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ERS Annual Congress Vienna

15 September 2012

Postgraduate Course 9 Progress on the treatment of COPD

Saturday, 1 September 2012 09:3013:00 Room: Lehar 3-4

Treating systemic effects of COPD

Prof. Mario Cazzola University of Rome Tor Vergata Dept of System Medicine Via Montpellier 1 00133 Rome Italy mario.cazzola@uniroma2.it

Aims
To briefly document that COPD is a chronic inflammatory airway disease with several systemic manifestations To explain why there is a strong need to look beyond the lungs in treating patients with COPD. To illustrate why classes of drugs that are mainly used for cardiovascular disease may be useful in COPD.

Summary
The emerging recognition that chronic obstructive pulmonary disease (COPD) is a complex disorder, characterized not only by local pulmonary inflammation, but also by systemic inflammation that might have an adverse impact on various extrapulmonary organs, such as the blood vessels and the heart, among others [1], emphasizes the need for new and more effective forms of therapy for this debilitating disorder [2, 3]. In the chronic systemic inflammatory state with multiple organ impairment, the centre of therapy should be shifted to the systemic inflammatory state. However, we still do not know whether the successful treatment of the comorbid diseases associated with COPD also positively influences the course of the lung disease [4]. In the last decade we have understood that treatment of comorbid diseases may reduce morbidity and mortality in patients with COPD, although so far there are few definite data that treatment of COPD comorbidities will reduce morbidity and mortality rates in these patients [5]. Contrary to early expectations, inhaled steroids do not seem to influence significantly systemic inflammation in COPD [6]. The role of roflumilast, a novel oral phosphodiesterase-4 inhibitor needs to be really explored in this setting [7]. Observational studies suggest that classes of drugs that are used for cardiovascular disease may be useful in COPD [8]. Progress in basic and translational research has led to a better understanding of pharmacological mechanisms that may explain the effects on COPD of drugs such as statins [9, 10], ACE inhibitors [10], AT1 receptor blockers [10], and -AR blockers [11]. Nonetheless, the role of these drugs in COPD is far from clear but some small clinical trial activity is beginning to generate promising results. In any case, we cannot exclude that the therapeutic approach should only consider pathological mechanisms that bind COPD to a specific comorbidity. Thus, we demonstrated that high glucose concentrations lead to hyperresponsiveness of human isolated bronchi and enhanced intracellular calcium release in cultured ASM cells via a Rho/ROCK and pMYPT1 dependent pathway, suggesting that these crucial pathways may contribute to the reduced lung function observed in diabetic patients [12]. These data suggest novel targets for the treatment of patients with respiratory diseases that also suffer from diabetes mellitus.

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References
1. Sinden NJ, Stockley RA. Systemic inflammation and comorbidity in COPD: a result of 'overspill' of inflammatory mediators from the lungs? Review of the evidence. Thorax. 2010 Oct;65(10):930-6 2. Cazzola M, Ciaprini C, Page CP, Matera MG. Targeting systemic inflammation: novel therapies for the treatment of chronic obstructive pulmonary disease. Expert Opin Ther Targets. 2007 Oct;11(10):1273-86 3. Cazzola M, Matera MG, Rogliani P, Page C. Treating systemic effects of COPD. Trends Pharmacol Sci. 2007 Oct;28(10):544-50 4. Matera MG, Calzetta L, Rinaldi B, Cazzola M. Treatment of COPD: moving beyond the lungs. Curr Opin Pharmacol. 2012 Jun;12(3):315-22 5. Rabe KF, Wedzicha JA. Controversies in treatment of chronic obstructive pulmonary disease. Lancet. 2011 Sep 10;378(9795):1038-47 6. Loke YK, Kwok CS, Singh S. Risk of myocardial infarction and cardiovascular death associated with inhaled corticosteroids in COPD. Eur Respir J. 2010 May;35(5):1003-21 7. Matera MG, Calzetta L, Segreti A, Cazzola M. Emerging drugs for chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2012 Mar;17(1):61-82 8. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J, 2009 May;33(5):1165-85 9. Young RP, Hopkins R, Eaton TE. Pharmacological actions of statins: potential utility in COPD. Eur Respir Rev. 2009 Dec;18(114):222-32 10. Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60 11. Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ. 2011 May 10;342:d2549. doi: 10.1136/bmj.d2549 12. Cazzola M, Calzetta L, Rogliani P, Lauro D, Novelli L, Page CP, Kanabar V, Matera MG. High glucose enhances responsiveness of human airways smooth muscle via Rho/ROCK pathway. Am J Respir Cell Mol Biol. 2012;doi:10.1165/rcmb.2011-0449OC

Evaluation
1. Which of the following statements about the prevalence and significance of extrapulmonary comorbid conditions is most likely correct? a. comorbidities are not common in COPD b. cardiovascular disease is the most frequent comorbidity in COPD c. the prevalence of cardiovascular risk in COPD is more common in middle-age d. the degree of bronchial obstruction does not influence the prevalence of comorbidities in COPD 2. ICSs are central in the treatment of systemic inflammation in COPD a. always b. only when combined with LABAs c. only at high doses d. never 3. Statins have anti-inflammatory effects in both arteries and airways through a. inhibition of mevalonate pathway b. reduction in GTPase (Rho) activity of circulating polymorphic neutrophils c. reduction in serum CRP d. all actions above e. none of the above actions Please find all answers at the back of your handout materials.

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UniversityofRomeTorVergata,Italy DepartmentofSystemMedicine UnitofRespiratoryClinicalPharmacology

TreatingsystemiceffectsofCOPD
Mario Cazzola

Facultydiscosure
Inthelast5years,Ihavereceivedhonorariafor speakingand/orconsultingfromAstraZeneca, BoehringerIngelheim,ChiesiFarmaceutici,Dey, GSK,Lallemand,Mundipharma,Novartis, Pfizer,andStallergenes.

Introduction
AIMS Aim1 TobrieflydocumentthatCOPDisa chronicinflammatoryairwaydiseasewith severalsystemicmanifestations. Aim2 Toexplainwhythereisastrongneedto lookbeyondthelungsintreatingpatientswith COPD. Aim3 Toillustratewhyclassesofdrugsthat aremainlyusedforcardiovasculardiseasemay beusefulinCOPD.

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Peoplewith( )andwithoutCOPD( )whoreportedcardiovascular comorbiditiesbyagegroupandgender(%oftheexaminedpopulation). = Total; =men; =women

Cazzolaetal.Respiration 2010

Comorbiditiesarecommoninpatientshospitalizedfora COPDexacerbation Almagro etal.Respir Med2010

*p<0.05vs men; **p<0.01vs men Datafromcrosssectionalstudyof398patients (353men,45women)hospitalizedforaCOPD exacerbation

ComplexpathwaylinkingCOPDandits keycomorbidities
PatelandHurst,ExpertRevRespirMed 2011

EvidenceofsystemicinflammationinCOPD
Inflammatory Marker Cytokines IL6 IL8 IL1 TNF Adipokines CRP Fibrinogen Serum amyloid A Surfactant D Monocytes Neutrophils Lymphocytes

Acutephase proteins

Circulating cells

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Systemicinflammation(CRP)andprognosisinCOPD

Dahletal,Am J Respir Crit CareMed 2007

ECLIPSEStudy:Proportionofpatientswithnone,one,ortwo(ormore) biomarkers(WBCcount,CRP,IL6andfibrinogen)intheupperquartileofthe COPDdistribution,atbaseline(leftbars)andafteroneyearfollowup(rightbars)

Agustietal,PLoSOne2012
ECLIPSEStudy:percentageofCOPDpatients,byGOLDstageofairflow limitationseverity,withnone(bluebars)or2+biomarkers(redbars)inthe upperquartileoftheCOPDdistributionofvaluesbothatbaselineandafter oneyearfollowup

Agustietal,PLoSOne2012

OddsratiosofcardiovascularmorbiditiesinCOPD accordingtoage

Cazzolaetal,Respir Med 2012

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SystemicInflammationinCOPD
ORIGIN?
Spill over from the lungs Hyperinflation Effect of hypoxia Smoking Bone marrow Skeletal muscle as a source of inflammation

Diagrammaticrepresentationofmechanismsthatinfluencethe processofoverspillanditsdetection.Severalprocesseswill influencethereleaseoflungcytokinesintothecirculation Cazzolaetal,TrendsPharmacol Sci 2007

Theinflammationinthelungspillsover intothesystemic circulationtoproducesystemiceffects,suchasmuscle weaknessorcardiovascularcomplications

SindenandStockley,Thorax 2010

Diagrammaticrepresentationofmechanismsthat influencetheprocessofoverspillanditsdetection

SindenandStockley,Thorax 2010

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COPD:Partofasystemicdisease?
Chronicsystemicinflammatorysyndrome

Inpatientsolderthan40years,withasmoking historyofmorethan10packyears,who developclinicalandfunctionalabnormalities compatiblewithCOPD,ithasbeensuggested nottorestrictthediagnosticapproachtoCOPD alonebuttosearchforsignsofthemore generaldisorderchronicsystemicinflammatory syndrome,withdetaileddescriptionofclinical andfunctionalabnormalitiesoftherespiratory, cardiovascular,andmetabolicsystems
FabbriandRabe,Lancet2007

Infliximab,aTNFinhibitor,didnotaffectthe systemicinflammatoryprofileinCOPDpatients

Lozaetal,RespirRes 2012

Hyperglycaemiaandairways
Glucoseisexclusivelysuppliedtotheairwaysfromcirculating blood,reachingthebasolateral sideofepithelialcells,where uptakeofglucosecanoccur[1]. Inhumans,glucoseconcentrationsinnormalairwaysurfaceliquid areapproximately12.5timeslowerthanbloodglucose concentrations[2]. Anairwaysglucosethresholdexists,sinceglucosedoesnot appearinairwayssecretionsuntilbloodglucosereachesa concentrationof6.79.7mmoll1[3]. Theconcentrationofglucoseintheairwaysurfaceliquidis increasedinhyperglycaemicnondiabeticanddiabeticsubjects [2]. Glucoseconcentrationsarealsoelevated inlowerairway secretions aspiratedviaendotrachealtubesfrompatientswith hyperglycaemiaundergoingmechanicalventilationonintensive care[4]. 1.Pezzulo etal,PLoS One2011
2.Bakeretal,JAppl Physiol 2007 3.Woodetal,Clin Sci (Lond) 2004 4. Philipsetal,Thorax2005

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Effectsofhighglucoseandmannitol (both44mM)onthetransmural stimulation(EFS3,10and25Hz)ofepitheliumintact(A)andepithelium denuded(B)humanisolatedbronchi.

EachvalueisexpressedasthemeanSEM ofn=4differentsubjects.*P<0.05and ***P<0.001vs control, P<0.001vs mannitol.

Cazzolaetal,AmJRespir CellMol Biol 2012

Effectsofhighglucoseandmannitol(both44mM)ontheintracellular calciumfluxinculturedhumanASMcellsstimulatedwithbradykininand influenceofY27632(1M),aselectiveROCKinhibitor

Cazzolaetal,AmJRespir CellMol Biol 2012

Effectsofhighglucoseandmannitol(both44mMfor6hours)onthe phosphorylationofmyosinphosphatasetargetsubunit1(MYTP1),a regulatorysubunitofproteinphosphatase1,inculturedhumanASMcells andinfluenceofthepretreatmentfor1hourwithY27632(1M).

Cazzolaetal,AmJRespir CellMol Biol 2012

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Thereisastrongneedtolookbeyondthe lungs
Severaldifferentcomorbiditiesareassociated withCOPD. Itisclear,therefore,thatthereisastrong needtolookbeyondthelungsintreating patientswithCOPD.

Thetwodifferentviewsrelatingtheobserved associationsbetweenCOPDandcomorbidities Importanttherapeuticconsequences Inthespillovertheory,theaimsoftherapyare primarilycentredinthelungs. Inthesystemicinflammatorystatewithmultiple organcompromise,thecentreoftherapyshouldbe shiftedtothesystemicinflammatorystate. However,wecannotexcludethatthetherapeutic approachshouldonlyconsiderpathological mechanismsthatbindCOPDtoaspecificcomorbid.

TreatingsystemiceffectsofCOPD
Traditional treatmentandits potential tomodify systemic effects ofCOPD
Smokingcessation Bronchodilators Inhaled corticosteroids (ICSs) Combinationtherapy

Potential morespecific antiinflammatory therapies

Selective phosphodiesterase inhibitors Glycosaminoglycans Antioxidant therapy Statins Angiotensinconverting enzyme (ACE)inhibitors andangiotensin II (Ang II)type 1(AT1)receptor blockers Peroxisome proliferatoractivated receptor (PPAR)agonists Cazzolaetal,TrendsPharmacol Sci 2007

57

Possibleprotectionbyinhaledbudesonide800g/die()vs. placebo()againstischaemiccardiaceventsinmildCOPD:the3 yrEUROSCOPstudy

Lofdahl etal.ERJ 2007

Onlyverylowdosesofinhaledcorticosteroidsmaybe associatedwithareductionintheriskofacute myocardialinfarction

Huiart etal,Eur Respir J 2005

RCTsfailedtoshowanysignificanteffectofICS therapyonMIorCVdeathinCOPDpatients
Myocardialinfarction Cardiovasculardeath

Lokeetal,ERJ2010

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EffectsoffluticasoneonCRPinCOPD

Sinetal,Am J Respir Crit CareMed 2004

Theeffects offluticasone withorwithout salmeterol onsystemic biomarkers ofinflammation inCOPD

Sinetal,Am J Respir Crit CareMed 2008

ICS/LABAcombinationmayreduceaorticpulsewavevelocityin patientswiththegreatestabnormalityinarterialstiffness

Dransfieldetal,RespirMed 2011
Changestotalcellcountandnumbersofneutrophilsand eosinophilsinsputum,ineosinophilcationicprotein(ECP),interleukin(IL)8and neutrophilelastase(NE),lactoferrinand2macroglobulinlevelsinsputum supernatantsduringroflumilast(blackbars)andplacebo(whitebars)treatment for4weeks

Grootendorst etal,Thorax 2007

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SurvivalofanimalsisincreasedbyPD4Itreatmentinsystemicinflammation KaplanMeiermethodwasusedtoanalysesurvivalofanimalsinthedifferent experimentalgroups

Carverley etal. Lancet 2009

ChangeinCreactiveproteinfrombaselinetolastpostrandomisation visitintwo1yearplacebocontrolled,doubleblind,multicentretrials withroflumilastinCOPD

Schick et al, J Physiol 2012

PD4Isblockedcapillaryleakageinpostcapillary venules

Schick et al, J Physiol 2012

cAMPlevels inmesenteric microvessels werereducedafter systemic LPSapplicationbuttheadditionofPD4IsdidnotchangecAMP levelssignificantly

Schick et al, J Physiol 2012

AntiinflammatoryeffectsofheparinrelevanttoCOPD
Heparinneutraliseselastase [1]andcathepsin G[2]. Heparininhibitsreleaseofelastase fromhuman neutrophils[3] Heparininhibitsfunctionofvariousadhesionmolecules onleukocytesandvascularendothelium[4]. Systemicheparininhibitsleukocytetraffickingintolung tissues[5]. Additionofenoxaparintothecombinationof salmeterol/fluticasoneimprovessymptomsinpatients withCOPD[6]. 1. Walshetal,ClinSci(Lond) 1991
2. Ledoux etal,FEBSLett 2003 3. Brownetal,BrJPharmacol 2003 4. Leveretal, BrJPharmacol 2000 5. LeverandPage,NatRevDrugDiscov 2002 6. Brownetal,PulmPharmacolTher 2006

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Reductionofmorbidityandmortalitybystatins,angiotensinconverting enzymeinhibitors,andangiotensinreceptorblockersinpatientswith COPD

*P<0.05and**P<0.01,whencomparedtobaselinevalueswithineachgroup

Brown etal,Pulm Pharmacol Ther 2006

AdditionalclinicalbenefitofenoxaparininCOPDpatients receivingsalmeterolandfluticasonepropionatein combination

Mancinietal,JAmCollCardiol 2006

Irbesartan elicits encouraging beneficial effects onemphysema severity, lung biomechanics andexercise capacity inanemphysema mousemodel
Healthy controls (white columns), emphysema micereceiving controlfood (grey)and emphysema micetreated withirbesartan (black)

Histological andfunctional parameters Runningdistance

A,mean linearintercept;B,static compliance;C, timeconstant

Raupachetal,PulmPharmacolTher 2011

UseACEinhibitorspriortoadmissionisassociated withdecreased mortalityinsubjectshospitalizedwithaCOPDexacerbation

Mortensen etal.Respir Res2009

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Irbesartanseemsabletoreducethehyperinflationin patientswithCOPDviaanunknownmechanism

Andreasetal,EurRespirJ 2006

AngiotensinconvertingenzymeinhibitorsandangiotensinIItype1 receptorantagonistsblocktheproinflammatory effect ofangiotensinII

Materaetal,Curr Opin Pharmacol 2012

StatininCOPD
Control Smoke

Effectofsimvastatin oncigarettesmokeinduced emphysemainrats

Smoke+statin Statin

Inammatorycells MMP9 eNOS Pulmonaryvascular remodelling

Leeetal,Am J Respir Crit CareMed 2005

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Statinuseattenuatesdeclineinlungfunctionintheelderly,with thesizeofthebeneficialeffectmodifiedbysmokingstatus

Alexeeff etal,Am J Respir Crit CareMed 2007

Inpatientsreceivingstatins,alowerFEV1 andFVCdeclinewas apparentinboththecurrentsmokerandtheexsmokergroups

Keddissi etal,Chest 2007

Insmokers andformer smokers,statins areassociated with aslower decline inpulmonary function,independent oftheunderlying lung disease

Keddissi etal,Chest 2007

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PatientswithCOPDandtakingstatinshavereducedhospitalisation forCOPD exacerbations,lowermortalityfromCOPDexacerbations(orchestinfections)and lowercardiovascularmortalitycomparedtothosenottakingstatins

Youngetal.EurRespirRev2009

Useofstatinspriortoadmissionisassociatedwithdecreased mortalityinsubjectshospitalizedwithaCOPDexacerbation

Mortensen etal.Respir Res2009

ChangesinhsCRPovertimeareassociatedwithcorresponding changesinexercisetoleranceunderstatintherapyinCOPD
Relativechanges inhsCRPlevels,i.e.,<1 mg/L(white bars),1to3mg/L(hatched bars),and>3mg/L(black bars) Improvement inexercise timein(top) responders but nochange in(bottom) nonresponders

Leeetal,AmJCardiol 2008

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BeneficialeffectsofstatinsinCOPD

Barnes andCelli,EurRespir J2009

Mechanismofactionofstatins
ThemechanismbywhichstatinscouldbeusedforthetreatmentofCOPD patientsseemstobethesameasthatobservedforcholesterollowering

Materaetal,CurrOpinPharmacol2012

HMGCoA,3hydroxy3methylglutarylcoenzyme A;FPP,farnesylpyrophosphate;FTase,farnesyl proteintransferase;SQase,squalenesynthase; GGPP,geranylgeranyldiphosphate;GGTase, geranylgeranylproteintransferase

Inhibitionofmevalonate pathway,whichtriggerstheprenylation ofsmallGTPases,bystatinspreventsthedetrimentaleffectsofLPS inhumanairways

Cazzolaetal,Am J Respir CellMol Biol 2011

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Statinsandpulmonaryinflammation
WhetherstatinshaveabeneficialeffectinCOPD

patientsbyprimarilyreducingcardiovascular complicationsorbecausetheyexhibitanaction directlytargetingpulmonaryinflammationisstilla matterofcontroversy. Intriguingly,Hurstetal. [1]reportedthat,while statinswereassociatedwithreducedplasmaIL6 concentrationinpatientswithCOPDandcomorbid CVD,thismightbenottrueinpatientswithoutCVD.

Hurstetal,Chest 2007

CumulativesurvivalofpatientswithCOPD accordingtoblockeruse
Rutten etal,Arch Intern Med 2010

CrudeandadjustedHazardRatios(HR)formortality accordingtoblockeruseinpatientswithadiagnosisof COPD

PatientswithCHFandCOPDtoleratedcarvedilolwellwithnosignificant reversibleairflowlimitation,butpatientswithCHFandasthmatolerated carvedilolpoorly.Theconcomitantuseofneitherinhaledbronchodilators norICSsduringthecarvediloltherapyinfluencedwhotoleratedcarvedilol andwhodidnot.

Kotlyar etal,J Heart Lung Transplant 2002

Survivalwassignificantlybetterinpatientswithheartfailure receivingblockersintheCHARMprogramme,irrespectiveof concurrentbronchodilatortherapy

Hawkinsetal,EurJHeartFail2010

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KaplanMeierestimateofprobabilityofsurvival amongpatientswithCOPDbyuseofblockers
Shortetal,BMJ 2011 Adjustedhazardratiosforallcausemortalityamongpatientswith COPDinreferencetothecontrolgroup(whoreceivedonlyinhaled therapywithshortactingagonistsorantimuscarinics)
Adjustedhazardratiosforemergencyoralcorticosteroid prescription amongpatientswithCOPDinreference tothecontrolgroup(who receivedonlyinhaledtherapywithshortactingagonistsor antimuscarinics)

Peroxisomeproliferatoractivated(PPAR)agonisteffects oninflammatoryandstructuralcells

Barnes andCelli,EurRespir J2009

EffectofaPPAR agonistonneutrophilia
10 8 6 4 2 0 ControlLPS Rosiglitazone Dex

Mouselungtissue
N.S. p<0.05

Birrell etal,Eur Resp J 2004

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Antiinflammatoryeffectsofdiabetictherapy
Metformininhibitsreleaseofproinflammatory cytokinesandactivationofNFB (1). Thiazolidinediones (glitazones)downregulate NF Bmediatedinflammatorypathwaysandreduce levelsofTNFandIL6(2). Insulinsuppressesproductionofreactiveoxygen speciesandinhibitsproinflammatorytranscription factorssuchasNFB (3).

1.Isoda et al,Arterioscler Thromb Biol 2006 2.Ceriello,DiabetesMetabResRev 2008 3.Dandona et al,JClin Invest 2005

InsulinisabletoinduceaconcentrationdependentASMcontraction, whichismediatedbythegenerationofcontractile prostaglandins

Schaafsma et al,BrJPharmacol 2007

Rhokinaseandphosphatidylinositol(PI)3kinasearerequired forinsulininducedcontractileproteinaccumulation

Schaafsma et al, Am J Physiol Cell Physiol 2007

Thehyperresponsivenessofhumanisolatedbronchiinducedbyhighglucose concentrationswasnotreversednormalizingtheglucoseconcentrationat5mM. Furthermore,Y27632(1M)wasineffectiveinreversingthehyperresponsiveness inducedbyhighglucoseconcentrations

Cazzolaetal,AmJRespir CellMol Biol 2012

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Effectsofhighglucose(44mM)onthetransmuralstimulation(EFS3,10and 25Hz)ofhumanisolatedbronchiandinfluenceoftheselectiveROCK inhibitorsY27632andSB772077B

Cazzolaetal,AmJRespir CellMol Biol 2012

Conclusion.I
ThecoexistenceofCOPDandotherdiseasesis frequent,butcommonlyignored. Inthelastdecadewe have understood that treatmentofcomorbid diseases may reduce morbidity andmortality inpatients withCOPD, although sofarthere arefew definitedatathat treatmentofCOPDcomorbidities will reduce morbidity andmortality rates inthese patients.

Conclusion.II
Itisstillunclearwhatmechanism(s)link(s)COPDandits comorbiddiseases. Itisalsounclearwhethertherapyaimedatoptimizing pulmonaryfunctioninCOPDresultsinareductionof systemicinflammationinthesepatientsorwhetherthe directtargetingofsystemicinflammationinfluencesthe naturalhistoryofCOPDand,consequently,whether treatmentofcomorbidconditionsaltersthenatural historyofCOPDorwhethertreatmentofCOPDis alteredbythepresenceofaconcomitantcomorbid disease.

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Conclusion.III
Progressinbasicandtranslationalresearchhasled toabetterunderstandingofpharmacological mechanismsthatmayexplaintheeffectsonCOPD ofdrugssuchasstatins,ACEinhibitors,AT1receptor blockers,andARblockers. Nonetheless,theroleofthesedrugsinCOPDisfar fromclearbutsomesmallclinicaltrialactivityis beginningtogeneratepromisingresults.

Conclusion.IV
Itisnowtimetomovefromproofofprincipletolargescale clinicalapplicability.Prospectiveinterventionaltrialsshould aimtoanswertheimportantquestionastowhetherthe successfultreatmentofthecomorbiddiseasesassociated withCOPDalsopositivelyinfluencesthecourseofthelung disease. However,whendesigningthesetrialsitshouldbekeptinthe mindthatCOPDisheterogeneous,inbothclinical manifestationsandresponsetotherapy. Moreover,comorbiditiesmayresultfromsharedgenetic susceptibility,suggestingthattherapiestargetingthese pathwayshavepotentialtotreatseveralconditions simultaneously.

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