卡介苗防治哮喘作用研究及新型PDE4抑制剂Zl-n-91抗COPD作用的初步探讨
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摘要
cAMP和cGMP能够介导多种生物反应,如调节细胞分泌、收缩、代谢和生长等重要的细胞功能,对PKA和PKG、鸟苷酸交换因子、环核苷酸门控的钠通道和钙通道有调节作用。调控细胞内的cAMP和cGMP水平能够对细胞生理产生重要影响。cAMP和cGMP在细胞内的水平主要通过腺苷酸环化酶和鸟苷酸环化酶的合成和多种磷酸二酯酶(phosphodiesterase,PDE)的水解来保持。PDE是细胞内存在的一种重要的酶类,分为11个家族,即PDE1-11,可以水解cAMP和cGMP中的磷酸二酯键,使其变为无活性的5'-AMP和5'-GMP。抑制磷酸二酯酶可以调节多种细胞功能,对呼吸系统疾病如哮喘和慢性阻塞性肺病有潜在的临床应用价值,其中PDE4抑制剂在呼吸系统疾病中的应用尤其受到重视,开发中的PDE4抑制剂主要包括roflumilast、cilomilast、piclomilast、tetomilst等,其中Roflumilast和Cilomilast最值得关注,已进入临床Ⅲ期研究,有望用于哮喘和COPD的治疗。
分支杆菌是最强的Th1反应诱导剂之一,卡介苗是减毒活牛分支杆菌,最初用作结核疫苗,后来有研究发现卡介苗能够调节Th1/Th2平衡,可以用于预防或治疗哮喘,但是卡介苗防治哮喘的机制尚未完全阐明,本论文第一部分以PDE为中心,观察了卡介苗及其相关成分免疫对哮喘大鼠症状的改善作用,并对Th1/Th2平衡以及对肺组织中的PDE活性和表达的影响,同时对cAMP及其信号通路的变化进行了检测,从而进一步阐明卡介苗防治哮喘的可能机制。
目的:观察卡介苗免疫对哮喘大鼠模型的治疗作用,并研究其可能的作用机制。方法:用OVA致敏并攻击复制大鼠哮喘模型,同时以卡介苗及其相关成分免疫大鼠,观察哮喘大鼠肺内的炎症变化,气道高反应性改变、Th1/Th2平衡、PDE活性及各PDE家族的表达、cAMP水平以及cAMP下游效应蛋白PKA和Epacl表达水平的变化;并用LPS刺激损伤A549细胞,模拟哮喘组织损伤的细胞模型,同时用卡介苗进行干预,观察卡介苗对细胞PDE以及PKA、Epacl表达水平的影响,从而推测卡介苗免疫治疗大鼠哮喘的可能机制。结果:卡介苗及其相关成分能够不同程度的减轻哮喘大鼠肺内的炎症,降低大鼠气道高反应性,抑制PDE活性和多种PDE的表达水平,降低cAMP和PKA水平,不同浓度的卡介苗也能够抑制A549细胞的PDE及PKA的表达。结论:卡介苗免疫能够改善哮喘大鼠的症状,而PDE抑制可能是其机制之一,卡介苗或其相关成分可能具有潜在的多重PDE抑制作用。
PDE4抑制剂在COPD治疗中的应用也受到了广泛关注,有临床数据显示Roflumilast和Cilomilast这两个进入临床Ⅲ期研究的PDE4抑制剂能够改善COPD患者的呼吸功能和恶化率,并能够有效改善生活质量。目前治疗COPD的方法十分有限,迫切需要开展一些全新的疗法,而PDE4抑制剂由于其能够有效抗炎而成为一类较有前景的COPD治疗药物。本论文第二部分初步研究了一新型PDE4抑制剂Zl-n-91对大鼠COPD模型的治疗作用,提示了其可能存在的临床应用价值。目的:初步探讨新型PDE4抑制剂Zl-n-91对于大鼠COPD模型的治疗作用,为其将来的临床应用提供依据。方法:熏烟及气道滴入LPS复制大鼠COPD模型,并用0.03mg/kg、0.3mg/kg、3mg/kg的Zl-n-91进行治疗,观察大鼠肺内的炎症变化,PDE4活性变化,肺组织MPO活性和MMP-9水平以及大鼠肺顺应性和肺阻力的改变。结果:各浓度的Zl-n-91能够不同程度的减少COPD大鼠肺组织的炎症浸润,有效抑制PDE4活性,降低MPO活性和MMP-9水平,对COPD大鼠的肺功能也有明显的改善作用。结论:Zl-n-91能够有效抑制COPD大鼠肺内的炎症,改善COPD症状,可能具有COPD治疗的临床应用价值。
cAMP and cGMP can mediate many biological responses(e.g.,regulation of important cell functions such as secretion,contraction,metabolism,and growth),they have regulatory effects on protein kinase A(PKA) and protein kinase G(PKG),the guanine-nucleotide exchange factors(GEFs),and the cyclic-nucleotide gated(CNG) sodium and calcium channel.Manipulation of cAMP and cGMP levels in the cell represents a powerful nechanism for controlling cellular physiology.To maintain their intracellular levels,cAMP and cGMP are synthesized by adenylyl cyclases(ACs) and guanylate cyclases(GCs) whereas their degradation(hydrolysis) is mediated by a variety of phosphodiesterases(PDEs) present in the cells.PDEs are a group of 11 families(PDE1-11) which is essential important in cells and hydrolyze the phosphodiester bond of cAMP and cGMP to provide the inactive products,e.g.,5'-AMP and 5'-GMR To inhibit PDEs can regulate a variety of cell functions and PDE inhibitors have potential value in therapy of lung diseases such as asthma and chronic obstructive pulmonary disease(COPD).Particular emphasis will be placed on PDE4 inhibitors which include roflumilast,cilomilast,piclomilast,tetomilst in development.Roflumilast and cilomilast had reached the stageⅢof clinical trials and may become available for treating asthma and COPD.
Mycobacteria are among the most potent inducers of T helper 1(Th1) type response, Bacillus Calmette-Guérin(BCG) is attenuated live Mycobacterium bovis and used as a vaccine for tuberculosis.There had studies shown that BCG infection regulates Th1/Th2 balance,and could be used in asthma,but the mechanism of which is not entirely clarified.The first part of this thesis studied the effect of BCG and its compositions on asthma in rats,and detected Th1/Th2,PDEs activity and mRNA expressions,cAMP and its signal pathways in asthma rats using PDEs as a center to further clarify the possible mechanism of it.
Objective:To study the effect of BCG on asthma in rats and find it possible mechanism. Methods:male Sprague-Dawley rats are sensitized and challenged with ovalbumin (OVA) and infected with BCG and its compositions,the inflammation in lungs and airway hyperresponsivness(AHR),Th1/Th2,the activity and mRNA expressions of PDEs,cAMP and PKA,Epac1 were detected.A549 cells were used to further study the effect of BCG on PDEs mRNA expressions and PKA,Epacl expressions with or without LPS injury.Results:BCG and its compositions inhibited inflammation in asthma rats and decreased AHR,inhibited PDEs activity and mRNA expressions, decreased cAMP and PKA.Different contents of BCG could also inhibit PDEs mRNA and PKA expression in A549 cells.Conclusion:BCG infection is of some benefit on asthma improvement and PDE inhibition may be one of the mechanism,and BCG and/or its composition may have potential multiple PDE inhibition effect.
PDE4 inhibitors is a group of significant importance among new therapeutic agents that are under development in COPD treatment.The two selective PDE4 inhibitors that are at PhaseⅢclinical trial stage are cilomilast and roflumilast.The studies have demonstrated that anti-inflammatory effects of cilomilast and roflumilast positively contribute to the respiratory function,frequency of exacerbations and quality of life of COPD patients.Treatment options for COPD are quite limited and there is an urgent need for new treatment strategies.PDE4 inhibitors is a group of potent COPD drugs with great prospect because of their anti-inflammatory actions.The second part of this thesis studied the effect of a new selective PDE4 inhibitor,Z1-n-91 on COPD rat,and suggested its potent value in clinical application.
Objective:To investigate the therapeutic effect of a new selective PDE4 inhibitor, Z1-n-91 on COPD rats,provide some basis for its futher clinical application.Methods: Male Sprague-Dawley rats are exposed to cigarette smoking and intracheal lipopolysaccharide(LPS) instillation to induce COPD.0.03,0.3 or 3mg/kg Z1-n-91 were administered.Cells in bronchoalveolar lavage fluid(BALF) were counted, cAMP-PDE and PDE4 activities were assayed,MPO activity and MMP-9 level were assayed using assay kits,and lung function of rats were measured.Results:Z1-n-91 at 0.03,0.3 and 3 mg/kg inhibited inflammatory cells infiltration in lungs and significantly decreased total number of cells and numbers of eosinophils and neutrophils in BALF, inhibited PDE4 activity and MPO activity,and decreased MMP-9 level in lungs, fininally Z1-n-91 markedly improved lung function.Conclusion:Z1-n-91 could inhibit inflammation and improve the symptoms in COPD rats,and it may be of therapeutic potential as an alternative medicine in COPD therapy.
分支杆菌是最强的Th1反应诱导剂之一,卡介苗是减毒活牛分支杆菌,最初用作结核疫苗,后来有研究发现卡介苗能够调节Th1/Th2平衡,可以用于预防或治疗哮喘,但是卡介苗防治哮喘的机制尚未完全阐明,本论文第一部分以PDE为中心,观察了卡介苗及其相关成分免疫对哮喘大鼠症状的改善作用,并对Th1/Th2平衡以及对肺组织中的PDE活性和表达的影响,同时对cAMP及其信号通路的变化进行了检测,从而进一步阐明卡介苗防治哮喘的可能机制。
目的:观察卡介苗免疫对哮喘大鼠模型的治疗作用,并研究其可能的作用机制。方法:用OVA致敏并攻击复制大鼠哮喘模型,同时以卡介苗及其相关成分免疫大鼠,观察哮喘大鼠肺内的炎症变化,气道高反应性改变、Th1/Th2平衡、PDE活性及各PDE家族的表达、cAMP水平以及cAMP下游效应蛋白PKA和Epacl表达水平的变化;并用LPS刺激损伤A549细胞,模拟哮喘组织损伤的细胞模型,同时用卡介苗进行干预,观察卡介苗对细胞PDE以及PKA、Epacl表达水平的影响,从而推测卡介苗免疫治疗大鼠哮喘的可能机制。结果:卡介苗及其相关成分能够不同程度的减轻哮喘大鼠肺内的炎症,降低大鼠气道高反应性,抑制PDE活性和多种PDE的表达水平,降低cAMP和PKA水平,不同浓度的卡介苗也能够抑制A549细胞的PDE及PKA的表达。结论:卡介苗免疫能够改善哮喘大鼠的症状,而PDE抑制可能是其机制之一,卡介苗或其相关成分可能具有潜在的多重PDE抑制作用。
PDE4抑制剂在COPD治疗中的应用也受到了广泛关注,有临床数据显示Roflumilast和Cilomilast这两个进入临床Ⅲ期研究的PDE4抑制剂能够改善COPD患者的呼吸功能和恶化率,并能够有效改善生活质量。目前治疗COPD的方法十分有限,迫切需要开展一些全新的疗法,而PDE4抑制剂由于其能够有效抗炎而成为一类较有前景的COPD治疗药物。本论文第二部分初步研究了一新型PDE4抑制剂Zl-n-91对大鼠COPD模型的治疗作用,提示了其可能存在的临床应用价值。目的:初步探讨新型PDE4抑制剂Zl-n-91对于大鼠COPD模型的治疗作用,为其将来的临床应用提供依据。方法:熏烟及气道滴入LPS复制大鼠COPD模型,并用0.03mg/kg、0.3mg/kg、3mg/kg的Zl-n-91进行治疗,观察大鼠肺内的炎症变化,PDE4活性变化,肺组织MPO活性和MMP-9水平以及大鼠肺顺应性和肺阻力的改变。结果:各浓度的Zl-n-91能够不同程度的减少COPD大鼠肺组织的炎症浸润,有效抑制PDE4活性,降低MPO活性和MMP-9水平,对COPD大鼠的肺功能也有明显的改善作用。结论:Zl-n-91能够有效抑制COPD大鼠肺内的炎症,改善COPD症状,可能具有COPD治疗的临床应用价值。
cAMP and cGMP can mediate many biological responses(e.g.,regulation of important cell functions such as secretion,contraction,metabolism,and growth),they have regulatory effects on protein kinase A(PKA) and protein kinase G(PKG),the guanine-nucleotide exchange factors(GEFs),and the cyclic-nucleotide gated(CNG) sodium and calcium channel.Manipulation of cAMP and cGMP levels in the cell represents a powerful nechanism for controlling cellular physiology.To maintain their intracellular levels,cAMP and cGMP are synthesized by adenylyl cyclases(ACs) and guanylate cyclases(GCs) whereas their degradation(hydrolysis) is mediated by a variety of phosphodiesterases(PDEs) present in the cells.PDEs are a group of 11 families(PDE1-11) which is essential important in cells and hydrolyze the phosphodiester bond of cAMP and cGMP to provide the inactive products,e.g.,5'-AMP and 5'-GMR To inhibit PDEs can regulate a variety of cell functions and PDE inhibitors have potential value in therapy of lung diseases such as asthma and chronic obstructive pulmonary disease(COPD).Particular emphasis will be placed on PDE4 inhibitors which include roflumilast,cilomilast,piclomilast,tetomilst in development.Roflumilast and cilomilast had reached the stageⅢof clinical trials and may become available for treating asthma and COPD.
Mycobacteria are among the most potent inducers of T helper 1(Th1) type response, Bacillus Calmette-Guérin(BCG) is attenuated live Mycobacterium bovis and used as a vaccine for tuberculosis.There had studies shown that BCG infection regulates Th1/Th2 balance,and could be used in asthma,but the mechanism of which is not entirely clarified.The first part of this thesis studied the effect of BCG and its compositions on asthma in rats,and detected Th1/Th2,PDEs activity and mRNA expressions,cAMP and its signal pathways in asthma rats using PDEs as a center to further clarify the possible mechanism of it.
Objective:To study the effect of BCG on asthma in rats and find it possible mechanism. Methods:male Sprague-Dawley rats are sensitized and challenged with ovalbumin (OVA) and infected with BCG and its compositions,the inflammation in lungs and airway hyperresponsivness(AHR),Th1/Th2,the activity and mRNA expressions of PDEs,cAMP and PKA,Epac1 were detected.A549 cells were used to further study the effect of BCG on PDEs mRNA expressions and PKA,Epacl expressions with or without LPS injury.Results:BCG and its compositions inhibited inflammation in asthma rats and decreased AHR,inhibited PDEs activity and mRNA expressions, decreased cAMP and PKA.Different contents of BCG could also inhibit PDEs mRNA and PKA expression in A549 cells.Conclusion:BCG infection is of some benefit on asthma improvement and PDE inhibition may be one of the mechanism,and BCG and/or its composition may have potential multiple PDE inhibition effect.
PDE4 inhibitors is a group of significant importance among new therapeutic agents that are under development in COPD treatment.The two selective PDE4 inhibitors that are at PhaseⅢclinical trial stage are cilomilast and roflumilast.The studies have demonstrated that anti-inflammatory effects of cilomilast and roflumilast positively contribute to the respiratory function,frequency of exacerbations and quality of life of COPD patients.Treatment options for COPD are quite limited and there is an urgent need for new treatment strategies.PDE4 inhibitors is a group of potent COPD drugs with great prospect because of their anti-inflammatory actions.The second part of this thesis studied the effect of a new selective PDE4 inhibitor,Z1-n-91 on COPD rat,and suggested its potent value in clinical application.
Objective:To investigate the therapeutic effect of a new selective PDE4 inhibitor, Z1-n-91 on COPD rats,provide some basis for its futher clinical application.Methods: Male Sprague-Dawley rats are exposed to cigarette smoking and intracheal lipopolysaccharide(LPS) instillation to induce COPD.0.03,0.3 or 3mg/kg Z1-n-91 were administered.Cells in bronchoalveolar lavage fluid(BALF) were counted, cAMP-PDE and PDE4 activities were assayed,MPO activity and MMP-9 level were assayed using assay kits,and lung function of rats were measured.Results:Z1-n-91 at 0.03,0.3 and 3 mg/kg inhibited inflammatory cells infiltration in lungs and significantly decreased total number of cells and numbers of eosinophils and neutrophils in BALF, inhibited PDE4 activity and MPO activity,and decreased MMP-9 level in lungs, fininally Z1-n-91 markedly improved lung function.Conclusion:Z1-n-91 could inhibit inflammation and improve the symptoms in COPD rats,and it may be of therapeutic potential as an alternative medicine in COPD therapy.
引文
[1]Busse WW,Lemanske RF.Asthma.N Engl J Med 2001;344:350-62.
[2]Bisgaard H,Hermansen MN,Loland L,Halkjaer LB and Buchvald F.Intermittent inhaled corticosteroids in infants with episodic wheezing.N Engl J Med 2006;354(19):1998-2005.
[3]Guilbert TW,Morgan WJ,Zeiger RS,Mauger DT,Boehmer SJ,Szefler SJ,et al.Long-term inhaled corticosteroids in preschool children at high risk for asthma.N Engl J Med 2006;354(19):1985-97.
[4]Lehmann S and Ott H.Glucocorticoid hypersensitivity as a rare but potentially fatal side effect of paediatric asthma treatment:a case report.J Med Case Reports 2008;2(1):186.
[5]Harrison TW,Oborne J,Newton S and Tattersfield AE.Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations:randomised controlled trial.Lancet 2004;363(9405):271-5.
[6]Chaudhuri R,Livingston E,McMahon AD,Thomson L,Borland W and Thomson NC.Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronicasthma.Am J Respir Crit Care Med 2003;168(11):1308-11.
[7]Israel E,Drazen JM,Liggett SB,Boushey HA,Cherniack RM,Chinchilli VM,et al.The effect of polymorphisms of the beta (2)-adrenergic receptor on the response to regular use of albuterol in asthma.Am J Respir Crit Care Med 2000;162(1):75-80.
[8]Israel E,Chinchilli VM,Ford JG,Boushey HA,Cherniack R,Craig TJ,et al.Use of regularly scheduled albuterol treatment in asthma:genotype-stratified,randomised,placebo-controlled cross-over trial.Lancet 2004;364(9444):1505-12.
[9]Taylor DR,Drazen JM,Herbison GP,Yandava CN,Hancox RJ and Town GI.Asthma exacerbations during long term beta agonist use:influence of beta (2) adrenoceptor polymorphism.Thorax 2000;55(9):762-7.
[10]Wechsler ME,Lehman E,Lazarus SC,Lemanske RF,Jr.,Boushey HA,et al.beta-Adrenergic receptor polymorphisms and response to salmeterol.Am J Respir Crit Care Med 2006;173(5):519-26.
[11]Bleecker ER,Yancey SW,Baitinger LA,Edwards LD,Klotsman M,Anderson WH,et al.Salmeterol response is not affected by beta2-adrenergic receptor genotype in subjects with persistent asthma.J Allergy Clin Immunol 2006;118(4):809-16.
[12]Toshihiro Ito,Akihiro Hasegawa,Hiroyuki Hosokawa,Masakatsu Yamashita,Shinichiro Motohashi,Takashi Naka,et al.Human Th1 differentiation induced by lipoarabinomannan/lipomannan from Mycobacterium bovis BCG Tokyo-172.International Immunology 2008;1-12.
[13]Herz U,Gerhold K,Gruber C,Braun A,Wahn U,Renz H,Paul K.BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model.J Allergy Clin Immunol.1998 Nov;102(5):867-74.
[14]Hopfenspirger MT,Agrawal DK.Airway hyperresponsiveness,late allergic response,and eosinophilia are reversed with mycobacterial antigens in ovalbumin-presensitized mice.J Immunol.2002 Mar 1;168(5):2516-22.
[15]Koh YI,Choi IS,Lee JJ.Effects of cytokine milieu secreted by BCG-treated dendritic cells on allergen-specific Th immune response.J Korean Med Sci.2004 Oct;19(5):640-6.
[16]ZHU Min-min,FU Cheng-zhang,ZHOU Qin-hai(朱敏敏,傅诚章,周钦深入细致 ).To establish a allergic asthma model of rat.Journal of Clinical Medicine in Practice(实用临床医药杂志),2003,7(1):71-72.(in Chinese)
[17]Jutta Schade,Michael Stephan,Andreas Schmiedl,et al.Regulation of Expression and Function of Dipeptidyl Peptidase 4(DP4),DP8/9,and DP10 in Allergic Responses of the Lung in Rats.Journal of Histochemistry & Cytochemistry,2008,56(2):147-155.
[18]Min Xie,Xian-Sheng Liu,Yong-Jian Xu,et al.ERK1/2 Signaling Pathway Modulates the Airway Smooth Muscle Cell Phenotype in the Rat Model of Chronic Asthma[J].Respiration,2007,74:680-690.
[19]Wu-Rui,YAO Wan-zhen,CHEN Ya-hong,et al(伍蕊,姚婉贞,陈亚红,等).The regulatory effect of endogenous hydrogen sulfide on acute asthma[J].Chin J Tuberc Respir Dis(中华结核和呼吸杂志),2007,30(7):522-526.(in Chinese)
[20]CHEN Yan,LI Zi-gang,TANG Hui-fang,et al(陈艳,李子刚,汤慧芳,等).The efects of rolipram on PDE activity and IL_4 level in the lung tissue of ovalbum in sensitized and repeatedly challenged rats[J].Chinese Pharmacological Bulletin(中国药理学通报),2006,22(4):447-451.(in Chinese)
[21]ZHU Min-min,QIAN Yan-ning,ZHU Wei,et al(朱敏敏,钱燕宁,朱伟,等).Protective effects of ketamine on allergen-induced airway inflammatory injure and high airway reactivity in asthma:experiment with rats[J].Natl Med J China(中华医学杂志),2007,87(19):1308-1313.(in Chinese)
[22]YU Jian-er,LI Li-qing,ZHANG Xiao-feng,et al(虞坚尔,李利清,张晚峰,等).Study of Pingchuan Formula's effects on Th1/Th2 of bronchial asthma in model rats[J].J.PEDIATRICS OF TCM(中华儿科杂志),2006,2(1):23-26.
[23]Tang HF,Song YH,Chen JC,Chen JQ and Wang P.Upregulation of phosphodiesterase-4in the lung of allergic rats.Am J Respir Crit Care Med 2005;171(8):823-8.
[24]HUANG Hua-qiong(黄华琼).Advancement of BCG in preventing diseases.Med Sci Sec Biol Proph Diagn Ther,Dec(国外医学预防诊断治疗用生物制品分册),2005,28(6):251-254.(in Chinese)
[25]Kai Wang,Hua-hao Shen,Hua-qiong Huang,Jun-chun Chen,Zhong Chen.Acetamide-45inhibited hyperresponsiveness and airway inflammation in mice partly depending on phosphodiesterase activeity suppression.Acta Pharmacol Sin 2008;29(10):1195-1201.
[26]LI Qiu-gen,YU Jiang-qing,XIONG Guo-liang,et al(李秋根,余江清,熊国亮,等).Effect of taking orally BCG on TH1/TH2 balance in asthma mice.Chin J Microbiol Immunol(中华微生物学和免疫学杂志),2007,27(1):32.(in Chinese)
[27]HE Ying,LI Chao-qian(何英,李超乾).Progress on research of preventing bronchus asthma by Bacillus Calmette-Guerin vaccine.J Respir(国际呼吸杂志),2007,27(6):443-445.(in Chinese)
[28]H.Shen,H.Huang,J.Wand,et al.Neonatal vaccination with Bacillus Calmette-Guerin elicits long-term protection in mouse-allergic responses.Allergy,2008,DOI:10.1111/j.1398-9995.
[29]Chi Hong Kim,Joong Hyun Ahn,Seung Joon Kim,et al.Co-Administration of vaccination with DNA encoding T cell epitope on the Der p and BCG inhibited airway remodeling in a Murine Model of Chronic Asthma.Journal of Asthma,2008,43:5345-353.
[30]C.C.Obihara,J.L.L.Kimpen,R.P.Giew,et al.Mycobacterium tuberculosisinfection may protect against allergy in a tuberculosis endemic area.Clinical and Experimental Allergy,2006,36:70-76.
[31]Cabana MD,McKean M,Wong AR,et al.Examining the hygiene hypothesis:the Trial of Infant Probiotic Supplementation.Paediatr Perinat Epidemiol.2007,21 Suppl 3:23-8.
[32]Samuli Rautava,Olli Ruuskanen,Arthur Ouwehand,et al.The Hygiene hypothesis of atopic disease—An extended version.Journal of Pediatric Gastroenterology and Nutrition.2004,38:378-388.
[33]X.YANQ S.WANG Y.FAN,et al.Systemic mycobacterial infection inhibits antigen-specific immunoglobulin E production,bronchial mucus production and eosinophilic inflammation induced by allergen.Immunology.1999,98:329-337.
[34]Kostic MM,Erdogan S,Rena G et al.Altered expression of PDE1 and PDE4 cyclic nucleotide phosphodiesterase isoforms in 7-oxoprostacyclin preconditioned rat heart.J Mol Cell Cardiol,1997,29:3135-3146.
[35]Youngil I.Koh,Inseon S.Choi,Je-Jung Lee.Effects of Cytokine Milieu Secreted by BCG-treated Dendritic Cells on Allergen-Specific Th Immune Response.J Korean Med Sci,2004,19:640-6.
[36]Hylkema MN,Timens W,Luinge M,Van Der Werf N and Hoekstra MO.The effect of bacillus Calmette-Guerin immunization depends on the genetic predisposition to Th2-type responsiveness.Am J Respir Cell Mol Biol 2002;27(2):244-9.
[37]Koh YI,Chio IS,Kim WY,Lee HC,Lee J.Effects of BCG infection on Schultz-Dale reaction,allergen-specific IgE levels,and Th2 immune response in sensitized rats.Korean J Intern Med 2001;16(3):180-6.
[38]Yang X,Wang S,Fan Y and Zhu L.Systemic mycobacterial infection inhibits antigen-specific immunoglobulin E production,bronchial mucus production and eosinophilic inflammation induced by allergen.Immunology 1999;98(3):329-37.
[39]Song Yan-hua,Chen Ji-qiang,Chen Jun-chun.Cyclic nucleotides phosphodiesterase activity in rats' lung model of asthma after BCG immunization.Chinese Pharmacological Bulletin 2005;21(8):1020-1.
[40]Youngil I.Koh,Inseon S.Chio,Seok-Chae Park,Kwang-Won Kang.BCG Infection during Pre-Sensitization or Even Post-Sensitization Inhibits Airway Sensitivity in an Animal Model of Allergic Ashtma.J Korean Med Sci 2000;15:265-72.
[41]Tang HF,Chen JQ,Xie QM,Zheng XY,Zhu YL,Adcock I,et al.The role of PDE4 in pulmonary inflammation and goblet cell hyperplasia in allergic rats.Biochim Biophys Acta 2006;1762(5):525-32.
[42]Xie QM,Chen JQ,Shen WH.Comparison of bronchodilating and antiinflammatory activities of oral formoterol and its(R,R)-enantiomers.Acta Pharmacol Sin.2003;24(3):277-282.
[43]Essayan DM.Cyclic nucleotide phosphodiesterases.J Allergy Clin Immunol 2001;108:71-80.
[44]Tang HF,Song YH,Chen JC,Chen JQ and Wang P.Upregulation of phosphodiesterase-4in the lung of allergic rats.Am J Respir Crit Care Med 2005;171(8):823-8.
[45]Zhang Y,Mahendran R,Yap LL,Esuvaranathan K and Khoo HE.The signalling pathway for BCG-induced interleukin-6 production in human bladder cancer cells.Biochem Pharmacol 2002;63(2):273-82.
[46]Zhang Shuling,Yin Guishan(张书岭,尹挂山).Adenylate cyclase assay method in tissue homogenate.Acta Academiae Medicinae Hebei(河北医学院学报)1991;12(2):18-20. (In Chinese)
[47]Leon D,Albasanz JL,Ruiz MA and Martin M.Chronic caffeine or theophylline intake during pregnancy inhibits Al receptor function in the rat brain.Neuroscience 2005;131(2):481-9.
[48]Phillips PG,Long L,Wilkins MR and Morrell NW.cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling.Am J Physiol Lung Cell Mol Physiol 2005;288(1):L103-15.
[49]Witwicka H,Kobialka M,Siednienko J,Mitkiewicz M and Gorczyca WA.Expression and activity of cGMP-dependent phosphodiesterases is up-regulated by lipopolysaccharide (LPS) in rat peritoneal macrophages.Biochim Biophys Acta 2007;1773(2):209-18.
[50]Naro F,Sette C,Vicini E,De Arcangelis V,Grange M,Conti M,et al.Involvement of type 4 cAMP-phosphodiesterase in the myogenic differentiation of L6 cells.Mol Biol Cell 1999;10(12):4355-67.
[51]Kostic MM,Erdogan S,Rena G,Borchert G,Hoch B,Bartel S,et al.Altered expression of PDE1 and PDE4 cyclic nucleotide phosphodiesterase isoforms in 7-oxo-pro stacyclin-preconditioned rat heart.J Mol Cell Cardiol 1997;29(11):3135-46.
[52]Magdalena J.Lorenowicz,Mar Fernandesz-Borja,Peter L.Hordijk.cAMP signaling in leukocyte transendothelial migration.Arterioscler Thromb Vasc Biol 2007;27:1014-1022.
[53]Mona Gupta and Stephen J.Yarwood.MAPI A Light Chain 2 Interacts with Exchange Protein Activated by Cyclic AMP1 (EPAC1) to Enhance Rapl GTPase Activity and Cell Adhesion.The Journal of Biological Chemistry 2005;28(9):8109-8116.
[54]Marco Conti,Joseph Beavo.Biochemistry and physiology of cyclic nucleotide phosphodiesterases:essential components in cyclic nucleotide signaling.Annu.Rev.Biochem,2007,76:25.1-25.31.
[55]Ghosh S,Janocha AJ,Aronica MA,Swaidani S,Comhair SA,Xu W,et al.Nitrotyrosine proteome survey in asthma identifies oxidative mechanism of catalase inactivation.J Immunol 2006;176(9):5587-97.
[56]Youngil I.Koh,Inseon S.Chio,Seok-Chae Park,Kwang-Won Kang.BCG Infection during Pre-Sensitization or Even Post-Sensitization Inhibits Airway Sensitivity in an Animal Model of Allergic Ashtma.J Korean Med Sci 2000;15:265-72.
[57]Toward TJ,Smith N and Broadley KJ.Effect of phosphodiesterase-5 inhibitor,sildenafil (Viagra),in animal models of airways disease.Am J Respir Crit Care Med 2004;169(2):227-34.
[58]Jones NA,Leport M,Holand T,Vos T,Morgan M,Fink M,et al.Phosphodiesterase (PDE) 7 in inflammatory cells from patients with asthma and COPD.Pulm Pharmacol Ther 2007;20(1):60-8.
[59]Kathrin Woyda,Silke Koebrich,Irwin Reiss,Silvia Rudloff,Soni S.Pullamsetti,Alexander Ruhlmann,et al.Inhibition of PDE4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia.Eur Respir J 2008;In press.
[60]Huanchen Wang,Ming-Sheng Peng,Yi Chen,Jie Geng,Howard Robinson,Miles D.Houslay,et al.Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors.Biochem.J.2007;408:193-201.
[61]Z.Huang,R.Dias,T.Jones,S.Liu,A.Styhler,D.Claveau,et al.L-454,560,a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition.Biochemical Pharmacology 2007;73:1971-1981.
[62]Hye Cheol Jeong,Sang Yeub Lee,Eun Joo Lee,Ki Hwan Jung,Eun Hae Kang,Sung Yong Lee,et al.Proteomic Analysis of Peripheral T-Lymphocytes in Patients With Asthma.Chest 2007;132:489-496.
[63]Hui-Fang Tang,Ji-Qiang Chen,Qiang-Min Xie,Xu-Yang Zheng,Yi-Liang Zhu,Ian Adcock,et al.The role of PDE4 in pulmonary inflammation and goblet cell hyperplasia in allergic rats.Biochimica et Biophysica Acta 2006;1762:525-532.
[64]B.Al Qadi-Nassar,F.Bichon-Laurent,K.Portet,P.Tramini,B.Arnoux,A.Michel.Effects of L-arginine and phosphodiesterase-5 inhibitor,sildenafil,on inflammation and airway responsiveness of sensitized BP2 mice.Fundam ClinPharmacol 2007;21(6):611-20.
[65]Toby J.Toward,Nicola Smith,and Kenneth J.Broadley.Effect of Phosphodiesterase-5 Inhibitor,Sildenafil (Viagra),in Animal Models of Airways Disease.Am J Respir Crit Care Med 2004;169:227-234.
[66]Ffongli Dong,Venera Osmanova,Paul M.Epstein,Stefan Brocke.Phosphodiesterase 8 (PDE8) regulates chemotaxis of activated lymphocytes.Biochemical and Biophysical Research Communications 2006;345:713-719.
[67]Kian Fan Chung.Phosphodiesterase inhibitors in airways disease.European Journal of Pharmacology 2006;110-117.
[68]Patricia Mendez-Samperio,Artemisa Trejo,Aline Perez.Mycobacterium bovis Bacillus Calmette-Guerin (BCG) stimulates IL-10 production via the PBK/Akt and p38 MAPK pathways in human lung epithelial cell.Cellular Immunology 2008;251:37-42.
[69]S.Verstraelen,K.Bloemen,I.Nelissen,H.Witters,G.Schoeters,R.Van Den Heuvel.Cell types involved in allergic asthma and their use in in vitro models to assess respiratory sensitization.Toxicology in Vitro 2008;In press.
[70]A.Borowski,M.Kuepper,U.Horn,et al.Interleukin-13 acts as an apoptotic effector on lung epithelial cells and induces pro-fibrotic gene expression in lung fibroblasts.Clinical and Experimental Allergy 2008;38(4):619-28.
[71]Lyndon C.Wright,Joachim Seybold,Annette Robichaud,Ian M.Adcock and Peter J.Barnes.Phosphodiesterase expression in human epithelial cells.Am J Physiol Lung Cell Mol Physiol 1998;275:694-700.
[72]Annamaria Morelli,Sandra Filippi,Rosa Mancina,Michaela Luconi,Linda Vignozzi,Mirca Marini,et al.Androgens Regulate Phosphodiesterase Type 5 Expression and Functional Activity in Corpora Cavernosa.Endocrinology 2004;145(5):2253-2263.
[73]Masaaki Hayashi,kazuhide Matsushima,Hiroshi Ohashi,Hiroshi Tsunoda,Sumio Murase,Yoshifumi Kawarada,et al.Molecular Cloning and Characterization of Human PDE8B,a Novel Thyroid-Specific Isozyme of 3',5'-Cyclic Nucleotide Phosphodiesterase.Biochemical and Biophysical Research Communications 1998;250:751-756.
[74]Zhu J,Zhang H,Xie Q.Effect of Cryptoporus polysaccharide on lipopolysaccharide-induced production of monocyte chemoattractant protein-1 in human alveolar epithelial cells.Zhejiang Da Xue Xue Bao Yi Xue Ban 2008;37(4):333-9.
[75]Del Vecchio M,Balducci E.Mono ADP-ribosylation inhibitors prevent inflammatory cytokine release in alveolar epithelial cells.Mol Cell Biochem 2008;310(1-2):77-83.
[76]Ning QM,Wang XR.Response of alveolar type Ⅱ epithelial cells to mechanical stretch and lipopolysaccharide.Respiration 2007;74(5):579-85.
[77]Mata M,Sarria B,Buenestado A,Cortijo J,Cerda M,Morcillo EJ.Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells.Thorax 2005;60(2):144-52.
[78]Patricia Mendez-Samperio,Artemisa Trejo,Aline Perez.Mycobacterium bovis Bacillus Calmette-Guerin (BCG) stimulates IL-10 production via the PI3K/Akt and p38 MAPK pathways in human lung epithelial cells.Cellular Immunology 2008;251:37-42.
[79]Lyndon C.Wright,Joachim Seybold,Annette Robichaud,Ian M.Adcock,Peter J.Barnes.Phosphodiesterase expression in human epithelial cells.Am J Physiol Lung Cell Mol Physiol 1998;275:694-700.
[80]G.Dent,S.R.White,H.Tenor,K.Bodtke,C.Schudt,A.R.Leff,et al.Cyclic Nucleotide Phosphodiesterase in Human Bronchial Epithelial Cells:Characterization of Isoenzymes and Functional Effects of PDE Inhibitors.Pulmonary Phamacology & Therapeutics 1998;11:47-56.
[81]D.M.Brown,L.Hutchison,K.Donaldson,S.J.Mac Kenzie,C.A.J.Dick,V.Stone.The effect of oxidative stress on macrophages and lung epithelial cells:The role of phosphodiesterase 1 and 4.Toxicology Letters 2007;168:1-6.
[82]Graeme P.Currie,Claire A.Butler,Wendy J.Anderson,Chris Skinner.Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease:a new approach to oral treatment.British Journal of Clinical Pharmacology,British Journal of Clinical Pharmacology 2008;65(6):803-810.
[83]Klaus F.Rabe,Suzanne Hurd,Antonio Anzueto,Peter J.Barnes,Sonia A.Buist,Peter Calverley et al.Global Strategy for the Diagnosis,Management,and Prevention of Chronic Obstructive Pulmonary Disease-GOLD Executive Summary.Am J Respir Crit Care Med 2007;176:532-555.
[84]Peter J.Barnes.Future Treatments for Chronic Obstructive Pulmonary Disease and Its Comorbidities.Proc Am Thorac Soc 2008;5:857-864.
[85]Martorana PA,Beume R,Lucattelli M,Wollin L,Lungarella G.Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke.Am J Respir Crit Care Med 2005;172:848-853.
[86]Christopher J.Lunniss,Anthony W.J.Cooper,Colin D.Eldred,Michael Kranz,Mika Lindvall,Fiona S.Lucas,et al.Quinolines as a novel structural class of potent and selective PDE4 inhibitors:Optimisation for oral administration.Bioorganic & Medicinal Chemistry Letters 2009;19:1380-1385.
[87]Neville KA,Szefler SJ,Abdel-Rahman SM,Lahu G Zech K,Herzog R,et al.Single-dose pharmacokinetics of roflumilast in children and adolescents.J Clin Pharmacol 2008;48(8):978-85.
[88]Rennard S,Knobil K,Rabe KF,Morris A,Schachter N,Locantore N,et al.The efficacy and safety of cilomilast in COPD.Drugs 2008;68 Suppl 2:3-57.
[89]De Visser YP,Walther FJ,Laghmani EH,van Wijngaarden S,Nieuwland K,Wagenaar GT.Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury.Eur Respir J 2008;31(3):633-44.
[90]Vestbo J,Tan L,Atkinson G Ward J.A controlled trial of 6 weeks' treatment with a novel inhaled PDE4 inhibitor in COPD.Eur Respir J 2009;In press.
[91]David A Groneberg,K Fan Chung.Models of Chronic obstructive pulmonary disease.Respiratory Research 2004;5:18.
[92]GE Zheng-hang,TAN Tao.Miao Nationality's Relieve Cough and Rdeuce Phlegm Herb interfere the levels of IL-8 and TNF-a in bronchoalveolar ronchoalveolar larvae fluid in the obstructive emphysema rat models.Cllinese Journal of the Practical Chinese with Modem Medicine 2004;4(17):2913-2916.
[93]Yoshiaki Takeuchi,Maki Takahashi,and Jun-ichi Fuchikami.Vulnerability of Gastric Mucosa to Prednisolone in Rats Chronically Exposed to Cigarette Smoke.J Pharmacol Sci 2008;106:585-592.
[94]Bai-Ling Luo,Rui-Chao Niu,Jun-Tao Feng,Cheng-Ping Hu,Xiao-Yun Xie,and Li-Juan Ma.Downregulation of Secretory Leukocyte Proteinase Inhibitor in Chronic Obstructive Lung Disease:The Role Of TGF-b/Smads Signaling Pathways.Archives of Medical Research 2008;39:388-396.
[95]Tang HF,Song YH,Chen JC,Chen JQ and Wang P.Upregulation of phosphodiesterase-4 in the lung of allergic rats.Am J Respir Crit Care Med 2005;171(8):823-8.
[96]Peter J.Barnes.Frontrunners in novel pharmacotherapy of COPD.Current Opinion in Pharmacology 2008;8:300-307.
[97]Victoria Boswell-Smith,Mario Cazzola and Clive P.Page.Are phosphodiesterase 4 inhibitors just more theophylline? J Allergy Clin Immunol 2006;117:1237-43.
[98]Torphy TJ.Phosphodiesterase isozymes:molecular targets for novel antiasthma agents.Am J Respir Crit Care Med 1998;157:z351-70.
[99]J.Chorostowska-Wynimko,J.Kus,E.Skopiriska-Rozewska.Teophylline inhibits free oxygen radicals production by human monocytes via phosphodiesterases inhibition.Journal of Physiology and Pharmacology 2007;58 suppl:95-103.
[100]Barnes AP,Livera G,Huanq P,Sun C,O'Neal WK,Conti M,et al.Phosphodiesterase 4D forms a cAMP diffusion barrier at the apical membrane of the airway epithelium.J Biol Chem 2005;280(9):7997-8003.
[101]Hui-Fang Tang,Ji-Qiang Chen,Qiang-Min Xie,Xu-Yang Zheng,Yi-Liang Zhu,Ian Adicock,et al.The role of PDE4 in pulmonary inflammation and goblet cell hyperplasia in allergic rats.Biochimica et Biophysica Acta2006;1762:525-532.
[102]Tang HF,Song YH,Chen JC,Chen JQ and Wang P.Upregulation of phosphodiesterase-4 in the lung of allergic rats.Am J Respir Crit Care Med 2005;171(8):823-8.
[103]Yuji Higashimoto,Takuya Iwata,Morihiro Okada,Hiroaki Satoh,Kanji Fukuda,Yuji Tohda.Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonary disease.Respiratory Medicine 2009;In press.
[104]Andrew Churg,Rona Wang,Xiaoshan Wang,Per-Ola Onnervik,Kerstin Thim and Joanne L Wright.Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs.Thorax 2007;62:706-713.
[105]Essayan DM.Cyclic nucleotide phosphodiesterases.J Allergy Clin Immunol 2001;108:71-80.
[106]Liu S,Veilleux A,Zhang L,Young A,Kwok E,Laliberte F,et al.Dynamic activation of cystic fibrosis transmenbrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors.J Pharmacol Exp Ther 2005;341(2):846-54.
[107]Arumugam Kodimuthali,S.Sugin Lai Jabaris,and Manojit Pal.Recent Advances on Phosphodiesterase 4 Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease.J.Med.Chem.2008;51 (18):5471-5489.
[108]Barnes PJ.Emerging pharmacotherapies for COPD.Chest 2008;134(6):1278-86.
[109]Christopher J.Lunniss,Anthony W.J.Cooper,Colin D.Eldred,Michael Kranz,Mika Lindvall,Fiona S.Lucas,et al.Quinolines as a novel structural class of potent and selective PDE4 inhibitors:Optimisation for oral administration.Bioorganic & Medicinal Chemistry Letters 2009;19:1380-1385.
[110]Ruihong Ma,Bin-yan Yang,Chang-you Wu.A selective phosphodiesterase 4 (PDE4) inhibitor Zl-n-91 suppresses IL-17 production by human memory Thl7 cells.International Immunopharmacology 2008;8:1408-1417.
[1]Barnes P.J.Chronic obstructive pulmonary disease:a growing but neglected epidemic.Plos Med 2007;4:e112.
[2]Mannino D.M.,Buist.A.S.Global burden of COPD:risk factors,prevalence,and future trends.Lancet 2007;370:765-773.
[3]Pearce N.Worldwide trends in the prevalence of asthma symptoms:phase Ⅲ of the International Study of Asthma and Allergies in Childhood (ISAAC).Thorax 2007;62:758-766.
[4]Peter J.Barnes.Immunology of asthma and chronic obstructive pulmonary disease.Nat Rev Immunol 2008;8(3):183-92.
[5]Barnes P.J.,Chung K.F.,Page C.P.Inflammatory mediators of asthma:an update.Pharmacol.Rev.1998;50:515-596.
[6]Barnes P.J.Mediators of chronic obstructive pulmonary disease.Pharm.Rev.2004;56:515-548.
[7]Benayoun L.,Druilhe A.,Dombret M.C.,Aubier M.,Pretolani M.Airway structural alterations selectively associated with severe asthma.Am.J.Respir.Crit.Care Med.2003;167:1360-1368.
[8]Siddiqui S.Vascular remodeling is a feature of asthma and nonasthmatic eosinophilic bronchitis.J.Allergy Clin.Immunol.2007;120:813-819.
[9]Ordonez C.L.Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression.Am.J.Respir.Crit.Care Med.2001;163:517-523.
[10]Hogg J.C.Pathophysiology of airway limitation in chronic obstructive pulmonary disease.Lancet 2004;364:709-721.
[11]Hogg J.C.The nature of small-airway obstruction in chronic obstructive pulmonary disease.N.Engl.J.Med.2004;350:2645-2653.
[12]Majo J.,Ghezzo H.,Cosio M.G Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema.Eur.Respir.J.2001;17:946-953.
[13]Taraseviciene-Stewart L.Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease? Proc.Am.Thorac.Soc.2006;3:687-690.
[14]Ohnishi K.,Takagi M.,Kurokawa Y.,Satomi S.,Konttinen Y.T.Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema.Lab.Invest.1998;78:1077-1087.
[15]Gene L Colice.New Drugs for Asthma.Respir Care 2008;53(6):688-696.
[16]Magdalena J.Lorenowicz,Mar Fernandez-Borja and Peter L.Hordijk.cAMP Signaling in Leukocyte Transendothelial Migration.Arterioscler.Thromb.Vase.Biol.2007;27:1014-1022.
[17]Adderley SP,Dufaux EA,Shridharan M,Bowles EA,Hanson MS,Stephenson AH,et al.Iloprost-and isoprterenol-induced increase in cAMP are regulated by different phophodiesterases in erythrocytes of both rabbits and humans.Am J Physiol Heart Circ Physiol 2009;In press.
[18]Graeme P.Currie,Claire A.Butler,Wendy J.Anderson,Chris Skinner.Phophodiesterase 4 inhibitors in chronic obstructive pulmonary disease:a new approach to oral treatment.British Journal of Clinical Pharmacology 2008;65(6):803-810.
[19]Marco Conti,Joseph Beavo.Biochemistry and Physiology of cyclic Nucleotide Phosphodiesterases:Essential Components in Cyclic Nucleotide Signaling.Annu.Rev.Biochem.2007;76:25.1-25.31.
[20]Arumugam Kodimuthali,S.Sugin Lai Jabaris,Manojit Pal.Recent Advances on Phosphodiesterase 4 Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease.J.Med.Chem.2008;51(18):5471-5489.
[21]Victoria Boswell-Smith,Mario Cazzola,Clive P.Page.Are phosphodiesterase 4 inhibitors just more theophylline? J Allergy Clin Immunol 2006;117:1237-43.
[22]Jin,S.L.,Conti,M.Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses.Proc.Natl.Acad.Sci.U.S.A.2002;99:7628-7633.
[23]Ariga,M.,Neitzert,B.,Nakae,S.,Mottin,G,Bertrand,C,Pruniaux,M.P.,et al.Nonredundant function of phosphodiesterases 4D and 4B in neutrophil recruitment to the site of inflammation.J.Immunol.2004;173:7531-7538.
[24]Hansen,G,Jin,S.,Umetsu,D.T.,Conti,M.Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D.Proc.Natl.Acad.Sci.U.S.A.2000;97:6751-6756.
[25]Sanz,M.J.,Cortijo,J.,Morcillo,E.J.PDE4 inhibitors as new anti-inflammatory drugs:effects on cell trafficking and cell adhesion molecules expression.Pharmacol.Ther 2005;106:269-297.
[26]Lagente V.,Pruniaux M.P.,Junien J.L.,Moodley I.Modulation of cytokine-induced eosinophil infiltration by phosphodiesterase inhibitors.Am.J.Respir.Crit.Care Med.1995;151:1720-1724.
[27]Lagente,V.,Moodley,I.,Perrin,S.,Mottin,G,Junien,J.L.Effects of isozyme-selective phosphodiesterase inhibitors on eosinophil infiltration in the guinea-pig lung.Eur.J.Pharmacol.1994;255:253-256.
[28]Toward,T.J.,Broadley,K.J.Chronic lipopolysaccharide exposure on airway function,cell infiltration,and nitric oxide generation in conscious guinea pigs:effect of rolipram and dexamethasone.J.Pharmacol.Exp.Ther.2001;298:298-306.
[29]Lazzeri,N.,Belvisi,M.G,Patel,H.J.,Yacoub,M.H.,Chung,K.F.,Mitchell,J.A.Effects of prostaglandin E2 and cAMP elevating drugs on GMCSF release by cultured human airway smooth muscle cells.Relevance to asthma therapy.Am.J.Respir.Cell Mol.Biol.2001;24:44-48.
[30]O'Donnell JM,Zhang HT.Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4).Trends Pharmacol Sci 2004;25:158-63.
[31]Renau TE.The potential of phosphodiesterase 4 inhibitors for the treatment of depression: opportunities and challenges.Curr Opin Invest Drugs 2004;5:34-9.
[32]Torphy TJ,Barnette MS,Underwood DC,Griswold DE,Christensen SB,Murdoch RD,et al.Ariflo (SB 207499),a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD:from concept to clinic.Pulm Pharmacol Ther 1999;12:131-5.
[33]Jacobitz S,McLaughlin MM,Livi GP,Burman M,Torphy TJ.Mapping the functional domains of human recombinant phosphodiesterase 4A:structural requirements for catalytic activity and rolipram binding.Mol Pharmacol 1996;50:891-9.
[34]Souness JE,Rao S.Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases.Cell Signal 1997;9:227-36.
[35]Profita,M.,Chiappara,G,Mirabella,E,Di Giorgi,R.,Chimenti,L.,Costanzo,G,et al.Effect of cilomilast (Ariflo) on TNF-alpha,IL-8,and GM-CSF release by airway cells of patients with COPD.Thorax 2003;58:573-579.
[36]Griswold,D.E.,Webb,E.F.,Badger,A.M.,Gorycki,P.D.,Levandoski,P.A.,Barnette,M.A.,et al.SB 207499 (ariflo),a second generation phosphodiesterase 4 inhibitor,reduces tumor necrosis factor alpha and interleukin-4 production in vivo.J.Pharmacol.Exp.Ther.1998;287:705-711.
[37]Souness,J.E.,Griffin,M.,Maslen,C,Ebsworth,K.,Scott,L.C.,Pollock,K.,et al.Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNF alpha generation from human monocytes by interacting with aTow-affinity' phosphodiesterase 4 conformer.Br.J.Pharmacol.1996;118:649-658.
[38]Goncalves,d.M.,V,Singer,M.,Vargaftig,B.B.,Chignard,M.Effects of rolipram on cyclic AMP levels in alveolar macrophages and lipopolysaccharide-induced inflammation in mouse lung.Br.J.Pharmacol.1998;123:631-636.
[39]Ouagued,M.,Martin-Chouly,C.A.,Brinchault,G,Leportier-Comoy,C,Depince,A.,Bertrand,C,et al.The novel phosphodiesterase 4 inhibitor,CI-1044,inhibits LPS-induced TNF-alpha production in whole blood from COPD patients.Pulm. Pharmacol.Ther.2005;18:49-54.
[40]Mata,M.,Sarria,B.,Buenestado,A.,Cortijo,J.,Cerda,M.,Morcillo,E.J.Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells.Thorax 2005;60:144-152.
[41]Belleguic,C,Corbel,M.,Germain,N.,Boichot,E.,Delaval,P.,Lagente,V.Reduction of matrix metalloproteinase-9 activity by the selective phosphodiesterase 4 inhibitor,RP 73-401 in sensitized mice.Eur.J.Pharmacol.2000;404:369-373.
[42]Kohyama,T.,Liu,X.,Wen,F.Q.,Zhu,Y.K.,Wang,H.,Kim,H.J.,et al.PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels.Am.J.Respir.Crit.Care Med.2002;26:694-701.
[43]Kohyama,T.,Liu,X.,Zhu,Y.K.,Wen,F.Q.,Wang,H.J.,Fang,Q.,et al.Phosphodiesterase 4 inhibitor cilomilast inhibits fibroblast-mediated collagen gel degradation induced by tumor necrosis factor-alpha and neutrophil elastase.Am.J.Respir.Crit.Care Med.2002;27:487-494.
[44]Martorana,P.A.,Beume,R.,Lucattelli,M.,Wollin,L.,Lungarella,G.Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke.Am.J.Respir.Crit.Care Med.2005;172:848-853.
[45]Rybalkin,S.D.,Rybalkina,I.G.,Shimizu-Albergine,M.,Tang,X.B.,Beavo,J.A.PDE5 is converted to an activated state upon cGMP binding to the GAF A domain.EMBO J.2003;22:469-478.
[46]Sebkhi,A.,Strange,J.W.,Phillips,S.C,Wharton,J.,Wilkins,M.R.Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension.Circulation 2003;107:3230-3235.
[47]Yanaka,N.,Kotera,J.,Ohtsuka,A.,Akatsuka,H.,Imai,Y,Michibata,H.,et al.Expression,structure and chromosomal localization of the human cGMP binding cGMP-specific phosphodiesterase PDE5A gene.Eur.J.Biochem.1998;255:391-399.
[48]Zhao,L.,Mason,N.A.,Morrell,N.W.,Kojonazarov,B.,Sadykov,A.,Maripov,A.,et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension.Circulation 2001;104:424-428.
[49]Sastry,B.K.,Narasimhan,C,Reddy,N.K.,Raju,B.S.Clinical efficacy of sildenafil in primary pulmonary hypertension:a randomized,placebocontrolled,double-blind,crossover study.J.Am.Coll.Cardiol.2004;43:1149-1153.
[50]Ghofrani,H.A.,Voswinckel,R.,Reichenberger,F.,Olschewski,H.,Haredza,P.,Karadas,B.,et al.Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension:a randomized prospective study.J.Am.Coll.Cardiol.2004;44:1488-1496.
[51]Wharton,J.,Strange,J.W.,Moller,G.M.,Growcott,E.J.,Ren,X.,Franklyn,A.P.,et al.Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells.Am.J.Respir.Crit.Care Med.2005;172:105-113.
[52]S.Faruqi,H.Fathi,A.H.Morice.Combination of sitaxentan and tadalafil for idiopathic pulmonary arterial hypertension following relapse on bosentan.International Journal of Cardiology 2009;In press.
[53]Bloom,T.J.,Beavo,J.A.Identification and tissue-specific expression of PDE7 phosphodiesterase splice variants.Proc.Natl.Acad.Sci.U.S.A.1996;93:14188-14192.
[54]Miro,X.,Perez-Torres,S.,Palacios,J.M.,Puigdomenech,P.,Mengod,G.Differential distribution of cAMP-specific phosphodiesterase 7A mRNA in rat brain and peripheral organs.Synapse 2001;40:201-214.
[55]Glavas,N.A.,Ostenson,C,Schaefer,J.B.,Vasta,V.,Beavo,J.A.T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3.Proc.Natl.Acad.Sci.U.S.A.2001;98:6319-6324.
[56]Smith,S.J.,Brookes-Fazakerley,S.,Donnelly,L.E.,Barnes,P.J.,Barnette,M.S.,Giembycz,M.A.Ubiquitous expression of phosphodiesterase 7A in human proinflammatory and immune cells.Am.J.Physiol.,Lung Cell.Mol.Physiol.2003;284:L279-L289.
[57]Smith,S.J.,Cieslinski,L.B.,Newton,R.,Donnelly,L.E.,Fenwick,P.S.,Nicholson,A.G,et al.Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene],a selective inhibitor of phosphodiesterase 7:in vitro studies in human monocytes,lung macrophages,and CD8+ T-lymphocytes.Mol.Pharmacol.2004;66:1679-1689.
[58]Yang,G,Mclntyre,K.W.,Townsend,R.M.,Shen,H.H.,Pitts,W.J.,Dodd,J.H.,et al.Phosphodiesterase 7Adeficient mice have functional T cells.J.Immunol.2003;171:6414-6420.
[59]Shakur,Y.,Hoist,L.S.,Landstrom,T.R.,Movsesian,M.,Degerman,E.,Manganiello,V.Regulation and function of the cyclic nucleotide phosphodiesterase (PDE3) gene family.Prog.Nucleic Acid Res.Mol.Biol.2001;66:241-277.
[60]Meacci,E.,Taira,M,Moos Jr.,M.,Smith,C.J.,Movsesian,M.A.,Degerman,E.,et al.Molecular cloning and expression of human myocardial cGMP-inhibited cAMP phosphodiesterase.Proc.Natl.Acad.Sci.U.S.A.1992;89:3721-3725.
[61]Kumar,R.K.,Herbert,C,Thomas,P.S.,Wollin,L.,Beume,R.,Yang,M.,et al.Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma.J.Pharmacol.Exp.Ther.2003;307:349-355.
[62]Ukena,D.,Rentz,K.,Reiber,C,Sybrecht,GW.Effects of the mixed phosphodiesterase Ⅲ/Ⅳ inhibitor,zardaverine,on airway function in patients with chronic airflow obstruction.Respir.Med.1995;89:441-444.
[63]Edmondson,S.D.,Mastracchio,A.,He,J.,Chung,C.C.,Forrest,M.J.,Hofsess,S.,et al.Benzyl vinylogous amide substituted aryldihydropyridazinones and aryldimethylpyrazolones as potent and selective PDE3B inhibitors.Bioorg.Med.Chem.Lett.2003;13:3983-3987.
[2]Bisgaard H,Hermansen MN,Loland L,Halkjaer LB and Buchvald F.Intermittent inhaled corticosteroids in infants with episodic wheezing.N Engl J Med 2006;354(19):1998-2005.
[3]Guilbert TW,Morgan WJ,Zeiger RS,Mauger DT,Boehmer SJ,Szefler SJ,et al.Long-term inhaled corticosteroids in preschool children at high risk for asthma.N Engl J Med 2006;354(19):1985-97.
[4]Lehmann S and Ott H.Glucocorticoid hypersensitivity as a rare but potentially fatal side effect of paediatric asthma treatment:a case report.J Med Case Reports 2008;2(1):186.
[5]Harrison TW,Oborne J,Newton S and Tattersfield AE.Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations:randomised controlled trial.Lancet 2004;363(9405):271-5.
[6]Chaudhuri R,Livingston E,McMahon AD,Thomson L,Borland W and Thomson NC.Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronicasthma.Am J Respir Crit Care Med 2003;168(11):1308-11.
[7]Israel E,Drazen JM,Liggett SB,Boushey HA,Cherniack RM,Chinchilli VM,et al.The effect of polymorphisms of the beta (2)-adrenergic receptor on the response to regular use of albuterol in asthma.Am J Respir Crit Care Med 2000;162(1):75-80.
[8]Israel E,Chinchilli VM,Ford JG,Boushey HA,Cherniack R,Craig TJ,et al.Use of regularly scheduled albuterol treatment in asthma:genotype-stratified,randomised,placebo-controlled cross-over trial.Lancet 2004;364(9444):1505-12.
[9]Taylor DR,Drazen JM,Herbison GP,Yandava CN,Hancox RJ and Town GI.Asthma exacerbations during long term beta agonist use:influence of beta (2) adrenoceptor polymorphism.Thorax 2000;55(9):762-7.
[10]Wechsler ME,Lehman E,Lazarus SC,Lemanske RF,Jr.,Boushey HA,et al.beta-Adrenergic receptor polymorphisms and response to salmeterol.Am J Respir Crit Care Med 2006;173(5):519-26.
[11]Bleecker ER,Yancey SW,Baitinger LA,Edwards LD,Klotsman M,Anderson WH,et al.Salmeterol response is not affected by beta2-adrenergic receptor genotype in subjects with persistent asthma.J Allergy Clin Immunol 2006;118(4):809-16.
[12]Toshihiro Ito,Akihiro Hasegawa,Hiroyuki Hosokawa,Masakatsu Yamashita,Shinichiro Motohashi,Takashi Naka,et al.Human Th1 differentiation induced by lipoarabinomannan/lipomannan from Mycobacterium bovis BCG Tokyo-172.International Immunology 2008;1-12.
[13]Herz U,Gerhold K,Gruber C,Braun A,Wahn U,Renz H,Paul K.BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model.J Allergy Clin Immunol.1998 Nov;102(5):867-74.
[14]Hopfenspirger MT,Agrawal DK.Airway hyperresponsiveness,late allergic response,and eosinophilia are reversed with mycobacterial antigens in ovalbumin-presensitized mice.J Immunol.2002 Mar 1;168(5):2516-22.
[15]Koh YI,Choi IS,Lee JJ.Effects of cytokine milieu secreted by BCG-treated dendritic cells on allergen-specific Th immune response.J Korean Med Sci.2004 Oct;19(5):640-6.
[16]ZHU Min-min,FU Cheng-zhang,ZHOU Qin-hai(朱敏敏,傅诚章,周钦深入细致 ).To establish a allergic asthma model of rat.Journal of Clinical Medicine in Practice(实用临床医药杂志),2003,7(1):71-72.(in Chinese)
[17]Jutta Schade,Michael Stephan,Andreas Schmiedl,et al.Regulation of Expression and Function of Dipeptidyl Peptidase 4(DP4),DP8/9,and DP10 in Allergic Responses of the Lung in Rats.Journal of Histochemistry & Cytochemistry,2008,56(2):147-155.
[18]Min Xie,Xian-Sheng Liu,Yong-Jian Xu,et al.ERK1/2 Signaling Pathway Modulates the Airway Smooth Muscle Cell Phenotype in the Rat Model of Chronic Asthma[J].Respiration,2007,74:680-690.
[19]Wu-Rui,YAO Wan-zhen,CHEN Ya-hong,et al(伍蕊,姚婉贞,陈亚红,等).The regulatory effect of endogenous hydrogen sulfide on acute asthma[J].Chin J Tuberc Respir Dis(中华结核和呼吸杂志),2007,30(7):522-526.(in Chinese)
[20]CHEN Yan,LI Zi-gang,TANG Hui-fang,et al(陈艳,李子刚,汤慧芳,等).The efects of rolipram on PDE activity and IL_4 level in the lung tissue of ovalbum in sensitized and repeatedly challenged rats[J].Chinese Pharmacological Bulletin(中国药理学通报),2006,22(4):447-451.(in Chinese)
[21]ZHU Min-min,QIAN Yan-ning,ZHU Wei,et al(朱敏敏,钱燕宁,朱伟,等).Protective effects of ketamine on allergen-induced airway inflammatory injure and high airway reactivity in asthma:experiment with rats[J].Natl Med J China(中华医学杂志),2007,87(19):1308-1313.(in Chinese)
[22]YU Jian-er,LI Li-qing,ZHANG Xiao-feng,et al(虞坚尔,李利清,张晚峰,等).Study of Pingchuan Formula's effects on Th1/Th2 of bronchial asthma in model rats[J].J.PEDIATRICS OF TCM(中华儿科杂志),2006,2(1):23-26.
[23]Tang HF,Song YH,Chen JC,Chen JQ and Wang P.Upregulation of phosphodiesterase-4in the lung of allergic rats.Am J Respir Crit Care Med 2005;171(8):823-8.
[24]HUANG Hua-qiong(黄华琼).Advancement of BCG in preventing diseases.Med Sci Sec Biol Proph Diagn Ther,Dec(国外医学预防诊断治疗用生物制品分册),2005,28(6):251-254.(in Chinese)
[25]Kai Wang,Hua-hao Shen,Hua-qiong Huang,Jun-chun Chen,Zhong Chen.Acetamide-45inhibited hyperresponsiveness and airway inflammation in mice partly depending on phosphodiesterase activeity suppression.Acta Pharmacol Sin 2008;29(10):1195-1201.
[26]LI Qiu-gen,YU Jiang-qing,XIONG Guo-liang,et al(李秋根,余江清,熊国亮,等).Effect of taking orally BCG on TH1/TH2 balance in asthma mice.Chin J Microbiol Immunol(中华微生物学和免疫学杂志),2007,27(1):32.(in Chinese)
[27]HE Ying,LI Chao-qian(何英,李超乾).Progress on research of preventing bronchus asthma by Bacillus Calmette-Guerin vaccine.J Respir(国际呼吸杂志),2007,27(6):443-445.(in Chinese)
[28]H.Shen,H.Huang,J.Wand,et al.Neonatal vaccination with Bacillus Calmette-Guerin elicits long-term protection in mouse-allergic responses.Allergy,2008,DOI:10.1111/j.1398-9995.
[29]Chi Hong Kim,Joong Hyun Ahn,Seung Joon Kim,et al.Co-Administration of vaccination with DNA encoding T cell epitope on the Der p and BCG inhibited airway remodeling in a Murine Model of Chronic Asthma.Journal of Asthma,2008,43:5345-353.
[30]C.C.Obihara,J.L.L.Kimpen,R.P.Giew,et al.Mycobacterium tuberculosisinfection may protect against allergy in a tuberculosis endemic area.Clinical and Experimental Allergy,2006,36:70-76.
[31]Cabana MD,McKean M,Wong AR,et al.Examining the hygiene hypothesis:the Trial of Infant Probiotic Supplementation.Paediatr Perinat Epidemiol.2007,21 Suppl 3:23-8.
[32]Samuli Rautava,Olli Ruuskanen,Arthur Ouwehand,et al.The Hygiene hypothesis of atopic disease—An extended version.Journal of Pediatric Gastroenterology and Nutrition.2004,38:378-388.
[33]X.YANQ S.WANG Y.FAN,et al.Systemic mycobacterial infection inhibits antigen-specific immunoglobulin E production,bronchial mucus production and eosinophilic inflammation induced by allergen.Immunology.1999,98:329-337.
[34]Kostic MM,Erdogan S,Rena G et al.Altered expression of PDE1 and PDE4 cyclic nucleotide phosphodiesterase isoforms in 7-oxoprostacyclin preconditioned rat heart.J Mol Cell Cardiol,1997,29:3135-3146.
[35]Youngil I.Koh,Inseon S.Choi,Je-Jung Lee.Effects of Cytokine Milieu Secreted by BCG-treated Dendritic Cells on Allergen-Specific Th Immune Response.J Korean Med Sci,2004,19:640-6.
[36]Hylkema MN,Timens W,Luinge M,Van Der Werf N and Hoekstra MO.The effect of bacillus Calmette-Guerin immunization depends on the genetic predisposition to Th2-type responsiveness.Am J Respir Cell Mol Biol 2002;27(2):244-9.
[37]Koh YI,Chio IS,Kim WY,Lee HC,Lee J.Effects of BCG infection on Schultz-Dale reaction,allergen-specific IgE levels,and Th2 immune response in sensitized rats.Korean J Intern Med 2001;16(3):180-6.
[38]Yang X,Wang S,Fan Y and Zhu L.Systemic mycobacterial infection inhibits antigen-specific immunoglobulin E production,bronchial mucus production and eosinophilic inflammation induced by allergen.Immunology 1999;98(3):329-37.
[39]Song Yan-hua,Chen Ji-qiang,Chen Jun-chun.Cyclic nucleotides phosphodiesterase activity in rats' lung model of asthma after BCG immunization.Chinese Pharmacological Bulletin 2005;21(8):1020-1.
[40]Youngil I.Koh,Inseon S.Chio,Seok-Chae Park,Kwang-Won Kang.BCG Infection during Pre-Sensitization or Even Post-Sensitization Inhibits Airway Sensitivity in an Animal Model of Allergic Ashtma.J Korean Med Sci 2000;15:265-72.
[41]Tang HF,Chen JQ,Xie QM,Zheng XY,Zhu YL,Adcock I,et al.The role of PDE4 in pulmonary inflammation and goblet cell hyperplasia in allergic rats.Biochim Biophys Acta 2006;1762(5):525-32.
[42]Xie QM,Chen JQ,Shen WH.Comparison of bronchodilating and antiinflammatory activities of oral formoterol and its(R,R)-enantiomers.Acta Pharmacol Sin.2003;24(3):277-282.
[43]Essayan DM.Cyclic nucleotide phosphodiesterases.J Allergy Clin Immunol 2001;108:71-80.
[44]Tang HF,Song YH,Chen JC,Chen JQ and Wang P.Upregulation of phosphodiesterase-4in the lung of allergic rats.Am J Respir Crit Care Med 2005;171(8):823-8.
[45]Zhang Y,Mahendran R,Yap LL,Esuvaranathan K and Khoo HE.The signalling pathway for BCG-induced interleukin-6 production in human bladder cancer cells.Biochem Pharmacol 2002;63(2):273-82.
[46]Zhang Shuling,Yin Guishan(张书岭,尹挂山).Adenylate cyclase assay method in tissue homogenate.Acta Academiae Medicinae Hebei(河北医学院学报)1991;12(2):18-20. (In Chinese)
[47]Leon D,Albasanz JL,Ruiz MA and Martin M.Chronic caffeine or theophylline intake during pregnancy inhibits Al receptor function in the rat brain.Neuroscience 2005;131(2):481-9.
[48]Phillips PG,Long L,Wilkins MR and Morrell NW.cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling.Am J Physiol Lung Cell Mol Physiol 2005;288(1):L103-15.
[49]Witwicka H,Kobialka M,Siednienko J,Mitkiewicz M and Gorczyca WA.Expression and activity of cGMP-dependent phosphodiesterases is up-regulated by lipopolysaccharide (LPS) in rat peritoneal macrophages.Biochim Biophys Acta 2007;1773(2):209-18.
[50]Naro F,Sette C,Vicini E,De Arcangelis V,Grange M,Conti M,et al.Involvement of type 4 cAMP-phosphodiesterase in the myogenic differentiation of L6 cells.Mol Biol Cell 1999;10(12):4355-67.
[51]Kostic MM,Erdogan S,Rena G,Borchert G,Hoch B,Bartel S,et al.Altered expression of PDE1 and PDE4 cyclic nucleotide phosphodiesterase isoforms in 7-oxo-pro stacyclin-preconditioned rat heart.J Mol Cell Cardiol 1997;29(11):3135-46.
[52]Magdalena J.Lorenowicz,Mar Fernandesz-Borja,Peter L.Hordijk.cAMP signaling in leukocyte transendothelial migration.Arterioscler Thromb Vasc Biol 2007;27:1014-1022.
[53]Mona Gupta and Stephen J.Yarwood.MAPI A Light Chain 2 Interacts with Exchange Protein Activated by Cyclic AMP1 (EPAC1) to Enhance Rapl GTPase Activity and Cell Adhesion.The Journal of Biological Chemistry 2005;28(9):8109-8116.
[54]Marco Conti,Joseph Beavo.Biochemistry and physiology of cyclic nucleotide phosphodiesterases:essential components in cyclic nucleotide signaling.Annu.Rev.Biochem,2007,76:25.1-25.31.
[55]Ghosh S,Janocha AJ,Aronica MA,Swaidani S,Comhair SA,Xu W,et al.Nitrotyrosine proteome survey in asthma identifies oxidative mechanism of catalase inactivation.J Immunol 2006;176(9):5587-97.
[56]Youngil I.Koh,Inseon S.Chio,Seok-Chae Park,Kwang-Won Kang.BCG Infection during Pre-Sensitization or Even Post-Sensitization Inhibits Airway Sensitivity in an Animal Model of Allergic Ashtma.J Korean Med Sci 2000;15:265-72.
[57]Toward TJ,Smith N and Broadley KJ.Effect of phosphodiesterase-5 inhibitor,sildenafil (Viagra),in animal models of airways disease.Am J Respir Crit Care Med 2004;169(2):227-34.
[58]Jones NA,Leport M,Holand T,Vos T,Morgan M,Fink M,et al.Phosphodiesterase (PDE) 7 in inflammatory cells from patients with asthma and COPD.Pulm Pharmacol Ther 2007;20(1):60-8.
[59]Kathrin Woyda,Silke Koebrich,Irwin Reiss,Silvia Rudloff,Soni S.Pullamsetti,Alexander Ruhlmann,et al.Inhibition of PDE4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia.Eur Respir J 2008;In press.
[60]Huanchen Wang,Ming-Sheng Peng,Yi Chen,Jie Geng,Howard Robinson,Miles D.Houslay,et al.Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors.Biochem.J.2007;408:193-201.
[61]Z.Huang,R.Dias,T.Jones,S.Liu,A.Styhler,D.Claveau,et al.L-454,560,a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition.Biochemical Pharmacology 2007;73:1971-1981.
[62]Hye Cheol Jeong,Sang Yeub Lee,Eun Joo Lee,Ki Hwan Jung,Eun Hae Kang,Sung Yong Lee,et al.Proteomic Analysis of Peripheral T-Lymphocytes in Patients With Asthma.Chest 2007;132:489-496.
[63]Hui-Fang Tang,Ji-Qiang Chen,Qiang-Min Xie,Xu-Yang Zheng,Yi-Liang Zhu,Ian Adcock,et al.The role of PDE4 in pulmonary inflammation and goblet cell hyperplasia in allergic rats.Biochimica et Biophysica Acta 2006;1762:525-532.
[64]B.Al Qadi-Nassar,F.Bichon-Laurent,K.Portet,P.Tramini,B.Arnoux,A.Michel.Effects of L-arginine and phosphodiesterase-5 inhibitor,sildenafil,on inflammation and airway responsiveness of sensitized BP2 mice.Fundam ClinPharmacol 2007;21(6):611-20.
[65]Toby J.Toward,Nicola Smith,and Kenneth J.Broadley.Effect of Phosphodiesterase-5 Inhibitor,Sildenafil (Viagra),in Animal Models of Airways Disease.Am J Respir Crit Care Med 2004;169:227-234.
[66]Ffongli Dong,Venera Osmanova,Paul M.Epstein,Stefan Brocke.Phosphodiesterase 8 (PDE8) regulates chemotaxis of activated lymphocytes.Biochemical and Biophysical Research Communications 2006;345:713-719.
[67]Kian Fan Chung.Phosphodiesterase inhibitors in airways disease.European Journal of Pharmacology 2006;110-117.
[68]Patricia Mendez-Samperio,Artemisa Trejo,Aline Perez.Mycobacterium bovis Bacillus Calmette-Guerin (BCG) stimulates IL-10 production via the PBK/Akt and p38 MAPK pathways in human lung epithelial cell.Cellular Immunology 2008;251:37-42.
[69]S.Verstraelen,K.Bloemen,I.Nelissen,H.Witters,G.Schoeters,R.Van Den Heuvel.Cell types involved in allergic asthma and their use in in vitro models to assess respiratory sensitization.Toxicology in Vitro 2008;In press.
[70]A.Borowski,M.Kuepper,U.Horn,et al.Interleukin-13 acts as an apoptotic effector on lung epithelial cells and induces pro-fibrotic gene expression in lung fibroblasts.Clinical and Experimental Allergy 2008;38(4):619-28.
[71]Lyndon C.Wright,Joachim Seybold,Annette Robichaud,Ian M.Adcock and Peter J.Barnes.Phosphodiesterase expression in human epithelial cells.Am J Physiol Lung Cell Mol Physiol 1998;275:694-700.
[72]Annamaria Morelli,Sandra Filippi,Rosa Mancina,Michaela Luconi,Linda Vignozzi,Mirca Marini,et al.Androgens Regulate Phosphodiesterase Type 5 Expression and Functional Activity in Corpora Cavernosa.Endocrinology 2004;145(5):2253-2263.
[73]Masaaki Hayashi,kazuhide Matsushima,Hiroshi Ohashi,Hiroshi Tsunoda,Sumio Murase,Yoshifumi Kawarada,et al.Molecular Cloning and Characterization of Human PDE8B,a Novel Thyroid-Specific Isozyme of 3',5'-Cyclic Nucleotide Phosphodiesterase.Biochemical and Biophysical Research Communications 1998;250:751-756.
[74]Zhu J,Zhang H,Xie Q.Effect of Cryptoporus polysaccharide on lipopolysaccharide-induced production of monocyte chemoattractant protein-1 in human alveolar epithelial cells.Zhejiang Da Xue Xue Bao Yi Xue Ban 2008;37(4):333-9.
[75]Del Vecchio M,Balducci E.Mono ADP-ribosylation inhibitors prevent inflammatory cytokine release in alveolar epithelial cells.Mol Cell Biochem 2008;310(1-2):77-83.
[76]Ning QM,Wang XR.Response of alveolar type Ⅱ epithelial cells to mechanical stretch and lipopolysaccharide.Respiration 2007;74(5):579-85.
[77]Mata M,Sarria B,Buenestado A,Cortijo J,Cerda M,Morcillo EJ.Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells.Thorax 2005;60(2):144-52.
[78]Patricia Mendez-Samperio,Artemisa Trejo,Aline Perez.Mycobacterium bovis Bacillus Calmette-Guerin (BCG) stimulates IL-10 production via the PI3K/Akt and p38 MAPK pathways in human lung epithelial cells.Cellular Immunology 2008;251:37-42.
[79]Lyndon C.Wright,Joachim Seybold,Annette Robichaud,Ian M.Adcock,Peter J.Barnes.Phosphodiesterase expression in human epithelial cells.Am J Physiol Lung Cell Mol Physiol 1998;275:694-700.
[80]G.Dent,S.R.White,H.Tenor,K.Bodtke,C.Schudt,A.R.Leff,et al.Cyclic Nucleotide Phosphodiesterase in Human Bronchial Epithelial Cells:Characterization of Isoenzymes and Functional Effects of PDE Inhibitors.Pulmonary Phamacology & Therapeutics 1998;11:47-56.
[81]D.M.Brown,L.Hutchison,K.Donaldson,S.J.Mac Kenzie,C.A.J.Dick,V.Stone.The effect of oxidative stress on macrophages and lung epithelial cells:The role of phosphodiesterase 1 and 4.Toxicology Letters 2007;168:1-6.
[82]Graeme P.Currie,Claire A.Butler,Wendy J.Anderson,Chris Skinner.Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease:a new approach to oral treatment.British Journal of Clinical Pharmacology,British Journal of Clinical Pharmacology 2008;65(6):803-810.
[83]Klaus F.Rabe,Suzanne Hurd,Antonio Anzueto,Peter J.Barnes,Sonia A.Buist,Peter Calverley et al.Global Strategy for the Diagnosis,Management,and Prevention of Chronic Obstructive Pulmonary Disease-GOLD Executive Summary.Am J Respir Crit Care Med 2007;176:532-555.
[84]Peter J.Barnes.Future Treatments for Chronic Obstructive Pulmonary Disease and Its Comorbidities.Proc Am Thorac Soc 2008;5:857-864.
[85]Martorana PA,Beume R,Lucattelli M,Wollin L,Lungarella G.Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke.Am J Respir Crit Care Med 2005;172:848-853.
[86]Christopher J.Lunniss,Anthony W.J.Cooper,Colin D.Eldred,Michael Kranz,Mika Lindvall,Fiona S.Lucas,et al.Quinolines as a novel structural class of potent and selective PDE4 inhibitors:Optimisation for oral administration.Bioorganic & Medicinal Chemistry Letters 2009;19:1380-1385.
[87]Neville KA,Szefler SJ,Abdel-Rahman SM,Lahu G Zech K,Herzog R,et al.Single-dose pharmacokinetics of roflumilast in children and adolescents.J Clin Pharmacol 2008;48(8):978-85.
[88]Rennard S,Knobil K,Rabe KF,Morris A,Schachter N,Locantore N,et al.The efficacy and safety of cilomilast in COPD.Drugs 2008;68 Suppl 2:3-57.
[89]De Visser YP,Walther FJ,Laghmani EH,van Wijngaarden S,Nieuwland K,Wagenaar GT.Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury.Eur Respir J 2008;31(3):633-44.
[90]Vestbo J,Tan L,Atkinson G Ward J.A controlled trial of 6 weeks' treatment with a novel inhaled PDE4 inhibitor in COPD.Eur Respir J 2009;In press.
[91]David A Groneberg,K Fan Chung.Models of Chronic obstructive pulmonary disease.Respiratory Research 2004;5:18.
[92]GE Zheng-hang,TAN Tao.Miao Nationality's Relieve Cough and Rdeuce Phlegm Herb interfere the levels of IL-8 and TNF-a in bronchoalveolar ronchoalveolar larvae fluid in the obstructive emphysema rat models.Cllinese Journal of the Practical Chinese with Modem Medicine 2004;4(17):2913-2916.
[93]Yoshiaki Takeuchi,Maki Takahashi,and Jun-ichi Fuchikami.Vulnerability of Gastric Mucosa to Prednisolone in Rats Chronically Exposed to Cigarette Smoke.J Pharmacol Sci 2008;106:585-592.
[94]Bai-Ling Luo,Rui-Chao Niu,Jun-Tao Feng,Cheng-Ping Hu,Xiao-Yun Xie,and Li-Juan Ma.Downregulation of Secretory Leukocyte Proteinase Inhibitor in Chronic Obstructive Lung Disease:The Role Of TGF-b/Smads Signaling Pathways.Archives of Medical Research 2008;39:388-396.
[95]Tang HF,Song YH,Chen JC,Chen JQ and Wang P.Upregulation of phosphodiesterase-4 in the lung of allergic rats.Am J Respir Crit Care Med 2005;171(8):823-8.
[96]Peter J.Barnes.Frontrunners in novel pharmacotherapy of COPD.Current Opinion in Pharmacology 2008;8:300-307.
[97]Victoria Boswell-Smith,Mario Cazzola and Clive P.Page.Are phosphodiesterase 4 inhibitors just more theophylline? J Allergy Clin Immunol 2006;117:1237-43.
[98]Torphy TJ.Phosphodiesterase isozymes:molecular targets for novel antiasthma agents.Am J Respir Crit Care Med 1998;157:z351-70.
[99]J.Chorostowska-Wynimko,J.Kus,E.Skopiriska-Rozewska.Teophylline inhibits free oxygen radicals production by human monocytes via phosphodiesterases inhibition.Journal of Physiology and Pharmacology 2007;58 suppl:95-103.
[100]Barnes AP,Livera G,Huanq P,Sun C,O'Neal WK,Conti M,et al.Phosphodiesterase 4D forms a cAMP diffusion barrier at the apical membrane of the airway epithelium.J Biol Chem 2005;280(9):7997-8003.
[101]Hui-Fang Tang,Ji-Qiang Chen,Qiang-Min Xie,Xu-Yang Zheng,Yi-Liang Zhu,Ian Adicock,et al.The role of PDE4 in pulmonary inflammation and goblet cell hyperplasia in allergic rats.Biochimica et Biophysica Acta2006;1762:525-532.
[102]Tang HF,Song YH,Chen JC,Chen JQ and Wang P.Upregulation of phosphodiesterase-4 in the lung of allergic rats.Am J Respir Crit Care Med 2005;171(8):823-8.
[103]Yuji Higashimoto,Takuya Iwata,Morihiro Okada,Hiroaki Satoh,Kanji Fukuda,Yuji Tohda.Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonary disease.Respiratory Medicine 2009;In press.
[104]Andrew Churg,Rona Wang,Xiaoshan Wang,Per-Ola Onnervik,Kerstin Thim and Joanne L Wright.Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs.Thorax 2007;62:706-713.
[105]Essayan DM.Cyclic nucleotide phosphodiesterases.J Allergy Clin Immunol 2001;108:71-80.
[106]Liu S,Veilleux A,Zhang L,Young A,Kwok E,Laliberte F,et al.Dynamic activation of cystic fibrosis transmenbrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors.J Pharmacol Exp Ther 2005;341(2):846-54.
[107]Arumugam Kodimuthali,S.Sugin Lai Jabaris,and Manojit Pal.Recent Advances on Phosphodiesterase 4 Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease.J.Med.Chem.2008;51 (18):5471-5489.
[108]Barnes PJ.Emerging pharmacotherapies for COPD.Chest 2008;134(6):1278-86.
[109]Christopher J.Lunniss,Anthony W.J.Cooper,Colin D.Eldred,Michael Kranz,Mika Lindvall,Fiona S.Lucas,et al.Quinolines as a novel structural class of potent and selective PDE4 inhibitors:Optimisation for oral administration.Bioorganic & Medicinal Chemistry Letters 2009;19:1380-1385.
[110]Ruihong Ma,Bin-yan Yang,Chang-you Wu.A selective phosphodiesterase 4 (PDE4) inhibitor Zl-n-91 suppresses IL-17 production by human memory Thl7 cells.International Immunopharmacology 2008;8:1408-1417.
[1]Barnes P.J.Chronic obstructive pulmonary disease:a growing but neglected epidemic.Plos Med 2007;4:e112.
[2]Mannino D.M.,Buist.A.S.Global burden of COPD:risk factors,prevalence,and future trends.Lancet 2007;370:765-773.
[3]Pearce N.Worldwide trends in the prevalence of asthma symptoms:phase Ⅲ of the International Study of Asthma and Allergies in Childhood (ISAAC).Thorax 2007;62:758-766.
[4]Peter J.Barnes.Immunology of asthma and chronic obstructive pulmonary disease.Nat Rev Immunol 2008;8(3):183-92.
[5]Barnes P.J.,Chung K.F.,Page C.P.Inflammatory mediators of asthma:an update.Pharmacol.Rev.1998;50:515-596.
[6]Barnes P.J.Mediators of chronic obstructive pulmonary disease.Pharm.Rev.2004;56:515-548.
[7]Benayoun L.,Druilhe A.,Dombret M.C.,Aubier M.,Pretolani M.Airway structural alterations selectively associated with severe asthma.Am.J.Respir.Crit.Care Med.2003;167:1360-1368.
[8]Siddiqui S.Vascular remodeling is a feature of asthma and nonasthmatic eosinophilic bronchitis.J.Allergy Clin.Immunol.2007;120:813-819.
[9]Ordonez C.L.Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression.Am.J.Respir.Crit.Care Med.2001;163:517-523.
[10]Hogg J.C.Pathophysiology of airway limitation in chronic obstructive pulmonary disease.Lancet 2004;364:709-721.
[11]Hogg J.C.The nature of small-airway obstruction in chronic obstructive pulmonary disease.N.Engl.J.Med.2004;350:2645-2653.
[12]Majo J.,Ghezzo H.,Cosio M.G Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema.Eur.Respir.J.2001;17:946-953.
[13]Taraseviciene-Stewart L.Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease? Proc.Am.Thorac.Soc.2006;3:687-690.
[14]Ohnishi K.,Takagi M.,Kurokawa Y.,Satomi S.,Konttinen Y.T.Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema.Lab.Invest.1998;78:1077-1087.
[15]Gene L Colice.New Drugs for Asthma.Respir Care 2008;53(6):688-696.
[16]Magdalena J.Lorenowicz,Mar Fernandez-Borja and Peter L.Hordijk.cAMP Signaling in Leukocyte Transendothelial Migration.Arterioscler.Thromb.Vase.Biol.2007;27:1014-1022.
[17]Adderley SP,Dufaux EA,Shridharan M,Bowles EA,Hanson MS,Stephenson AH,et al.Iloprost-and isoprterenol-induced increase in cAMP are regulated by different phophodiesterases in erythrocytes of both rabbits and humans.Am J Physiol Heart Circ Physiol 2009;In press.
[18]Graeme P.Currie,Claire A.Butler,Wendy J.Anderson,Chris Skinner.Phophodiesterase 4 inhibitors in chronic obstructive pulmonary disease:a new approach to oral treatment.British Journal of Clinical Pharmacology 2008;65(6):803-810.
[19]Marco Conti,Joseph Beavo.Biochemistry and Physiology of cyclic Nucleotide Phosphodiesterases:Essential Components in Cyclic Nucleotide Signaling.Annu.Rev.Biochem.2007;76:25.1-25.31.
[20]Arumugam Kodimuthali,S.Sugin Lai Jabaris,Manojit Pal.Recent Advances on Phosphodiesterase 4 Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease.J.Med.Chem.2008;51(18):5471-5489.
[21]Victoria Boswell-Smith,Mario Cazzola,Clive P.Page.Are phosphodiesterase 4 inhibitors just more theophylline? J Allergy Clin Immunol 2006;117:1237-43.
[22]Jin,S.L.,Conti,M.Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses.Proc.Natl.Acad.Sci.U.S.A.2002;99:7628-7633.
[23]Ariga,M.,Neitzert,B.,Nakae,S.,Mottin,G,Bertrand,C,Pruniaux,M.P.,et al.Nonredundant function of phosphodiesterases 4D and 4B in neutrophil recruitment to the site of inflammation.J.Immunol.2004;173:7531-7538.
[24]Hansen,G,Jin,S.,Umetsu,D.T.,Conti,M.Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D.Proc.Natl.Acad.Sci.U.S.A.2000;97:6751-6756.
[25]Sanz,M.J.,Cortijo,J.,Morcillo,E.J.PDE4 inhibitors as new anti-inflammatory drugs:effects on cell trafficking and cell adhesion molecules expression.Pharmacol.Ther 2005;106:269-297.
[26]Lagente V.,Pruniaux M.P.,Junien J.L.,Moodley I.Modulation of cytokine-induced eosinophil infiltration by phosphodiesterase inhibitors.Am.J.Respir.Crit.Care Med.1995;151:1720-1724.
[27]Lagente,V.,Moodley,I.,Perrin,S.,Mottin,G,Junien,J.L.Effects of isozyme-selective phosphodiesterase inhibitors on eosinophil infiltration in the guinea-pig lung.Eur.J.Pharmacol.1994;255:253-256.
[28]Toward,T.J.,Broadley,K.J.Chronic lipopolysaccharide exposure on airway function,cell infiltration,and nitric oxide generation in conscious guinea pigs:effect of rolipram and dexamethasone.J.Pharmacol.Exp.Ther.2001;298:298-306.
[29]Lazzeri,N.,Belvisi,M.G,Patel,H.J.,Yacoub,M.H.,Chung,K.F.,Mitchell,J.A.Effects of prostaglandin E2 and cAMP elevating drugs on GMCSF release by cultured human airway smooth muscle cells.Relevance to asthma therapy.Am.J.Respir.Cell Mol.Biol.2001;24:44-48.
[30]O'Donnell JM,Zhang HT.Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4).Trends Pharmacol Sci 2004;25:158-63.
[31]Renau TE.The potential of phosphodiesterase 4 inhibitors for the treatment of depression: opportunities and challenges.Curr Opin Invest Drugs 2004;5:34-9.
[32]Torphy TJ,Barnette MS,Underwood DC,Griswold DE,Christensen SB,Murdoch RD,et al.Ariflo (SB 207499),a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD:from concept to clinic.Pulm Pharmacol Ther 1999;12:131-5.
[33]Jacobitz S,McLaughlin MM,Livi GP,Burman M,Torphy TJ.Mapping the functional domains of human recombinant phosphodiesterase 4A:structural requirements for catalytic activity and rolipram binding.Mol Pharmacol 1996;50:891-9.
[34]Souness JE,Rao S.Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases.Cell Signal 1997;9:227-36.
[35]Profita,M.,Chiappara,G,Mirabella,E,Di Giorgi,R.,Chimenti,L.,Costanzo,G,et al.Effect of cilomilast (Ariflo) on TNF-alpha,IL-8,and GM-CSF release by airway cells of patients with COPD.Thorax 2003;58:573-579.
[36]Griswold,D.E.,Webb,E.F.,Badger,A.M.,Gorycki,P.D.,Levandoski,P.A.,Barnette,M.A.,et al.SB 207499 (ariflo),a second generation phosphodiesterase 4 inhibitor,reduces tumor necrosis factor alpha and interleukin-4 production in vivo.J.Pharmacol.Exp.Ther.1998;287:705-711.
[37]Souness,J.E.,Griffin,M.,Maslen,C,Ebsworth,K.,Scott,L.C.,Pollock,K.,et al.Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNF alpha generation from human monocytes by interacting with aTow-affinity' phosphodiesterase 4 conformer.Br.J.Pharmacol.1996;118:649-658.
[38]Goncalves,d.M.,V,Singer,M.,Vargaftig,B.B.,Chignard,M.Effects of rolipram on cyclic AMP levels in alveolar macrophages and lipopolysaccharide-induced inflammation in mouse lung.Br.J.Pharmacol.1998;123:631-636.
[39]Ouagued,M.,Martin-Chouly,C.A.,Brinchault,G,Leportier-Comoy,C,Depince,A.,Bertrand,C,et al.The novel phosphodiesterase 4 inhibitor,CI-1044,inhibits LPS-induced TNF-alpha production in whole blood from COPD patients.Pulm. Pharmacol.Ther.2005;18:49-54.
[40]Mata,M.,Sarria,B.,Buenestado,A.,Cortijo,J.,Cerda,M.,Morcillo,E.J.Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells.Thorax 2005;60:144-152.
[41]Belleguic,C,Corbel,M.,Germain,N.,Boichot,E.,Delaval,P.,Lagente,V.Reduction of matrix metalloproteinase-9 activity by the selective phosphodiesterase 4 inhibitor,RP 73-401 in sensitized mice.Eur.J.Pharmacol.2000;404:369-373.
[42]Kohyama,T.,Liu,X.,Wen,F.Q.,Zhu,Y.K.,Wang,H.,Kim,H.J.,et al.PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels.Am.J.Respir.Crit.Care Med.2002;26:694-701.
[43]Kohyama,T.,Liu,X.,Zhu,Y.K.,Wen,F.Q.,Wang,H.J.,Fang,Q.,et al.Phosphodiesterase 4 inhibitor cilomilast inhibits fibroblast-mediated collagen gel degradation induced by tumor necrosis factor-alpha and neutrophil elastase.Am.J.Respir.Crit.Care Med.2002;27:487-494.
[44]Martorana,P.A.,Beume,R.,Lucattelli,M.,Wollin,L.,Lungarella,G.Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke.Am.J.Respir.Crit.Care Med.2005;172:848-853.
[45]Rybalkin,S.D.,Rybalkina,I.G.,Shimizu-Albergine,M.,Tang,X.B.,Beavo,J.A.PDE5 is converted to an activated state upon cGMP binding to the GAF A domain.EMBO J.2003;22:469-478.
[46]Sebkhi,A.,Strange,J.W.,Phillips,S.C,Wharton,J.,Wilkins,M.R.Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension.Circulation 2003;107:3230-3235.
[47]Yanaka,N.,Kotera,J.,Ohtsuka,A.,Akatsuka,H.,Imai,Y,Michibata,H.,et al.Expression,structure and chromosomal localization of the human cGMP binding cGMP-specific phosphodiesterase PDE5A gene.Eur.J.Biochem.1998;255:391-399.
[48]Zhao,L.,Mason,N.A.,Morrell,N.W.,Kojonazarov,B.,Sadykov,A.,Maripov,A.,et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension.Circulation 2001;104:424-428.
[49]Sastry,B.K.,Narasimhan,C,Reddy,N.K.,Raju,B.S.Clinical efficacy of sildenafil in primary pulmonary hypertension:a randomized,placebocontrolled,double-blind,crossover study.J.Am.Coll.Cardiol.2004;43:1149-1153.
[50]Ghofrani,H.A.,Voswinckel,R.,Reichenberger,F.,Olschewski,H.,Haredza,P.,Karadas,B.,et al.Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension:a randomized prospective study.J.Am.Coll.Cardiol.2004;44:1488-1496.
[51]Wharton,J.,Strange,J.W.,Moller,G.M.,Growcott,E.J.,Ren,X.,Franklyn,A.P.,et al.Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells.Am.J.Respir.Crit.Care Med.2005;172:105-113.
[52]S.Faruqi,H.Fathi,A.H.Morice.Combination of sitaxentan and tadalafil for idiopathic pulmonary arterial hypertension following relapse on bosentan.International Journal of Cardiology 2009;In press.
[53]Bloom,T.J.,Beavo,J.A.Identification and tissue-specific expression of PDE7 phosphodiesterase splice variants.Proc.Natl.Acad.Sci.U.S.A.1996;93:14188-14192.
[54]Miro,X.,Perez-Torres,S.,Palacios,J.M.,Puigdomenech,P.,Mengod,G.Differential distribution of cAMP-specific phosphodiesterase 7A mRNA in rat brain and peripheral organs.Synapse 2001;40:201-214.
[55]Glavas,N.A.,Ostenson,C,Schaefer,J.B.,Vasta,V.,Beavo,J.A.T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3.Proc.Natl.Acad.Sci.U.S.A.2001;98:6319-6324.
[56]Smith,S.J.,Brookes-Fazakerley,S.,Donnelly,L.E.,Barnes,P.J.,Barnette,M.S.,Giembycz,M.A.Ubiquitous expression of phosphodiesterase 7A in human proinflammatory and immune cells.Am.J.Physiol.,Lung Cell.Mol.Physiol.2003;284:L279-L289.
[57]Smith,S.J.,Cieslinski,L.B.,Newton,R.,Donnelly,L.E.,Fenwick,P.S.,Nicholson,A.G,et al.Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene],a selective inhibitor of phosphodiesterase 7:in vitro studies in human monocytes,lung macrophages,and CD8+ T-lymphocytes.Mol.Pharmacol.2004;66:1679-1689.
[58]Yang,G,Mclntyre,K.W.,Townsend,R.M.,Shen,H.H.,Pitts,W.J.,Dodd,J.H.,et al.Phosphodiesterase 7Adeficient mice have functional T cells.J.Immunol.2003;171:6414-6420.
[59]Shakur,Y.,Hoist,L.S.,Landstrom,T.R.,Movsesian,M.,Degerman,E.,Manganiello,V.Regulation and function of the cyclic nucleotide phosphodiesterase (PDE3) gene family.Prog.Nucleic Acid Res.Mol.Biol.2001;66:241-277.
[60]Meacci,E.,Taira,M,Moos Jr.,M.,Smith,C.J.,Movsesian,M.A.,Degerman,E.,et al.Molecular cloning and expression of human myocardial cGMP-inhibited cAMP phosphodiesterase.Proc.Natl.Acad.Sci.U.S.A.1992;89:3721-3725.
[61]Kumar,R.K.,Herbert,C,Thomas,P.S.,Wollin,L.,Beume,R.,Yang,M.,et al.Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma.J.Pharmacol.Exp.Ther.2003;307:349-355.
[62]Ukena,D.,Rentz,K.,Reiber,C,Sybrecht,GW.Effects of the mixed phosphodiesterase Ⅲ/Ⅳ inhibitor,zardaverine,on airway function in patients with chronic airflow obstruction.Respir.Med.1995;89:441-444.
[63]Edmondson,S.D.,Mastracchio,A.,He,J.,Chung,C.C.,Forrest,M.J.,Hofsess,S.,et al.Benzyl vinylogous amide substituted aryldihydropyridazinones and aryldimethylpyrazolones as potent and selective PDE3B inhibitors.Bioorg.Med.Chem.Lett.2003;13:3983-3987.