that targets interleukin-6 receptors,
is effective in several inflammatory diseases,130 but studies
in COPD have not yet been done. Th17 cells have recently
been identified as a separate cell population that produce
interleukin 17, which causes neutrophilia.131,132
The concentrations of CXC (cysteine-X-cysteine)-type
chemokines, including CXCL5 and interleukin 8
(CXCL8), are increased during exacerbations and, since
they all signal through a common receptor (CXCR2),
specific antagonists of this receptor could be useful for
treatment of exacerbations. A small molecule antagonist
of CXCR1 and CXCR2 inhibits sputum neutrophils by
about 80% after inhaled endotoxin,133 suggesting that this
oral drug could be useful for exacerbations.
LTB4 activates the corresponding receptor BLT1, which
is expressed on neutrophils and T cells. Since LTB4
concentration is raised during exacerbations, specific
BLT1 antagonists could be beneficial for the treatment of
exacerbations.7 However, BLT1 antagonists have a small
effect on neutrophil chemotaxis in response to
chemotactic factors in COPD sputum134 and have not
proved to be effective for treatment of stable COPD.
NFκB is activated during exacerbations and simulta-
neously has a key role in upregulating expression of many
inflammatory genes.135 Oxidative stress, bacteria, and
viruses probably activate NFκB, making NFκB a logical
target for inhibition. Selective inhibitors of IκB kinase-2
(IKK2) have been developed,136 but have not yet been tested
clinically for their anti-inflammatory effects in COPD.
Since IKK2 inhibitors cause impaired innate immunity,
their long-term safety is a concern, but they could be useful
for acute treatment of exacerbations, especially if inhaled.
p38 MAPK is activated by bacteria and viruses, and
therefore is another target for inhibition.47 Several p38
MAPK inhibitors are in clinical development, but these
are expected to have toxic effects, which would make
752
inhalation of such drugs necessary. Phosphoinositide-3-
kinases δ and γ have been implicated in inflammation,
and inhibition of the δ subtype has been shown to restore
corticosteroid sensitivity in mice.137
Other treatment modalities
In a 3-year study, the putative antioxidant and mucolytic
acetylcysteine was not effective,138 but carbocisteine
effectively prevented exacerbations in Chinese patients
with COPD who were not receiving any other treatments.139
Mucoactive drugs and drugs to treat airway mucus
hypersecretion have been developed.140 These drugs target
inhibitors of EGF-receptor tyrosine kinase and human
calcium-activated chloride channel blockers; surfactant
protein B is also associated with COPD exacerbations.141
Importantly mucus can be protective as part of the
mucociliary escalator, but can be harmful when infected
and impairing oxygenation. A study using inhaled
recombinant DNAse to treat acute exacerbations of COPD
ended early because of increased mortality.142
Despite major advances in our understanding of the
processes of fibrosis,48,49 proteolysis,53 lung ageing,143 and
repair,144,145 drugs acting against these targets, and also to
attempt lung regeneration,146,147 are unlikely to be used in
the near future as treatments for acute exacerbations.
Conclusions
Improved anti-infective and antioxidant treatment,
coupled with new approaches directed against the innate
immune system, are promising for treatment of COPD
exacerbations. Our understanding of bacterial and viral
interactions with the human immune system is advancing
rapidly. Additionally, we have increased knowledge of
steroid-insensitive inflammation, autoimmunity, fibrosis,
aberrant repair, accelerated ageing, and systemic disease
and comorbidities. Validated biomarkers for COPD
exacerbations and challenge models for COPD in animals
and man are needed to improve assessment and direction
of new treatments, and clinical trials should assess both
the treatment and prevention of COPD exacerbations.
With extensive collaboration between scientists, clinicians,
the pharmaceutical industry, and drug regulators it is
likely that novel treatments for exacerbations of COPD
can be defined.
Contributors
TTH and PJB worked together on all aspects of this Review.
Conflicts of interest
TTH has been a speaker for AstraZeneca and Thomson Reuters, and works
in a unit that undertakes testing of novel compounds for the treatment of
respiratory disease. The unit has received research grants from Novartis,
GlaxoSmithKline, Roche, Oxagen, Institute of Medicinal Molecular Design,
Pfizer, Merck, and Altana Pharmaceuticals. PJB has received research
funding and been a member of scientific advisory boards for AstraZeneca,
Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Novartis,
Pfizer, Teva, and Union Chimique Belge, some of which are marketing and
developing treatments for COPD.
Acknowledgments
We thank Gary Anderson for his invaluable critical review, and
Andrew J Tan for his assistance with the figures and references.
www.thelancet.com Vol 374 August 29, 2009

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