【《支气管哮喘流行病学及发病机制研究文献综述》5900字】

支气管哮喘流行病学及发病机制研究文献综述目录TOC\o"1-3"\h\u22958支气管哮喘流行病学及发病机制研究文献综述 1124251.1.1流行病学 1166431.1.2哮喘的发病机制 2187911.1.3哮喘急性发作的诱因 3225121.1.4哮喘表型 430119参考文献 6哮喘是一种慢性气道炎症性疾病，临床上主要表现为反复发作的气急、喘息、咳嗽、胸闷，同时伴有AHR和可逆的气流受限。随着病程延长，支气管哮喘最终可导致气道重塑。流行病学随着社会及经济的发展，以及生活方式城市化，近几十年来，哮喘发病在世界各地的儿童和成人中都越来越普遍，哮喘的患病率逐年增加。2015年全球疾病负担研究[GlobalBurdenofDisease(GBD)study]结果显示，全球哮喘患者达3.58亿，患病率较1990年增加了12.6%ADDINEN.CITE<EndNote><Cite><Year>2017</Year><RecNum>3</RecNum><DisplayText>[1]</DisplayText><record><rec-number>3</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617888288">3</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors></contributors><titles><title>Global,regional,andnationaldeaths,prevalence,disability-adjustedlifeyears,andyearslivedwithdisabilityforchronicobstructivepulmonarydiseaseandasthma,1990-2015:asystematicanalysisfortheGlobalBurdenofDiseaseStudy2015</title><secondary-title>LancetRespirMed</secondary-title></titles><periodical><full-title>LancetRespirMed</full-title></periodical><pages>691-706</pages><volume>5</volume><number>9</number><edition>2017/08/22</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged,80andover</keyword><keyword>Asthma/*epidemiology</keyword><keyword>BayesTheorem</keyword><keyword>CauseofDeath</keyword><keyword>Female</keyword><keyword>GlobalBurdenofDisease/*statistics&numericaldata</keyword><keyword>GlobalHealth/*statistics&numericaldata</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Male</keyword><keyword>MiddleAged</keyword><keyword>Prevalence</keyword><keyword>PulmonaryDisease,ChronicObstructive/*epidemiology</keyword><keyword>*Quality-AdjustedLifeYears</keyword><keyword>RegressionAnalysis</keyword><keyword>RiskFactors</keyword></keywords><dates><year>2017</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>2213-2600(Print) 2213-2600</isbn><accession-num>28822787</accession-num><urls></urls><custom2>PMC5573769</custom2><electronic-resource-num>10.1016/s2213-2600(17)30293-x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[1]。一项时间跨越1992年-2010年的综述分析，对亚洲9个国家的哮喘患病率进行总结，哮喘患病率在0.7%-11.9%（平均不超过5%），且亚洲平均患病率也呈上升趋势ADDINEN.CITE<EndNote><Cite><Author>Song</Author><Year>2014</Year><RecNum>18</RecNum><DisplayText>[16]</DisplayText><record><rec-number>18</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617893759">18</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Song,W.J.</author><author>Kang,M.G.</author><author>Chang,Y.S.</author><author>Cho,S.H.</author></authors></contributors><auth-address>DepartmentofInternalMedicine,SeoulNationalUniversityCollegeofMedicine,Seoul110-799,Korea.;InstituteofAllergyandClinicalImmunology,SeoulNationalUniversityMedicalResearchCenter,Seoul110-799,Korea. DepartmentofInternalMedicine,SeoulNationalUniversityCollegeofMedicine,Seoul110-799,Korea.;InstituteofAllergyandClinicalImmunology,SeoulNationalUniversityMedicalResearchCenter,Seoul110-799,Korea.;DepartmentofInternalMedicine,SeoulNationalUniversityBundangHospital,Seongnam463-707,Korea.</auth-address><titles><title>EpidemiologyofadultasthmainAsia:towardabetterunderstanding</title><secondary-title>AsiaPacAllergy</secondary-title></titles><periodical><full-title>AsiaPacAllergy</full-title></periodical><pages>75-85</pages><volume>4</volume><number>2</number><edition>2014/05/09</edition><keywords><keyword>Asia</keyword><keyword>Asthma</keyword><keyword>Epidemiology</keyword><keyword>Review</keyword></keywords><dates><year>2014</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>2233-8276(Print) 2233-8276</isbn><accession-num>24809012</accession-num><urls></urls><custom2>PMC4005350</custom2><electronic-resource-num>10.5415/apallergy.205</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[16]。世界卫生组织在2002年-2003年对70个国家哮喘患病率进行调查，研究发现全球哮喘患病率在这些调查国家或地区相差多达21倍，其中医生诊断的成人哮喘、经过临床治疗的哮喘、喘息症状的全球患病率分别为4.3％，4.5％和8.6％ADDINEN.CITE<EndNote><Cite><Author>To</Author><Year>2012</Year><RecNum>5</RecNum><DisplayText>[3]</DisplayText><record><rec-number>5</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617889137">5</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>To,T.</author><author>Stanojevic,S.</author><author>Moores,G.</author><author>Gershon,A.S.</author><author>Bateman,E.D.</author><author>Cruz,A.A.</author><author>Boulet,L.P.</author></authors></contributors><auth-address>ChildHealthEvaluativeSciences,TheHospitalforSickChildren,Toronto,Ontario,Canada.teresa.to@sickkids.ca</auth-address><titles><title>Globalasthmaprevalenceinadults:findingsfromthecross-sectionalworldhealthsurvey</title><secondary-title>BMCPublicHealth</secondary-title></titles><periodical><full-title>BMCPublicHealth</full-title></periodical><pages>204</pages><volume>12</volume><edition>2012/03/21</edition><keywords><keyword>Adult</keyword><keyword>Asthma/*epidemiology</keyword><keyword>Australia/epidemiology</keyword><keyword>Cross-SectionalStudies</keyword><keyword>Female</keyword><keyword>HealthSurveys</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>WorldHealthOrganization</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar19</date></pub-dates></dates><isbn>1471-2458</isbn><accession-num>22429515</accession-num><urls></urls><custom2>PMC3353191</custom2><electronic-resource-num>10.1186/1471-2458-12-204</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[3]。对全世界46个国家进行死亡率的分析，结果显示全球哮喘死亡率从1993年到2006年有所降低，从每100000人中0.44例死亡（90％CI0.39-0.48）降低至每100000人中0.19例死亡（0.18-0.21）；但在2006到2012年，尽管世界上某些国家和地区明显减少，全球哮喘死亡率没有明显变化ADDINEN.CITE<EndNote><Cite><Author>Ebmeier</Author><Year>2017</Year><RecNum>19</RecNum><DisplayText>[17]</DisplayText><record><rec-number>19</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617893951">19</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ebmeier,S.</author><author>Thayabaran,D.</author><author>Braithwaite,I.</author><author>Bénamara,C.</author><author>Weatherall,M.</author><author>Beasley,R.</author></authors></contributors><auth-address>MedicalResearchInstituteofNewZealand,Wellington,NewZealand. DepartmentofMedicine,UniversityofOtagoWellington,Wellington,NewZealand. MedicalResearchInstituteofNewZealand,Wellington,NewZealand.Electronicaddress:richard.beasley@mrinz.ac.nz.</auth-address><titles><title>Trendsininternationalasthmamortality:analysisofdatafromtheWHOMortalityDatabasefrom46countries(1993-2012)</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>935-945</pages><volume>390</volume><number>10098</number><edition>2017/08/12</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Asthma/*mortality</keyword><keyword>CauseofDeath</keyword><keyword>Child</keyword><keyword>Child,Preschool</keyword><keyword>*DataInterpretation,Statistical</keyword><keyword>*Databases,Factual</keyword><keyword>Female</keyword><keyword>GlobalHealth</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Mortality/*trends</keyword><keyword>*WorldHealthOrganization</keyword><keyword>YoungAdult</keyword></keywords><dates><year>2017</year><pub-dates><date>Sep2</date></pub-dates></dates><isbn>0140-6736</isbn><accession-num>28797514</accession-num><urls></urls><electronic-resource-num>10.1016/s0140-6736(17)31448-4</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[17]。抽样方法及哮喘定义差异导致了中国哮喘流行病学调查的结果差异。2010年2月至2012年8月在中国大陆进行“全国支气管哮喘患病情况及相关危险因素流行病学调查”，基于病史和肺功能检查进行哮喘诊断，通过多阶段整群随机选出样本人群，进行入户问卷调查，研究结果显示我国14岁以上临床诊断哮喘患病率为1.24%，新诊断的哮喘患者占25.61%ADDINEN.CITEADDINEN.CITE.DATA[18]。在另一项全国横断面中国肺健康研究[ChinaPulmonaryHealth(CPH)study]，采用多阶段分层抽样方法，哮喘诊断根据患者自我报告的病史或前12个月的喘息症状确定，所有参与者均通过标准哮喘问卷进行评估，结果显示中国20岁以上人群总体哮喘患病率为4.2%（95%CI，3.1-5.6）ADDINEN.CITEADDINEN.CITE.DATA[2]。而中国一项关于评估儿童哮喘患病率及亚组，包括性别，年龄和区域的荟萃分析研究，纳入了1988年至2014年在中国大陆发布的117项研究，表明儿童哮喘的总体当前患病率为2.112％，终生患病率稍高，为2.502％，并且男性和女性患者的患病率差异显著ADDINEN.CITE<EndNote><Cite><Author>Guo</Author><Year>2018</Year><RecNum>21</RecNum><DisplayText>[19]</DisplayText><record><rec-number>21</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617895299">21</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Guo,X.</author><author>Li,Z.</author><author>Ling,W.</author><author>Long,J.</author><author>Su,C.</author><author>Li,J.</author><author>Liang,S.</author><author>Su,L.</author></authors></contributors><auth-address>FromtheDepartmentofEpidemiology,SchoolofPublicHealth,GuangxiMedicalUniversity,Nanning,Guangxi,China. DepartmentofRespiratoryMedicine,TheFirstAffiliatedHospitalofGuangxiMedicalUniversity,Nanning,Guangxi,China.</auth-address><titles><title>EpidemiologyofchildhoodasthmainmainlandChina(1988-2014):Ameta-analysis</title><secondary-title>AllergyAsthmaProc</secondary-title></titles><periodical><full-title>AllergyAsthmaProc</full-title></periodical><pages>15-29</pages><volume>39</volume><number>3</number><edition>2018/04/20</edition><keywords><keyword>*AgeFactors</keyword><keyword>Asthma/*epidemiology</keyword><keyword>Child</keyword><keyword>Child,Preschool</keyword><keyword>China/epidemiology</keyword><keyword>Cross-SectionalStudies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>RiskFactors</keyword><keyword>*SexFactors</keyword></keywords><dates><year>2018</year><pub-dates><date>May1</date></pub-dates></dates><isbn>1088-5412(Print) 1088-5412</isbn><accession-num>29669661</accession-num><urls></urls><custom2>PMC5911512</custom2><electronic-resource-num>10.2500/aap.2018.39.4131</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[19]。哮喘的长期发作，会导致气道重构，肺功能进行性下降，影响患者的生活质量及日常工作，增加了患者致残可能及公共卫生和经济负担。美国研究分析估计未控制哮喘相关的20年直接总成本为3,006亿美元，加上间接成本，总经济负担将为9,635亿美元ADDINEN.CITEADDINEN.CITE.DATA[4]。尤其是伴有合并症及难治性哮喘耗费大量的医疗资源，造成巨大的医疗及经济负担ADDINEN.CITEADDINEN.CITE.DATA[5,6]。哮喘对患者造成的生活负担、以及对公共卫生及经济造成的巨大负担，使研究哮喘急性发作及加重的危险因素尤为重要。既往研究表明室外空气污染物暴露可增加新发哮喘发病率，提高哮喘患病率，与哮喘急性发作相关ADDINEN.CITEADDINEN.CITE.DATA[10]。进一步深入探讨空气污染与哮喘急性发作、及与不同表型哮喘的关系，从环境控制角度提出哮喘防治策略，具有重要的临床意义及临床应用价值。哮喘的发病机制哮喘是一种异质性疾病，具有多样的临床特征和不同的生物学标志物，其主要病因是基因-环境相互作用。目前哮喘的发病机制仍未完全阐明，主要是。包括气道炎症、气道高反应性、气道重构等，但其机制目前尚未完全明确。哮喘是一种与多基因有关的遗传倾向疾病。现已确定的与儿童和成人哮喘相关的遗传基因有：IL-33，IL1RL1（RecombinantInterleukin1ReceptorLikeProtein1，白介素1受体样蛋白1）/IL18R1（Interleukin-18receptor1，白介素18受体1），HLA-DQ（humanleukocyteantigen，人类白细胞抗原），SMAD3（mothersagainstDPPhomolog3，母亲DPP同源物3）和IL2RB9（Interleukin-2receptorbeta，白细胞介素-2受体β链9），这些基因多态性与17q21号染色体位点（包括基因ZPBP2，GSDMB和orMDL3）存在关联。研究表明这些基因在机体主要影响两方面，其一为先天性和适应性免疫反应功能，其二为上皮屏障功能，提示这些功能异常与哮喘发生发展相关ADDINEN.CITEADDINEN.CITE.DATA[20,21]。另一项针对Th2型儿童哮喘研究，哮喘易感基因DENND1B通过控制TCR（Tcellreceptor，T细胞抗原受体）内在化来控制Th2细胞因子的生成，这为DENND1B在哮喘发病中的作用奠定了分子基础ADDINEN.CITE<EndNote><Cite><Author>Godar</Author><Year>2016</Year><RecNum>24</RecNum><DisplayText>[22]</DisplayText><record><rec-number>24</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617895626">24</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Godar,M.</author><author>Lambrecht,B.N.</author></authors></contributors><auth-address>VIBInflammationResearchCenter(IRC),GentUniversity,Zwijnaarde9052B,Belgium;argenx,Technologiepark30,9052Zwijnaarde,Belgium. VIBInflammationResearchCenter(IRC),GentUniversity,Zwijnaarde9052B,Belgium;DepartmentofRespiratoryMedicine,GentUniversityHospital,Gent9000,Belgium;DepartmentofPulmonaryMedicine,ErasmusMC,Rotterdam3015GE,theNetherlands.Electronicaddress:bart.lambrecht@ugent.be.</auth-address><titles><title>ANewaDENNDumtoGeneticsofChildhoodAsthma</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>11-13</pages><volume>164</volume><number>1-2</number><edition>2016/01/16</edition><keywords><keyword>Animals</keyword><keyword>Asthma/*immunology</keyword><keyword>DeathDomainReceptorSignalingAdaptorProteins/*metabolism</keyword><keyword>Female</keyword><keyword>GuanineNucleotideExchangeFactors/*metabolism</keyword><keyword>Humans</keyword><keyword>Receptors,Antigen,T-Cell/*metabolism</keyword><keyword>*SignalTransduction</keyword><keyword>Th2Cells/*immunology</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan14</date></pub-dates></dates><isbn>0092-8674</isbn><accession-num>26771480</accession-num><urls></urls><electronic-resource-num>10.1016/j.cell.2015.12.045</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[22]。根据气道-免疫炎症反应机制及相应的临床表现、生物学标志物可将哮喘划分为各种表型。划分标准不同，哮喘表型分类存在差异。根据诱导痰中嗜酸性粒细胞所占百分比，哮喘可分为嗜酸性粒细胞哮喘（分为过敏与非过敏性哮喘）、非嗜酸性细胞哮喘以及混合细胞性哮喘。非嗜酸性细胞哮喘分为2类，其中Paucigranulocytic哮喘主要特征是没有气道嗜酸性粒细胞炎症和中性粒细胞炎症，但伴有气道上皮的损害；另一类则是中性粒细胞性哮喘ADDINEN.CITE<EndNote><Cite><Author>Papi</Author><Year>2018</Year><RecNum>9</RecNum><DisplayText>[7]</DisplayText><record><rec-number>9</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617889996">9</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Papi,A.</author><author>Brightling,C.</author><author>Pedersen,S.E.</author><author>Reddel,H.K.</author></authors></contributors><auth-address>ResearchCentreonAsthmaandCOPD,DepartmentofMedicalSciences,UniversityofFerrara,Ferrara,Italy.Electronicaddress:ppa@unife.it. InstituteforLungHealth,LeicesterNationalInstituteforHealthResearchBiomedicalResearchCentre,DepartmentofInfection,Immunity,andInflammation,UniversityofLeicesterandUniversityHospitalsofLeicesterNHSTrust,Leicester,UK. DepartmentofPaediatrics,UniversityofSouthernDenmark,KoldingHospital,Kolding,Denmark. ClinicalManagementGroupandNHMRCCentreofResearchExcellenceinSevereAsthma,WoolcockInstituteofMedicalResearch,UniversityofSydney,NSW,Australia.</auth-address><titles><title>Asthma</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>783-800</pages><volume>391</volume><number>10122</number><edition>2017/12/24</edition><keywords><keyword>Adult</keyword><keyword>Anti-AsthmaticAgents/therapeuticuse</keyword><keyword>Anti-InflammatoryAgents/therapeuticuse</keyword><keyword>*Asthma/diagnosis/etiology/therapy</keyword><keyword>Child</keyword><keyword>Humans</keyword><keyword>RespiratoryFunctionTests</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb24</date></pub-dates></dates><isbn>0140-6736</isbn><accession-num>29273246</accession-num><urls></urls><electronic-resource-num>10.1016/s0140-6736(17)33311-1</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[7]。过敏性哮喘患者接触环境中的致敏原，致敏原通过气道上皮细胞，在胸腺基质淋巴细胞生成素、IL25、IL-33等因子的刺激下激活树突状细胞摄取、处理致敏原，并呈递给CD4T淋巴细胞，促进Th2细胞分化趋势，Th2型细胞因子生成增多，主要为IL-5，IL-4和IL-13ADDINEN.CITE<EndNote><Cite><Author>Papi</Author><Year>2018</Year><RecNum>9</RecNum><DisplayText>[7]</DisplayText><record><rec-number>9</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617889996">9</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Papi,A.</author><author>Brightling,C.</author><author>Pedersen,S.E.</author><author>Reddel,H.K.</author></authors></contributors><auth-address>ResearchCentreonAsthmaandCOPD,DepartmentofMedicalSciences,UniversityofFerrara,Ferrara,Italy.Electronicaddress:ppa@unife.it. InstituteforLungHealth,LeicesterNationalInstituteforHealthResearchBiomedicalResearchCentre,DepartmentofInfection,Immunity,andInflammation,UniversityofLeicesterandUniversityHospitalsofLeicesterNHSTrust,Leicester,UK. DepartmentofPaediatrics,UniversityofSouthernDenmark,KoldingHospital,Kolding,Denmark. ClinicalManagementGroupandNHMRCCentreofResearchExcellenceinSevereAsthma,WoolcockInstituteofMedicalResearch,UniversityofSydney,NSW,Australia.</auth-address><titles><title>Asthma</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>783-800</pages><volume>391</volume><number>10122</number><edition>2017/12/24</edition><keywords><keyword>Adult</keyword><keyword>Anti-AsthmaticAgents/therapeuticuse</keyword><keyword>Anti-InflammatoryAgents/therapeuticuse</keyword><keyword>*Asthma/diagnosis/etiology/therapy</keyword><keyword>Child</keyword><keyword>Humans</keyword><keyword>RespiratoryFunctionTests</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb24</date></pub-dates></dates><isbn>0140-6736</isbn><accession-num>29273246</accession-num><urls></urls><electronic-resource-num>10.1016/s0140-6736(17)33311-1</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[7]。IL-5是嗜酸性粒细胞存活和成熟的关键细胞因子；IL-4是驱动B细胞同种型转换和促进IgE合成的重要细胞因子，IgE与肥大细胞膜表面高亲和力IgE受体结合，促使肥大细胞活化ADDINEN.CITE<EndNote><Cite><Author>Papi</Author><Year>2018</Year><RecNum>9</RecNum><DisplayText>[7]</DisplayText><record><rec-number>9</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617889996">9</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Papi,A.</author><author>Brightling,C.</author><author>Pedersen,S.E.</author><author>Reddel,H.K.</author></authors></contributors><auth-address>ResearchCentreonAsthmaandCOPD,DepartmentofMedicalSciences,UniversityofFerrara,Ferrara,Italy.Electronicaddress:ppa@unife.it. InstituteforLungHealth,LeicesterNationalInstituteforHealthResearchBiomedicalResearchCentre,DepartmentofInfection,Immunity,andInflammation,UniversityofLeicesterandUniversityHospitalsofLeicesterNHSTrust,Leicester,UK. DepartmentofPaediatrics,UniversityofSouthernDenmark,KoldingHospital,Kolding,Denmark. ClinicalManagementGroupandNHMRCCentreofResearchExcellenceinSevereAsthma,WoolcockInstituteofMedicalResearch,UniversityofSydney,NSW,Australia.</auth-address><titles><title>Asthma</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>783-800</pages><volume>391</volume><number>10122</number><edition>2017/12/24</edition><keywords><keyword>Adult</keyword><keyword>Anti-AsthmaticAgents/therapeuticuse</keyword><keyword>Anti-InflammatoryAgents/therapeuticuse</keyword><keyword>*Asthma/diagnosis/etiology/therapy</keyword><keyword>Child</keyword><keyword>Humans</keyword><keyword>RespiratoryFunctionTests</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb24</date></pub-dates></dates><isbn>0140-6736</isbn><accession-num>29273246</accession-num><urls></urls><electronic-resource-num>10.1016/s0140-6736(17)33311-1</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[7]。非过敏性哮喘分为中性粒细胞性哮喘和非过敏性嗜酸性粒细胞哮喘。研究表明Th17型细胞因子IL-17A和IL-17F与嗜中性气道炎症的发生有关ADDINEN.CITEADDINEN.CITE.DATA[8]，其在中性粒细胞性哮喘中发挥关键作用。气道中性粒细胞增多与肺功能低下、空气滞留增多、气道壁增厚（通过计算机断层扫描测量）和基质金属蛋白酶表达增多有关ADDINEN.CITEADDINEN.CITE.DATA[23-25]。持续的局部气道嗜中性炎症最终导致气道重构。非过敏性嗜酸性粒细胞性哮喘中，上皮细胞被污染物和微生物破坏后释放PG-D2以及上皮来源的胸腺基质淋巴细胞生成素、IL-33、IL-25，进一步促进IL-5和IL-13的生成，导致嗜酸性粒细胞炎症ADDINEN.CITE<EndNote><Cite><Author>Papi</Author><Year>2018</Year><RecNum>9</RecNum><DisplayText>[7]</DisplayText><record><rec-number>9</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617889996">9</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Papi,A.</author><author>Brightling,C.</author><author>Pedersen,S.E.</author><author>Reddel,H.K.</author></authors></contributors><auth-address>ResearchCentreonAsthmaandCOPD,DepartmentofMedicalSciences,UniversityofFerrara,Ferrara,Italy.Electronicaddress:ppa@unife.it. InstituteforLungHealth,LeicesterNationalInstituteforHealthResearchBiomedicalResearchCentre,DepartmentofInfection,Immunity,andInflammation,UniversityofLeicesterandUniversityHospitalsofLeicesterNHSTrust,Leicester,UK. DepartmentofPaediatrics,UniversityofSouthernDenmark,KoldingHospital,Kolding,Denmark. ClinicalManagementGroupandNHMRCCentreofResearchExcellenceinSevereAsthma,WoolcockInstituteofMedicalResearch,UniversityofSydney,NSW,Australia.</auth-address><titles><title>Asthma</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>783-800</pages><volume>391</volume><number>10122</number><edition>2017/12/24</edition><keywords><keyword>Adult</keyword><keyword>Anti-AsthmaticAgents/therapeuticuse</keyword><keyword>Anti-InflammatoryAgents/therapeuticuse</keyword><keyword>*Asthma/diagnosis/etiology/therapy</keyword><keyword>Child</keyword><keyword>Humans</keyword><keyword>RespiratoryFunctionTests</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb24</date></pub-dates></dates><isbn>0140-6736</isbn><accession-num>29273246</accession-num><urls></urls><electronic-resource-num>10.1016/s0140-6736(17)33311-1</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[7]。混合细胞性哮喘，即变态反应依赖性和非变态反应机制驱动嗜酸性炎症和非嗜酸性炎症可以共同发生，导致混合性粒细胞性炎症。这类哮喘目前机制不明，可能与Treg的失衡有关，有研究显示严重哮喘中编码IL-4受体α链(Il4ra(R576))的基因可促进外周的Treg(iTreg)细胞向Th17细胞转化ADDINEN.CITEADDINEN.CITE.DATA[26]。关于气道高反应性的机制目前有以下几种。第一，受到外界刺激时，气道高反应性表现为气道平滑肌(ASM)收缩增加/功能障碍。ASM中的肥大细胞在气道高反应性中起关键作用，其通过释放包括组胺，前列腺素D2(PG-D2)和半胱氨酸发挥特定作用ADDINEN.CITE<EndNote><Cite><Author>Brightling</Author><Year>2002</Year><RecNum>29</RecNum><DisplayText>[27]</DisplayText><record><rec-number>29</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617896430">29</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Brightling,C.E.</author><author>Bradding,P.</author><author>Symon,F.A.</author><author>Holgate,S.T.</author><author>Wardlaw,A.J.</author><author>Pavord,I.D.</author></authors></contributors><auth-address>DivisionofRespiratoryMedicine,InstituteforLungHealth,Leicester-WarwickMedicalSchoolandUniversityHospitalsofLeicester,Leicester,UnitedKingdom.</auth-address><titles><title>Mast-cellinfiltrationofairwaysmoothmuscleinasthma</title><secondary-title>NEnglJMed</secondary-title></titles><periodical><full-title>NEnglJMed</full-title></periodical><pages>1699-705</pages><volume>346</volume><number>22</number><edition>2002/05/31</edition><keywords><keyword>Adult</keyword><keyword>Asthma/*immunology/physiopathology</keyword><keyword>BasementMembrane/pathology</keyword><keyword>Biopsy</keyword><keyword>Bronchi/*immunology/pathology</keyword><keyword>Bronchitis/*immunology</keyword><keyword>Eosinophilia/immunology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>*MastCells</keyword><keyword>MiddleAged</keyword><keyword>Muscle,Smooth/*immunology/pathology</keyword><keyword>ReferenceValues</keyword></keywords><dates><year>2002</year><pub-dates><date>May30</date></pub-dates></dates><isbn>0028-4793</isbn><accession-num>12037149</accession-num><urls></urls><electronic-resource-num>10.1056/NEJMoa012705</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[27]。第二，氧化应激和吸入环境污染物等刺激因素也会增加气道ASM收缩，引起AHRADDINEN.CITEADDINEN.CITE.DATA[28]。第三，在哮喘中，气道平滑肌过度收缩，与机械转导有关，机械应激的支气管上皮细胞是分泌的组织因子的来源，而外泌体可能是组织因子信号的关键载体ADDINEN.CITEADDINEN.CITE.DATA[29]。气道重塑是复杂的宿主与环境长期相互作用的结果，是导致气流受限的重要因素。长期的氧化应激损伤、气道慢性炎症、气道高反应性会导致气道重塑。气道重塑有各方面的表现，比如上皮屏障功能损伤，纤毛运动障碍，网状薄层和网状基底膜增厚，杯状细胞增生ADDINEN.CITE<EndNote><Cite><Author>Brightling</Author><Year>2002</Year><RecNum>29</RecNum><DisplayText>[27]</DisplayText><record><rec-number>29</rec-number><foreign-keys><keyapp="EN"db-id="s00p0vz9jsrdroet0p95r9ag2w0zwwrwvxva"timestamp="1617896430">29</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Brightling,C.E.</author><author>Bradding,P.</author><author>Symon,F.A.</author><author>Holgate,S.T.</author><author>Wardlaw,A.J.</author><author>Pavord,I.D.</author></authors></contributors><auth-address>DivisionofRespiratoryMedicine,InstituteforLungHealth,Leicester-WarwickMedicalSchoolandUniversityHospitalsofLeicester,Leicester,UnitedKingdom.</auth-address><titles><title>Mast-cellinfiltrationofairwaysmoothmuscleinasthma</title><secondary-title>NEnglJMed</secondary-title></titles><periodical><full-title>NEnglJMed</full-title></periodical><pages>1699-705</pages><volume>346</volume><number>22</number><edition>2002/05/31</edition><keywords><keyword>Adult</keyword><keyword>Asthma/*immunology/physiopathology</keyword><keyword>BasementMembrane/pathology</keyword><keyword>Biopsy</keyword><keyword>Bronchi/*immunology/pathology</keyword><keyword>Bronchitis/*immunology</keyword><keyword>Eosinophilia/immunology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>*MastCells</keyword><keyword>MiddleAged</keyword><keyword>Muscle,Smooth/*immunology/pathology</keyword><keyword>ReferenceValues</keyword></keywords><dates><year>2002</year><pub-dates><date>May30</date></pub-dates></dates><isbn>0028-4793</isbn><accession-num>12037149</accession-num><urls></urls><electronic-resource-num>10.1056/NEJMoa012705</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[27]，血管生成增加，气道平滑肌肥大ADDINE