炎症反应的双通道.ppt

Slide1,哮喘症状由尚未被控制的气道炎症所致,炎症反应的双通道,Slide2,AdaptedfromNationalInstitutesofHealth,GlobalInitiativeforAsthma:GlobalStrategyforAsthmaManagementand,Prevention:APocketGuideforPhysiciansandNurses,.PublicationNo.95-3659B.Bethesda,MD:NationalInstitutes,ofHealth,2019;BjermerL,RespirMed,2019;95:703-719.,炎症反应在哮喘中的重要性,?,哮喘本质上是一种炎症反应疾病,?,炎症反应导致气管收缩及气道高反应性，从而,产生症状,?,对轻中度哮喘病人应首先进行控制炎症的治疗,Slide3,?,抑制多种炎症介质,细胞因子,粘附分子,可诱导的酶,?,对炎性反应的多种作用,AdaptedfromPeters-GoldenM,SampsonAP,JAllergyClinImmunol,2019;111(suppl1):S37-S48.,炎症反应的双通道,皮质激素的作用,Slide4,尽管使用了吸入激素，气道炎症仍持续存在,ICS=inhaledcorticosteroids;OCS,ICS=receivedoralcorticosteroidswithorwithoutICS,AdaptedfromLouisRetal,AmJRespirCritCareMed,2000;161:9-16.,20,000,10,000,1,000,100,10,1,Eosinophil,?,10,3,/g,sputum,Control,group,轻到中度哮喘,ICS,low-dose,(n=10),ICS,high-dose,(n=15),OCS,(n=10),OCS,ICS,(n=7),重度哮喘,p0.01,p0.001,p0.001,p0.01,n=74,Slide5,白三烯,其它炎性介质,Thisslideisanartisticrendition.,AdaptedfromHolgateST,Peters-GoldenM,JAllergyClinImmunol,2019;111(1suppl):S1-S4;HolgateSTetal,JAllergy,ClinImmunol,2019;111(1suppl):S18-S36;HendersonWRJretal,AmJRespirCritCareMed,2019;165:108-116;Peters-,GoldenM,SampsonAP,JAllergyClinImmunol,2019;111(1suppl):S37-S42;VarnerAE,LemanskeRFJr.In,Asthmaand,Rhinitis,.Oxford,UK:BlackwellScience,2000:1172-1185.,无炎症反应,炎症反应,哮喘,白三烯：在哮喘早期及疾病全程中的重要性,Slide6,炎症反应的双通道,半胱氨酰白三烯受体的表达,Neutrophil,Monocyte,Macrophage,Basophil,Pluripotent,hemopoietic,stemcell,TCells,Eosinophil,BLymphocyte,CCR3,CD4+,CD8+,CD19,M-CSF,GM-CSF,IL-3,LTC,4,LTD,4,LTE,4,LN5,MastCell,LTC,4,LTD,4,LTE,4,M-CSF,GM-CSF,IL-5,IL-3,GM-CSF,LTC,4,LTD,4,LTE,4,CD14,IL5R,Representsthe,CysLT,1,receptor,AdaptedfromFigueroaDJetal,AmJRespirCritCareMed,2001;163:226-233;Melloretal,ProcNatlAcadSciUSA,2019;98:7964-7969,CysLT,1,R,CD34+,Slide7,炎症反应的双通道,半胱氨酰白三烯在炎性细胞受体上的作用,嗜酸细胞,肺巨噬细胞,Smooth-,muscle,cell,B,淋巴细胞,CysLT=cysteinylleukotriene;PBMC=peripheralbloodmononuclearcells,AdaptedfromFigueroaDJetal,AmJRespirCritCareMed,2001;163:226-233.,单核细胞,Slide8,AdaptedfromPeters-GoldenM,SampsonAP,JAllergyClinImmunol,2019;111(suppl1):S37-S48.,炎症反应的双通道,白三烯是强大的炎症介质,其它介质受体,其它介质,光胱氨酰,白三烯受体,光胱氨酰,白三烯,Slide9,AdaptedfromHayDWPetal,TrendsPharmacolSci,2019;16:304-309.,炎症细胞,(,肥大细胞,嗜酸性细胞,),感觉神经,(C,纤维,),CysLTs,水肿,血管,粘液转运减少,嗜酸性细胞,内流,阳离子蛋白释放，,上皮细胞损伤,收缩和增生,气道平滑肌,粘液分泌增多,气道上皮,炎症反应的双通道,半胱氨酰白三烯在哮喘中的核心作用,Slide10,p=NSbetweengroups,AdaptedfromOShaughnessyKMetal,AmRevRespirDis,1993;147:1472-1476.,18.7,20,16,12,8,4,0,UrinaryLTE,4,excretion,(ng/mmol,creatinine),18.4,Placebo,Fluticasone,propionate,吸入丙酸氟替卡松对尿中白三烯量的影响,1000,g,虽然氟替卡松明显改善了过敏原诱导的支气管狭窄,(p0.02),但在降低尿,LTE4,浓度方面无显著效果,治疗期,14,天,洗脱期,21,天后交叉，最后一天过敏原刺激,N=10,Slide11,*,*p0.05vs.baseline,AdaptedfromDworskiRetal,AmJRespirCritCareMed,1994;149:953-959.,0.3,0.2,0.1,0,UrinaryLTE,4,(ng/mg,creatinine),Post-allergen,challenge,Baseline,Control,Prednisone,*,口服强的松对尿中白三烯量的影响,Slide12,*p0.02vs.normalindividuals;*p0.05vs.normalindividuals,AdaptedfromPavordIDetal,AmJRespirCritCareMed,2019;160:1905-1909.,14,12,10,8,6,4,2,0,Sputum,CysLTlevels,(ng/ml),Controls,控制,(n=10),6.4,Allpatients,withasthma,所有哮喘患者,(n=26),9.4*,Patientswith,persistent,asthma,持续性哮喘,(n=10),11.4*,Patientswith,acuteattacks,急性发作,(n=12),13*,吸入糖皮质激素对痰中白三烯水平的影响,Slide13,LABA=long-actingbeta,2,agonist,AdaptedfromCurrieGPetal,AmJRespirCritCareMed,(inpress).,0,100,200,Changein,eosinophils,(,?,10,6,/L),fromrun-in,ICS+LABA+,Montelukast,ICS+,LABA,ICS,ICS+,Montelukast,p0.05,p0.05,而白三烯受体拮抗剂孟鲁司特在,ICS,基础上可进一步减少气道炎症,炎症反应的双通道,长效,?,2,受体激动剂不具有抗炎作用,Slide14,*p0.05comparedwithbeclomethasone,AdaptedfromLaVioletteMetal,AmJRespirCritCareMed,2019;160:1862-1868.,0.12,0.10,0.08,0.06,0.04,0.02,0,Eosinophil,counts,(change,from,baseline,?,10,3,/,l),Placebo,Beclomethasone,Montelukast,+,beclomethasone,Montelukast,*,1*,Treatmentgroup,同时针对炎症双通道的治疗可更好控制哮喘炎症,炎症反应的双通道,白三烯受体拮抗剂孟鲁司特可进一步减少气道炎症,Slide15,block,steroid-,sensitive,mediators,blocksthe,effectsof,CysLTs,吸入激素,孟鲁司特,白三烯受体拮抗剂与皮质激素联合，,作用于炎症反应的双通道,Thesliderepresentsanartisticrendition.,AdaptedfromPeters-GoldenM,SampsonAP,JAllergyClinImmunol,2019;111(1suppl):S37-S42;BisgaardH,Allergy,2019;56(suppl66):7-11.,对类固醇敏感的介质,playakeyrole,inasthmatic,inflammation,光胱氨酰白三烯,playakeyrole,inasthmatic,inflammation,类固醇不能抑制有症状的哮喘病人气道中的半胱氨酰白三烯的形成,双通道,Slide16,?,抑制多种用炎症介质,(TNF,、,IL-6,、粘附分子）,?,抑制炎症反应过程,通过白三烯通道,通过对激素敏感的通道,LTRAs=leukotrienereceptorantagonists,AdaptedfromPeters-GoldenM,SampsonAP,JAllergyClinImmunol,2019;111(suppl1):S37-S48.,炎症反应的双通道,白三烯受体拮抗剂的作用,Slide17,18,阿司匹林哮喘的发病机制,花生四烯酸,环氧化酶,脂氧化酶,（,COX,）,（,5-LO,）,前列腺素,白,三,烯,（,LTC,4,合成酶）,19,阿司匹林哮喘的治疗与管理,?,避免使用阿司匹林和非类固醇类抗炎药,（,NSAIDs,）,?,脱敏治疗,?,白三烯受体拮抗剂及合成阻断剂,?,鼻部疾病的治疗,20,避免使用相关类药物,?,COX-1,和,COX-2,的抑制剂（在首次接触该药时，与低激发,剂量发生交叉反应）：吲哚美辛或消炎痛,布洛芬等,?,COX-1,和,COX-2,的弱抑制剂（少部分患者与高剂量的这些,药发生交叉反应）：对乙酰氨基酚（扑热息痛）,双水,杨酸等,?,相对的,COX-2,抑制剂和弱,COX-1,抑制剂（只在高剂量时反,生交叉反应且症状相对较轻）：尼美舒利和美洛昔康,?,选择性,COX-2,抑制剂（理论上讲不应该发生交叉反应，但,还未进行研究）：,celecoxib,rofecoxib,阿司匹林哮喘的治疗与管理,Slide21,IMPACT,研究,一项比较,ICS,治疗未达控制的慢性哮喘患者,联用白三烯调节剂,Vs.,联用沙美特罗,对哮喘控制的疗效,Slide22,IMPACT,研究,研究设计和目的,MP=,孟鲁司特钠,安慰剂,;SP=,沙美特罗安慰剂,10.BjermerL,BisgaardH,BousquetJ,etal.Montelukastorsalmeterolcombinedwithaninhaledsteroidinadultasthma:designandrationaleofarandomized,double-blind,comparativestudy(theIMPACTInvestigationofMontelukastasaPartnerAgentforComplementaryTherapy-trial)RespirMed.2000;94:612,621.11.BjermerL,BisgaardH,BousquetJ,etal.Montelukastandfluticasonecomparedwithsalmeterolandfluticasoneinprotectingagainstasthmaexacerbationinadults:oneyear,doubleblind,randomised,IMPACT,是一个为期,52,周、随机双盲、双模拟、平行组、多中心研究。,4,周导入期（,1,期）,+48,周双盲治疗期（,2,期）共,1490,例患者。,钠,主要研究终点,为至少一次哮,喘急性发作的,患者百分比。,Slide23,与基线相比，,痰嗜酸性粒细胞,评分,(0,3,分,),a,孟鲁司特钠,10mg+,氟替卡松,200ug,b,沙美特罗,100ug+,氟替卡松,200mg.,痰液分析在所有参加,IMPACT,研究的的芬兰中心的病人中进行,.,孟鲁司特钠,+,氟替卡松,(n=25),a,沙美特罗,+,氟替卡松,(n=16),b,-0.7,-0.6,-0.5,-0.4,-0.3,-0.2,-0.1,0,0.1,0.2,0.3,0.4,降低,40%,P,0.05vs.,基线,),P,=0.011,11.BjermerL,BisgaardH,BousquetJ,etal.Montelukastandfluticasonecomparedwithsalmeterolandfluticasoneinprotecting,againstasthmaexacerbationinadults:oneyear,doubleblind,randomised,comparativetrial.BMJ.2019;327:891,895.,Slide25,I