红霉素对慢性阻塞性肺疾病大鼠MMP-9水平的影响
摘要
目的:本实验通过COPD大鼠模型并予以红霉素干预观察大鼠肺内MMP-9表达水平的变化。通过本实验认识和探讨体内实验红霉素对COPD大鼠肺内MMP-9表达的影响,进一步认识红霉素的抗炎作用,开拓红霉素在COPD的应用价值。
方法:健康雄性Wistar大鼠36只(中南大学实验动物学部提供),雄性,白色,SPF级,体重220±20 g。在安静、室温、避强光的环境中自由进食和饮水一周。36只Wister大鼠随机分为3组,每组12只:COPD模型组,第1、14天注射脂多糖(LPS)200ug/100ul,第2～13天、15～30天每日上午在72升(30cm×40cm×60cm)自制有机玻璃箱内被动吸烟,每天上午1次,每次12支,每次持续0.5h。红霉素干预组,造模方法同COPD组,每天熏烟前用红霉素灌胃治疗(剂量100mg/kg,配制成1.25%红霉素口服液),从第17天开始进行,经气管内注入LPS的条件、烟熏条件以及持续时间均同COPD组,给药2周;正常对照组,标准饲养30天,不做任何干预,第1、14天气管内注入生理盐水100ul。大鼠肺功能测定由湘雅医学院病理生理研究所完成,经微机处理计算出FEV0.3/FVC、R1及Cdyn。左肺10%的中性福尔马林灌注固定20min,再浸入福尔马林固定,常规脱水,石蜡包埋,切片,HE染色,以进行病理形态学观察和免疫组化检测。用免疫组化方法检测各组大鼠肺组织MMP-9的表达,逆转录聚合酶链反应(reverse transcription-polymerase chain reaction,RT-PCR)检测各组大鼠肺组织MMP-9 mRNA表达水平。
结果:(1)模型组及干预组大鼠渐出现饮食、活动减少,平均体重较正常对照组减轻,后期可见毛发干枯、发黄,可听到喘息音,正常对照组未见以上情况出现。(2)模型组及干预组大鼠FEV0.3/FVC(%)、R1(气道阻力)、Cdyn(动态肺顺应性)均明显低于正常对照组,差异有显著性(均P＜0.05),说明小气道气道阻力增加,存在明显气流受限、阻塞性肺通气功能障碍。(3)光镜下模型组及干预组大鼠肺组织符合慢性支气管炎和阻塞性肺气肿病理改变。(4)模型组肺组织中MMP-9蛋白平均阳性系数显著高于对照组(P＜0.05),干预组与模型组比较阳性系数降低(P＜0.05)。(5)模型组大鼠肺组织中MMP-9mRNA表达量高,其光密度比值显著高于正常对照组(P＜0.05);干预组与模型组光密度比值比较亦降低(P＜0.05)。
结论:(1)采用被动吸烟和LPS气道内滴注相结合构建的大鼠COPD模型,能成功复制出COPD大鼠模型。(2)COPD大鼠肺组织中MMP-9水平显著增高,在COPD的发病机制中可能起重要作用。(3)红霉素治疗COPD大鼠从基因水平下调MMP-9的表达抑制炎症细胞的移行而减弱炎症反应。
Objective:The experiment observed the changes of lung MMP-9 expression level by erythromycin intervention in rat model of COPD.Our goal is to study and understand the effect of erythromycin on lung MMP-9 expression in vivo experiment of COPD rat,a further understanding of the anti-inflammatory effects of erythromycin,and developing the application of erythromycin in COPD.
Methods:36 male rats were averagely divided into 3 groups in random.The COPD model group was established by the way of giving passive smoking for one month and endotracheal injection of LPS.Passive smoking was given once daily(0.5 hour)in a plexiglass box from the second day to the thirteen day and the fifteen day to the thirty day.In the first day and forteen day,LPS(200ug / 100ul)was given in trachea.The Erythromycin intervention group was treated with erythromycin gavage from the seventeenth day for 2 weeks,modelling method was the same with COPD group.The normal control was not given passive smoking. And in the first and forteen day,we gave each rat endotracheal injection of stroke-physiological saline solution instead of LPS.Lung function tests were performed for each rat one month later and we tested FEV0.3/FVC,Rl and Cdyn.Then the rat was put to death and the lung was taken out.Sections of paraffin-embedded left lungs tissue were cut, stained with HE,and processed for pathological observation. Immunohistochemistry was permormed for study the expression of MMP-9.The right lungs tissue was prepared for the examination of the expression of MMP-9 mRNA.
Results:(1)COPD and Erythromycin intervention rats gradually emerged diet and activity decreasing,the average body weight mitigated compared with normal control group,in the later period appearing dry and yellow hair and the sound of gasping could be heard. The normal control group was out of this situation.(2)Lung function tests showed that FEV0.3/FVC,Rl and Cdyn values were significantly lower in the COPD and Erythromycin intervention groups than in the normal control group(P＜0.05).(3)The COPD and Erythromycin intervention groups lung tissue showed chronic obstructive bronchitis and emphysema pathological changes by light microscope.(4)Compared with the rats of normal control group,the expression MMP-9 protein increased significantly(P＜0.05)in the COPD rats.The positive coefficience of Erythromycin intervention group was lower than COPD group(P＜0.05).(5)In the COPD group MMP-9 mRNA in lungs increased significantly than normal control group(P＜0.05),the optical density ratio of Erythromycin intervention group was also lower than COPD group(P＜0.05).
Conclusion:(1)The rat model of COPD which was established by the way of giving passive smoking for one month and endotracheal injection of LPS was successful,which was proofed by lung function tests and pathological observation.(2)MMP-9 levels in COPD rat lung tissue was significantly higher than normal rats,it plays an important role in the pathogenesis of COPD.(3)Erythromycin treatment of COPD rats reduced MMP-9 protein and mRNA expression levels can inhibit the migration of inflammatory cells and weaken inflammatory response.
方法:健康雄性Wistar大鼠36只(中南大学实验动物学部提供),雄性,白色,SPF级,体重220±20 g。在安静、室温、避强光的环境中自由进食和饮水一周。36只Wister大鼠随机分为3组,每组12只:COPD模型组,第1、14天注射脂多糖(LPS)200ug/100ul,第2～13天、15～30天每日上午在72升(30cm×40cm×60cm)自制有机玻璃箱内被动吸烟,每天上午1次,每次12支,每次持续0.5h。红霉素干预组,造模方法同COPD组,每天熏烟前用红霉素灌胃治疗(剂量100mg/kg,配制成1.25%红霉素口服液),从第17天开始进行,经气管内注入LPS的条件、烟熏条件以及持续时间均同COPD组,给药2周;正常对照组,标准饲养30天,不做任何干预,第1、14天气管内注入生理盐水100ul。大鼠肺功能测定由湘雅医学院病理生理研究所完成,经微机处理计算出FEV0.3/FVC、R1及Cdyn。左肺10%的中性福尔马林灌注固定20min,再浸入福尔马林固定,常规脱水,石蜡包埋,切片,HE染色,以进行病理形态学观察和免疫组化检测。用免疫组化方法检测各组大鼠肺组织MMP-9的表达,逆转录聚合酶链反应(reverse transcription-polymerase chain reaction,RT-PCR)检测各组大鼠肺组织MMP-9 mRNA表达水平。
结果:(1)模型组及干预组大鼠渐出现饮食、活动减少,平均体重较正常对照组减轻,后期可见毛发干枯、发黄,可听到喘息音,正常对照组未见以上情况出现。(2)模型组及干预组大鼠FEV0.3/FVC(%)、R1(气道阻力)、Cdyn(动态肺顺应性)均明显低于正常对照组,差异有显著性(均P＜0.05),说明小气道气道阻力增加,存在明显气流受限、阻塞性肺通气功能障碍。(3)光镜下模型组及干预组大鼠肺组织符合慢性支气管炎和阻塞性肺气肿病理改变。(4)模型组肺组织中MMP-9蛋白平均阳性系数显著高于对照组(P＜0.05),干预组与模型组比较阳性系数降低(P＜0.05)。(5)模型组大鼠肺组织中MMP-9mRNA表达量高,其光密度比值显著高于正常对照组(P＜0.05);干预组与模型组光密度比值比较亦降低(P＜0.05)。
结论:(1)采用被动吸烟和LPS气道内滴注相结合构建的大鼠COPD模型,能成功复制出COPD大鼠模型。(2)COPD大鼠肺组织中MMP-9水平显著增高,在COPD的发病机制中可能起重要作用。(3)红霉素治疗COPD大鼠从基因水平下调MMP-9的表达抑制炎症细胞的移行而减弱炎症反应。
Objective:The experiment observed the changes of lung MMP-9 expression level by erythromycin intervention in rat model of COPD.Our goal is to study and understand the effect of erythromycin on lung MMP-9 expression in vivo experiment of COPD rat,a further understanding of the anti-inflammatory effects of erythromycin,and developing the application of erythromycin in COPD.
Methods:36 male rats were averagely divided into 3 groups in random.The COPD model group was established by the way of giving passive smoking for one month and endotracheal injection of LPS.Passive smoking was given once daily(0.5 hour)in a plexiglass box from the second day to the thirteen day and the fifteen day to the thirty day.In the first day and forteen day,LPS(200ug / 100ul)was given in trachea.The Erythromycin intervention group was treated with erythromycin gavage from the seventeenth day for 2 weeks,modelling method was the same with COPD group.The normal control was not given passive smoking. And in the first and forteen day,we gave each rat endotracheal injection of stroke-physiological saline solution instead of LPS.Lung function tests were performed for each rat one month later and we tested FEV0.3/FVC,Rl and Cdyn.Then the rat was put to death and the lung was taken out.Sections of paraffin-embedded left lungs tissue were cut, stained with HE,and processed for pathological observation. Immunohistochemistry was permormed for study the expression of MMP-9.The right lungs tissue was prepared for the examination of the expression of MMP-9 mRNA.
Results:(1)COPD and Erythromycin intervention rats gradually emerged diet and activity decreasing,the average body weight mitigated compared with normal control group,in the later period appearing dry and yellow hair and the sound of gasping could be heard. The normal control group was out of this situation.(2)Lung function tests showed that FEV0.3/FVC,Rl and Cdyn values were significantly lower in the COPD and Erythromycin intervention groups than in the normal control group(P＜0.05).(3)The COPD and Erythromycin intervention groups lung tissue showed chronic obstructive bronchitis and emphysema pathological changes by light microscope.(4)Compared with the rats of normal control group,the expression MMP-9 protein increased significantly(P＜0.05)in the COPD rats.The positive coefficience of Erythromycin intervention group was lower than COPD group(P＜0.05).(5)In the COPD group MMP-9 mRNA in lungs increased significantly than normal control group(P＜0.05),the optical density ratio of Erythromycin intervention group was also lower than COPD group(P＜0.05).
Conclusion:(1)The rat model of COPD which was established by the way of giving passive smoking for one month and endotracheal injection of LPS was successful,which was proofed by lung function tests and pathological observation.(2)MMP-9 levels in COPD rat lung tissue was significantly higher than normal rats,it plays an important role in the pathogenesis of COPD.(3)Erythromycin treatment of COPD rats reduced MMP-9 protein and mRNA expression levels can inhibit the migration of inflammatory cells and weaken inflammatory response.
引文
[1]Holland WW.Chronic obstructive lung disease prevention[J].Br J Dis Chest,1988,82(1):32.
[2]Burge PS.Occupation and Chronic Obstructive Pulmonary Disease (COPD)[J].Eur Respir J 1994,7:1033.
[3]Petty TL.Chronic obstructive pulmonary disease-can we do better[J].Chest,1990,97(2 Suppl):2.
[4]Luisetti M,Piccioni PD,Donnetta,et al.Protease-antiprotease imbalance:local evaluation with bronchoalveolar lavage.Respiration,1992,59 Suppl 1:24-27.
[5]Jain R,Danziger LH.The macrolide antibiotics:a pharmacokinetic and pharmacodynamic overview.Curr Pharm Des 2004,10(25):3045.
[6]Hogg,J.C.,and R.M.Senior.2002.Chronic obstructive pulmonary disease:part 2.Pathology and biochemistry of emphysema.Thorax 57:830-834.
[7]白晶,万小华,梁国荣等.红霉素在慢性阻塞性肺部疾病气道炎症作用[J].实用中西医结合临床,2006,6(5):3-4.
[8]郑鸿翱.建立慢性阻塞性肺疾病动物模型方法的研究进展[J].中国实验动物学报,2003,11(4):249.
[9]许三林,吴人亮,陈春莲,等.E-cadherin在吸烟小鼠气道上皮损伤修复中表达的研究[J].中华结核和呼吸杂志,1999,22:417-419.
[10]Marino G.Vitamin C helps cigarette- smoking hamster[J].Science News,1994,146:86-86.
[11]迟春花,何冰,汤秀英,等.烟草雾吸入导致慢阻肺机制的实验研究-大鼠Clara细胞结构及其分泌蛋白的变化[J].心肺血管病杂志,2000,19:224-227.
[12]Tavares JL,Wangoo A,Dilworth P,et al.Thalidomide reduces tumournecrosis factor-alpha production by human alveolar macrophages[J].Respir Med,1997,91:31-39.
[13]Li D,Godfky R,Rogers AV,et al.Endotoxin-induced airway intro-epithelial neutrophilia.Goblet cell hyperplasia and metaplasia in the rat:a light and electron microscopic study[J]. Eur Respir J,1996,9:424.
[14]马楠,崔德健,梁延杰,等.气道内注入脂多糖法建立大鼠慢性支气管炎模型[J].中华结核和呼吸杂志,1999,22:371-372.
[15]宋一平,崔德健,茅培英,等.慢性阻塞性肺疾病大鼠模型气道重塑及生长因子的研究[J].中华结核和呼吸杂志,2001,24:283-287.
[16]Visse R,Nagase H:Matrix metalloproteinases and tissue inhibitors of metalloproteinases:structure,function,and biochemistry.Circ Res 2003,92:827-839.
[17]Betsuyaku T,Nishimura M,Takeyabu K,Tanino M,Venge P,Xu S,Kawakami Y:Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema.Am J Respir Crit Care Med 1999,159:198-1991.
[18]Culpitt SV,Rogers DF,Traves SL,Barnes PJ,Donnelly LE:Sputum matrix metalloproteases:comparison between chronic obstructive pulmonary disease and asthma.Respir Med 2005,99:703-710.
[19]Vignola AM,Riccobono L,Mirabella A,Profita M,Chanez P,Bellia V,Mautino G,D'accardi P,Bousquet J,Bonsignore G:Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis.Am J Respir Crit Care Med 1998,158:1945-1950.
[20]Finlay GA,Russell KJ,Mc Mahon KJ,D'Arcy EM,Masterson JB,Fitz Gerald MX,O'Connor CM:Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients.Thorax 1997,52:502-506.
[21]Finlay GA,O'Driscoll LR,Russell KJ,D'Arcy EM,Masterson JB,FitzGerald MX,O'Connor CM:Matrix metalloproteinase expression and production by alveolar macrophages in emphysema.Am J Respir Crit Care Med 1997,156:240-247.
[22]Leppert D,Waubant E,Galardy R,Bunnett NW,Hauser SL.T cell gelatinases mediate basement membrane transmigration in vitro.J Immunol 1995;154:4379-89.
[23]Xia M,Leppert D,Hauser SL,Sreedharan SP,Nelson PJ,Krensky AM,et al.Stimulus specificity of matrix metalloproteinase dependence of human T cell migration through a model basement membrane.J Immunol 1996;156:160-7.
[24]Delclaux C,Delacourt C,D' Ortho MP,Boyer V,Lafuma C,Harf A.Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane.Am J Respir Cell Mol Biol 1996;14:288-95.
[25]Okada S,Kita H,George TJ,Gleich GJ,Leiferman KM.Migration of eosinophils through basement membrane components in vitro:role of matrix metalloproteinase-9.Am J Respir Cell Mol Biol 1997;17:519-28.
[26]Hibbs MS,Hoidal JR,Kang AH.Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured human alveolar macrophages.J Clin Invest 1987;80:1644-50.
[27]Herouy Y,Mellios P,Bandemir E,Dichmann S,Nockowski P,Schopf E.Inflammation in stasis dermatitis upregulates MMP-1,MMP-2 and MMP-13 expression.J Dermatol Sci 2001;25:98-205.
[28]Ohno I,Ohtani H,Nitta Y.Eosinophils as a source of matrix metalloproteinase-9 in asthmatic airway inflammation.Am J Respir Cell Mol Biol 1997;16:212-219.
[29]Corbel M,Langente V,Boichot E.Pulmonary inflammation and tissue remodeling:role of metalloproteinase,2003,234(3):456-233.
[30]孔英君,孙文学.慢性阻塞性肺疾病患者肺组织中基质金属蛋白酶抑制剂-1及基质金属蛋白酶-9与细胞黏附因子表达的关系.中华结核和呼吸杂志,2008,31:129-133.
[31]Hogg JC,Senior RM:Chronic obstructive pulmonary disease -part 2:pathology and biochemistry of emphysema.Thorax 2002,57:830-834.
[32]Atkinson JJ,Senior RM:Matrix metalloproteinase-9 in lung remodeling.Am J Respir Cell Mol Biol 2003,28:12-24.
[33]Barnes PJ:New treatments for COPD.Nat Rev Drug Discov 2002,1:437-446.
[34]Kang MJ,Oh YM.Lung matrix metalloproteinase-9 correlates with cigarette smoking and obstruction of airflow.J Korean Med Sci.2003Dec;18(6):821-7.
[35]Atsuko Hozumi,Yoshihiro Nishimura,Teruaki Nishiuma,Yoshikazu Kotani,and Mitsuhiro Yokoyama.Induction of MMP-9 in normal human bronchial epithelial cells by TNF-α via NF-κB -mediated pathway . Am J Physiol Lung Cell Mol Physiol 2001; 281: 1444-1452.
[36] Xu XM, Sun TY, Lin, JB , et al. The role of matrix metalloproteinases-9 and tissue inhibitor of metalloproteinase-1 in chronic obstructive pulmonary disease[J]. Zhonghua Yi Xue Za Zhi, 2003, 83(13): 1138-1141.
[37]Keatings VM, Collins PD, Scoee DM , et al. Differences of interleukin-8 and tumo rdisease of asthma. J Resp ir Crit Care Med, 1996, 153: 530-534.
[38] Pesci A, Balbi B, Majori M, et al. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J, 1998, 12: 380-386.
[39]Turato G, L uinR, Miniati M, et al. Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radio logic emphysema. Am J Resp ir crit car Med, 2002, 116: 105-110.
[40] Saetta M, Baraldo S, Corbino L, et al. CD8-+ ve cells in the lungs of smokers, with chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 1999, 160: 711-717.
[41] O' shoughnessy TC, Ansari TW , Barnes NC, et al. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8-+ T-lymphocytes with FEV 1. Am J Respir Crit Care Med, 1997, 155: 852-857.
[42] Retamales I, Elliott WM, Meshi B, et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Me d, 2001, 164: 469-473.
[43]Mikami M, Llewellyn-Jones CG, Bayley D, et al. The chemotactic activity of sputum from patients with bronchiectasis. Am J Respic Crit Care Med, 1998, 157: 732-728.
[44] Williams JD. Non-antimicrobial activities of macrolides. Int J Antimicrob Agents , 2001, 18(suppl 1): S89-91.
[45] Sugihara E, Effect of macrolide antibiotics on neutrophil function in human peripheral blood. Kansenshogaku Zasshi, 1997, 71(4): 329.
[46]Miyachi Y, Yoshioka A, Imamura S, et al. Effect of antibiotics on the generation of reactive oxygen species.J Invest Dermatol,1986,86(4):449.
[47]Maria Jesus Sanz,Yafa Naim,Abu Nabah,et al.Erythromycin exerts in vivo anti-inflammatory activity downregulating cell adhesion molecule expression.Br J Pharmacol Advance(online publication),2004,doi:10.1038/sj.bjp.0706021.
[48]Yingji Li,Arata Azuma,Satoru Takahashi,et al.Fourteen-membered ring macrolides inhibit vascular cell adhesion molecule 1 messenger RNA induction and leukocyte migaration.Chest,2002,122:2137.
[49]何志义,邹朝霞,钟南山.红霉素对支气管上皮细胞转录因子核因子κB、激活蛋白1活性的影响.中华结核和呼吸杂志.2004,27(9):637.
[50]钟小宁,白晶,施焕中,等.慢性支气管炎与肺气肿大鼠气道炎症与气道重建的实验研究.中华结核和呼吸杂志,2003,26(11):750-755.
[51]Nashimoto N,Kawabe T,Hara T,et al.Effect of erythromylin on matrix metalloproteinase-9 and cell migration.J Lab Med.2001 Mar,137(3):176-83.
[52]Kanai K,Asano K,Hisamitsu T,Suzaki H.Suppression of matrix metalloproteinase-9 production from neutropbils by a macrolide antibiotic,roxithromycin,in vitro.Mediators Inframm.2004 Dec;13(5-6):313-9.
[53]Wasylyk C,Gutman A,Nicholson R,Wasylyk B.The c-Ets on coprotein activates the stromelysin promoter through the same elements as several non-nuclear oncoprotein.EMBO J 1991;10:1127-1134.
[54]Sato H,Seiki M.Regulatory mechanism of 92 kDa type Ⅳ collagenase gene expression which is associated with invasiveness of tumor cells.Oncogene 1993;8:395-405.
[1]Desaki M,Takizawa H,Ohtoshi T,et al.Erythromycin suppress nuclear factor- kappa B and activator protein21 activation in human bronchial epithelial cells.Biochem Biophys Res Commun,2000,267:124-128.
[2]Abe S,Nakamura H,Inoue S,et al.Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells.Am J Respir Cell Mol Biol,2000,22:51-60.
[3]Khair OA,Devalia JL,Abdelazia MM,et al.Effect of erythromycin on Haemophilus influenzae endotoxin-induced released of IL-6/ IL -8 and Sicam-1 by cultured human bronchial epithelial cells.Europen Respir J,1995,8:1451-1457.
[4]Sakito O,Kadota J,Kohno S,et al.Interleukin 1 beta,tumor necrosis factor alpha,and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis:a potential mechanism of macrolide therapy.Respira- tion,1996,63:42-48.
[5]Schultz MJ,Speelman P,Hack CE,et al.Intravenous infusion of erythroraycin inhibits CXC chemokine production, but aguement neutrophil degranulation in whole blood stimulated with streptococcus pneumonia. J Antimicrob Chemother, 2000, 46: 235 — 240.
[6] Sato E, Nelson DK, Koyama S, et al. Erythromycin modulates eosinphil chemotactic cytokines production by human lung fibroblasts in vitro. Antimicrob Agents Chemother, 2001, 45: 401-406.
[7] Khair OA, Devalia JL, Abdelaziz MM, et al. Effects of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6 , IL-8 and SICAM-1 by cultured human bronchial epithelial cells. Eur Respir J, 1995, 8: 1451-1457.
[8] Takizawa H, Desaki T, Ohtoshi T, et al. Erythromycin and clarithromycin attenuate cytokine — induced endothelin — 1 expression in human bronchial epithelial cells. Eur Respir J , 1998, 12: 57-63.
[9] Macleod C M, Hamid Q A, Cameron L, et al. Anti1000-seed weight activity of clarithromycin in adults with chronically inflamed sinus mucosa [J]. Adv Ther, 2001, 18(2): 75.
[10] Schultz MJ, Speelman P. Erythromycin inhibits Pseudomonas aeruginosa- induced tumor necrosis factor-alpha production in human whole blood [J]. J Antimicrob Chemother, 2001, 48(2): 275.
[11]Culic O, Erakovic V, Parnham M J. Anti-inflammatory effects of macrolide antibiotics [J]. Eur J Pharmacol, 2001, 429(123): 209.
[12] Shimane T, Asano K, Mizutani T, et al. Inhibitory action of roxithromycin on tumor necrosis factor-alpha production from mast cells in vitro[J]. In Vivo, 1999, 13(6): 503.
[13]Sugihara E, Koyanagi T, Niizeki T, et al. Macrolide antibiotics directly reduce active oxygen generation by neutrophils in human peripheral blood. Kurume Med J, 2003, 50: 9-15.
[14]Theron AJ, Feldman C, Anderson R. Investigation of the anti-inflammatory and membrane-stabilizing potential of spiramycin in vitro. J Antimicrob Chemother, 2000, 46: 269-271.
[15] Sugihura E. Effects of macrolide aqntibiotics on neutrophils function in human peripheral blood. Kansenshogaku Zasshi, 1997, 71 : 329-336.
[16] Yaraaryo T, Oishi K, Yoshimine H , et al. Fourteen-Member Macrolides Promote the Phosphatidylserine Receptor-Dependent Phagocytosis of Apototic Neutrophils by Alveolar Macrophages. Antimicrobial Agents Chemother, 2003, 47(1): 48-53.
[17] Inamura K, Ohta N, Fukase S, et al. The effects of erythromycin on human peripheral neutrophil apoptosis[J]. Rhinology, 2000, 38 (3): 124.
[18]Noma T, Sugawara Y, Fujiwara S, et al. Effect of roxithromycin on induction of apoptosis in peripheral blood lymphocytes from patients with bronchial asthma [J] . Jpn J Antibiot, 2001, 54 (Suppl A): 148.
[19] Ao.shiba K, Nagai A, Konno K. Erythromycin shortens neutrophil survival by accelerating apoptosis[J]. Antimicrob Agents Chemother, 1997, 41(8): 1847.
[20] Kanno N, Glaser S, Chowdhury U, et al. Gatin inhibits cholangiocarcinoma growth through increased apoptosis by activation of Ca2 +-dependent protein kinase C-alpha [J]. J Hepatol, 2001, 34 (2): 284.
[21] Zhao D M, Xue H H, Chida K, et al. Effect of erythromycin on ATP-induced intracellular calcium response in A549 cells[J]. Am J Physiol Lung Cell Mol Physiol, 2000, 278 (4): L726.
[22] Mitsuyama T, Tanaka T, Hidaka K, et al. Inhibition by erythrmycin of superoxide anion production by human polymorphonuclear leukocytes through the action of cyclic AMP-dependent protein kinase [J]. Respi ration, 1995, 62 (5): 269.
[23] Ianaro A, Ialenti A, Maffia P, et al. Anti-inflammatory activity of Macrolide antibiotics [J]. J Pharmacol Ex p Ther, 2000, 292: 156.
[24] Kohri K, Tamaoki J, Kondo M, et al. Macrolide anibiotics inhibit nitricoxide generation by rat pulmonary alveolar macrophages [J]. Eur Respir J, 2000, 15(1): 62.
[25] ChanT A. Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention [J]. Lancet Oncol, 2002, 3(3): 166.
[26] Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin supperlesses interleukin-6 expression by human bronchial epithelial cells: a potential mechanism of its anti-inflammatory action[J].Biochem Biophys Res Commun,1995,210:781.
[27]Shao R,Hu M C,Zhou B P,et al.ElA sensitizes cells to tumor necrosis factor-induced apoptosis through inhibition of Ⅰ-kappaB kinases and nuclear factor kappaB activities[J].J Biol Chem.1999,30;274(31):495.
[28]Ichiyama T,Nishikawa M,Yoshitomi T,et al.Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells[J].Antimicrob Agents Chemother,2001,45(1):44.
[29]何志义,邹朝霞,钟南山,等.红霉素对支气管上皮细胞转录因子核因子κB、激活蛋白1活性的影响.中华结核和呼吸杂志,2004,27(9):637.
[30]Desaki M,Okazakih.Molecular mechanisms of anti-inflammatory action of erythromycin that regulates nuclear factor-kappa B activation.Antimicrob Agents Chemother,2004,48(5):1581.
[31]Puchelle E,Bajolet O,Abely M.Airway mucus in cystic fibrosis.Paediatr Respir Rev.2002;3:115-119.
[32]Prescott E,Lange P,Vestbo J.Chronic mucus hypersecretion in COPD and death from pulmonary infection.Eur Respir J.1995;8:1333-1338.
[33]Vestbo J,Prescott E,Lange P,for the Copenhagen City Heart Study Group.Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity.Am J Respir Crit Care Med.1996;153:1530-1535.
[34]Goswami SK,Kivity S,Marom Z.Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro.Am Rev Respir Dis.1990;141:72-78.
[35]Tagaya E,Tamaoki J,Kondo M,et al.Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion.Chest,2002,122:213-218.
[36]App EM,Konig K,Duffner U,et al.The effects of azithromycin therapy on sputum inflammation in CF lung disease.Am J Respir Crit Care Med,2000,161:A758-763.
[37]Rubin BK,Druce H,Ramirez OE,et al.Effects of clarithromycin on nasal mucus properities in healthy subjects and in patients with purulent rhinitis. Am J Respir Crit Care Med, 1997, 155: 2018-2023.
[38] Cazzola M, Salzillo A, Diamare F. Potential role of macrolide in the treatment of the asthma. Monaldi Arch Chest Dis, 2000 , 55: 231-236.
[39]Shoji T, Yoshida S,Sakamoto H, et al. Anti-inflammatory effects of rothromycin in patients with aspirin-intolerant asthma. Clin Exp Allergy, 1999, 29: 950-956.
[40] Eitches RW, Rachelef sky GS, Katz RM , et al. Methylprednisolone and troleandomycin in treatment of steroid-dependent asthmatic children. Am J Dis Child, 1985, 139: 264-268.
[41] Ball BD, Hill MR, Brenner M, et al. Effects of low-dose troleandomycin on glucocorticoid pharmacokinetics and airway hyperresponsiveness in severely asthmatic children. Ann Allergy, 1990, 65: 37-45.
[42] Garey KW, Rubinstein I, Gotfried MH , et al. Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma. Chest, 2000, 118: 1826-1827.
[43] Shimizu T, Kato M, Mochizuki H, et al. Roxithromycin reduces the degree of bronchial hyperresponsiveness in children with asthma. Chest, 1994, 106: 458-461.
[44] Monica K, Gail H , Jun BS, et al. Mycoplasma pneumoniae and chlamydia pneumoniae in asthma : Effect of clarithromycin. Chest, 2002, 121 : 1782-1788.
[45] Feldman C, Anderson R, Theron A, et al. The effects of ketolides on bioactive phospholipids-induced injury to human respiratory epithelium in vitro. Eur Respir J, 1999, 13: 1022-1028.
[46]Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol, 2001, 429: 209-229.
[47] Tsang KW, Ho PI, Chan KN, et al. A pilot study of low-dose erythromycin in bronchiectasis. Eur Respir J, 1999, 13: 361-364.
[48] Khair OA , Devalia JL, Abdelaziz MM, et al. Effects of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6 , IL-8 and SICAM-1 by cultured human bronchial epithelial cells. Eur Respir J , 1995, 8: 1451-1457.
[49] App EM, Konig K, Duffner U, et al. The effects of azithromycin therapy on sputum inflammation in CF lung disease. Am J Respir Crit Care Med , 2000, 161: A758-763.
[50] Wolter J,Seeney S,Bell S, et al. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis : a randomized trial. Throax, 2002, 57: 212-216.
[51]Equi A, Balfour-Lynn IM, Bush A, et al. Long term azithromycin in children with cystic fibrosis: a randomized, placebo-controlled crossover trial. Lancet, 2002, 360: 978-984.
[52] Basyigit I, Yildiz F, Ozkara SK, et al. The effect of clarit hromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacot her, 2004, 38 (9): 1400-1405.
[53] Banerjee D, Honeybourne D, Khair OA. The effect of oral clarit hromycin on bronchial airway inflammation in moderate to severe stable COPD: a randomized controlled trial . Treat Respir Med , 2004 , 3(1): 59-65.
[54] Peinado VI, Barbera JA, Abate P, et al. Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 1999, 159 (5pt1): 1605-1611.
[2]Burge PS.Occupation and Chronic Obstructive Pulmonary Disease (COPD)[J].Eur Respir J 1994,7:1033.
[3]Petty TL.Chronic obstructive pulmonary disease-can we do better[J].Chest,1990,97(2 Suppl):2.
[4]Luisetti M,Piccioni PD,Donnetta,et al.Protease-antiprotease imbalance:local evaluation with bronchoalveolar lavage.Respiration,1992,59 Suppl 1:24-27.
[5]Jain R,Danziger LH.The macrolide antibiotics:a pharmacokinetic and pharmacodynamic overview.Curr Pharm Des 2004,10(25):3045.
[6]Hogg,J.C.,and R.M.Senior.2002.Chronic obstructive pulmonary disease:part 2.Pathology and biochemistry of emphysema.Thorax 57:830-834.
[7]白晶,万小华,梁国荣等.红霉素在慢性阻塞性肺部疾病气道炎症作用[J].实用中西医结合临床,2006,6(5):3-4.
[8]郑鸿翱.建立慢性阻塞性肺疾病动物模型方法的研究进展[J].中国实验动物学报,2003,11(4):249.
[9]许三林,吴人亮,陈春莲,等.E-cadherin在吸烟小鼠气道上皮损伤修复中表达的研究[J].中华结核和呼吸杂志,1999,22:417-419.
[10]Marino G.Vitamin C helps cigarette- smoking hamster[J].Science News,1994,146:86-86.
[11]迟春花,何冰,汤秀英,等.烟草雾吸入导致慢阻肺机制的实验研究-大鼠Clara细胞结构及其分泌蛋白的变化[J].心肺血管病杂志,2000,19:224-227.
[12]Tavares JL,Wangoo A,Dilworth P,et al.Thalidomide reduces tumournecrosis factor-alpha production by human alveolar macrophages[J].Respir Med,1997,91:31-39.
[13]Li D,Godfky R,Rogers AV,et al.Endotoxin-induced airway intro-epithelial neutrophilia.Goblet cell hyperplasia and metaplasia in the rat:a light and electron microscopic study[J]. Eur Respir J,1996,9:424.
[14]马楠,崔德健,梁延杰,等.气道内注入脂多糖法建立大鼠慢性支气管炎模型[J].中华结核和呼吸杂志,1999,22:371-372.
[15]宋一平,崔德健,茅培英,等.慢性阻塞性肺疾病大鼠模型气道重塑及生长因子的研究[J].中华结核和呼吸杂志,2001,24:283-287.
[16]Visse R,Nagase H:Matrix metalloproteinases and tissue inhibitors of metalloproteinases:structure,function,and biochemistry.Circ Res 2003,92:827-839.
[17]Betsuyaku T,Nishimura M,Takeyabu K,Tanino M,Venge P,Xu S,Kawakami Y:Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema.Am J Respir Crit Care Med 1999,159:198-1991.
[18]Culpitt SV,Rogers DF,Traves SL,Barnes PJ,Donnelly LE:Sputum matrix metalloproteases:comparison between chronic obstructive pulmonary disease and asthma.Respir Med 2005,99:703-710.
[19]Vignola AM,Riccobono L,Mirabella A,Profita M,Chanez P,Bellia V,Mautino G,D'accardi P,Bousquet J,Bonsignore G:Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis.Am J Respir Crit Care Med 1998,158:1945-1950.
[20]Finlay GA,Russell KJ,Mc Mahon KJ,D'Arcy EM,Masterson JB,Fitz Gerald MX,O'Connor CM:Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients.Thorax 1997,52:502-506.
[21]Finlay GA,O'Driscoll LR,Russell KJ,D'Arcy EM,Masterson JB,FitzGerald MX,O'Connor CM:Matrix metalloproteinase expression and production by alveolar macrophages in emphysema.Am J Respir Crit Care Med 1997,156:240-247.
[22]Leppert D,Waubant E,Galardy R,Bunnett NW,Hauser SL.T cell gelatinases mediate basement membrane transmigration in vitro.J Immunol 1995;154:4379-89.
[23]Xia M,Leppert D,Hauser SL,Sreedharan SP,Nelson PJ,Krensky AM,et al.Stimulus specificity of matrix metalloproteinase dependence of human T cell migration through a model basement membrane.J Immunol 1996;156:160-7.
[24]Delclaux C,Delacourt C,D' Ortho MP,Boyer V,Lafuma C,Harf A.Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane.Am J Respir Cell Mol Biol 1996;14:288-95.
[25]Okada S,Kita H,George TJ,Gleich GJ,Leiferman KM.Migration of eosinophils through basement membrane components in vitro:role of matrix metalloproteinase-9.Am J Respir Cell Mol Biol 1997;17:519-28.
[26]Hibbs MS,Hoidal JR,Kang AH.Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured human alveolar macrophages.J Clin Invest 1987;80:1644-50.
[27]Herouy Y,Mellios P,Bandemir E,Dichmann S,Nockowski P,Schopf E.Inflammation in stasis dermatitis upregulates MMP-1,MMP-2 and MMP-13 expression.J Dermatol Sci 2001;25:98-205.
[28]Ohno I,Ohtani H,Nitta Y.Eosinophils as a source of matrix metalloproteinase-9 in asthmatic airway inflammation.Am J Respir Cell Mol Biol 1997;16:212-219.
[29]Corbel M,Langente V,Boichot E.Pulmonary inflammation and tissue remodeling:role of metalloproteinase,2003,234(3):456-233.
[30]孔英君,孙文学.慢性阻塞性肺疾病患者肺组织中基质金属蛋白酶抑制剂-1及基质金属蛋白酶-9与细胞黏附因子表达的关系.中华结核和呼吸杂志,2008,31:129-133.
[31]Hogg JC,Senior RM:Chronic obstructive pulmonary disease -part 2:pathology and biochemistry of emphysema.Thorax 2002,57:830-834.
[32]Atkinson JJ,Senior RM:Matrix metalloproteinase-9 in lung remodeling.Am J Respir Cell Mol Biol 2003,28:12-24.
[33]Barnes PJ:New treatments for COPD.Nat Rev Drug Discov 2002,1:437-446.
[34]Kang MJ,Oh YM.Lung matrix metalloproteinase-9 correlates with cigarette smoking and obstruction of airflow.J Korean Med Sci.2003Dec;18(6):821-7.
[35]Atsuko Hozumi,Yoshihiro Nishimura,Teruaki Nishiuma,Yoshikazu Kotani,and Mitsuhiro Yokoyama.Induction of MMP-9 in normal human bronchial epithelial cells by TNF-α via NF-κB -mediated pathway . Am J Physiol Lung Cell Mol Physiol 2001; 281: 1444-1452.
[36] Xu XM, Sun TY, Lin, JB , et al. The role of matrix metalloproteinases-9 and tissue inhibitor of metalloproteinase-1 in chronic obstructive pulmonary disease[J]. Zhonghua Yi Xue Za Zhi, 2003, 83(13): 1138-1141.
[37]Keatings VM, Collins PD, Scoee DM , et al. Differences of interleukin-8 and tumo rdisease of asthma. J Resp ir Crit Care Med, 1996, 153: 530-534.
[38] Pesci A, Balbi B, Majori M, et al. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J, 1998, 12: 380-386.
[39]Turato G, L uinR, Miniati M, et al. Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radio logic emphysema. Am J Resp ir crit car Med, 2002, 116: 105-110.
[40] Saetta M, Baraldo S, Corbino L, et al. CD8-+ ve cells in the lungs of smokers, with chronic obstructive pulmonary disease[J]. Am J Respir Crit Care Med, 1999, 160: 711-717.
[41] O' shoughnessy TC, Ansari TW , Barnes NC, et al. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8-+ T-lymphocytes with FEV 1. Am J Respir Crit Care Med, 1997, 155: 852-857.
[42] Retamales I, Elliott WM, Meshi B, et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Me d, 2001, 164: 469-473.
[43]Mikami M, Llewellyn-Jones CG, Bayley D, et al. The chemotactic activity of sputum from patients with bronchiectasis. Am J Respic Crit Care Med, 1998, 157: 732-728.
[44] Williams JD. Non-antimicrobial activities of macrolides. Int J Antimicrob Agents , 2001, 18(suppl 1): S89-91.
[45] Sugihara E, Effect of macrolide antibiotics on neutrophil function in human peripheral blood. Kansenshogaku Zasshi, 1997, 71(4): 329.
[46]Miyachi Y, Yoshioka A, Imamura S, et al. Effect of antibiotics on the generation of reactive oxygen species.J Invest Dermatol,1986,86(4):449.
[47]Maria Jesus Sanz,Yafa Naim,Abu Nabah,et al.Erythromycin exerts in vivo anti-inflammatory activity downregulating cell adhesion molecule expression.Br J Pharmacol Advance(online publication),2004,doi:10.1038/sj.bjp.0706021.
[48]Yingji Li,Arata Azuma,Satoru Takahashi,et al.Fourteen-membered ring macrolides inhibit vascular cell adhesion molecule 1 messenger RNA induction and leukocyte migaration.Chest,2002,122:2137.
[49]何志义,邹朝霞,钟南山.红霉素对支气管上皮细胞转录因子核因子κB、激活蛋白1活性的影响.中华结核和呼吸杂志.2004,27(9):637.
[50]钟小宁,白晶,施焕中,等.慢性支气管炎与肺气肿大鼠气道炎症与气道重建的实验研究.中华结核和呼吸杂志,2003,26(11):750-755.
[51]Nashimoto N,Kawabe T,Hara T,et al.Effect of erythromylin on matrix metalloproteinase-9 and cell migration.J Lab Med.2001 Mar,137(3):176-83.
[52]Kanai K,Asano K,Hisamitsu T,Suzaki H.Suppression of matrix metalloproteinase-9 production from neutropbils by a macrolide antibiotic,roxithromycin,in vitro.Mediators Inframm.2004 Dec;13(5-6):313-9.
[53]Wasylyk C,Gutman A,Nicholson R,Wasylyk B.The c-Ets on coprotein activates the stromelysin promoter through the same elements as several non-nuclear oncoprotein.EMBO J 1991;10:1127-1134.
[54]Sato H,Seiki M.Regulatory mechanism of 92 kDa type Ⅳ collagenase gene expression which is associated with invasiveness of tumor cells.Oncogene 1993;8:395-405.
[1]Desaki M,Takizawa H,Ohtoshi T,et al.Erythromycin suppress nuclear factor- kappa B and activator protein21 activation in human bronchial epithelial cells.Biochem Biophys Res Commun,2000,267:124-128.
[2]Abe S,Nakamura H,Inoue S,et al.Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells.Am J Respir Cell Mol Biol,2000,22:51-60.
[3]Khair OA,Devalia JL,Abdelazia MM,et al.Effect of erythromycin on Haemophilus influenzae endotoxin-induced released of IL-6/ IL -8 and Sicam-1 by cultured human bronchial epithelial cells.Europen Respir J,1995,8:1451-1457.
[4]Sakito O,Kadota J,Kohno S,et al.Interleukin 1 beta,tumor necrosis factor alpha,and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis:a potential mechanism of macrolide therapy.Respira- tion,1996,63:42-48.
[5]Schultz MJ,Speelman P,Hack CE,et al.Intravenous infusion of erythroraycin inhibits CXC chemokine production, but aguement neutrophil degranulation in whole blood stimulated with streptococcus pneumonia. J Antimicrob Chemother, 2000, 46: 235 — 240.
[6] Sato E, Nelson DK, Koyama S, et al. Erythromycin modulates eosinphil chemotactic cytokines production by human lung fibroblasts in vitro. Antimicrob Agents Chemother, 2001, 45: 401-406.
[7] Khair OA, Devalia JL, Abdelaziz MM, et al. Effects of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6 , IL-8 and SICAM-1 by cultured human bronchial epithelial cells. Eur Respir J, 1995, 8: 1451-1457.
[8] Takizawa H, Desaki T, Ohtoshi T, et al. Erythromycin and clarithromycin attenuate cytokine — induced endothelin — 1 expression in human bronchial epithelial cells. Eur Respir J , 1998, 12: 57-63.
[9] Macleod C M, Hamid Q A, Cameron L, et al. Anti1000-seed weight activity of clarithromycin in adults with chronically inflamed sinus mucosa [J]. Adv Ther, 2001, 18(2): 75.
[10] Schultz MJ, Speelman P. Erythromycin inhibits Pseudomonas aeruginosa- induced tumor necrosis factor-alpha production in human whole blood [J]. J Antimicrob Chemother, 2001, 48(2): 275.
[11]Culic O, Erakovic V, Parnham M J. Anti-inflammatory effects of macrolide antibiotics [J]. Eur J Pharmacol, 2001, 429(123): 209.
[12] Shimane T, Asano K, Mizutani T, et al. Inhibitory action of roxithromycin on tumor necrosis factor-alpha production from mast cells in vitro[J]. In Vivo, 1999, 13(6): 503.
[13]Sugihara E, Koyanagi T, Niizeki T, et al. Macrolide antibiotics directly reduce active oxygen generation by neutrophils in human peripheral blood. Kurume Med J, 2003, 50: 9-15.
[14]Theron AJ, Feldman C, Anderson R. Investigation of the anti-inflammatory and membrane-stabilizing potential of spiramycin in vitro. J Antimicrob Chemother, 2000, 46: 269-271.
[15] Sugihura E. Effects of macrolide aqntibiotics on neutrophils function in human peripheral blood. Kansenshogaku Zasshi, 1997, 71 : 329-336.
[16] Yaraaryo T, Oishi K, Yoshimine H , et al. Fourteen-Member Macrolides Promote the Phosphatidylserine Receptor-Dependent Phagocytosis of Apototic Neutrophils by Alveolar Macrophages. Antimicrobial Agents Chemother, 2003, 47(1): 48-53.
[17] Inamura K, Ohta N, Fukase S, et al. The effects of erythromycin on human peripheral neutrophil apoptosis[J]. Rhinology, 2000, 38 (3): 124.
[18]Noma T, Sugawara Y, Fujiwara S, et al. Effect of roxithromycin on induction of apoptosis in peripheral blood lymphocytes from patients with bronchial asthma [J] . Jpn J Antibiot, 2001, 54 (Suppl A): 148.
[19] Ao.shiba K, Nagai A, Konno K. Erythromycin shortens neutrophil survival by accelerating apoptosis[J]. Antimicrob Agents Chemother, 1997, 41(8): 1847.
[20] Kanno N, Glaser S, Chowdhury U, et al. Gatin inhibits cholangiocarcinoma growth through increased apoptosis by activation of Ca2 +-dependent protein kinase C-alpha [J]. J Hepatol, 2001, 34 (2): 284.
[21] Zhao D M, Xue H H, Chida K, et al. Effect of erythromycin on ATP-induced intracellular calcium response in A549 cells[J]. Am J Physiol Lung Cell Mol Physiol, 2000, 278 (4): L726.
[22] Mitsuyama T, Tanaka T, Hidaka K, et al. Inhibition by erythrmycin of superoxide anion production by human polymorphonuclear leukocytes through the action of cyclic AMP-dependent protein kinase [J]. Respi ration, 1995, 62 (5): 269.
[23] Ianaro A, Ialenti A, Maffia P, et al. Anti-inflammatory activity of Macrolide antibiotics [J]. J Pharmacol Ex p Ther, 2000, 292: 156.
[24] Kohri K, Tamaoki J, Kondo M, et al. Macrolide anibiotics inhibit nitricoxide generation by rat pulmonary alveolar macrophages [J]. Eur Respir J, 2000, 15(1): 62.
[25] ChanT A. Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention [J]. Lancet Oncol, 2002, 3(3): 166.
[26] Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin supperlesses interleukin-6 expression by human bronchial epithelial cells: a potential mechanism of its anti-inflammatory action[J].Biochem Biophys Res Commun,1995,210:781.
[27]Shao R,Hu M C,Zhou B P,et al.ElA sensitizes cells to tumor necrosis factor-induced apoptosis through inhibition of Ⅰ-kappaB kinases and nuclear factor kappaB activities[J].J Biol Chem.1999,30;274(31):495.
[28]Ichiyama T,Nishikawa M,Yoshitomi T,et al.Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells[J].Antimicrob Agents Chemother,2001,45(1):44.
[29]何志义,邹朝霞,钟南山,等.红霉素对支气管上皮细胞转录因子核因子κB、激活蛋白1活性的影响.中华结核和呼吸杂志,2004,27(9):637.
[30]Desaki M,Okazakih.Molecular mechanisms of anti-inflammatory action of erythromycin that regulates nuclear factor-kappa B activation.Antimicrob Agents Chemother,2004,48(5):1581.
[31]Puchelle E,Bajolet O,Abely M.Airway mucus in cystic fibrosis.Paediatr Respir Rev.2002;3:115-119.
[32]Prescott E,Lange P,Vestbo J.Chronic mucus hypersecretion in COPD and death from pulmonary infection.Eur Respir J.1995;8:1333-1338.
[33]Vestbo J,Prescott E,Lange P,for the Copenhagen City Heart Study Group.Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity.Am J Respir Crit Care Med.1996;153:1530-1535.
[34]Goswami SK,Kivity S,Marom Z.Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro.Am Rev Respir Dis.1990;141:72-78.
[35]Tagaya E,Tamaoki J,Kondo M,et al.Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion.Chest,2002,122:213-218.
[36]App EM,Konig K,Duffner U,et al.The effects of azithromycin therapy on sputum inflammation in CF lung disease.Am J Respir Crit Care Med,2000,161:A758-763.
[37]Rubin BK,Druce H,Ramirez OE,et al.Effects of clarithromycin on nasal mucus properities in healthy subjects and in patients with purulent rhinitis. Am J Respir Crit Care Med, 1997, 155: 2018-2023.
[38] Cazzola M, Salzillo A, Diamare F. Potential role of macrolide in the treatment of the asthma. Monaldi Arch Chest Dis, 2000 , 55: 231-236.
[39]Shoji T, Yoshida S,Sakamoto H, et al. Anti-inflammatory effects of rothromycin in patients with aspirin-intolerant asthma. Clin Exp Allergy, 1999, 29: 950-956.
[40] Eitches RW, Rachelef sky GS, Katz RM , et al. Methylprednisolone and troleandomycin in treatment of steroid-dependent asthmatic children. Am J Dis Child, 1985, 139: 264-268.
[41] Ball BD, Hill MR, Brenner M, et al. Effects of low-dose troleandomycin on glucocorticoid pharmacokinetics and airway hyperresponsiveness in severely asthmatic children. Ann Allergy, 1990, 65: 37-45.
[42] Garey KW, Rubinstein I, Gotfried MH , et al. Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma. Chest, 2000, 118: 1826-1827.
[43] Shimizu T, Kato M, Mochizuki H, et al. Roxithromycin reduces the degree of bronchial hyperresponsiveness in children with asthma. Chest, 1994, 106: 458-461.
[44] Monica K, Gail H , Jun BS, et al. Mycoplasma pneumoniae and chlamydia pneumoniae in asthma : Effect of clarithromycin. Chest, 2002, 121 : 1782-1788.
[45] Feldman C, Anderson R, Theron A, et al. The effects of ketolides on bioactive phospholipids-induced injury to human respiratory epithelium in vitro. Eur Respir J, 1999, 13: 1022-1028.
[46]Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol, 2001, 429: 209-229.
[47] Tsang KW, Ho PI, Chan KN, et al. A pilot study of low-dose erythromycin in bronchiectasis. Eur Respir J, 1999, 13: 361-364.
[48] Khair OA , Devalia JL, Abdelaziz MM, et al. Effects of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6 , IL-8 and SICAM-1 by cultured human bronchial epithelial cells. Eur Respir J , 1995, 8: 1451-1457.
[49] App EM, Konig K, Duffner U, et al. The effects of azithromycin therapy on sputum inflammation in CF lung disease. Am J Respir Crit Care Med , 2000, 161: A758-763.
[50] Wolter J,Seeney S,Bell S, et al. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis : a randomized trial. Throax, 2002, 57: 212-216.
[51]Equi A, Balfour-Lynn IM, Bush A, et al. Long term azithromycin in children with cystic fibrosis: a randomized, placebo-controlled crossover trial. Lancet, 2002, 360: 978-984.
[52] Basyigit I, Yildiz F, Ozkara SK, et al. The effect of clarit hromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacot her, 2004, 38 (9): 1400-1405.
[53] Banerjee D, Honeybourne D, Khair OA. The effect of oral clarit hromycin on bronchial airway inflammation in moderate to severe stable COPD: a randomized controlled trial . Treat Respir Med , 2004 , 3(1): 59-65.
[54] Peinado VI, Barbera JA, Abate P, et al. Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 1999, 159 (5pt1): 1605-1611.