慢性阻塞性肺疾病免疫发病机制研究进展
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摘要
慢性阻塞性肺疾病(COPD)是呼吸内科的常见病和高发病,对患者健康的危害极大。COPD的发病与气道炎症、蛋白酶及抗蛋白酶失衡、氧化应激、自主神经功能失衡、营养不良、气候变化等机制有关,但具体机制尚不清楚。近年来,免疫因素成为COPD发病机制的研究热点,固有免疫、获得性免疫、T细胞介导的免疫失衡及自身免疫在COPD的发病机制中发挥着重要作用,免疫反应与慢性炎症相互作用,最终导致COPD的发生发展。免疫因素及免疫基因的介入可能进一步阐明COPD的发病机制,为寻找新的COPD靶点提供新的理论思路。
Chronic obstructive pulmonary disease( COPD) is a common disease of high incidence in respiratory medicine,and it is extremely harmful to health. The specific pathogenesis of COPD is still not very clear,while scholars generally believe that it is related to airway inflammation,protease and anti-protease imbalance,oxidative stress,autonomic dysfunction,malnutrition,climate change and other mechanisms. In recent years,immune factors have become a research hotspot in the pathogenesis of COPD. More and more studies have shown that innate immunity,acquired immunity,T cell-mediated immune imbalance and autoimmunity play an important role in the pathogenesis of COPD,and the immune response interacts with chronic inflammation,which ultimately leads to the occurrence and development of COPD. The involvement of immune factors and immune genes may further elucidate the pathogenesis of COPD,providing new theoretical ideas for finding new targets of COPD and.
Chronic obstructive pulmonary disease( COPD) is a common disease of high incidence in respiratory medicine,and it is extremely harmful to health. The specific pathogenesis of COPD is still not very clear,while scholars generally believe that it is related to airway inflammation,protease and anti-protease imbalance,oxidative stress,autonomic dysfunction,malnutrition,climate change and other mechanisms. In recent years,immune factors have become a research hotspot in the pathogenesis of COPD. More and more studies have shown that innate immunity,acquired immunity,T cell-mediated immune imbalance and autoimmunity play an important role in the pathogenesis of COPD,and the immune response interacts with chronic inflammation,which ultimately leads to the occurrence and development of COPD. The involvement of immune factors and immune genes may further elucidate the pathogenesis of COPD,providing new theoretical ideas for finding new targets of COPD and.
引文
[1]王蕾,杨汀,王辰.2017年版慢性阻塞性肺疾病诊断、处理和预防全球策略解读[J].中国临床医生杂志,2017,45(1):104-108.
[2]葛均波,徐永健,王辰,等.内科学[M].9版.北京:人民卫生出版社,2018:21.
[3]Lange P,Celli B,Agusti A,et al.Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease[J].N Engl JMed,2015,373(2):111-122.
[4]Robbins CS,Franco F,Mouded M,et al.Cigarette smoke exposure impairs dendritic cell maturation and T cell proliferation in thoracic lymph nodes of mice[J].J Immunol,2008,180(10):6623-6628.
[5]Lams BE,Sousa AR,Rees PJ,et al.Immunopathology of the small-airway submucosa in smokers with and without chronic obstructive pulmonary disease[J].Am J Respir Crit Care Med,1998,158(5 Pt 1):1518-1523.
[6]Feghali-Bostwick CA,Gadgil AS,Otterbein LE,et al.Autoantibodies in patients with chronic obstructive pulmonary disease[J].Am J Respir Crit Care Med,2008,177(2):156-163.
[7]李少军,韩冬,李满祥.肺部固有免疫力相关指标与COPD急性加重关系的研究进展[J].国际呼吸杂志,2014(15):1189-1192.
[8]Laucho-Contreras ME,Polverino F,Gupta K,et al.Protective role for club cell secretory protein-16(CC16)in the development of COPD[J].Eur Respir J,2015,45(6):1544-1556.
[9]Vestbo J,Edwards LD,Scanlon PD,et al.Changes in Forced Expiratory Volume in 1 Second over Time in COPD[J].N Engl JMed,2011,365(13):1184-1192.
[10]Eldeek SE,Makhlouf HA,Saleem TH,et al.Surfactant protein D,soluble intercellular adhesion molecule-1 and high-sensitivity Creactive protein as biomarkers of chronic obstructive pulmonary disease[J].Med Princ Pract,2013,22(5):469-474.
[11]Akiki Z,Fakih D,Jounblat R,et al.Surfactant protein D,a clinical biomarker for chronic obstructive pulmonary disease with excellent discriminant values[J].Exp Ther Med,2016,11(3):723-730.
[12]Parameswaran GI,Sethi S,Murphy TF.Effects of bacterial infection on airway antimicrobial peptides and proteins in COPD[J].Chest,2011,140(3):611-617.
[13]Sullivan AL,Dafforn T,Hiemstra PS,et al.Neutrophil elastase reduces secretion of secretory leukoproteinase inhibitor(SLPI)by lung epithelial cells:Role of charge of the proteinase-inhibitor complex[J].Respir Res,2008,9(1):60.
[14]张继华,古利明,高明,等.不同人群肺泡灌洗液中SIgA水平及其临床意义研究[J].云南医药,2012(2):121-123.
[15]Medzhitov R,Preston-Hurlburt P,Janeway Jr CA.A human homologue of the Drosophila Toll protein signals activation of adaptive immunity[J].Nature,1997,388(6640):394-397.
[16]Baines KJ,Simpson JL,Gibson PG.Innate immune responses are increased in chronic obstructive pulmonary disease[J].PLo SOne,2011,6(3):e18426.
[17]Tripathi PM,Kant S,Yadav RS,et al.Expression of Toll-like Receptor 2 and 4 in Peripheral Blood Neutrophil Cells from Patients with Chronic Obstructive Pulmonary Disease[J].Oman Med J,2017,32(6):477-485.
[18]芦晓帆.基于TLR4/NF-κB信号通路中医序贯治疗对“AE-COPD-危险窗”大鼠炎症反应调控机制[D].北京:北京中医药大学,2016.
[19]段敏超,钟小宁,何志义,等.CD4+白细胞介素-17+辅助性T细胞对香烟暴露小鼠肺部炎症及肺气肿的作用[J].中华结核和呼吸杂志,2011,34(4):259-264.
[20]林江涛.呼吸内科学科进展报告[M].北京:人民卫生出版社,2014:129-130.
[21]Maeno T,Houghton AM,Quintero PA,et al.CD8+T Cells are required for inflammation and destruction in cigarette smokeinduced emphysema in mice[J].J Immunol,2007,178(12):8090-8096.
[22]White L,Krishnan S,Strbo N,et al.Differential effects of IL-21and IL-15 on perforin expression,lysosomal degranulation,and proliferation in CD8 T cells of patients with human immunodeficiency virus-1(HIV)[J].Blood,2007,109(9):3873-3880.
[23]Shan M,Cheng HF,Song LZ,et al.Lung myeloid dendritic cells coordinately induce TH1 and TH17 responses in human emphysema[J].Sci Transl Med,2009,1(4):4-10.
[24]Moermans C,Heinen V,Nguyen M,et al.Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease[J].Cytokine,2011,56(2):298-304.
[25]Sullivan AK,Simonian PL,Falta MT,et al.Oligoclonal CD4+Tcells in the lungs of patients with severe emphysema[J].Am JRespir Crit Care Med,2005,172(5):590-596.
[26]Harrington LE,Hatton RD,Mangan PR,et al.Interleukin 17-producing CD4+effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages[J].Nat Immunol,2005,6(11):1123-1132.
[27]Park H,Li Z,Yang XO,et al.A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17[J].Nat Immunol,2005,6(11):1133-1141.
[28]蒋鲲,陈和斌,王莹,等.IL-17和TGF-β1在支气管哮喘患儿血清及支气管肺泡灌洗液中的变化及临床意义[J].中国当代儿科杂志,2013,15(8):604-608.
[29]Halwani R,Al-Muhsen S,Hamid Q.T helper 17 cells in airway diseases:From laboratory bench to bedside[J].Chest,2013,143(2):494-501.
[30]Riley CH,Jensen MK,Brimnes MK,et al.Increase in circulating CD4+CD25+Foxp3+T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-α[J].Blood,2011,118(8):2170-2173.
[31]王成阳,刘向国,彭青和,等.慢性阻塞性肺疾病的炎症反应与Foxp3、T-bet、GATA3表达失衡有关[J].细胞与分子免疫学杂志,2014,30(7):704-707,712.
[32]Hou J,Sun Y,Hao Y,et al.Imbalance between subpopulations of regulatory T cells in COPD[J].Thorax,2013,68(12):1131-1139.
[33]Chu S,Zhong X,Zhang J,et al.The expression of Foxp3 and RORgamma t in lung tissues from normal smokers and chronic obstructive pulmonary disease patients[J].Int Immunopharmacol,2011,11(11):1780-1788.
[34]Wang H,Ying H,Wang S,et al.Imbalance of peripheral blood Th17 and Treg responses in patients with chronic obstructive pulmonary disease[J].Clin Respir J,2014,9(3):330-341.
[35]Yokota S,Imagawa T,Mori M,et al.Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis:A randomised,double-blind,placebo-controlled,withdrawal phaseⅢtrial[J].Lancet,2008,371(9617):998-1006.
[36]Lee SH,Goswami S,Grudo A,et al.Antielastin autoimmunity in tobacco smoking-induced emphysema[J].Nat Med,2007,13(5):567-569.
[37]Rinaldi M,An L,Heulens N,et al.Antielastin B-cell and T-cell immunity in patients with chronic obstructive pulmonary disease[J].Thorax,2012,67(8):694-700.
[38]Cheng G,Zhang N,Wang Y,et al.Antibodies of Ig G,Ig A and Ig M against Human Bronchial Epithelial Cell in Patients with Chronic Obstructive Pulmonary Disease[J].Clin Lab,2016,62(6):1101-1108.
[39]Xiong Y,Gao S,Luo G,et al.Increased Circulating Autoantibodies Levels of Ig G,Ig A,Ig M Against Cytokeratin 18 and Cytokeratin19 in Chronic Obstructive Pulmonary Disease[J].Arch Med Res,2017,48(1):79-87.
[2]葛均波,徐永健,王辰,等.内科学[M].9版.北京:人民卫生出版社,2018:21.
[3]Lange P,Celli B,Agusti A,et al.Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease[J].N Engl JMed,2015,373(2):111-122.
[4]Robbins CS,Franco F,Mouded M,et al.Cigarette smoke exposure impairs dendritic cell maturation and T cell proliferation in thoracic lymph nodes of mice[J].J Immunol,2008,180(10):6623-6628.
[5]Lams BE,Sousa AR,Rees PJ,et al.Immunopathology of the small-airway submucosa in smokers with and without chronic obstructive pulmonary disease[J].Am J Respir Crit Care Med,1998,158(5 Pt 1):1518-1523.
[6]Feghali-Bostwick CA,Gadgil AS,Otterbein LE,et al.Autoantibodies in patients with chronic obstructive pulmonary disease[J].Am J Respir Crit Care Med,2008,177(2):156-163.
[7]李少军,韩冬,李满祥.肺部固有免疫力相关指标与COPD急性加重关系的研究进展[J].国际呼吸杂志,2014(15):1189-1192.
[8]Laucho-Contreras ME,Polverino F,Gupta K,et al.Protective role for club cell secretory protein-16(CC16)in the development of COPD[J].Eur Respir J,2015,45(6):1544-1556.
[9]Vestbo J,Edwards LD,Scanlon PD,et al.Changes in Forced Expiratory Volume in 1 Second over Time in COPD[J].N Engl JMed,2011,365(13):1184-1192.
[10]Eldeek SE,Makhlouf HA,Saleem TH,et al.Surfactant protein D,soluble intercellular adhesion molecule-1 and high-sensitivity Creactive protein as biomarkers of chronic obstructive pulmonary disease[J].Med Princ Pract,2013,22(5):469-474.
[11]Akiki Z,Fakih D,Jounblat R,et al.Surfactant protein D,a clinical biomarker for chronic obstructive pulmonary disease with excellent discriminant values[J].Exp Ther Med,2016,11(3):723-730.
[12]Parameswaran GI,Sethi S,Murphy TF.Effects of bacterial infection on airway antimicrobial peptides and proteins in COPD[J].Chest,2011,140(3):611-617.
[13]Sullivan AL,Dafforn T,Hiemstra PS,et al.Neutrophil elastase reduces secretion of secretory leukoproteinase inhibitor(SLPI)by lung epithelial cells:Role of charge of the proteinase-inhibitor complex[J].Respir Res,2008,9(1):60.
[14]张继华,古利明,高明,等.不同人群肺泡灌洗液中SIgA水平及其临床意义研究[J].云南医药,2012(2):121-123.
[15]Medzhitov R,Preston-Hurlburt P,Janeway Jr CA.A human homologue of the Drosophila Toll protein signals activation of adaptive immunity[J].Nature,1997,388(6640):394-397.
[16]Baines KJ,Simpson JL,Gibson PG.Innate immune responses are increased in chronic obstructive pulmonary disease[J].PLo SOne,2011,6(3):e18426.
[17]Tripathi PM,Kant S,Yadav RS,et al.Expression of Toll-like Receptor 2 and 4 in Peripheral Blood Neutrophil Cells from Patients with Chronic Obstructive Pulmonary Disease[J].Oman Med J,2017,32(6):477-485.
[18]芦晓帆.基于TLR4/NF-κB信号通路中医序贯治疗对“AE-COPD-危险窗”大鼠炎症反应调控机制[D].北京:北京中医药大学,2016.
[19]段敏超,钟小宁,何志义,等.CD4+白细胞介素-17+辅助性T细胞对香烟暴露小鼠肺部炎症及肺气肿的作用[J].中华结核和呼吸杂志,2011,34(4):259-264.
[20]林江涛.呼吸内科学科进展报告[M].北京:人民卫生出版社,2014:129-130.
[21]Maeno T,Houghton AM,Quintero PA,et al.CD8+T Cells are required for inflammation and destruction in cigarette smokeinduced emphysema in mice[J].J Immunol,2007,178(12):8090-8096.
[22]White L,Krishnan S,Strbo N,et al.Differential effects of IL-21and IL-15 on perforin expression,lysosomal degranulation,and proliferation in CD8 T cells of patients with human immunodeficiency virus-1(HIV)[J].Blood,2007,109(9):3873-3880.
[23]Shan M,Cheng HF,Song LZ,et al.Lung myeloid dendritic cells coordinately induce TH1 and TH17 responses in human emphysema[J].Sci Transl Med,2009,1(4):4-10.
[24]Moermans C,Heinen V,Nguyen M,et al.Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease[J].Cytokine,2011,56(2):298-304.
[25]Sullivan AK,Simonian PL,Falta MT,et al.Oligoclonal CD4+Tcells in the lungs of patients with severe emphysema[J].Am JRespir Crit Care Med,2005,172(5):590-596.
[26]Harrington LE,Hatton RD,Mangan PR,et al.Interleukin 17-producing CD4+effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages[J].Nat Immunol,2005,6(11):1123-1132.
[27]Park H,Li Z,Yang XO,et al.A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17[J].Nat Immunol,2005,6(11):1133-1141.
[28]蒋鲲,陈和斌,王莹,等.IL-17和TGF-β1在支气管哮喘患儿血清及支气管肺泡灌洗液中的变化及临床意义[J].中国当代儿科杂志,2013,15(8):604-608.
[29]Halwani R,Al-Muhsen S,Hamid Q.T helper 17 cells in airway diseases:From laboratory bench to bedside[J].Chest,2013,143(2):494-501.
[30]Riley CH,Jensen MK,Brimnes MK,et al.Increase in circulating CD4+CD25+Foxp3+T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-α[J].Blood,2011,118(8):2170-2173.
[31]王成阳,刘向国,彭青和,等.慢性阻塞性肺疾病的炎症反应与Foxp3、T-bet、GATA3表达失衡有关[J].细胞与分子免疫学杂志,2014,30(7):704-707,712.
[32]Hou J,Sun Y,Hao Y,et al.Imbalance between subpopulations of regulatory T cells in COPD[J].Thorax,2013,68(12):1131-1139.
[33]Chu S,Zhong X,Zhang J,et al.The expression of Foxp3 and RORgamma t in lung tissues from normal smokers and chronic obstructive pulmonary disease patients[J].Int Immunopharmacol,2011,11(11):1780-1788.
[34]Wang H,Ying H,Wang S,et al.Imbalance of peripheral blood Th17 and Treg responses in patients with chronic obstructive pulmonary disease[J].Clin Respir J,2014,9(3):330-341.
[35]Yokota S,Imagawa T,Mori M,et al.Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis:A randomised,double-blind,placebo-controlled,withdrawal phaseⅢtrial[J].Lancet,2008,371(9617):998-1006.
[36]Lee SH,Goswami S,Grudo A,et al.Antielastin autoimmunity in tobacco smoking-induced emphysema[J].Nat Med,2007,13(5):567-569.
[37]Rinaldi M,An L,Heulens N,et al.Antielastin B-cell and T-cell immunity in patients with chronic obstructive pulmonary disease[J].Thorax,2012,67(8):694-700.
[38]Cheng G,Zhang N,Wang Y,et al.Antibodies of Ig G,Ig A and Ig M against Human Bronchial Epithelial Cell in Patients with Chronic Obstructive Pulmonary Disease[J].Clin Lab,2016,62(6):1101-1108.
[39]Xiong Y,Gao S,Luo G,et al.Increased Circulating Autoantibodies Levels of Ig G,Ig A,Ig M Against Cytokeratin 18 and Cytokeratin19 in Chronic Obstructive Pulmonary Disease[J].Arch Med Res,2017,48(1):79-87.
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