炎癥反應(yīng)的雙通道ppt課件

1、Slide 1,哮喘癥狀由尚未被控制的氣道炎癥所致炎癥反應(yīng)的雙通道,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 Re

2、spir Med 2001;95:703-719.,炎癥反應(yīng)在哮喘中的重要性,哮喘本質(zhì)上是一種炎癥反應(yīng)疾病 炎癥反應(yīng)導(dǎo)致氣管收縮及氣道高反應(yīng)性，從而產(chǎn)生癥狀 對輕中度哮喘病人應(yīng)首先進(jìn)行控制炎癥的治療,Slide 3,抑制多種炎癥介質(zhì) 細(xì)胞因子 粘附分子 可誘導(dǎo)的酶 對炎性反應(yīng)的多種作用,Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48.,炎癥反應(yīng)的雙通道皮質(zhì)激素的作用,Slide 4,盡管使用了吸入激素，氣道炎癥仍持續(xù)存在,ICS=inhaled corticost

3、eroids; 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 103/gsputum,Controlgroup,輕到中度哮喘,ICSlow-dose (n=10),ICShigh-dose (n=15),OCS(n=10),OCS ICS(n=7),重度哮喘,n=74,Slide 5,白三烯,其它炎性介質(zhì),Thi

4、s 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 I

5、mmunol 2003;111(1 suppl):S37-S42; Varner AE, Lemanske RF Jr. In Asthma and Rhinitis. Oxford, UK: Blackwell Science, 2000:1172-1185.,無炎癥反應(yīng),炎癥反應(yīng),哮喘,白三烯：在哮喘早期及疾病全程中的重要性,Slide 6,炎癥反應(yīng)的雙通道 半胱氨酰白三烯受體的表達(dá),Neutrophil,Monocyte,Macrophage,Basophil,Pluripotent hemopoieticstem cell,T Cells,Eosinophil,B Lymphocyte

6、,CCR3,CD4+,CD8+,CD19,M-CSF, GM-CSF, IL-3,LTC4, LTD4, LTE4,LN5,Mast Cell,LTC4,LTD4,LTE4,M-CSF,GM-CSF,IL-5,IL-3,GM-CSF,LTC4,LTD4,LTE4,CD14,IL5R,Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163:226-233; Mellor et al Proc Natl Acad Sci USA 2001;98:7964-7969,CysLT1R,CD34+,Slide 7,炎癥反應(yīng)的雙通

7、道 半胱氨酰白三烯在炎性細(xì)胞受體上的作用,嗜酸細(xì)胞,肺巨噬細(xì)胞,Smooth- musclecell,B淋巴細(xì)胞,CysLT=cysteinyl leukotriene; PBMC=peripheral blood mononuclear cells Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163:226-233.,單核細(xì)胞,Slide 8,Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-

8、S48.,炎癥反應(yīng)的雙通道白三烯是強(qiáng)大的炎癥介質(zhì),其它介質(zhì)受體,其它介質(zhì),光胱氨酰 白三烯受體,光胱氨酰 白三烯,Slide 9,Adapted from Hay DWP et al Trends Pharmacol Sci 1995;16:304-309.,炎癥細(xì)胞 (肥大細(xì)胞,嗜酸性細(xì)胞),感覺神經(jīng) (C纖維),CysLTs,水腫,血管,粘液轉(zhuǎn)運減少,嗜酸性細(xì)胞 內(nèi)流,陽離子蛋白釋放， 上皮細(xì)胞損傷,收縮和增生,粘液分泌增多,氣道上皮,炎癥反應(yīng)的雙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 OShaughne

9、ssy KM et al Am Rev Respir Dis 1993;147:1472-1476.,18.7,20 16 12 8 4 0,Urinary LTE4excretion (ng/mmolcreatinine),18.4,Placebo,Fluticasone propionate,吸入丙酸氟替卡松對尿中白三烯量的影響,1000g,雖然氟替卡松明顯改善了過敏原誘導(dǎo)的支氣管狹窄(p 0.02),但在降低尿LTE4濃度方面無顯著效果,治療期14天,洗脫期21天后交叉，最后一天過敏原刺激,N=10,Slide 11,*,*p0.05 vs. baseline Adapted from

10、Dworski R et al Am J Respir Crit Care Med 1994;149:953-959.,0.3 0.2 0.1 0,Urinary LTE4(ng/mgcreatinine),Post-allergen challenge,Baseline,ControlPrednisone,*,口服強(qiáng)的松對尿中白三烯量的影響,Slide 12,*p0.02 vs. normal individuals; *p0.05 vs. normal individuals Adapted from Pavord ID et al Am J Respir Crit Care Med 19

11、99;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 持續(xù)性哮喘 (n=10),11.4*,Patients with acute attacks 急性發(fā)作(n=12),13*,吸入糖皮質(zhì)激素對痰中白三烯水平的影響,Slide 13,LABA = long-acting beta2 agonist Adapted from Cur

12、rie GP et al Am J Respir Crit Care Med (in press).,0 100 200,Change ineosinophils( 106/L)from run-in,ICS + LABA + Montelukast,ICS +LABA,ICS,ICS +Montelukast,p0.05,p0.05,而白三烯受體拮抗劑孟魯司特在ICS基礎(chǔ)上可進(jìn)一步減少氣道炎癥,炎癥反應(yīng)的雙通道長效2受體激動劑不具有抗炎作用,Slide 14,*p0.05 compared with beclomethasone Adapted from LaViolette M et al

13、 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 103/l),Placebo,Beclomethasone,Montelukast+ beclomethasone,Montelukast,*,1*,Treatment group,同時針對炎癥雙通道的治療可更好控制哮喘炎癥,炎癥反應(yīng)的雙通道白三烯受體拮抗劑孟魯司特可進(jìn)一步減少氣道炎癥,Slide 15,block steroid-sensitivemediato

14、rs,blocks the effects of CysLTs,吸入激素,孟魯司特,白三烯受體拮抗劑與皮質(zhì)激素聯(lián)合，作用于炎癥反應(yīng)的雙通道,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.,對類固醇敏感的介質(zhì)play a key role in asthmatic inflammation,光

15、胱氨酰白三烯play a key role in asthmatic inflammation,類固醇不能抑制有癥狀的哮喘病人氣道中的半胱氨酰白三烯的形成,雙通道,Slide 16,抑制多種用炎癥介質(zhì)(TNF、IL-6、粘附分子） 抑制炎癥反應(yīng)過程 通過白三烯通道 通過對激素敏感的通道,LTRAs = leukotriene receptor antagonists Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48.,炎癥反應(yīng)的雙通道白三烯受體拮抗劑的作用,Slid

16、e 17,.,18,阿司匹林哮喘的發(fā)病機(jī)制,花生四烯酸 環(huán)氧化酶 脂氧化酶 （COX） （5-LO） 前列腺素 白 三 烯 （LTC4合成酶）,.,19,阿司匹林哮喘的治療與管理,避免使用阿司匹林和非類固醇類抗炎藥（NSAIDs） 脫敏治療 白三烯受體拮抗劑及合成阻斷劑 鼻部疾病的治療,.,20,避免使用相關(guān)類藥物,COX-1和COX-2的抑制劑（在首次接觸該藥時，與低激發(fā)劑量發(fā)生交叉反應(yīng)）：吲哚美辛或消炎痛,布洛芬等 COX-1和COX-2的弱抑制劑（少部分患者與高劑量的這些藥發(fā)生交叉反應(yīng)）：對乙酰氨基酚（撲熱息痛）, 雙水楊酸等 相對的COX-2抑制劑和弱COX-1抑制劑（只在高劑量時反生

17、交叉反應(yīng)且癥狀相對較輕）：尼美舒利和美洛昔康 選擇性COX-2抑制劑（理論上講不應(yīng)該發(fā)生交叉反應(yīng)，但還未進(jìn)行研究）：celecoxib ,rofecoxib,阿司匹林哮喘的治療與管理,Slide 21,IMPACT 研究 一項比較ICS治療未達(dá)控制的慢性哮喘患者 聯(lián)用白三烯調(diào)節(jié)劑 Vs. 聯(lián)用沙美特羅 對哮喘控制的療效,Slide 22,IMPACT 研究研究設(shè)計和目的,MP = 孟魯司特鈉 安慰劑 ; SP = 沙美特羅安慰劑,10. Bjermer L, Bisgaard H, Bousquet J, et al. Montelukast or salmeterol combined wi

18、th 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. 11. Bjermer L, Bisgaard H, Bousquet J, et al. Montelukast and fluticaso

19、ne compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial. BMJ. 2003;327:891895.,IMPACT是一個為期52周、隨機(jī)雙盲、雙模擬、平行組、多中心研究。4周導(dǎo)入期（1期）+ 48周雙盲治療期（2期）共1490例患者。,鈉,主要研究終點為至少一次哮喘急性發(fā)作的患者百分比。,Slide 23,與基線相比， 痰嗜酸性粒細(xì)胞評分(03分),a

20、 孟魯司特鈉10 mg +氟替卡松 200 ug, b 沙美特羅 100 ug +氟替卡松 200 mg. 痰液分析在所有參加 IMPACT 研究的的芬蘭中心的病人中進(jìn)行.,孟魯司特鈉+ 氟替卡松 (n=25)a,沙美特羅+ 氟替卡松 (n=16)b,在對41例病人的亞組分析顯示，孟魯司特鈉顯著降低痰中嗜酸性粒細(xì)胞計數(shù),IMPACT 研究順爾寧(孟魯司特鈉)+氟替卡松較沙美特羅+氟替卡松更顯著降低痰嗜酸性粒細(xì)胞,11. Bjermer L, Bisgaard H, Bousquet J, et al. Montelukast and fluticasone compared with salm

21、eterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial. BMJ. 2003;327:891895.,Slide 24,與基線相比，48周血嗜酸性粒細(xì)胞計數(shù)平均改變 (x103/ L),a 孟魯司特 鈉10 mg +氟替卡松 200 ug,P=-0.04 (0.001), b 沙美特羅 100 ug +氟替卡松 200 ug. P=-0.01 (0.01) 數(shù)值表示為與基線相比的最小二乘均數(shù).

22、 P-值為兩組間差異。 兩組基線值 = 0.3 x 103/mL.。,孟魯司特鈉+ 氟替卡松 (n=747)a,沙美特羅+ 氟替卡松 (n=743)b,-0.05,-0.04,-0.03,-0.02,-0.01,0,IMPACT 研究順爾寧(孟魯司特鈉)+氟替卡松較沙美特羅+氟替卡松更顯著降低血嗜酸性粒細(xì)胞,-0.04 (P0.001 vs. 基線),-0.01 (P0.05 vs. 基線),P=0.011,11. Bjermer L, Bisgaard H, Bousquet J, et al. Montelukast and fluticasone compared with salmeterol and flutic