New drugs for exacerbations of chronic obstructive

8/7/2019 New drugs for exacerbations of chronic obstructive

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

New drugs for exacerbations of chronic obstructive

pulmonary diseaseTrevor T Hansel, Peter J Barnes

Tobacco smoking is the dominant risk factor for chronic obstructive pulmonary disease (COPD), but viral and bacterialinfections 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 thehypothesis that COPD is an archetypal disease of innate immunity. COPD is characterised by abnormal response toinjury, with altered barrier function of the respiratory tract, an acute phase reaction, and excessive activation of macrophages, neutrophils, and broblasts in the lung. The activated non-specic immune system then mediates theprocesses of inammation and repair, brosis, and proteolysis. COPD is also associated with corticosteroid resistance,abnormal macrophage and T-cell populations in the airway, autoinammation and autoimmunity, aberrant brosis,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 preventionand treatment of COPD exacerbations.

IntroductionDisease exacerbations have a profound effect on patientswith chronic obstructive pulmonary disease (COPD)worldwide,1 resulting in poor health and high mortality. 2 Although the precise denition of an exacerbation of COPD remains controversial, according to guidelinesof the Global initiative for chronic Obstructive LungDisease (GOLD) it is an event in the natural courseof the disease characterized by a change in the patientsbaseline dyspnea, cough, and/or sputum that is beyondnormal day-to-day variations, is acute in onset, and may

warrant a change in regular medication in a patientwith underlying COPD. 3In a study of the natural history of COPD, Fletcher

and Peto 4 showed that male smokers with the diseasehave an increased loss of forced expiratory volume in1 s (FEV1) every year.5 The Lung Health Study in theUSA and Canada subsequently noted that lower-respiratory-tract illnesses promote FEV 1 reduction incurrent smokers, 6 and evidence is growing thatexacerbations accelerate progressive decline in lungfunction in patients with COPD (gure 1), 2,5,7 but therelation between exacerbations and natural history hasnot been established conclusively. 8

Extra-pulmonary factors could have a role in

exacerbations. For example, the BODE indexbody-mass index (B), obstruction (O), dyspnoea (D), andexercise endurance from 6-min walk distance (E)is abetter predictor of risk of death for patients with COPDthan is FEV 1 alone. 9 Inammation might be responsiblefor systemic manifestations and comorbidities of COPDsuch as muscle dysfunction, cachexia, cardiovasculardisease, normocytic anaemia, osteoporosis, depression,diabetes, and other endocrine disorders. 10

COPD has complex genetic aspects yet contributingenvironmental factorstobacco smoke and otherinhaled irritantsare known. 11 However, severe-antitrypsin deciency is the only proven genetic risk

factor for COPD. 12 Most candidate genes have not yetbeen validated, but polymorphic variations in surfactantprotein B and mannose-binding lectin have beenassociated with exacerbations of COPD. 13,14

Hogg and colleagues 15 assessed the immunopathologyof small airways in surgically resected lung tissue frompatients with different severities of COPD. They notedthat the progression into severe stages of COPD wasassociated with increased thickness and inammationof the bronchiolar wall, resulting in obstruction of thelumen, and raised numbers of neutrophils, macrophages,

and lymphocytes. In COPD of GOLD stages III (severe)and IV (very severe), lymphoid follicles are prominentin areas of respiratory bronchiolitis (gure 2). Hoggsgroup postulated that the pathology of early COPDindicates activation of innate immunity, whereas

Lancet 2009; 374: 74455

National Heart and LungInstitute, Imperial College,

London, UK(T T Hansel FRCPath,

Prof P J Barnes FRS)

Correspondence to:Dr Trevor T Hansel, Imperial

Clinical Respiratory ResearchUnit, St Marys Hospital, Mint

Wing, Praed Street, Paddington,London W2 INY, UK

[email protected]

Search strategy and selection criteria

We searched PubMed for reports published in English usingthe search term COPD in combination withexacerbations, new drugs, cigarette smoke,immunity-innate, oxidants, virus, rhinovirus,respiratory syncytial virus, inuenza, bacteria,inammation, epithelial barrier, acute phase reactant,biomarker, mucus, brosis, proteolysis,corticosteroid, bronchodilator, TLR, scavengerreceptor, danger, RAGE, MyD88, interleukin,cytokine, GM-CSF, TNF, chemokine, adhesionmolecule, PDE4, NFB, signalling, statin, aging,apoptosis, death, resolution, repair, resolvingregeneration, stem cell, blood, sputum, breath,epithelial, broblast, T-cell, Treg, Th17, smoothmuscle, anti-oxidants, antibiotic, anti-viral, andcell-signalling. We selected reports published in the past3 years, but we also included older papers that we deemedrelevant. The date of the last search was June, 2009.


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presence of lymphoid follicles in severe COPD might bedue to viral and bacterial infections of the lower airways,associated with an adaptive immune response. 15 Lymphoid follicles contain B cells and T cells thatoverexpress the chemokine receptor CXCR3 (cysteine-X-cysteine receptor 3), suggesting that this receptorcould be important for localisation of these cells. 16 Additionally, oligoclonal B cells have been detected infollicles without bacterial or viral nucleic acids, whichcould relate to an antigen-specic process that is notcaused by microbes. 17

Causes of COPD and exacerbationsThe major cause of COPD in developed countries ismany years of heavy tobacco smoking during the asymp-tomatic, initial phase of COPD. Tobacco smoke contains

reactive oxygen species (ROS)18

and many differentchemical components, both of which cause toxic effectsin the lung. 19 ROS originate from oxygen (superoxideanion) and nitrogen (nitric oxide and peroxynitrite), andreactive aldehydes produce carbonyl adducts on proteinsand DNA (gure 3). Additionally, hydrogen sulphide is apotent antioxidant and vasorelaxant. 20 ROS cause damageto host cells from lipid peroxidation, protein carbonylation,and formation of DNA adducts. This damage can causeboth immuno suppression and pro inam matory effectssuch as stimulation of phago cytosis.21 Additionally thearyl hydrocarbon receptor is activated by environ mentalpollutants 22 such as particulate matter, which is a keycomponent of air pollution. 23

Causes of exacerbations include infection, continuedoxidant damage, air pollution, systemic COPD,comorbidities of COPD, pulmonary hypertension,pulmonary embolus, and cor pulmonale, but manypatients have exacerbations where no specic cause canbe identied. Infective exacerbations occur in severedisease, causing clinically unstable COPD. Increasinglyadvanced diagnostic techniques for viruses (eg, PCR)have shown that most COPD exacerbations are caused byinfection. 24

Rhinovirus is a common cause of COPD exacerbation 25 and directly infects the upper-respiratory and lower-respiratory tract. 26 Upregulation of the rhinovirusreceptor ICAM1 (intercellular adhesion molecule 1) on

epithelial cells occurs in COPD, and might predisposepatients to infection. 27 A model of human rhinovirus-induced COPD exacerbation has been developed toimprove understanding of the immunological andinammatory mechanisms of such exacerbations. 28 Respiratory syncytial virus has been identied in adultswith COPD 29 and can persist in stable COPD. 30 Seasonalinuenza is an important cause of exacerbations, raisingconcern that an inuenza pandemic could cause highmortality in patients with COPD. 31

Bacterial colonisation is often reported in patients withCOPD,32,33 and is associated with the frequency of exacerbations. 34 Persistent colonisation can occur with

Haemophilus inuenzae, Streptococcus pneumoniae, andPseudomonas aeruginosa. Patients with severe COPD whoreceive inappropriate antibiotic treatment are vulnerable

to multidrug-resistant infections.35

Innate immunityEpithelial barrier and acute phase responseThe innate immune system is the rst line of defence inthe respiratory tract. Airways and alveolar interstitium,including the respiratory epithelial mucociliary escalatorand alveolar surfactant, act as a barrier to infection ordamage. However, tobacco smoke increases thepermeability of respiratory epithelium, thus compromisingthe barrier (gure 4). Respiratory viruses target respiratoryepithelial cells in preference to other cell types, and canthereby initiate non-specic inammation.

The acute phase response leads to production of

substantially raised concentrations of reactants such asC-reactive protein, coagulation proteins (coagulationfactors, brinogen, and anticoagulants), complementfactors, mannose-binding lectin, and serum amyloid A,which makes them useful biomarkers for exacerbations(gure 4).36 C-reactive protein, mannose-binding lectin,and serum amyloid A can bind to pathogens.

Inammation, brosis, and proteolysisThe host responds to damage from ROS with cycles of inammation and repair; these cycles repeat after everycigarette is smoked, but with increased concentration of factors that participate in inammation and repair after

25 50Age (years)

75

30

50

80

100

F E V

1 ( %

o f p r e

d i c t e d )

Stage I

Stage II

Stage III

Stage IV

Asymptomatic

Signs and symptomsViral and bacterial infections

Smoke from tobacco and biomass fuel contains ROS,toxins, and particulate matter

Progressive dyspnoea

Systemic diseaseComorbidities

Respiratory failureDeath

Figure 1:Physiology of exacerbations in a hypothetical regular smoker with chronic obstructive pulmonarydisease (COPD) by stage of severityNatural history of COPD is characterised by an accelerated loss of forced expiratory volume in 1 s (FEV1) withageing; reactive oxygen species (ROS) cause lung damage throughout the natural history, whereas viral andbacterial infections cause exacerbations that tend to occur in severe COPD. Stages of severity are dened by theGlobal initiative for chronic Obstructive Lung Disease.3 Red arrows indicate onset of exacerbations.


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an exacerbation. Susceptible smokers eventually respondby developing the features of COPD: increased mucusproduction in large airways causing chronic bronchitis,bronchiolar brosis and airway remodelling in smallairways causing obstructive bronchiolitis, and destructionof third-order bronchioles (with attached alveoli) andlung interstitium causing centrilobular emphysema thatpredominantly affects the upper lobes (gure 2).

Exacerbations are indicative of an increase in thesame type of inammation as in stable COPD, withcorresponding increases in neutrophils, cytokines,chemokines, and proteases in the airways. 37 Trans-epithelial migration of neutrophils 38 and macrophageactivation39 are closely linked with dendritic andepithelial cells. 40 A range of T cells are implicated inexacerbations: 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 withautoimmune components, 44 such as circulatingpulmonary epithelial IgG autoantibodies 45 and anti-elastin autoimmune factors. 46 Inammation in COPDmight also be regarded as autoinammatory owing tothe production of interleukins 1 and 6. 47

Although inammation, brosis, and proteolysis areclosely related, these processes are able to occurseparatelyfor example, very little inammation can bepresent in idiopathic pulmonary brosis. 48 Fibrosis in thesmall airways causes obstructive bronchiolitis, butexcessive brosis can also contribute to emphysema. Themolecular basis of brosis is becoming understood and is

providing a range of targets for new drugs.49,50

By contrast,-antitrypsin deciency is a genetic disease that shows theimportance of proteases in causing a subtype of COPD. 51,52 Neutrophil elastase, 53 and matrix metalloproteases 9 54 and 1255 have been implicated in the pathogenesis of COPDand are therefore targets for drug development.

Danger signals and pattern recognitionPenetration of the respiratory barrier is followed byactivation of pattern recognition receptors (PRRs) bydanger signals such as ROS, pathogen-associatedmolecular patterns (PAMPs), and damage-associatedmolecular patterns (DAMPs; gure 5). Improvedunderstanding of molecular and cellular activation of

innate immunity56

has indicated that PRRs are able to drivechronic lung inammation, 57 repair processes, brosis,and proteolysis. A unied theory suggests that develop-ment of mild-to-moderate COPD and exacerbations of COPD is mediated by activation of the innate immunesystem by interaction of PRRs with molecular patterns onROS, viruses, bacteria, and dead and damaged cells. 58

PAMPs are present in nucleic acids of viruses infectingthe respiratory epithelium, and in a range of cell wall andcytoplasmic components of bacteria. 59 Matzinger 60

proposed the danger model in which the immune systemis important for recognition of entities that can dodamage, rather than for discrimination of self from

Chronic bronchitis

Obstructive bronchiolitis

Centrilobular emphysema

Collapsed lumen

Increased mucus

Goblet cell metaplasia

Smooth musclecell hypertrophy

Lung lobule section Bronchioles and alveoli

Inammation withbrosis

Loss of alveolarattachments

Destruction andconuence of respiratorybronchioles

Relative sparingof peripheralalveoli

Destruction andconuence of bronchioles

Lymphoid follicle(severe COPD only)

Increased mucus

Goblet cell hyperplasia

Inammation with brosis

Submucosal bronchialgland hypertrophy

Smooth musclecell hypertrophy

Figure 2:Pathology of chronic obstructive pulmonary disease (COPD)


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foreign material. Such DAMPs might include HMGB1

(high mobility group box 1), S100 proteins, heat shockproteins, and extracellular matrix hyaluronans.Toll-like receptors (TLRs) were discovered in Drosophila

melanogaster , and 13 types with widespread cellulardistribution have been identied in man (gure 5). ROSactivate TLR261 and TLR4 using MyD88 (myeloiddifferentiation primary response gene 88) signalling, 62,63 and can also damage membrane lipids, cell proteins, andDNA; these processes lead to activation of DAMPs. 64,65 Bacterial compon ents acti vate different cell surfaceTLRsfor example, the cell wall of gram-negative bacteriacontains lipopolysaccharide that activates TLR4. Bycontrast, 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 andreceptor for advanced glycation end-products (RAGE)undergo extensive cross-talk (gure 5). 67,68 Additionally,TLRs within endosomes recognise viral nucleic acids, andcytoplasmic PRRsretinoic acid-inducible gene 1 (RIG1)-like receptors (RLRs) and NOD-like receptors (NLRs)recognise viral RNA and bacterial PAMPs, respectively. InCOPD, PRRs are activated on epithelial cells, neutrophils,macrophages, smooth muscle cells, 69 broblasts, andother airway cells. Tobacco smoke acutely activatesMyD88, which is an intracellular toll/interleukin-1receptor adaptor protein. 63

Clinical studies

Challenge modelsModels of smoking-induced COPD in animals have beenused to study proteaseantiprotease imbalance,inammation and autoimmunity, remodelling andmucus production, and emphysema. 70 Animal models of innate immunity and viral exacerbation of COPD areneeded to test novel therapies pre-clinically. Assessmentsof new treatments need to establish whether the treatmentis acting on the intended target from phase 1/2 studies inhuman beings, and the optimum dose and dose intervalfrom clinical pharmacology studies. Just as inhaled andnasal allergen challenge have been used to assess anti-inammatory drugs for asthma, challenge models withlipopolysaccharide71 and other TLR agonists should be

used to study the action of drugs for COPD in man.

BiomarkersFor clinical assessment of new treatments for COPDexacerbations, validated biomarkers would be useful. 72 Potential biomarkers have been measured in blood,urine, sputum, and exhaled breath, and frombronchoscopic and protein microarray techniques; non-invasive methods will probably be most applicable.Raised blood biomarkers in COPD include C-reactiveprotein, coagulation proteins including coagulationfactors (eg, brinogen and anticoagulants), complementfactors, serum amyloid A, cardiac troponin, B-type

Oxygen-based generation

O2

(superoxide radical)present in smoke fromtobacco and biomassfuel, and generated bycells

HOCI(hypochlorous acid)

SOD

Xanthine oxidase andother oxidases

MyeloperoxidaseEosinopil peroxidaseCI-

Carbonylation

Polyunsaturatedfatty acids

ROSMichaeladditionHydroperoxidation

(addition of HO2 group)Reactive aliphatic aldehydes(addition of CHO group)

Aliphatic carbonyl adducts form onproteins and DNA, resulting in alteredactivity and degradation

H2O2(hydrogen peroxide)

HO(hydroxyl radical)

O2

Fe2+

O2

NO2(nitrogendioxideradical)

RSNO(nitrosothiols)

NO2(nitrite)

NO3(nitrate)

ONOO

(peroxynitrite)

NO(nitric oxide radical)present in tobaccosmoke and generated by NOS

Thiylradical

NOS L-citrulline

Nitrogen-based generation

L-arginine

OH

Nitrotyrosine

NO2

Figure 3:Generation of reactive oxygen species (ROS) and downstream pathwaysNOS=nitric oxide synthase. SOD=superoxide dismutase.


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natriuretic peptide, and cytokines (eg, tumour necrosis

factor [TNF], and interleukins 6 and 1). Plasmaleptin concentrations are increased during acuteexacerbations, possibly indicating that negative energybalance and systemic oxidative stress is present.

Several inammatory markers increase in sputum of patients with COPD during acute exacerbations: leuko-triene B 4 (LTB4 ), interleukin 6, interleukin 8 (cysteine-X-cysteine ligand 8 [CXCL8]), endothelin 1, CCL5(cysteine-cysteine ligand 5), and CXCL5. Sputum prote o-mics have been used for inammatory lung disease andcould potentially be used for COPD exacerbations.

When exhaled nitric oxide is partitioned by themultiple ow technique, peripheral nitric oxide(including small airways and lung parenchyma) is

increased. This technique could be useful to detectincreased exhaled nitric oxide during exacerbations of COPD. Use of exhaled breath condensate has severalmethodological problems but is a non-invasivemeasurement and is suited to serial measurementsduring an exacerbation.

Studies of exacerbationsAn acute exacerbation for which the patient needs hospitaladmission is associated with high mortality, intensivemonitoring and treatment, and substantial health-carecosts. 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, andtime to next exacerbation. Available treatments have littleeffect on exacerbations, and therefore studies of theeffects of new drugs on exacerbations would be useful.Such studies would need a rigorous denition of inclusioncriteria, which features to monitor, and criteria for rescuetherapy. To aid drug development, regulatory authoritiescould expedite the assessment of treatments forexacerbations.

New drugs for exacerbationsImprovements to existing drug classesPresent treatments for exacerbations are outside thescope of this Review; we refer to guidelines from GOLD, 3

and published reviews.7375

Extensive efforts in drugdevelopment have focused on inhibition of corticosteroid-insensitive neutrophil inammation 76,77and prevention of exacerbations, rather than treatment of acuteexacerbations. 78 Guidance for industry from the US Foodand Drug Administration about drug development forCOPD concentrates on stable COPD, not treatment of acute exacerbations. 79

Bronchodilators are the mainstay of management.Development of bronchodilators has focused onimproving inhaled longacting 2 agonists and longactingmuscarinic antagonists. 80 The active R,R-enanti omer of formoterolarformoterolis available for COPD

ROS from tobacco smoke and pollutionPathogen-associated molecular patterns (PAMPs) from viruses and bacteria

Damage-associated molecular patterns (DAMPs)

Acute phase response comprises release of: C-reactive protein, mannose-binding lectin Complement factors Coagulation factors Serum amyloid A Anti-proteases

Epithelial barrier compromised: Abnormal mucociliary clearance Mucus and surfactant impaired Epithelial tight junctions damaged

ROS activate epithelial cells and macrophages Chemotactic factors, chemokines, cytokines,

and proteases released Neutrophil, macrophage, and T-cellpopulations (Th1, Th 17, Tc1, Treg) increase

Mucus hypersecretion:chronic bronchitis

Inammation

Fibroblasts and myobroblasts are resident,or are derived from blood-borne brocytes

or epithelialmesenchymal transition

Fibrosis:obstructive bronchiolitis

Fibrogenic factors: TGF Endothelin 1, angiotensin II CTGF, PDGF, IGF1 TNF, interleukins 1 and 13

Fibrosis

Tissue destruction:centrilobular emphysema

Neutrophils and tissue macrophages are arich source of proteases:

Neutrophil elastase Matrix metalloproteases Serine proteases Thrombin activates PAR1 and generates

active TGF

Proteolysis

Pattern recognition receptors (PRRs)

Figure 4:Inammation, brosis, and proteolysis in the respiratory tractCTGF=connective tissue growth factor. IGF1=insulin-like growth factor 1. PAR1=protease-activated receptor 1. PDGF=platelet-derived growth factor. ROS=reactiveoxygen species. Tc1=cytotoxic T cell of type 1. TGF=transforming growth factor . Th1=T helper lymphocyte of type 1. Th17=T helper cell producing interleukin 17.TNF=tumour necrosis factor . Treg=regulatory T cell.


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treatment in some countries, but has not been studiedfor acute exacerbations. 81 Longacting 2 agonists with aduration of more than 24 h, such as indacaterol andcarmoterol, are in development for treatment of stableCOPD. Tiotropium is an effective bronchodilator forstable COPD and reduces exacerbations, but is not suited

as a reliever for acute exacerbations because of its slowonset of action. Aclidinium is a new anticholinergic drugwith acute onset; so far it has disappointed in trials butmight be suited to acute symptomatic relief. 82 Novelclasses of bronchodilator have been diffi cult to developbecause they often affect vascular smooth muscle,resulting in postural hypotension and headache.

Early treatment with antibiotics is benecial forexacerbations of bacterial origin. 83 Non-invasiveventilation has proven useful in selected patients withrespiratory acidosis, 84 and non-pharmacologicalapproaches such as pulmonary rehabilitation arerecommended. Systemic corticosteroids reduce systemic

inammation and can have some effect on acute airwayinammation, 85 but a form of corticosteroid resistancehas been reported in some patients with COPD. 76 Low-dose theophylline can increase the anti-inammatoryeffects of steroids during exacerbations of COPD, 86 andthe drug can also restore reduced histone deacetylase

activity seen in macrophages in patients with COPD.87

Antioxidants and combating pathogensThe causes of COPD exacerbationsoxidative stress,viruses, and bacteriaare rational targets for drugdevelopment. These factors activate the innate immunesystem and therefore drugs that inhibit innate immunitycould potentially treat acute exacerbations, provided thatthey do not suppress the immune system and causeimmunodeciency.

Increased oxidative stress might play a key part inCOPD exacerbations because it amplies theinammatory response and might inhibit anti-

Danger signals

ROSFrom tobacco smoke andpollutants activateTLR2 and TLR4

DAMPsMolecular patterns (alarmins) onendogenous intracellular proteins Damage to cells by ROS HMGB1 (nucleus to lysosome) S100 proteins (cytoplasm) Heat shock proteins (exosomes) Extracellular matrix hyaluronans Uric acid

PAMPsMolecular patterns onbacteria and viruses

Bacteria Lipopolysaccharide: TLR4 Peptidoglycan: TLR2 Lipoteichoic acid: TLR2, TLR6 Flagellin: TLR5

PRRs have extensive cross-talk: TLRs Scavenger receptors RAGE RLRs NLRs

RAGE

RLRsCytoplasmic PRRs that recogniseviral RNA PAMPs and generatetype 1 interferons

NLRsCytoplasmic PRRs that recognisebacterial PAMPs and activateinammasome

InammasomeCaspase-1 activation causes release of interleukins 1 and 18, and can causedeath of host cell

Cycles of inammation,brosis, destruction,regeneration, and repair

Cell activation in macrophages,neutrophils, epithelial cells, and broblasts

Antimicrobial or anti-inammatory products

Defensins (small antimicrobial peptides) Resolvins or protectins Eicosanoids that resolve inammation

Viruses RNA (double-stranded): TLR3 RNA (single-stranded): TLR7 Cytosine-phosphoryl-guanine: TLR9

TLR2, TLR4, TLR1/2,TLR6/2, TLR5, TLR11

Scavenger receptors Scavenger receptor A MARCO CD36 Scavenger receptor B1

Soluble PRRs C-reactive protein Mannose-binding lectin Surfactant proteins A and D

TLR

TLR3, TLR7, TLR9Endosome

HMGB1

Figure 5:Activation of innate immunity by danger signalsDAMPs=damage-associated molecular patterns. HMGB1=high mobility group box 1. MARCO=macrophage receptor with collagenous structure. NLRs=NOD-like receptors. PAMPs=pathogen-associatemolecular patterns. PRRs=pattern recognition receptors. RAGE=receptor for advanced glycation end-products. RLRs=RIG1 (retinoic acid-inducible gene 1)-like receptors. ROS=reactive oxygen speciesTLR=toll-like receptor.


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inammatory effects of corticosteroids, even in highdoses. Therefore treatment with antioxidants could beuseful. 88 Dietary polyphenols in red wine (resveratrol),tomatoes (stilbenes), and tumeric (curcumin) act asantioxidants, but these are unlikely to achieve suffi cientconcentrations in established COPD. Effective anti-oxidants in development include glutathione com-pounds with increased stability, superoxide dismutaseanalogues, and radical scavengers. Nitrone spin-trapantioxidants have increased potency and generatestable compounds to inhibit formation of intracellularROS, and thioredoxin is a redox sensor inhibitor.Hydrogen sulphide is a potent endogenous antioxidant;the molecule GYY4137 releases hydrogen sulphide andprotects 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 infectionin healthy individuals, are prone to cause lower-respiratory-tract infection and acute severe exacerbationsof COPD,2 but improved diagnostic techniques shouldhelp to manage such acute exacerbations. The mostcommon single cause of COPD exacerbationsrhinovirusas yet has no approved treatment, but apotential target is airway mucin production that isdependent on TLR3 and epidermal growth factor (EGF)receptor. 90,91 Treatment of respiratory syncytial virusinfection remains largely supportive, but the monoclonalantibody palivizumab against the viral F protein islicensed for specialist use in restricted circumstances. 92

The present swine-origin inuenza A H1N1 pandemiccould have extremely serious consequences for patientswith pre-existing lung disorders if the virus mutates. Allpatients with COPD should have adequate inuenzaimmunisation, and be considered for early treatmentwith zanamivir and oseltamivir 93 in the event of aninuenza-induced exacerbation. Development of resistance against these drugs is substantial and newantivirals are being actively sought against inuenza. 94

Similarly, resistance to antibiotics is an importantbarrier to effective treatment of bacterial infections.Development of new antibiotics has become increasinglydiffi cult, and new types of treatment are urgentlyneeded. Bacteriophages have been used in Russia for

many decades, but other developed countries have notadopted their use. 95 Lytic phages are highly specic toparticular bacteria, are well tolerated with no risk of overgrowth of intestinal ora, and they can be inhaled,so could be effective for treatment of respiratory bacterialinfections. Antimicrobial peptides such as -defensins,-defensins, and cathelicidins are produced fromepithelial and other cells in the respiratory tract andhave a key role in innate immunity and stimulatingadaptive immune responses. 96 These peptides could beuseful for treatment since they are small, have a lowprobability of resistance, and interact with inuenza Avirus. 97 Macrolide antibiotics with rings of 14 and

15 members have several anti-inammatory effects, butthe molecular mechanisms for these effects areunknown. 98 Non-antibiotic macrolides could also beuseful against inammation and could be inhaledduring an exacerbation. An erythromycin derivativeinhibits neutrophilic inammation, release of transforming growth factor (TGF), and brosis in ableomycin model of pulmonary brosis. 99

Another approach for treatment is to block interactionof PRRs, especially with TLRs activated by oxidants andpathogens. TLRs are closely associated with exacerbations:rhinovirus causes mucin production through a pathwaymediated by TLR3 and EGF receptor, 91 respiratory syncytialvirus activates TLR2100 and can interact withlipopolysaccharide activation of TLR4,101 and severeinuenza of any type depresses systemic responses to TLR

ligands.102

Release of defensins during viral infectionpromotes production of proinammatory cytokines, andtherefore defensins could potentially be developed fortreatment. 97,103 Intensive efforts are underway to developagonists and antagonists of TLRs to treat diseases in whichinammation and infection occur, 104 and soluble RAGE-modulating drugs to treat vascular disorders. Improvedmolecular understanding of activation of innate immunityhas also helped to identify targets. For example, PRRsactivate several signal transduction pathways (eg, nuclearfactor B [NFB], mitogen-activated protein kinase[MAPK], and type 1 interferon), 105 and MyD88 is a commonadapter protein that participates in signalling pathways forseveral TLRs (TLR2, TLR4, TLR7, TLR8, and TLR9).63,106

Preservation of the epithelial barrier and targeting of acutephase reactants could also be benecial.

Anti-inammatory treatmentsApproaches to treatment of pulmonary and systemicinammation, and inammation associated with co-morbidities include statins, phosphodiesterase-4 (PDE4)inhibitors, cytokine-directed therapy, and chemokine-receptor antagonists (gure 6). Corticosteroids haveproven poorly effective in treating stable COPD andexacerbations. Alternative anti-inammatory treatmentsare expected to effectively treat increased inammationduring an exacerbation, possibly by inhalation. However,all anti-inammatory approaches risk increasing the

extent of infection by blunting host defence mechanisms.COPD is associated with complex systemic symptoms,such as inammation associated with cachexia and skeletalmuscle weakness, 10 and comorbidities like cardiovasculardisease. 107 Since statins have a range of anti-inammatoryeffects, they are attractive treatments for COPD. 108 Statinsincrease survival in patients with COPD, 109111 includingthose with coexisting peripheral arterial disease. 112 Statinscould reduce COPD exacerbations, 113 but prospectivestudies are needed to fully assess their benet forprevention and treatment of exacerbations. 114

PDE4 inhibitors have a broad range of anti-inammatoryeffects, but their effectiveness in human beings has been


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limited by side-effects such as nausea, diarrhoea, andheadache. 115,116 Such side-effects suggest that use of oralPDE4 inhibitors for acute anti-inammatory treatmentwould not be possible. Cilomilast showed good resultsfor the rst 6 weeks of treatment for stable COPD 117 butwas less effi cacious in a 6-month study. 118 Roumilast hadsome effi cacy in studies lasting 24 weeks 119 and 1 year,120 but results for prevention of COPD exacerbations areawaited. Future development of inhaled PDE4 inhibitorsmight help to reduce side-effects.

In patients with COPD, inammatory cells that inltratethe airways have a range of abnormalities. For example,alveolar macrophages have a distinct activation state thatis induced by tobacco smoke, 121 and respiratory viralinfection causes macrophage activation by CD1D-dependent natural killer T cells, causing interleukin-13production and chronic inammatory lung disease. 122 Inpatients with stable COPD, cytotoxic T cells increase andregulatory T-cell responses are blunted, 123 and early COPDexacerbations are accompanied by increased Tc2s. 42 In

Ageing and cell deathDamage induced by reactive oxygen speciesSirtuins: SIRT1-specic activatorp38 MAPK, phosphoinositide-3-kinase, histonedeacetylaseVascular endothelial growth factor

Treatment of systemic and concomitantdisease, and comorbidities

Cardiovascular disease: statinsDiabetes mellitusCachexiaMuscle disease

Lung regenerationRetinoic acid receptor agonistMesenchymal stem cellsWNT signalling familyHMGB1Hyaluronase

Anti-proteasesNeutrophil elastase1-antitrypsinMatrix metalloproteaseSerine proteaseThrombin and other coagulation factors

Mucoactive drugsInhibitors of EGF-receptor tyrosine kinase

Calcium-activated chloride channel inhibitorsSurfactant protein B

Oral anti-inammatory treatmentPDE4 inhibitors

StatinsNew corticosteroids

Manipulating the innate immune systemEpithelial barrier preservationAcute phase reactants: C-reactive protein, mannose-bindinglectin, serum amyloid APRRs: TLRs, scavenger receptors, HMGB1 and RAGE

New antibiotics and antivirals

New bronchodilatorsNew corticosteroids

Reversal of steroid resistanceTheophylline and histone deacetylase 2

Targeting processes in COPD

Targeting causes of exacerbations and interactions with PRRs

Improvements to existing drugs

Cell-directed treatmentMacrophage skewing (M1/M2)Th17, Treg, TcCD1D-restricted natural killer T cells

Cytokine and chemokine inhibitorsGM-CSF, TNFInterleukins 1, 6 and 8 (CXCL8)Interferons, TGF, interleukins 10 and 17CXCR1, CXCR2, CXCR3, CCR2, CCR5

Adhesion molecules

Integrins, ICAM1E selectin

Cell signalling and transcriptionMyD88p38 MAPKPhosphoinositide-3-kinase and NFB, inhibitor of B kinase JAK, SYKHistone deacetylasePPAR activators

Inhibition of brosisTGF (PAR1)Connective tissue growth factor, platelet-derivedgrowth factorEndothelin 1Insulin-like growth factor 1Interleukins 1 and 13Serum amyloid PImatinib

AntioxidantsDietary polyphenolsNitrone spin traps, iNOS inhibitorsRedox sensor inhibitors: thioredoxinEnzyme mimetics: SOD-SalensGlutathione peroxidase mimetic: ebselenH2S-releasing molecule: GYY4137

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-activatedprotein kinase. MyD88=myeloid differentiation primary response gene 88. NFB=nuclear factor B. 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. TGF=transforming growth factor . Th17=T helper cell producing interleukin 17. TLR=toll-like receptor.TNF=tumour necrosis factor . Treg=regulatory T cell. WNT=wingless.


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mice, chronic tobacco smoke causes T cells to expressinterferon gamma or interleukin 17, representing a Th1(T helper lymphocyte of type 1) and Th17 subtype, and thisis associated with airspace enlargement. 124

Although blocking TNF is not effective in patients withstable COPD, 125,126 such treatment during an acuteexacerbation might be effective since TNF concentrationincreases during exacerbations. However, the TNFantibody iniximab increased the occurrence of respiratorycancers in patients with COPD, 125 and increased othertypes of cancer and infections in those with severeasthma. 127 Such safety concerns with anti-TNF treatmentcould have substantial implications for other anti-inammatory treatment for exacerbations of COPD.

Monoclonal antibodies against interleukins 6, 1, and17, TGF, and GM-CSF could be useful for COPD.

Tobacco smoke inhibits lipopolysaccharide-induced GM-CSF release by bronchial epithelial cells, 128 and GM-CSFregulates alveolar macrophage responses to Pseudomonas endotoxins. 129 Hence, tobacco smoke might causedefective anti-bacterial responses. Tocilizumab, amonoclonal antibody that targets interleukin-6 receptors,is effective in several inammatory diseases, 130 but studiesin COPD have not yet been done. Th17 cells have recentlybeen identied as a separate cell population that produceinterleukin 17, which causes neutrophilia. 131,132

The concentrations of CXC (cysteine-X-cysteine)-typechemokines, including CXCL5 and interleukin 8(CXCL8), are increased during exacerbations and, sincethey all signal through a common receptor (CXCR2),

specic antagonists of this receptor could be useful fortreatment of exacerbations. A small molecule antagonistof CXCR1 and CXCR2 inhibits sputum neutrophils byabout 80% after inhaled endotoxin, 133 suggesting that thisoral drug could be useful for exacerbations.

LTB4 activates the corresponding receptor BLT 1, whichis expressed on neutrophils and T cells. Since LTB 4 concentration is raised during exacerbations, specicBLT1 antagonists could be benecial for the treatment of exacerbations. 7 However, BLT 1 antagonists have a smalleffect on neutrophil chemotaxis in response tochemotactic factors in COPD sputum 134 and have notproved to be effective for treatment of stable COPD.

NFB is activated during exacerbations and simulta-

neously has a key role in upregulating expression of manyinammatory genes. 135 Oxidative stress, bacteria, andviruses probably activate NFB, making NFB a logicaltarget for inhibition. Selective inhibitors of IB kinase-2(IKK2) have been developed,136 but have not yet been testedclinically for their anti-inammatory effects in COPD.Since IKK2 inhibitors cause impaired innate immunity,their long-term safety is a concern, but they could be usefulfor acute treatment of exacerbations, especially if inhaled.

p38 MAPK is activated by bacteria and viruses, andtherefore is another target for inhibition. 47 Several p38MAPK inhibitors are in clinical development, but theseare expected to have toxic effects, which would make

inhalation of such drugs necessary. Phosphoinositide-3-kinases and have been implicated in inammation,and inhibition of the subtype has been shown to restorecorticosteroid sensitivity in mice. 137

Other treatment modalitiesIn a 3-year study, the putative antioxidant and mucolytic acetylcysteine was not effective, 138 but carbocisteineeffectively prevented exacerbations in Chinese patientswith COPD who were not receiving any other treatments. 139 Mucoactive drugs and drugs to treat airway mucushypersecretion have been developed. 140 These drugs targetinhibitors of EGF-receptor tyrosine kinase and humancalcium-activated chloride channel blockers; surfactantprotein B is also associated with COPD exacerbations. 141 Importantly mucus can be protective as part of the

mucociliary escalator, but can be harmful when infectedand impairing oxygenation. A study using inhaledrecombinant DNAse to treat acute exacerbations of COPDended early because of increased mortality. 142

Despite major advances in our understanding of theprocesses of brosis, 48,49 proteolysis, 53 lung ageing, 143 andrepair, 144,145 drugs acting against these targets, and also toattempt lung regeneration, 146,147are unlikely to be used inthe near future as treatments for acute exacerbations.

ConclusionsImproved anti-infective and antioxidant treatment,coupled with new approaches directed against the innateimmune system, are promising for treatment of COPD

exacerbations. Our understanding of bacterial and viralinteractions with the human immune system is advancingrapidly. Additionally, we have increased knowledge of steroid-insensitive inammation, auto immunity, brosis,aberrant repair, accelerated ageing, and systemic diseaseand comorbidities. Validated biomarkers for COPDexacerbations and challenge models for COPD in animalsand man are needed to improve assessment and directionof new treatments, and clinical trials should assess boththe treatment and prevention of COPD exacerbations.With extensive collaboration between scientists, clinicians,the pharmaceutical industry, and drug regulators it islikely that novel treatments for exacerbations of COPDcan be dened.

ContributorsTTH and PJB worked together on all aspects of this Review.

Conicts of interestTTH has been a speaker for AstraZeneca and Thomson Reuters, and worksin 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,Pzer, Merck, and Altana Pharmaceuticals. PJB has received researchfunding and been a member of scientic advisory boards for AstraZeneca,Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Novartis,Pzer, Teva, and Union Chimique Belge, some of which are marketing anddeveloping treatments for COPD.

AcknowledgmentsWe thank Gary Anderson for his invaluable critical review, andAndrew J Tan for his assistance with the gures and references.


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