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Review

New drugs for exacerbations of chronic obstructive


pulmonary disease
Trevor T Hansel, Peter J Barnes

Lancet 2009; 374: 744–55 Tobacco smoking is the dominant risk factor for chronic obstructive pulmonary disease (COPD), but viral and bacterial
National Heart and Lung infections are the major causes of exacerbations in later stages of disease. Reactive oxygen species (ROS), pathogen-
Institute, Imperial College, associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs) activate families of
London, UK
pattern recognition receptors (PRRs) that include the toll-like receptors (TLRs). This understanding has led to the
(T T Hansel FRCPath,
Prof P J Barnes FRS) hypothesis that COPD is an archetypal disease of innate immunity. COPD is characterised by abnormal response to
Correspondence to: injury, with altered barrier function of the respiratory tract, an acute phase reaction, and excessive activation of
Dr Trevor T Hansel, Imperial macrophages, neutrophils, and fibroblasts in the lung. The activated non-specific immune system then mediates the
Clinical Respiratory Research processes of inflammation and repair, fibrosis, and proteolysis. COPD is also associated with corticosteroid resistance,
Unit, St Mary’s Hospital, Mint
abnormal macrophage and T-cell populations in the airway, autoinflammation and autoimmunity, aberrant fibrosis,
Wing, Praed Street, Paddington,
London W2 INY, UK accelerated ageing, systemic and concomitant disease, and defective regeneration. Such concepts have been used to
t.hansel@imperial.ac.uk 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 factor for COPD.12 Most candidate genes have not yet
Disease exacerbations have a profound effect on patients been validated, but polymorphic variations in surfactant
with chronic obstructive pulmonary disease (COPD) protein B and mannose-binding lectin have been
worldwide,1 resulting in poor health and high mortality.2 associated with exacerbations of COPD.13,14
Although the precise definition of an exacerbation of Hogg and colleagues15 assessed the immunopathology
COPD remains controversial, according to guidelines of small airways in surgically resected lung tissue from
of the Global initiative for chronic Obstructive Lung patients with different severities of COPD. They noted
Disease (GOLD) it is “…an event in the natural course that the progression into severe stages of COPD was
of the disease characterized by a change in the patient’s associated with increased thickness and inflammation
baseline dyspnea, cough, and/or sputum that is beyond of the bronchiolar wall, resulting in obstruction of the
normal day-to-day variations, is acute in onset, and may lumen, and raised numbers of neutrophils, macrophages,
warrant a change in regular medication in a patient and lymphocytes. In COPD of GOLD stages III (severe)
with underlying COPD”.3 and IV (very severe), lymphoid follicles are prominent
In a study of the natural history of COPD, Fletcher in areas of respiratory bronchiolitis (figure 2). Hogg’s
and Peto4 showed that male smokers with the disease group postulated that the pathology of early COPD
have an increased loss of forced expiratory volume in indicates activation of innate immunity, whereas
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 Search strategy and selection criteria
current smokers,6 and evidence is growing that We searched PubMed for reports published in English using
exacerbations accelerate progressive decline in lung the search term “COPD” in combination with
function in patients with COPD (figure 1),2,5,7 but the “exacerbations”, “new drugs”, “cigarette smoke”,
relation between exacerbations and natural history has “immunity-innate”, “oxidants”, “virus”, “rhinovirus”,
not been established conclusively.8 “respiratory syncytial virus”, “influenza”, “bacteria”,
Extra-pulmonary factors could have a role in “inflammation”, “epithelial barrier”, “acute phase reactant”,
exacerbations. For example, the BODE index—body- “biomarker”, “mucus”, “fibrosis”, “proteolysis”,
mass index (B), obstruction (O), dyspnoea (D), and “corticosteroid”, “bronchodilator”, “TLR”, “scavenger
exercise endurance from 6-min walk distance (E)—is a receptor”, “danger”, “RAGE”, “MyD88”, ”interleukin”,
better predictor of risk of death for patients with COPD “cytokine”, “GM-CSF”, “TNF”, “chemokine”, “adhesion
than is FEV1 alone.9 Inflammation might be responsible molecule”, ”PDE4”, “NFκB”, “signalling”, “statin”, “aging”,
for systemic manifestations and comorbidities of COPD “apoptosis”, “death”, “resolution”, “repair”, “resolving”
such as muscle dysfunction, cachexia, cardiovascular “regeneration”, “stem cell”, “blood”, “sputum”, “breath”,
disease, normocytic anaemia, osteoporosis, depression, “epithelial”, “fibroblast”, “T-cell”, “Treg”, “Th17”, “smooth
diabetes, and other endocrine disorders.10 muscle”, “anti-oxidants”, “antibiotic”, “anti-viral”, and
COPD has complex genetic aspects yet contributing “cell-signalling”. We selected reports published in the past
environmental factors—tobacco smoke and other 3 years, but we also included older papers that we deemed
inhaled irritants—are known.11 However, severe relevant. The date of the last search was June, 2009.
α₁-antitrypsin deficiency is the only proven genetic risk

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presence of lymphoid follicles in severe COPD might be


due to viral and bacterial infections of the lower airways, Smoke from tobacco and biomass fuel contains ROS,
associated with an adaptive immune response.15 toxins, and particulate matter
Lymphoid follicles contain B cells and T cells that
Viral and bacterial infections
overexpress the chemokine receptor CXCR3 (cysteine- Signs and symptoms
X-cysteine receptor 3), suggesting that this receptor 100
could be important for localisation of these cells.16 Asymptomatic
Stage I
Additionally, oligoclonal B cells have been detected in
80
follicles without bacterial or viral nucleic acids, which Stage II Progressive dyspnoea
could relate to an antigen-specific process that is not

FEV1 (% of predicted)
caused by microbes.17
50
Causes of COPD and exacerbations Stage III Systemic disease
The major cause of COPD in developed countries is Comorbidities
many years of heavy tobacco smoking during the asymp- 30
tomatic, initial phase of COPD. Tobacco smoke contains Stage IV Respiratory failure
Death
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 25 50 75
Age (years)
reactive aldehydes produce carbonyl adducts on proteins
and DNA (figure 3). Additionally, hydrogen sulphide is a Figure 1: Physiology of exacerbations in a hypothetical regular smoker with chronic obstructive pulmonary
potent antioxidant and vasorelaxant.20 ROS cause damage disease (COPD) by stage of severity
to host cells from lipid peroxidation, protein carbonylation, Natural history of COPD is characterised by an accelerated loss of forced expiratory volume in 1 s (FEV1) with
and formation of DNA adducts. This damage can cause 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
both immunosuppression and proinflammatory effects Global initiative for chronic Obstructive Lung Disease.3 Red arrows indicate onset of exacerbations.
such as stimulation of phagocytosis.21 Additionally the
aryl hydrocarbon receptor is activated by environmental Haemophilus influenzae, Streptococcus pneumoniae, and
pollutants22 such as particulate matter, which is a key Pseudomonas aeruginosa. Patients with severe COPD who
component of air pollution.23 receive inappropriate antibiotic treatment are vulnerable
Causes of exacerbations include infection, continued to multidrug-resistant infections.35
oxidant damage, air pollution, systemic COPD,
comorbidities of COPD, pulmonary hypertension, Innate immunity
pulmonary embolus, and cor pulmonale, but many Epithelial barrier and acute phase response
patients have exacerbations where no specific cause can The innate immune system is the first line of defence in
be identified. Infective exacerbations occur in severe the respiratory tract. Airways and alveolar interstitium,
disease, causing clinically unstable COPD. Increasingly including the respiratory epithelial mucociliary escalator
advanced diagnostic techniques for viruses (eg, PCR) and alveolar surfactant, act as a barrier to infection or
have shown that most COPD exacerbations are caused by damage. However, tobacco smoke increases the
infection.24 permeability of respiratory epithelium, thus compromising
Rhinovirus is a common cause of COPD exacerbation25 the barrier (figure 4). Respiratory viruses target respiratory
and directly infects the upper-respiratory and lower- epithelial cells in preference to other cell types, and can
respiratory tract.26 Upregulation of the rhinovirus thereby initiate non-specific inflammation.
receptor ICAM1 (intercellular adhesion molecule 1) on The acute phase response leads to production of
epithelial cells occurs in COPD, and might predispose substantially raised concentrations of reactants such as
patients to infection.27 A model of human rhinovirus- C-reactive protein, coagulation proteins (coagulation
induced COPD exacerbation has been developed to factors, fibrinogen, and anticoagulants), complement
improve understanding of the immunological and factors, mannose-binding lectin, and serum amyloid A,
inflammatory mechanisms of such exacerbations.28 which makes them useful biomarkers for exacerbations
Respiratory syncytial virus has been identified in adults (figure 4).36 C-reactive protein, mannose-binding lectin,
with COPD29 and can persist in stable COPD.30 Seasonal and serum amyloid A can bind to pathogens.
influenza is an important cause of exacerbations, raising
concern that an influenza pandemic could cause high Inflammation, fibrosis, and proteolysis
mortality in patients with COPD.31 The host responds to damage from ROS with cycles of
Bacterial colonisation is often reported in patients with inflammation and repair; these cycles repeat after every
COPD,32,33 and is associated with the frequency of cigarette is smoked, but with increased concentration of
exacerbations.34 Persistent colonisation can occur with factors that participate in inflammation and repair after

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Review

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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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 Challenge models
proteins, and extracellular matrix hyaluronans. Models of smoking-induced COPD in animals have been
Toll-like receptors (TLRs) were discovered in Drosophila used to study protease–antiprotease imbalance,
melanogaster, and 13 types with widespread cellular inflammation and autoimmunity, remodelling and
distribution have been identified in man (figure 5). ROS mucus production, and emphysema.70 Animal models of
activate TLR261 and TLR4 using MyD88 (myeloid innate immunity and viral exacerbation of COPD are
differentiation primary response gene 88) signalling,62,63 needed to test novel therapies pre-clinically. Assessments
and can also damage membrane lipids, cell proteins, and of new treatments need to establish whether the treatment
DNA; these processes lead to activation of DAMPs.64,65 is acting on the intended target from phase 1/2 studies in
Bacterial components activate different cell surface human beings, and the optimum dose and dose interval
TLRs—for example, the cell wall of gram-negative bacteria from clinical pharmacology studies. Just as inhaled and
contains lipopolysaccharide that activates TLR4. By nasal allergen challenge have been used to assess anti-
contrast, viral nucleic acid motifs activate TLR3, TLR7, inflammatory drugs for asthma, challenge models with
and TLR9, all of which are located on the inner surface of lipopolysaccharide71 and other TLR agonists should be
the endosomal membrane. used to study the action of drugs for COPD in man.
PRRs including TLRs,59 scavenger receptors,66 and
receptor for advanced glycation end-products (RAGE) Biomarkers
undergo extensive cross-talk (figure 5).67,68 Additionally, For clinical assessment of new treatments for COPD
TLRs within endosomes recognise viral nucleic acids, and exacerbations, validated biomarkers would be useful.72
cytoplasmic PRRs—retinoic acid-inducible gene 1 (RIG1)- Potential biomarkers have been measured in blood,
like receptors (RLRs) and NOD-like receptors (NLRs)— urine, sputum, and exhaled breath, and from
recognise viral RNA and bacterial PAMPs, respectively. In bronchoscopic and protein microarray techniques; non-
COPD, PRRs are activated on epithelial cells, neutrophils, invasive methods will probably be most applicable.
macrophages, smooth muscle cells,69 fibroblasts, and Raised blood biomarkers in COPD include C-reactive
other airway cells. Tobacco smoke acutely activates protein, coagulation proteins including coagulation
MyD88, which is an intracellular toll/interleukin-1 factors (eg, fibrinogen and anticoagulants), complement
receptor adaptor protein.63 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 mechanical ventilation, features of respiratory failure,
factor α [TNFα], and interleukins 6 and 1β). Plasma vital functions, length of hospital stay, biomarkers, and
leptin concentrations are increased during acute time to next exacerbation. Available treatments have little
exacerbations, possibly indicating that negative energy effect on exacerbations, and therefore studies of the
balance and systemic oxidative stress is present. effects of new drugs on exacerbations would be useful.
Several inflammatory markers increase in sputum of Such studies would need a rigorous definition of inclusion
patients with COPD during acute exacerbations: leuko- criteria, which features to monitor, and criteria for rescue
triene B4 (LTB4), interleukin 6, interleukin 8 (cysteine-X- therapy. To aid drug development, regulatory authorities
cysteine ligand 8 [CXCL8]), endothelin 1, CCL5 could expedite the assessment of treatments for
(cysteine-cysteine ligand 5), and CXCL5. Sputum proteo- exacerbations.
mics have been used for inflammatory lung disease and
could potentially be used for COPD exacerbations. New drugs for exacerbations
When exhaled nitric oxide is partitioned by the Improvements to existing drug classes
multiple flow technique, peripheral nitric oxide Present treatments for exacerbations are outside the
(including small airways and lung parenchyma) is scope of this Review; we refer to guidelines from GOLD,3
increased. This technique could be useful to detect and published reviews.73–75 Extensive efforts in drug
increased exhaled nitric oxide during exacerbations of development have focused on inhibition of corticosteroid-
COPD. Use of exhaled breath condensate has several insensitive neutrophil inflammation76,77 and prevention of
methodological problems but is a non-invasive exacerbations, rather than treatment of acute
measurement and is suited to serial measurements exacerbations.78 Guidance for industry from the US Food
during an exacerbation. and Drug Administration about drug development for
COPD concentrates on stable COPD, not treatment of
Studies of exacerbations acute exacerbations.79
An acute exacerbation for which the patient needs hospital Bronchodilators are the mainstay of management.
admission is associated with high mortality, intensive Development of bronchodilators has focused on
monitoring and treatment, and substantial health-care improving inhaled longacting β2 agonists and longacting
costs. Clinical studies in hospital can measure a range of muscarinic antagonists.80 The active R,R-enantiomer of
acute endpoints including mortality, need for invasive 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 inflammation and can have some effect on acute airway
for acute exacerbations.81 Longacting β2 agonists with a inflammation,85 but a form of corticosteroid resistance
duration of more than 24 h, such as indacaterol and has been reported in some patients with COPD.76 Low-
carmoterol, are in development for treatment of stable dose theophylline can increase the anti-inflammatory
COPD. Tiotropium is an effective bronchodilator for effects of steroids during exacerbations of COPD,86 and
stable COPD and reduces exacerbations, but is not suited the drug can also restore reduced histone deacetylase
as a reliever for acute exacerbations because of its slow activity seen in macrophages in patients with COPD.87
onset of action. Aclidinium is a new anticholinergic drug
with acute onset; so far it has disappointed in trials but Antioxidants and combating pathogens
might be suited to acute symptomatic relief.82 Novel The causes of COPD exacerbations—oxidative stress,
classes of bronchodilator have been difficult to develop viruses, and bacteria—are rational targets for drug
because they often affect vascular smooth muscle, development. These factors activate the innate immune
resulting in postural hypotension and headache. system and therefore drugs that inhibit innate immunity
Early treatment with antibiotics is beneficial for could potentially treat acute exacerbations, provided that
exacerbations of bacterial origin.83 Non-invasive they do not suppress the immune system and cause
ventilation has proven useful in selected patients with immunodeficiency.
respiratory acidosis,84 and non-pharmacological Increased oxidative stress might play a key part in
approaches such as pulmonary rehabilitation are COPD exacerbations because it amplifies the
recommended. Systemic corticosteroids reduce systemic inflammatory response and might inhibit anti-

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

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

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Review

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

752 www.thelancet.com Vol 374 August 29, 2009


Review

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