以树突状细胞为标靶的哮喘中西医认识及治疗手段
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摘要
哮喘是以气道高反应及慢性气道炎症为特征的异质性疾病,最终可导致气道重塑等不可逆器质性损害。哮喘发病机制极为复杂,涉及多种炎性细胞、细胞因子、趋化因子和炎性反应递质等,并受环境因素和表观遗传因子调控。随着近年分子生物学和遗传学研究的不断深入,树突状细胞(DC)作为一类有众多表型及不同功能亚群的生物系统,被发现是参与哮喘发病的重要细胞,在启动哮喘免疫反应和维持免疫耐受方面发挥着关键作用。DC具有摄取、加工和提呈抗原,激活初始T淋巴细胞,介导免疫应答及免疫耐受等重要功能,直接影响着哮喘的发生发展。糖皮质激素至今仍被证实是预防哮喘发作的最有效药物,但其引发的不良反应备受关注;而中医药多靶点治疗哮喘的机制研究已引起越来越多国内外专家学者的重视,DC无疑是探索哮喘发病机制和探索安全有效的免疫疗法及研发天然中药产品的一个重要研究靶点。现从DC的研究概况、DC与哮喘发病的中西医认识及其相关性、主要研究工作等整理论述,以期为今后阐释中医药防治哮喘的作用机制及新药研发提供部分思路。
Asthma is a heterogeneous disease characterized by airway hyperreaction and chronic airway inflammation,which can eventually lead to airway remodeling and other irreversible organic damage. The pathogenesis of asthma is complex,involving a variety of inflammatory cells,cytokines,chemokines and inflammatory mediators,and is regulated by environmental factors and epigenetic factors. With the development of molecular biology and genetics in recent years,Dendritic cells (DC) are considered to be a biological system composed of a variety of phenotypic and functional subsets. It is an important cell involved in the pathogenesis of asthma,and plays a key role in initiating immune response and maintaining immune tolerance in asthma. Different phenotypes of DC have different functions such as uptake,processing and presentation antigens,activation of initial T lymphocytes,mediating immune response and immune tolerance,which directly affect the development of asthma. Glucocorticoids are still proven to be the most effective drugs for preventing asthma attacks,but their side effects attract much attention. Instead,more and more experts and scholars have paid more attention to the mechanism of multi target treatment of asthma by traditional Chinese medicine. DC is undoubtedly an important target for exploring the pathogenesis of asthma and exploring the safe and effective immunotherapy and the development of natural Chinese medicine products. In the paper,the general situation of DC,the understanding and correlation between DC and the pathogenesis of asthma between traditional Chinese medicine and Western medicine and the main research work are stated in order to provide some ideas for future interpretation of traditional Chinese medicine in the prevention and treatment of asthma mechanism and the research and development of new drugs.
Asthma is a heterogeneous disease characterized by airway hyperreaction and chronic airway inflammation,which can eventually lead to airway remodeling and other irreversible organic damage. The pathogenesis of asthma is complex,involving a variety of inflammatory cells,cytokines,chemokines and inflammatory mediators,and is regulated by environmental factors and epigenetic factors. With the development of molecular biology and genetics in recent years,Dendritic cells (DC) are considered to be a biological system composed of a variety of phenotypic and functional subsets. It is an important cell involved in the pathogenesis of asthma,and plays a key role in initiating immune response and maintaining immune tolerance in asthma. Different phenotypes of DC have different functions such as uptake,processing and presentation antigens,activation of initial T lymphocytes,mediating immune response and immune tolerance,which directly affect the development of asthma. Glucocorticoids are still proven to be the most effective drugs for preventing asthma attacks,but their side effects attract much attention. Instead,more and more experts and scholars have paid more attention to the mechanism of multi target treatment of asthma by traditional Chinese medicine. DC is undoubtedly an important target for exploring the pathogenesis of asthma and exploring the safe and effective immunotherapy and the development of natural Chinese medicine products. In the paper,the general situation of DC,the understanding and correlation between DC and the pathogenesis of asthma between traditional Chinese medicine and Western medicine and the main research work are stated in order to provide some ideas for future interpretation of traditional Chinese medicine in the prevention and treatment of asthma mechanism and the research and development of new drugs.
引文
[1]中华医学会儿科学分会呼吸学组,《中华儿科杂志》编辑委员会.儿童支气管哮喘诊断与防治指南(2016年版)[J].中华儿科杂志,2016,54(3):167-181.
[2]Vroman H,Hendriks RW,Kool M.Dendritic Cell Subsets in Asthma:Impaired Tolerance or Exaggerated Inflammation?[J].Front Immunol,2017,8:941.
[3]Manicassamy S,Pulendran B.Dendritic cell control of tolerogenic responses[J].Immunol Rev,2011,241(1):206-227.
[4]Huang HJ,Lin YL,Liu CF,et al.Mite allergen decreases DC-SIGNexpression and modulates human dendritic cell differentiation and function in allergic asthma[J].Mucosal Immunol,2011,4(5):519-527.
[5]Eisenbarth SC,Williams A,Colegio OR,et al.NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells[J].Nature,2012,484(7395):510-513.
[6]De Nardo D.Toll-like receptors:Activation,signalling and transcriptional modulation[J].Cytokine,2015,74(2):181-189.
[7]邵惠训.树突状细胞疫苗的现状与未来[J].中国医药生物技术,2012,7(1):62-65,77.
[8]Gaurav R,Agrawal DK.Clinical view on the importance of dendritic cells in asthma[J].Expert Rev Clin Immunol,2013,9(10):899-919.
[9]徐灵芝,杨平常.树突状细胞活化或耐受诱导物的研究进展[J].细胞与分子免疫学杂志,2016,32(5):703-706.
[10]Fedulov AV,Kobzik L.Allergy risk is mediated by dendritic cells with congenital epigenetic changes[J].Am J Respir Cell Mol Biol,2011,44(3):285-292.
[11]白易,钱程,曹雪涛.树突状细胞亚群的不同迁移模式及相关研究进展[J].中国免疫学杂志,2010,26(9):845-849.
[12]Vroman H,Hendriks RW,Kool M.Dendritic Cell Subsets in Asthma:Impaired Tolerance or Exaggerated Inflammation?[J].Front Immunol,2017,8:941.
[13]宋佳,尹月,王丹,等.树突状细胞在自身免疫性疾病中的作用[J].细胞与分子免疫学杂志,2015,31(5):708-712.
[14]刘美璇,陈小东,等.树突状细胞在支气管哮喘中的作用研究进展[J].国际呼吸杂志,2010,30(15):179-182.
[15]Pichavant M,Charbonnier AS,Taront S,et al.Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment[J].J Allergy Clin Immunol,2005,115(4):771-778.
[16]Barnes PJ.Immunology of asthma and chronic obstructive pulmonary disease[J].Nat Rev Immunol,2008,8(3):183-192.
[17]Lin R,Choi YH,Zidar DA,et al.β-Arrestin-2-Dependent Signaling Promotes CCR4-mediated Chemotaxis of Murine T-Helper Type 2Cells[J].Am J Respir Cell Mol Biol,2018,58(6):745-755.
[18]Fainaru O,Shseyov D,Hantisteanu S,et al.Accelerated chemokine receptor 7-mediated dendritic cell migration in Runx3 knockout mice and the spontaneous development of asthma-like disease[J].Proc Natl Acad Sci U S A,2005,102(30):10598-10603.
[19]Otero K,Vecchi A,Hirsch E,et al.Nonredundant role of CCRL2 in lung dendritic cell trafficking[J].Blood,2010,116(16):2942-2949.
[20]Nakano H,Free ME,Whitehead GS,et al.Pulmonary CD103(+)dendritic cells prime Th2 responses to inhaled allergens[J].Mucosal Immunol,2012,5(1):53-65.
[21]李俊奇,罗征秀.CD103+树突状细胞与慢性免疫性炎症疾病研究进展[J].儿科药学杂志,2016,22(2):49-52.
[22]万梦智,许飞.树突状细胞在支气管哮喘中的研究进展[J].中华肺部疾病杂志(连续型电子期刊),2013,6(4):46-49.
[23]Hirose K,Iwata A,Tamachi T,et al.Allergic airway inflammation:key players beyond the Th2 cell pathway[J].Immunol Rev,2017,278(1):145-161.
[24]Feng S,Zhang L,Bian XH,et al.Role of the TSLP-DC-OX40L pathway in asthma pathogenesis and airway inflammation in mice[J].Biochem Cell Biol,2018,96(3):306-316.
[25]Zhou LF,Zhang MS,Hu AH,et al.Selective blockade of NF-kappaBby novel mutated IkappaBalpha suppresses CD3/CD28-induced activation of memory CD4+T cells in asthma[J].Allergy,2010,63(5):509-517.
[26]Fallarino F,Grohmann U,You S,et al.The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells[J].J Immunol,2006,176(11):6752-6761.
[27]Chen W.IDO:more than an enzyme[J].Nat Immunol,2011,12(9):809-811.
[28]Sharma MD,Baban B,Chandler P,et al.Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase[J].J Clin Invest,2007,117(9):2570-2582.
[29]Raitala A,Karjalainen J,Oja SS,et al.Indoleamine 2,3-dioxygenase(IDO)activity is lower in atopic than in non-atopic individuals and is enhanced by environmental factors protecting from atopy[J].Mol Immunol,2006,43(7):1054-1056.
[30]Maneechotesuwan K,Supawita S,Kasetsinsombat K,et al.Sputum indoleamine-2,3-dioxygenase activity is increased in asthmatic airways by using inhaled corticosteroids[J].J Allergy Clin Immunol,2008,121(1):43-50.
[31]Yeh CH,Kuo CH,Yang SN,et al.Prostaglandin I2 analogs suppress tumor necrosis factorαproduction and the maturation of human monocyte-derived dendritic cells[J].J Investig Med,2011,59(7):1109-1115.
[32]Hayashi M,Koya T,Kawakami H,et al.A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice[J].Clin Exp Allergy,2010,40(2):317-326.
[33]陈娜,张双,高春燕.CRTH2受体拮抗剂对支气管哮喘树突状细胞功能的影响[J].免疫学杂志,2017,33(1):63-67.
[34]马光宇,吴雅琼,高玉环.树突状细胞免疫受体是治疗哮喘的新靶点[J].免疫学杂志,2014,30(4):282-287.
[35]虞念成,花奕.止咳平喘颗粒对婴幼儿哮喘患儿外周血树突细胞共刺激分子的影响分析[J].中国妇幼保健,2016,31(19):3984-3986.
[36]王丽新,赵霞,宋英.温阳补肾方对哮喘小鼠脾脏树突细胞的免疫调控机制研究[J].上海中医药杂志,2013,47(7):83-86.
[37]张丽,赵辉,孙义田,等.射干麻黄汤加味对哮喘小鼠气道炎症及树突细胞的影响[J].成都中医药大学学报,2014,37(2):42-43.
[38]李家伦,雷世庸.六味地黄汤对免疫功能低下小鼠的药理作用[J].中国医药指南,2008,6(16):13-14.
[39]黄婷,王孟清,罗银河,等.五虎汤对婴幼儿哮喘患儿外周血树突状细胞表面共刺激分子表达的影响[J].中国中西医结合杂志,2009,29(10):889-891.
[40]Tian Y,Li X,Li H,et al.Astragalus mongholicus regulate the Tolllike-receptor 4 meditated signal transduction of dendritic cells to restrain stomach cancer cells[J].Afr J Tradit Complement Altern Med,2014,11(3):92-96.
[41]Gu X,Zhou L,Du Q,et al.Hesperetin inhibits the maturation and function of monocyte-derived dendritic cells from patients with asthma[J].Mol Med Rep,2009,2(3):509-513.
[42]李红岩,张业清,肖庆龄,等.芹菜素对哮喘小鼠肺组织OX40表达、气道炎症和气道高反应性的影响[J].江苏医药,2016,42(6):621-624,封2.
[43]Hu Z,Jiao Q,Ding J,et al.Berberine induces dendritic cell apoptosis and has therapeutic potential for rheumatoid arthritis[J].Arthritis Rheum,2011,63(4):949-959.
[44]侯伟,刘海燕,杨旭东,等.氧化苦参碱对哮喘小鼠肺及脾脏组织中树突状细胞分布变化影响的研究[J].中国当代儿科杂志,2011,13(1):40-43.
[45]Chiang CY,Lee CC,Fan CK,et al.Osthole treatment ameliorates Th2-mediated allergic asthma and exerts immunomodulatory effects on dendritic cell maturation and function[J].Cell Mol Immunol,2017,14(1):1-13.
[46]王丽新,喻晓,石克华,等.穴位敷贴对哮喘大鼠肺脏树突状细胞表达的影响[J].上海中医药杂志,2010,44(8):74-76.
[47]许琬茹.邵氏“五针法”对哮喘模型大鼠DC及NF-κB表达影响的实验研究[D].郑州:河南中医学院,2012.
[48]杨昆,黄春红,王飞,等.冬病夏治中药敷贴对哮喘大鼠树突状细胞免疫功能的影响[J].四川中医,2016,34(6):49-52.
[2]Vroman H,Hendriks RW,Kool M.Dendritic Cell Subsets in Asthma:Impaired Tolerance or Exaggerated Inflammation?[J].Front Immunol,2017,8:941.
[3]Manicassamy S,Pulendran B.Dendritic cell control of tolerogenic responses[J].Immunol Rev,2011,241(1):206-227.
[4]Huang HJ,Lin YL,Liu CF,et al.Mite allergen decreases DC-SIGNexpression and modulates human dendritic cell differentiation and function in allergic asthma[J].Mucosal Immunol,2011,4(5):519-527.
[5]Eisenbarth SC,Williams A,Colegio OR,et al.NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells[J].Nature,2012,484(7395):510-513.
[6]De Nardo D.Toll-like receptors:Activation,signalling and transcriptional modulation[J].Cytokine,2015,74(2):181-189.
[7]邵惠训.树突状细胞疫苗的现状与未来[J].中国医药生物技术,2012,7(1):62-65,77.
[8]Gaurav R,Agrawal DK.Clinical view on the importance of dendritic cells in asthma[J].Expert Rev Clin Immunol,2013,9(10):899-919.
[9]徐灵芝,杨平常.树突状细胞活化或耐受诱导物的研究进展[J].细胞与分子免疫学杂志,2016,32(5):703-706.
[10]Fedulov AV,Kobzik L.Allergy risk is mediated by dendritic cells with congenital epigenetic changes[J].Am J Respir Cell Mol Biol,2011,44(3):285-292.
[11]白易,钱程,曹雪涛.树突状细胞亚群的不同迁移模式及相关研究进展[J].中国免疫学杂志,2010,26(9):845-849.
[12]Vroman H,Hendriks RW,Kool M.Dendritic Cell Subsets in Asthma:Impaired Tolerance or Exaggerated Inflammation?[J].Front Immunol,2017,8:941.
[13]宋佳,尹月,王丹,等.树突状细胞在自身免疫性疾病中的作用[J].细胞与分子免疫学杂志,2015,31(5):708-712.
[14]刘美璇,陈小东,等.树突状细胞在支气管哮喘中的作用研究进展[J].国际呼吸杂志,2010,30(15):179-182.
[15]Pichavant M,Charbonnier AS,Taront S,et al.Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment[J].J Allergy Clin Immunol,2005,115(4):771-778.
[16]Barnes PJ.Immunology of asthma and chronic obstructive pulmonary disease[J].Nat Rev Immunol,2008,8(3):183-192.
[17]Lin R,Choi YH,Zidar DA,et al.β-Arrestin-2-Dependent Signaling Promotes CCR4-mediated Chemotaxis of Murine T-Helper Type 2Cells[J].Am J Respir Cell Mol Biol,2018,58(6):745-755.
[18]Fainaru O,Shseyov D,Hantisteanu S,et al.Accelerated chemokine receptor 7-mediated dendritic cell migration in Runx3 knockout mice and the spontaneous development of asthma-like disease[J].Proc Natl Acad Sci U S A,2005,102(30):10598-10603.
[19]Otero K,Vecchi A,Hirsch E,et al.Nonredundant role of CCRL2 in lung dendritic cell trafficking[J].Blood,2010,116(16):2942-2949.
[20]Nakano H,Free ME,Whitehead GS,et al.Pulmonary CD103(+)dendritic cells prime Th2 responses to inhaled allergens[J].Mucosal Immunol,2012,5(1):53-65.
[21]李俊奇,罗征秀.CD103+树突状细胞与慢性免疫性炎症疾病研究进展[J].儿科药学杂志,2016,22(2):49-52.
[22]万梦智,许飞.树突状细胞在支气管哮喘中的研究进展[J].中华肺部疾病杂志(连续型电子期刊),2013,6(4):46-49.
[23]Hirose K,Iwata A,Tamachi T,et al.Allergic airway inflammation:key players beyond the Th2 cell pathway[J].Immunol Rev,2017,278(1):145-161.
[24]Feng S,Zhang L,Bian XH,et al.Role of the TSLP-DC-OX40L pathway in asthma pathogenesis and airway inflammation in mice[J].Biochem Cell Biol,2018,96(3):306-316.
[25]Zhou LF,Zhang MS,Hu AH,et al.Selective blockade of NF-kappaBby novel mutated IkappaBalpha suppresses CD3/CD28-induced activation of memory CD4+T cells in asthma[J].Allergy,2010,63(5):509-517.
[26]Fallarino F,Grohmann U,You S,et al.The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells[J].J Immunol,2006,176(11):6752-6761.
[27]Chen W.IDO:more than an enzyme[J].Nat Immunol,2011,12(9):809-811.
[28]Sharma MD,Baban B,Chandler P,et al.Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase[J].J Clin Invest,2007,117(9):2570-2582.
[29]Raitala A,Karjalainen J,Oja SS,et al.Indoleamine 2,3-dioxygenase(IDO)activity is lower in atopic than in non-atopic individuals and is enhanced by environmental factors protecting from atopy[J].Mol Immunol,2006,43(7):1054-1056.
[30]Maneechotesuwan K,Supawita S,Kasetsinsombat K,et al.Sputum indoleamine-2,3-dioxygenase activity is increased in asthmatic airways by using inhaled corticosteroids[J].J Allergy Clin Immunol,2008,121(1):43-50.
[31]Yeh CH,Kuo CH,Yang SN,et al.Prostaglandin I2 analogs suppress tumor necrosis factorαproduction and the maturation of human monocyte-derived dendritic cells[J].J Investig Med,2011,59(7):1109-1115.
[32]Hayashi M,Koya T,Kawakami H,et al.A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice[J].Clin Exp Allergy,2010,40(2):317-326.
[33]陈娜,张双,高春燕.CRTH2受体拮抗剂对支气管哮喘树突状细胞功能的影响[J].免疫学杂志,2017,33(1):63-67.
[34]马光宇,吴雅琼,高玉环.树突状细胞免疫受体是治疗哮喘的新靶点[J].免疫学杂志,2014,30(4):282-287.
[35]虞念成,花奕.止咳平喘颗粒对婴幼儿哮喘患儿外周血树突细胞共刺激分子的影响分析[J].中国妇幼保健,2016,31(19):3984-3986.
[36]王丽新,赵霞,宋英.温阳补肾方对哮喘小鼠脾脏树突细胞的免疫调控机制研究[J].上海中医药杂志,2013,47(7):83-86.
[37]张丽,赵辉,孙义田,等.射干麻黄汤加味对哮喘小鼠气道炎症及树突细胞的影响[J].成都中医药大学学报,2014,37(2):42-43.
[38]李家伦,雷世庸.六味地黄汤对免疫功能低下小鼠的药理作用[J].中国医药指南,2008,6(16):13-14.
[39]黄婷,王孟清,罗银河,等.五虎汤对婴幼儿哮喘患儿外周血树突状细胞表面共刺激分子表达的影响[J].中国中西医结合杂志,2009,29(10):889-891.
[40]Tian Y,Li X,Li H,et al.Astragalus mongholicus regulate the Tolllike-receptor 4 meditated signal transduction of dendritic cells to restrain stomach cancer cells[J].Afr J Tradit Complement Altern Med,2014,11(3):92-96.
[41]Gu X,Zhou L,Du Q,et al.Hesperetin inhibits the maturation and function of monocyte-derived dendritic cells from patients with asthma[J].Mol Med Rep,2009,2(3):509-513.
[42]李红岩,张业清,肖庆龄,等.芹菜素对哮喘小鼠肺组织OX40表达、气道炎症和气道高反应性的影响[J].江苏医药,2016,42(6):621-624,封2.
[43]Hu Z,Jiao Q,Ding J,et al.Berberine induces dendritic cell apoptosis and has therapeutic potential for rheumatoid arthritis[J].Arthritis Rheum,2011,63(4):949-959.
[44]侯伟,刘海燕,杨旭东,等.氧化苦参碱对哮喘小鼠肺及脾脏组织中树突状细胞分布变化影响的研究[J].中国当代儿科杂志,2011,13(1):40-43.
[45]Chiang CY,Lee CC,Fan CK,et al.Osthole treatment ameliorates Th2-mediated allergic asthma and exerts immunomodulatory effects on dendritic cell maturation and function[J].Cell Mol Immunol,2017,14(1):1-13.
[46]王丽新,喻晓,石克华,等.穴位敷贴对哮喘大鼠肺脏树突状细胞表达的影响[J].上海中医药杂志,2010,44(8):74-76.
[47]许琬茹.邵氏“五针法”对哮喘模型大鼠DC及NF-κB表达影响的实验研究[D].郑州:河南中医学院,2012.
[48]杨昆,黄春红,王飞,等.冬病夏治中药敷贴对哮喘大鼠树突状细胞免疫功能的影响[J].四川中医,2016,34(6):49-52.