炎症反应的双通道.ppt

Click to edit Master text styles,Bullet 2,Slide Title,Slide,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Slide,1,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,Slide,2,Adapted from National Institutes of Health,Global Initiative for Asthma:Global Strategy for Asthma Management and Prevention:A Pocket Guide for Physicians and Nurses,.Publication No.95-3659B.Bethesda,MD:National Institutes of Health,1998;Bjermer L,Respir Med,2001;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,Slide,3,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,Adapted from,Peters-Golden M,Sampson AP,J Allergy Clin Immunol,2003;111(suppl 1):S37-S48.,炎症反应的双通道,皮质激素的作用,Slide,4,尽管使用了吸入激素，气道炎症仍持续存在,ICS=inhaled corticosteroids;OCS ICS=received oral corticosteroids with or without ICS,Adapted from Louis R et al,Am J Respir Crit Care Med,2000;161:9-16.,20,000,10,000,1,000,100,10,1,Eosinophil,10,3,/gsputum,Controlgroup,轻到中度哮喘,ICSlow-dose,(n=10),ICShigh-dose,(n=15),OCS(n=10),OCS ICS(n=7),重度哮喘,p0.01,p0.001,p0.001,p0.01,n=74,Slide,5,白三烯,其它炎性介质,This slide is an artistic rendition.,Adapted from Holgate ST,Peters-Golden M,J Allergy Clin Immunol,2003;111(1 suppl):S1-S4;Holgate ST et al,J Allergy Clin Immunol,2003;111(1 suppl):S18-S36;,Henderson WR Jr et al,Am J Respir Crit Care Med,2002;165:108-116;Peters-Golden M,Sampson AP,J Allergy Clin Immunol,2003;111(1 suppl):S37-S42;,Varner AE,Lemanske RF Jr.In,Asthma and Rhinitis,.Oxford,UK:Blackwell Science,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,Slide,6,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 hemopoieticstem cell,T Cells,Eosinophil,B Lymphocyte,CCR3,CD4+,CD8+,CD19,M-CSF,GM-CSF,IL-3,LTC,4,LTD,4,LTE,4,LN5,Mast Cell,LTC,4,LTD,4,LTE,4,M-CSF,GM-CSF,IL-5,IL-3,GM-CSF,LTC,4,LTD,4,LTE,4,CD14,IL5R,Represents the CysLT,1,receptor,Adapted from Figueroa DJ et al,Am J Respir Crit Care Med,20,01;163:226-233;Mellor et al,Proc Natl Acad Sci USA,2001;98:7964-7969,CysLT,1,R,CD34+,Slide,7,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-musclecell,B,淋巴细胞,CysLT=cysteinyl leukotriene;,PBMC=peripheral blood mononuclear cells,Adapted from Figueroa DJ et al,Am J Respir Crit Care Med,20,01;163:226-233.,单核细胞,Slide,8,Adapted from,Peters-Golden M,Sampson AP,J Allergy Clin Immunol,2003;111(suppl 1):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,Slide,9,Adapted from Hay DWP et al,Trends Pharmacol Sci,1995;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,Slide,10,p=NS between groups,Adapted from OShaughnessy KM et al,Am Rev Respir Dis,1993;147:1472-1476.,18.7,20,16,12,8,4,0,Urinary LTE,4,excretion,(ng/mmolcreatinine),18.4,Placebo,Fluticasone propionate,吸入丙酸氟替卡松对尿中白三烯量的影响,1000g,虽然氟,替卡松明显改善了过敏原诱导的支气管狭窄,(p 0.02),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,Slide,11,*,*p0.05 vs.baseline,Adapted from Dworski R et al,Am J Respir Crit Care Med,1994;149:953-959.,0.3,0.2,0.1,0,Urinary LTE,4,(ng/mgcreatinine),Post-allergen challenge,Baseline,ControlPrednisone,*,口服强的松对尿中白三烯量的影响,Slide,12,*p0.02 vs.normal individuals;*p0.05 vs.normal individuals,Adapted from Pavord ID et al,Am J Respir Crit Care Med,1999;160:1905-1909.,14,12,10,8,6,4,2,0,SputumCysLT levels(ng/ml),Controls,控制,(n=10),6.4,All patients with asthma,所有哮喘患者,(n=26),9.4*,Patients with persistent asthma,持续性哮喘,(n=10),11.4*,Patients with acute attacks,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,Slide,13,LABA=long-acting beta,2,agonist,Adapted from Currie GP et al,Am J Respir Crit Care Med,(in press,).,0,100,200,Change ineosinophils(,10,6,/L)from run-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,Slide,14,*p0.05 compared with beclomethasone,Adapted from LaViolette M et al,Am J Respir Crit Care Med,1999;160:1862-1868.,0.12,0.10,0.08,0.06,0.04,0.02,0,Eosinophilcounts,(changefrom baseline,10,3,/l),Placebo,Beclomethasone,Montelukast+beclomethasone,Montelukast,*,1*,Treatment group,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,Slide,15,block steroid-sensitivemediators,blocks the effects of 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,The slide represents an artistic rendition.,Adapted from Peters-Golden M,Sampson AP,J Allergy Clin Immunol,2003;111(1 suppl):S37-S42;Bisgaard H,Allergy,2001;56(suppl 66):7-11.,对类固醇敏感的介质,play a key role in asthmatic inflammation,光胱氨酰白三烯,play a key role in asthmatic 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,Slide,16,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=leukotriene receptor antagonists,Adapted from,Peters-Golden M,Sampson AP,J Allergy Clin Immunol,2003;111(suppl 1):S37-S48.,炎症反应的双通道,白三烯受体拮抗剂的作用,Slide,17,18,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,Slide,21,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,Slide,22,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,.Bjermer L,Bisgaard H,Bousquet J,et al.Montelukast or salmeterol combined with an inhaled steroid in adult asthma:design and rationale of a randomized,double-blind comparative study(the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy-trial)Respir Med.2000;94:612621.,1,1,.Bjermer L,Bisgaard H,Bousquet J,et al.Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults:one year,double blindrandomised,comparative trial.BMJ.2003;327:891895.,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。,Slide,23,与基线相比，,痰嗜酸性粒细胞评分,(03,分,),a,孟鲁司特钠,10 mg+,氟替卡松,200 ug,b,沙美特罗,100 ug+,氟替卡松,200 mg.,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,0.05 vs.,基线,),P,=0.011,11.Bjermer L,Bisgaard H,Bousquet J,et al.Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults:one year,double blind,randomised,comparative trial.BMJ.2003;327:891895.,Slide,25,IMPACT,研究,顺尔宁,(,孟鲁司特钠,),+,氟替卡松,-,不良事件发生率显著低于沙美特罗,+,氟替卡松,74%,P,=0.01,61%,P,=0.02,6.3%,10.0%,4.6%,7.4%,11.Bjermer L,Bisgaard H,Bousquet J,et al.Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults:one year,double blind,randomised,comparative trial.BMJ.2003;327:891895.,Slide,26,半胱氨酰白三烯和对类固醇敏感的介质是哮喘炎症反应中的两条通道,激素不能阻断半胱氨酰白三烯介导的炎症通路,同时作用哮喘病人气道炎症的两条通路，可以达到更好的炎症控制及哮喘控制,Adapted from Peters-Golden M,Sampson AP,J Allergy Clin Immunol,2003;111(1 suppl):S37-S42;Bisgaard H,Allergy,2001;56(suppl 66):7-11.,总结,同时作用炎症反应双通道，加强哮喘控制,Slide,27,谢谢分享,