Emerging pharmaceutical therapies for COPD

References

• FerkolTSchraufnagelDThe global burden of respiratory diseaseAnn Am Thorac Soc201411340440624673696
   PubMedGoogle Scholar
• HeronMDeaths: leading causes for 2013Natl Vital Stat Rep201565295
   Google Scholar
• Centers for Disease Control and Prevention (CDC)Chronic obstructive pulmonary disease among adults – United States, 2011MMWR Morb Mortal Wkly Rep2012614693894323169314
   PubMedGoogle Scholar
• BarnesPJNew anti-inflammatory targets for chronic obstructive pulmonary diseaseNat Rev Drug Discov201312754355923977698
   PubMed Web of Science ®Google Scholar
• VestboJHurdSSAgustiAGGlobal strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summaryAm J Respir Crit Care Med2013187434736522878278
   PubMed Web of Science ®Google Scholar
• WoodruffPGAgustiARocheNSinghDMartinezFJCurrent concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised managementLancet201538599791789179825943943
   PubMed Web of Science ®Google Scholar
• CaramoriGCasolariPBarczykADurhamALDi StefanoAAdcockICOPD immunopathologySemin Immunopathol201638449751527178410
   PubMed Web of Science ®Google Scholar
• WiegmanCHMichaeloudesCHajiGOxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary diseaseJ Allergy Clin Immunol2015136376978025828268
   PubMed Web of Science ®Google Scholar
• Vedel-KroghSNielsenSFLangePVestboJNordestgaardBGBlood eosinophils and exacerbations in chronic obstructive pulmonary disease. The Copenhagen General Population StudyAm J Respir Crit Care Med2016193996597426641631
   PubMed Web of Science ®Google Scholar
• Abbott-BannerKHPageCPDual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseasesBasic Clin Pharmacol Toxicol2014114536537624517491
   PubMed Web of Science ®Google Scholar
• PavordIDJonesPWBurgelPRRabeKFExacerbations of COPDInt J Chron Obstruct Pulmon Dis201611Spec Iss213026937187
   PubMedGoogle Scholar
• TseHNRaiteriLWongKYNgLYYeeKSTsengCZBenefits of high-dose N-acetylcysteine to exacerbation-prone patients with COPDChest2014146361162324833327
   PubMed Web of Science ®Google Scholar
• MartinezFJCalverleyPMGoehringUMBroseMFabbriLMRabeKFEffect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trialLancet2015385997185786625684586
   PubMed Web of Science ®Google Scholar
• CelliBRMacNeeWStandards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paperEur Respir J200423693294615219010
   PubMed Web of Science ®Google Scholar
• CelliBRThomasNEAndersonJAEffect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH studyAm J Respir Crit Care Med2008178433233818511702
   PubMed Web of Science ®Google Scholar
• VestboJAndersonJABrookRDFluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trialLancet2016387100301817182627203508
   PubMed Web of Science ®Google Scholar
• BafadhelMMcKennaSTerrySAcute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkersAm J Respir Crit Care Med2011184666267121680942
   PubMed Web of Science ®Google Scholar
• SoterSBartaIAntusBPredicting sputum eosinophilia in exacerbations of COPD using exhaled nitric oxideInflammation20133651178118523681903
   PubMed Web of Science ®Google Scholar
• BrightlingCEMonteiroWWardRSputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trialLancet200035692401480148511081531
   PubMed Web of Science ®Google Scholar
• ChanezPVignolaAMO’ShaugnessyTCorticosteroid reversibility in COPD is related to features of asthmaAm J Respir Crit Care Med19971555152915349154853
   PubMed Web of Science ®Google Scholar
• PizzichiniEPizzichiniMMGibsonPSputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitisAm J Respir Crit Care Med19981585 pt 1151115179817701
   PubMed Web of Science ®Google Scholar
• PaceEGiarratanoAFerraroMTLR4 upregulation underpins airway neutrophilia in smokers with chronic obstructive pulmonary disease and acute respiratory failureHum Immunol2011721546220888880
   PubMed Web of Science ®Google Scholar
• MortazEAdcockIMItoKKraneveldADNijkampFPFolkertsGCigarette smoke induces CXCL8 production by human neutrophils via activation of TLR9 receptorEur Respir J20103651143115419840968
   PubMed Web of Science ®Google Scholar
• HoggJCChuFUtokaparchSThe nature of small-airway obstruction in chronic obstructive pulmonary diseaseN Engl J Med2004350262645265315215480
   PubMed Web of Science ®Google Scholar
• BurgelPRBourdinAChanezPUpdate on the roles of distal airways in COPDEur Respir Rev20112011972221357888
   PubMedGoogle Scholar
• ChungKFAdcockIMMultifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destructionEur Respir J20083161334135618515558
   PubMed Web of Science ®Google Scholar
• McDonoughJEYuanRSuzukiMSmall-airway obstruction and emphysema in chronic obstructive pulmonary diseaseN Engl J Med2011365171567157522029978
   PubMed Web of Science ®Google Scholar
• LozaMJWattRBaribaudFBarnathanESRennardSISystemic inflammatory profile and response to anti-tumor necrosis factor therapy in chronic obstructive pulmonary diseaseRespir Res2012131222300528
   PubMed Web of Science ®Google Scholar
• HoggJCChuFSTanWCSurvival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathologyAm J Respir Crit Care Med2007176545445917556723
   PubMed Web of Science ®Google Scholar
• BarnesPJMechanisms and resistance in glucocorticoid control of inflammationJ Steroid Biochem Mol Biol20101202–3768520188830
   PubMed Web of Science ®Google Scholar
• BarnesPJCorticosteroid resistance in patients with asthma and chronic obstructive pulmonary diseaseJ Allergy Clin Immunol2013131363664523360759
   PubMed Web of Science ®Google Scholar
• BarnesPJRole of HDAC2 in the pathophysiology of COPDAnnu Rev Physiol20097145146418817512
   PubMed Web of Science ®Google Scholar
• CosioBGTsaprouniLItoKJazrawiEAdcockIMBarnesPJTheophylline restores histone deacetylase activity and steroid responses in COPD macrophagesJ Exp Med2004200568969515337792
   PubMed Web of Science ®Google Scholar
• SubramanianRagulanJindalAViswambharVArun BabuVThe study of efficacy, tolerability and safety of theophylline given along with formoterol plus budesonide in COPDJ Clin Diagn Res201592OC10OC13
   Google Scholar
• CosioBGShafiekHIglesiasAOral low-dose theophylline on top of inhaled fluticasone-salmeterol does not reduce exacerbations in patients with severe COPD: a pilot clinical trialChest2016150112313027107490
   PubMed Web of Science ®Google Scholar
• SuzukiMBetsuyakuTItoYDown-regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary diseaseAm J Respir Cell Mol Biol200839667368218566336
   PubMed Web of Science ®Google Scholar
• MalhotraDThimmulappaRKMercadoNDenitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patientsJ Clin Invest2011121114289430222005302
   PubMed Web of Science ®Google Scholar
• MarwickJACaramoriGStevensonCSInhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in miceAm J Respir Crit Care Med2009179754254819164702
   PubMed Web of Science ®Google Scholar
• BoardmanCChachiLGavrilaAMechanisms of glucocorticoid action and insensitivity in airways diseasePulm Pharmacol Ther201429212914325218650
   PubMed Web of Science ®Google Scholar
• MercadoNHakimAKobayashiYRestoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthmaPLoS One201277e4158222911818
   PubMed Web of Science ®Google Scholar
• MilaraJLluchJAlmudeverPFreireJXiaozhongQCortijoJRoflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary diseaseJ Allergy Clin Immunol2014134231432224636089
   PubMed Web of Science ®Google Scholar
• RennardSICalverleyPMGoehringUMBredenbrokerDMartinezFJReduction of exacerbations by the PDE4 inhibitor roflumilast – the importance of defining different subsets of patients with COPDRespir Res2011121821272339
   PubMed Web of Science ®Google Scholar
• CaramoriGAdcockIMDi StefanoAChungKFCytokine inhibition in the treatment of COPDInt J Chron Obstruct Pulmon Dis2014939741224812504
   PubMed Web of Science ®Google Scholar
• RennardSIDaleDCDonohueJFCXCR2 antagonist MK-7123. A phase 2 proof-of-concept trial for chronic obstructive pulmonary diseaseAm J Respir Crit Care Med201519191001101125695403
   PubMed Web of Science ®Google Scholar
• KirstenAMForsterKRadeczkyEThe safety and tolerability of oral AZD5069, a selective CXCR2 antagonist, in patients with moderate-to-severe COPDPulm Pharmacol Ther201531364125681277
   PubMed Web of Science ®Google Scholar
• KerstjensHABjermerLErikssonLDahlstromKVestboJTolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in moderate to severe COPD patientsRespir Med201010491297130320466530
   PubMed Web of Science ®Google Scholar
• BaiJSongHCaiCZhangMXuSTanJThe association of monocyte chemotactic protein-1 and CC chemokine receptor 2 gene variants with chronic obstructive pulmonary diseaseDNA Cell Biol20123161058106322276574
   PubMed Web of Science ®Google Scholar
• MonzonMEFortezaRMCasalino-MatsudaSMMCP-1/CCR2B-dependent loop upregulates MUC5AC and MUC5B in human airway epitheliumAm J Physiol Lung Cell Mol Physiol20113002L204L21521097527
   PubMed Web of Science ®Google Scholar
• BotelhoFMBauerCMFinchDIL-1alpha/IL-1R1 expression in chronic obstructive pulmonary disease and mechanistic relevance to smoke-induced neutrophilia in micePLoS One2011612e2845722163019
   PubMed Web of Science ®Google Scholar
• RoglianiPCalzettaLOraJMateraMGCanakinumab for the treatment of chronic obstructive pulmonary diseasePulm Pharmacol Ther201531152725660162
   PubMed Web of Science ®Google Scholar
• VarricchiGBagnascoDBorrielloFHefflerECanonicaGWInterleukin-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needsCurr Opin Allergy Clin Immunol201616218620026859368
   PubMed Web of Science ®Google Scholar
• RoosABSandenCMoriMBjermerLStampfliMRErjefaltJSIL-17A is elevated in end-stage chronic obstructive pulmonary disease and contributes to cigarette smoke-induced lymphoid neogenesisAm J Respir Crit Care Med2015191111232124125844618
   PubMed Web of Science ®Google Scholar
• ZhangJChuSZhongXLaoQHeZLiangYIncreased expression of CD4+IL-17+ cells in the lung tissue of patients with stable chronic obstructive pulmonary disease (COPD) and smokersInt Immunopharmacol2013151586623127823
   PubMed Web of Science ®Google Scholar
• ShanMChengHFSongLZLung myeloid dendritic cells coordinately induce TH1 and TH17 responses in human emphysemaSci Transl Med2009144ra10
   PubMed Web of Science ®Google Scholar
• RoosABSethiSNikotaJIL-17A and the promotion of neutrophilia in acute exacerbation of chronic obstructive pulmonary diseaseAm J Respir Crit Care Med2015192442843726039632
   PubMed Web of Science ®Google Scholar
• JinYWanYChenGTreg/IL-17 ratio and Treg differentiation in patients with COPDPLoS One2014910e11104425329073
   PubMed Web of Science ®Google Scholar
• FreemanCMMartinezCHTodtJCAcute exacerbations of chronic obstructive pulmonary disease are associated with decreased CD4+ & CD8+ T cells and increased growth & differentiation factor-15 (GDF-15) in peripheral bloodRespir Res2015169426243260
   PubMed Web of Science ®Google Scholar
• ZhangXZhengHZhangHIncreased interleukin (IL)-8 and decreased IL-17 production in chronic obstructive pulmonary disease (COPD) provoked by cigarette smokeCytokine201156371772521996014
   PubMed Web of Science ®Google Scholar
• FreemanCMMcCubbreyALCrudgingtonSBasal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent molecular correlates of airflow obstruction and emphysema extentPLoS One201495e9642124805101
   PubMed Web of Science ®Google Scholar
• KangMJChoiJMKimBHIL-18 induces emphysema and airway and vascular remodeling via IFN-gamma, IL-17A, and IL-13Am J Respir Crit Care Med2012185111205121722383501
   PubMed Web of Science ®Google Scholar
• NakajimaTOwenCInterleukin-18: the master regulator driving destructive and remodeling processes in the lungs of patients with chronic obstructive pulmonary disease?Am J Respir Crit Care Med2012185111137113922661518
   PubMed Web of Science ®Google Scholar
• MedImmune LLCA study to evaluate the safety of MEDI2338 in subjects with chronic obstructive pulmonary disease2013 Available from: https://clinicaltrials.gov/ct2/show/results/NCT1322594?term=MEDI2338&rank=1. NLM identifier: NCT1322594Accessed January 15, 2016
   Google Scholar
• HodgeGReynoldsPNHolmesMHodgeSDifferential expression of pro-inflammatory cytokines in intra-epithelial T cells between trachea and bronchi distinguishes severity of COPDCytokine201260384384822929410
   PubMed Web of Science ®Google Scholar
• NormanPInvestigational p38 inhibitors for the treatment of chronic obstructive pulmonary diseaseExpert Opin Investig Drugs2015243383392
   PubMed Web of Science ®Google Scholar
• RobinsonCXiaKRussellPA 12 week, randomized, double-blind, placebo controlled study of the efficacy of RV568 (JNJ49095397), a narrow spectrum kinase inhibitor, in COPD patientsAm J Respir Crit Care Med2016193A6843
   Google Scholar
• Fung-LeungWPPhosphoinositide 3-kinase delta (PI3Kdelta) in leukocyte signaling and functionCell Signal201123460360820940048
   PubMed Web of Science ®Google Scholar
• DownKAmourABaldwinIROptimization of novel indazoles as highly potent and selective inhibitors of phosphoinositide 3-kinase delta for the treatment of respiratory diseaseJ Med Chem201558187381739926301626
   PubMed Web of Science ®Google Scholar
• WatzHBockDMeyerMInhaled pan-selectin antagonist bimosiamose attenuates airway inflammation in COPDPulm Pharmacol Ther201326226527023257347
   PubMed Web of Science ®Google Scholar
• LakshmiSPReddyATZhangYDown-regulated peroxisome proliferator-activated receptor gamma (PPARgamma) in lung epithelial cells promotes a PPARgamma agonist-reversible proinflammatory phenotype in chronic obstructive pulmonary disease (COPD)J Biol Chem2014289106383639324368768
   PubMed Web of Science ®Google Scholar
• LeaSPlumbJMetcalfeHThe effect of peroxisome proliferator-activated receptor-gamma ligands on in vitro and in vivo models of COPDEur Respir J201443240942023794466
   PubMed Web of Science ®Google Scholar
• ShanMYouRYuanXAgonistic induction of PPARgamma reverses cigarette smoke-induced emphysemaJ Clin Invest201412431371138124569375
   PubMed Web of Science ®Google Scholar
• RinneSTLiuCFFeemsterLCThiazolidinediones are associated with a reduced risk of COPD exacerbationsInt J Chron Obstruct Pulmon Dis2015101591159726300638
   PubMed Web of Science ®Google Scholar
• ShujaatABajwaAACuryJDPulmonary hypertension secondary to COPDPulm Med2012201220395222973510
   PubMedGoogle Scholar
• ValerioGBraccialePGrazia D’AgostinoAEffect of bosentan upon pulmonary hypertension in chronic obstructive pulmonary diseaseTher Adv Respir Dis200931152119293199
   PubMedGoogle Scholar
• ZakynthinosEDaniilZPapanikolaouJMakrisDPulmonary hypertension in COPD: pathophysiology and therapeutic targetsCurr Drug Targets201112450151321194405
   PubMed Web of Science ®Google Scholar
• StolzDRaschHLinkaAA randomised, controlled trial of bosentan in severe COPDEur Respir J200832361962818448495
   PubMed Web of Science ®Google Scholar
• CrinerGJConnettJEAaronSDSimvastatin for the prevention of exacerbations in moderate-to-severe COPDN Engl J Med2014370232201221024836125
   PubMed Web of Science ®Google Scholar
• NeukammAHoisethADEinvikGRosuvastatin treatment in stable chronic obstructive pulmonary disease (RODEO): a randomized controlled trialJ Intern Med20152781596725495178
   PubMed Web of Science ®Google Scholar
• DinavahiSSNyayapathySPerumalYDharmarajanSViswanadhaSCombined inhibition of PDE4 and PI3Kdelta modulates the inflammatory component involved in the progression of chronic obstructive pulmonary diseaseDrug Res (Stuttg)201464421421924105104
   PubMedGoogle Scholar
• MulhallAMDroegeCAErnstNEPanosRJZafarMAPhosphodi-esterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugsExpert Opin Investig Drugs2015241215971611
   PubMed Web of Science ®Google Scholar
• De SaviCCoxRJWarnerDJEfficacious inhaled PDE4 inhibitors with low emetic potential and long duration of action for the treatment of COPDJ Med Chem201457114661467624785301
   PubMed Web of Science ®Google Scholar
• OstridgeKWilliamsNKimVRelationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPDThorax201671212613226645414
   PubMed Web of Science ®Google Scholar
• ChurgAWangRWangXOnnervikPOThimKWrightJLEffect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsThorax200762870671317311841
   PubMed Web of Science ®Google Scholar
• MacNeeWOxidants/antioxidants and COPDChest20001175 suppl 1303S317S
   PubMed Web of Science ®Google Scholar
• BernardoIBozinovskiSVlahosRTargeting oxidant-dependent mechanisms for the treatment of COPD and its comorbiditiesPharmacol Ther2015155607926297673
   PubMed Web of Science ®Google Scholar
• BocciVValacchiGNrf2 activation as target to implement therapeutic treatmentsFront Chem20153425699252
   PubMed Web of Science ®Google Scholar
• WiseRAHolbrookJTCrinerGLack of effect of oral sulforaphane administration on Nrf2 expression in COPD: a randomized, double-blind, placebo controlled trialPLoS One20161111e016371627832073
   PubMed Web of Science ®Google Scholar
• Dal NegroRWViscontiMTurcoPEfficacy of erdosteine 900 versus 600 mg/day in reducing oxidative stress in patients with COPD exacerbations: results of a double blind, placebo-controlled trialPulm Pharmacol Ther201533475126116425
   PubMed Web of Science ®Google Scholar
• MorettiMErdosteine: its relevance in COPD treatmentExpert Opin Drug Metab Toxicol20095333334319331595
   PubMed Web of Science ®Google Scholar
• TseHNRaiteriLWongKYHigh-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE studyChest2013144110611823348146
   PubMed Web of Science ®Google Scholar
• ZhengJPWenFQBaiCXTwice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trialLancet Respir Med20142318719424621680
   PubMed Web of Science ®Google Scholar
• DecramerMRutten-van MolkenMDekhuijzenPNEffects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trialLancet200536594701552156015866309
   PubMed Web of Science ®Google Scholar
• PelaRCalcagniAMSubiacoSIsidoriPTubaldiASanguinettiCMN-acetylcysteine reduces the exacerbation rate in patients with moderate to severe COPDRespiration199966649550010575333
   PubMed Web of Science ®Google Scholar
• SchermerTChavannesNDekhuijzenRFluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitisRespir Med2009103454255119138505
   PubMed Web of Science ®Google Scholar
• YuHLiQKolosovVPPerelmanJMZhouXRegulation of cigarette smoke-mediated mucin expression by hypoxia-inducible factor-1alpha via epidermal growth factor receptor-mediated signaling pathwaysJ Appl Toxicol201232428229221544845
   PubMed Web of Science ®Google Scholar
• RubinBKPriftisKNSchmidtHJHenkeMOSecretory hyperresponsiveness and pulmonary mucus hypersecretionChest2014146249650725091755
   PubMed Web of Science ®Google Scholar
• PolosukhinVVCatesJMLawsonWEHypoxia-inducible factor-1 signalling promotes goblet cell hyperplasia in airway epitheliumJ Pathol2011224220321121557221
   PubMed Web of Science ®Google Scholar
• CurranDRCohnLAdvances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway diseaseAm J Respir Cell Mol Biol201042326827519520914
   PubMed Web of Science ®Google Scholar
• RennardSISunSXTourkodimitrisSRoflumilast and dyspnea in patients with moderate to very severe chronic obstructive pulmonary disease: a pooled analysis of four clinical trialsInt J Chron Obstruct Pulmon Dis2014965767325018629
   PubMed Web of Science ®Google Scholar
• Grubek-JaworskaHPaplinskaMHermanowicz-SalamonJIL-6 and IL-13 in induced sputum of COPD and asthma patients: correlation with respiratory testsRespiration201284210110722311051
   PubMed Web of Science ®Google Scholar
• LeeJSRosengartMRKondraguntaVInverse association of plasma IL-13 and inflammatory chemokines with lung function impairment in stable COPD: a cross-sectional cohort studyRespir Res200786417868461
   PubMed Web of Science ®Google Scholar
• TanabeTKanohSTsushimaKYamazakiYKuboKRubinBKClarithromycin inhibits interleukin-13-induced goblet cell hyperplasia in human airway cellsAm J Respir Cell Mol Biol20114551075108321642590
   PubMed Web of Science ®Google Scholar
• RennardSIFlavinSKAgarwalPKLoKHBarnathanESLong-term safety study of infliximab in moderate-to-severe chronic obstructive pulmonary diseaseRespir Med2013107342443223246078
   PubMed Web of Science ®Google Scholar
• AaronSDVandemheenKLMaltaisFTNFalpha antagonists for acute exacerbations of COPD: a randomised double-blind controlled trialThorax201368214214823161645
   PubMed Web of Science ®Google Scholar
• ChungKFInflammatory mediators in chronic obstructive pulmonary diseaseCurr Drug Targets Inflamm Allergy20054661962517305518
   PubMedGoogle Scholar
• BettsJCMayerRJTal-SingerRGene expression changes caused by the p38 MAPK inhibitor dilmapimod in COPD patients: analysis of blood and sputum samples from a randomized, placebo-controlled clinical trialPharmacol Res Perspect201531e0009425692013
   PubMedGoogle Scholar
• MacNeeWAllanRJJonesIDe SalvoMCTanLFEfficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trialThorax201368873874523539534
   PubMed Web of Science ®Google Scholar
• SinghDSmythLBorrillZSweeneyLTal-SingerRA randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patientsJ Clin Pharmacol20105019410019880675
   PubMed Web of Science ®Google Scholar
• WatzHBarnacleHHartleyBFChanREfficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trialLancet Respir Med201421637224461903
   PubMed Web of Science ®Google Scholar
• GeraghtyPHardiganAForonjyRFCigarette smoke activates the proto-oncogene c-src to promote airway inflammation and lung tissue destructionAm J Respir Cell Mol Biol201450355957024111605
   PubMed Web of Science ®Google Scholar
• GagliardoRChanezPProfitaMIkappaB kinase-driven nuclear factor-kappaB activation in patients with asthma and chronic obstructive pulmonary diseaseJ Allergy Clin Immunol20111283635645e631e63221571356
   PubMed Web of Science ®Google Scholar
• MarianEBaraldoSVisentinAUp-regulated membrane and nuclear leukotriene B4 receptors in COPDChest200612961523153016778270
   PubMed Web of Science ®Google Scholar
• WoodruffPGAlbertRKBaileyWCRandomized trial of zileuton for treatment of COPD exacerbations requiring hospitalizationCOPD201181212921299475
   PubMedGoogle Scholar
• SnellNFosterMVestboJEfficacy and safety of AZD1981, a CRTH2 receptor antagonist, in patients with moderate to severe COPDRespir Med2013107111722173023827726
   PubMed Web of Science ®Google Scholar
• MantellSJonesRTrevethickMDesign and application of locally delivered agonists of the adenosine A(2A) receptorExpert Rev Clin Pharmacol201031557222111533
   PubMedGoogle Scholar
• MathioudakisAChatzimavridou-GrigoriadouVEvangelopoulouEMathioudakisGVasoactive intestinal Peptide inhaled agonists: potential role in respiratory therapeuticsHippokratia2013171121623935337
   PubMed Web of Science ®Google Scholar
• BurianBStorkaAMarzlufBAVasoactive intestinal peptide (VIP) receptor expression in monocyte-derived macrophages from COPD patientsPeptides201031460360820026142
   PubMed Web of Science ®Google Scholar
• OnoueSAokiYMatsuiTFormulation design and in vivo evaluation of dry powder inhalation system of new vasoactive intestinal peptide derivative ([R(15, 20, 21), L(17), A(24, 25), des-N(28)]-VIP-GRR) in experimental asthma/COPD model ratsInt J Pharm20114101–2546021419198
   PubMed Web of Science ®Google Scholar
• WuDLeeDSungYKProspect of vasoactive intestinal peptide therapy for COPD/PAH and asthma: a reviewRespir Res2011124521477377
   PubMed Web of Science ®Google Scholar
• StollPBahkerAUlrichMThe dendritic cell high-affinity IgE receptor is overexpressed in both asthma and severe COPDClin Exp Allergy201646457558326503747
   PubMed Web of Science ®Google Scholar
• RaverdeauMMillsKHModulation of T cell and innate immune responses by retinoic AcidJ Immunol201419272953295824659788
   PubMed Web of Science ®Google Scholar
• HoTWTsaiYJRuanSYIn-hospital and one-year mortality and their predictors in patients hospitalized for first-ever chronic obstructive pulmonary disease exacerbations: a nationwide population-based studyPLoS One2014912e11486625490399
   PubMed Web of Science ®Google Scholar
• KaczmarekPSladekKSkuchaWThe influence of simvastatin on selected inflammatory markers in patients with chronic obstructive pulmonary diseasePol Arch Med Wewn20101201–2111720150839
   PubMed Web of Science ®Google Scholar
• LawesCMThornleySYoungRStatin use in COPD patients is associated with a reduction in mortality: a national cohort studyPrim Care Respir J2012211354022218819
   PubMedGoogle Scholar
• HodgeGJersmannHTranHBLymphocyte senescence in COPD is associated with decreased histone deacetylase 2 expression by pro-inflammatory lymphocytesRespir Res20151613026498345
   PubMed Web of Science ®Google Scholar
• PodolinPLFoleyJPCarpenterDCT cell depletion protects against alveolar destruction due to chronic cigarette smoke exposure in miceAm J Physiol Lung Cell Mol Physiol20133045L312L32323292810
   PubMed Web of Science ®Google Scholar
• MorettoNCarusoPBoscoRCHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administrationJ Pharmacol Exp Ther2015352355956725576075
   PubMed Web of Science ®Google Scholar
• VillettiGCarniniCBattipagliaLCHF6001 II: a novel phosphodiesterase 4 inhibitor, suitable for topical pulmonary administration – in vivo preclinical pharmacology profile defines a potent anti-inflammatory compound with a wide therapeutic windowJ Pharmacol Exp Ther2015352356857825576073
   PubMed Web of Science ®Google Scholar
• WatzHMistrySJLazaarALInvestigators IPCSafety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPDPulm Pharmacol Ther201326558859523701917
   PubMed Web of Science ®Google Scholar
• GoudieARLipworthBJHopkinsonPJWeiLStruthersADTadalafil in patients with chronic obstructive pulmonary disease: a randomised, double-blind, parallel-group, placebo-controlled trialLancet Respir Med20142429330024717626
   PubMed Web of Science ®Google Scholar
• KunaPJenkinsMO’BrienCDFahyWAAZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPDRespir Med2012106453153922197578
   PubMed Web of Science ®Google Scholar
• HenriksenPAThe potential of neutrophil elastase inhibitors as anti-inflammatory therapiesCurr Opin Hematol2014211232824241342
   PubMed Web of Science ®Google Scholar
• DahlRTitlestadILindqvistAEffects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trialPulm Pharmacol Ther201225216917722306193
   PubMed Web of Science ®Google Scholar
• WoodruffPGWolffMHohlfeldJMSafety and efficacy of an inhaled epidermal growth factor receptor inhibitor (BIBW 2948 BS) in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med2010181543844520007923
   PubMed Web of Science ®Google Scholar
• DameraGJesterWFJiangMInhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammationExp Lung Res2010362758420205598
   PubMed Web of Science ®Google Scholar
• HaEVRogersDFNovel therapies to inhibit mucus synthesis and secretion in airway hypersecretory diseasesPharmacology2016971–28410026674354
   PubMed Web of Science ®Google Scholar
• AstrandABHemmerlingMRootJLinking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibitionAm J Physiol Lung Cell Mol Physiol20153081L22L3225361567
   PubMed Web of Science ®Google Scholar
• BlackPNMorgan-DayAMcMillanTEPoolePJYoungRPRandomised, controlled trial of N-acetylcysteine for treatment of acute exacerbations of chronic obstructive pulmonary disease [ISRCTN21676344]BMC Pulm Med200441315581425
   PubMedGoogle Scholar
• Ayfer AytemurZBaysakAOzdemirOKoseTSayinerAN-acetylcysteine in patients with COPD exacerbations associated with increased sputumWien Klin Wochenschr20151277–825626125595117
   PubMed Web of Science ®Google Scholar
• DransfieldMTWilhelmAMFlanaganBAcquired cystic fibrosis transmembrane conductance regulator dysfunction in the lower airways in COPDChest2013144249850623538783
   PubMed Web of Science ®Google Scholar
• BodasMMinTMazurSVijNCritical modifier role of membrane-cystic fibrosis transmembrane conductance regulator-dependent ceramide signaling in lung injury and emphysemaJ Immunol2011186160261321135173
   PubMed Web of Science ®Google Scholar
• JonesPWRamesADTESRA (treatment of emphysema with a selective retinoid agonist) study resultsAm J Respir Crit Care Med2011183A6418
   Web of Science ®Google Scholar
• StolkJStockleyRAStoelBCRandomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptorEur Respir J201240230631222282548
   PubMed Web of Science ®Google Scholar