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溴结构域蛋白4在哮喘上皮-间质转化中作用的研究进展

2017-01-15李秋根

中国医学科学院学报 2017年3期
关键词:表型重塑气道

郑 岩,汪 俊,李秋根

1南昌大学医学部,南昌 3300062江西省人民医院呼吸内科,南昌 330006



·综 述·

溴结构域蛋白4在哮喘上皮-间质转化中作用的研究进展

郑 岩1,汪 俊2,李秋根2

1南昌大学医学部,南昌 3300062江西省人民医院呼吸内科,南昌 330006

气道炎症和气道重塑是支气管哮喘的重要特征,慢性气道炎症可以通过诱导上皮-间质转化(EMT)参与支气管哮喘气道重塑过程。溴结构域蛋白4(BRD4)是哺乳动物体内一种重要转录调节因子,近年越来越多证据表明,其可能是通过核因子-κB/RelA信号通路调控哮喘气道重塑过程。本文总结了BRD4调控哮喘EMT的研究进展,旨在进一步探讨哮喘的分子机制,为哮喘的防治提供新的策略。

上皮-间质转化;哮喘;气道重塑;溴结构域蛋白4;核因子-κB/RelA信号通路

Research Advances in the Role of Bromodomain-containing Protein 4 inEpithelial-mesenchymal Transition in Asthma

ActaAcadMedSin,2017,39(3):425-431

支气管哮喘是以气道慢性炎症和重塑为主要病理特征,以反复发作的喘息、气促、胸闷和/或咳嗽等为主要临床特征的肺部疾病。目前全球哮喘发病率为0.17%~3.34%[1],国内发病率约为1%,儿童可达3%[2]。哮喘严重影响了患者生活质量,而且造成了巨大的个人和社会经济负担。支气管哮喘的发病机制极其复杂,普遍认为是一种多基因遗传病,具有遗传异质性,同时也受环境等外界因素影响,其主要致病因素包括免疫、神经、精神、内分泌、环境和遗传因素。环境改变(如空气质量下降、粉尘及花粉增多等)会使呼吸道反复病毒感染,进而提高呼吸道对环境污染物(香烟、烟雾)的敏感性,最终导致哮喘发生[3]。哮喘发病率跨国差异较大,约有50%的哮喘患者发病与遗传性过敏有关[4]。目前针对哮喘的治疗仍依赖于支气管扩张剂和皮质类固醇激素,而非针对疾病的潜在发病机制进行有效干预和治疗。

上皮-间质转化(epithelial-mesenchymal transition,EMT)过程在慢性炎症疾病、组织修复中发挥重要作用。活化的核因子-κB(nuclear factor-κB,NF-κB)信号通路可诱导EMT相关基因表达,抑制上皮细胞表型相关基因表达,促进间质细胞表型相关基因表达,参与EMT过程。溴结构域蛋白4(bromodomain-containing protein 4,BRD4)是溴化结构和超末端结构家族成员,在整个细胞周期中通过溴结构域结合乙酰化的组蛋白。目前BRD4调控核因子-κB/RelA(nuclear factor-κB/RelA,NF-κB/RelA)通路的研究范围较广,大部分研究主要集中在BRD4促进肿瘤发生和发展,本文总结了BRD4调控NF-κB/RelA 通路控制EMT过程在支气管哮喘气道重塑中的研究进展。

EMT参与哮喘气道重塑

支气管哮喘与气道重塑 支气管哮喘是由多种细胞(如嗜酸性粒细胞、肥大细胞、淋巴细胞及气道上皮细胞等)和细胞组分参与的气道慢性炎症性疾病。气道慢性炎症和重塑为支气管哮喘主要病理生理特征。哮喘气道炎症的形成除炎症细胞、活化的T细胞、肥大细胞及巨噬细胞参与外,气道结构细胞(如上皮细胞、成纤维细胞及平滑肌细胞)也可通过释放炎症介质、细胞因子、趋化因子及生长因子等引起慢性持续性炎症,这将导致气道基质胶原沉积、上皮下纤维化、平滑肌增生和肥大、肌成纤维细胞增殖、上皮下网状层增厚和微血管生成,即气道重塑[5]。研究发现,哮喘患者EMT相关转录基因Snail,基质金属蛋白酶- 2及Ⅰ、Ⅲ型胶原蛋白表达均明显增高[6],这表明EMT过程参与哮喘气道重塑,并且受众多体内细胞因子或信号通路调控。

EMT与气道重塑 EMT是指上皮细胞通过特定程序转化为具有间质表型细胞的生物学过程,在胚胎发育、慢性炎症、组织重建、肿瘤侵袭转移和多种纤维化疾病中发挥了重要作用,并在与细胞间连接缺失相关联的组织修复和重构中同样发挥关键性作用[7- 8]。EMT分为3种类型:1型与胚胎发育和器官形成相关;3型主要参与上皮细胞来源恶性肿瘤相关的表型转化及肿瘤转移;2型与损伤修复、组织再生和器官纤维化相关。EMT是一种细胞亚稳定状态,其维持需要Snail、Twist、ZEB等关键调节基因的参与,短暂的EMT主要参与组织修复过程,持续的EMT则与慢性气道炎症性疾病的气道重塑有关,并最终引起肺功能进行性下降[9- 10]。主要表现为正常上皮完整性丧失和细胞间黏附因子表达减少,如E-钙黏蛋白、紧密连接蛋白;间质细胞表型特征标志蛋白表达增多,如波形蛋白、α-平滑肌动蛋白;同时伴有转录基因表达改变,如Snail、Twist、ZEB等[11];使得细胞骨架及形态上具有了间充质细胞的特征。而哮喘患者气道重塑正是由于上皮下纤维化、平滑肌增生和肥大、肌成纤维细胞增殖等导致气道狭窄,引起一系列病理生理反应。这表明哮喘通过EMT过程引起气道上皮细胞转化为成纤维细胞、上皮表型蛋白减少、间质表型蛋白增多等导致哮喘气道重塑。

EMT的信号转导调控

哮喘气道炎症因子诱导EMT过程 EMT是一个多因子调控、多层次进行的复杂过程,需要一系列细胞因子和生长因子共同调节完成。在其进程中,上游信号通过细胞基质的生长因子引起转录因子锌指蛋白E盒、Twist、Snail及Slug等的活化,抑制E-钙黏蛋白表达,从而破坏细胞与细胞间的紧密连接,降低细胞骨架和连接支架的稳定性,促进EMT的发生发展[12- 13]。哮喘患者气道炎症细胞和结构细胞均可表达炎症因子转录生长因子-β(transforming growth fator-β,TGF-β),而TGF-β参与了哮喘气道炎症反应及重塑过程[10,14- 15],其参与哮喘EMT过程机制主要是通过Smad依赖通路和非Smad依赖通路完成的[16]。TGF-β/Smad信号通路的基本过程为:TGF-β在细胞外与TGF-βRⅡ结合,激活TGF-βRⅠ,活化的TGF-βRⅠ使Smad2/3磷酸化后,进一步与Smad4形成复合物,Smad复合物进入细胞核与EMT相关基因启动子区的Smad结合元件相结合,抑制EMT过程中关键因子E-cadherin及其他上皮表型分子的表达,同时促进间质表型分子的表达[17- 19]。TGF-β通过受体激活Smad信号通路的同时,还可激活非Smad信号通路、Erk非-Smad信号通路、INK/p38非-Smad信号通路、GTPase非-Smad信号通路等,并且独立于TGF-β/Smad信号通路而发挥作用[20]。

NF-κB转录因子调控EMT的作用机制 EMT的发生不仅可以通过炎症因子诱导调控,还涉及多种信号转导通路的协同作用,如Wnt/β-连环蛋白(β-catenin)通路、PI3K/AKT通路、Notch通路、IL- 6/STAT3通路及NF-κB通路等[21]。细胞外信号与细胞表面的特异性受体结合,通过相应的胞内信号转导通路,活化核内的转录因子,调控基因表达,最终诱发EMT。不同信号转导通路调控EMT过程,使得EMT呈现不同的生理病理效应,其中活化NF-κB信号通路通过诱导EMT相关基因的表达,使Snail、Twist、ZEB转录因子表达增高,抑制上皮细胞表型相关基因(E-cadherin,γ-catenin 等)表达,诱导间质细胞表型相关基因(vimentin)参与EMT过程。

NF-κB是具有特殊DNA结合序列的转录因子蛋白家族,参与调节细胞分化、增殖过程,也是EMT过程中关键的调节因子[22- 23]。NF-κB 转录因子蛋白家族包括 c-Rel、RelA、RelB、p50(NF-κB1)、p52(NF-κB2) 5个亚单位[24- 27],亚单位之间可形成不同的同源或异源二聚体,其中最典型的是p65与p50组成的异源二聚体[28]。在静息细胞中,NF-κB/RelA和IκB形成复合体,以无活性形式存在于胞浆中,并且IκB蛋白掩盖NF-κB上的核定位基序,阻止NF-κB向细胞核内转移[29]。当细胞外信号分子与特异性受体结合,导致NF-κB/RelAⅠκB 激酶复合体(IκB kinase,IKK)活化。活化的IKK促进IκB的DSGXXS基序上的Ser 32和Ser 36磷酸化,IκB构象改变,被SCFβ-trcpE3连接酶所识别,进而泛素化降解[30]。IκB降解使NF-κB/RelA核定位基序暴露,并迅速移位到细胞核,NF-κB/RelA第276 位特异性丝氨酸磷酸化。磷酸化的第276 位丝氨酸对于进一步诱导炎症转录延伸基因的活化具有重要意义[31]。活化NF-κB 信号通路通过诱导EMT过程目的基因的表达,使Snail、Twist、ZEB转录因子表达增高,上皮细胞表型相关基因表达抑制及间质细胞表型相关基因表达增多[32- 34]。

特异性抑制NF-κB通路可显著逆转EMT过程目的基因mRNA转录水平的改变趋势,同样,通过使用IkBα激酶特异性拮抗剂或Ikkα基因敲除技术对NF-κB 通路进行抑制后,发现小鼠Twist、ZEB、Snail表达均受到明显抑制[35]。这表明NF-κB 信号通路在调控EMT过程中,对于上皮表型及间质表型基因、蛋白表达作用极其显著。在研究NF-κB通路调控支气管哮喘EMT过程发现,NF-κB信号通路受BRD4的调控,而出现目的基因的转录起始、转录延伸和蛋白翻译过程。

BRD4调控NF-κB/RelA信号通路参与哮喘气道重塑

BRD4是最近在哺乳动物中发现的一种转录调节因子,属于溴化结构和超末端结构(bromodomains and extraterminal,BET)族,由110个氨基酸组成高度紧密序列,形成4个反向平行的α-螺旋结构,其结构包含2个溴化结构域,可优势结合乙酰化染色质,通过对转录因子等非组蛋白的乙酰化修饰,刺激细胞周期依赖性激酶9(cyclin-dependent protein kinase 9,CDK9)活化、募集;并与磷酸化的RNA聚合酶Ⅱ羧基末端结构域进行交互,广泛参与细胞周期调控、细胞分化、信号转导等过程[36]。

BRD4在哮喘中的作用 BRD4研究范围较广,早期研究发现BRD4与原癌基因(c-Myc)一起调控细胞增殖,促进肿瘤细胞的增殖、分化、浸润及转移发展;BRD4抑制剂可一定程度抑制肿瘤细胞增殖和促进其凋亡[37- 39]。而根据对BRD4在细胞增殖、炎症反应中的深入研究后发现,BRD4通过识别乙酰化组蛋白标志物,调控单核、巨噬细胞中NF-κB诱导的炎症基因表达,参与肺纤维化、血管内皮间质转化过程及慢性炎症性疾病病理生理过程,并在不同浓度BRD4抑制剂均表现出对疾病进展的抑制作用[40- 41]。

上皮下纤维化、成纤维细胞畸形生长及平滑肌细胞肥大引起的气道结构变化,导致支气管哮喘患者气道重塑;且在哮喘慢性气道炎症反应中,由于细胞因子、生长因子以及蛋白酶的表达增多,从而诱导气道上皮细胞表型变化[42]。Perry等[43]通过对比哮喘患者与健康者气道上皮(airway epithelial,AE)细胞及使用BRD4抑制剂干预后AE细胞增殖和炎症因子IL- 6、IL- 8水平发现,哮喘患者AE细胞增殖及炎症因子表达IL- 6、IL- 8明显高于正常AE细胞,且BRD4抑制剂可明显抑制上述现象。他们认为BRD4是通过募集活化的NF-κB异二聚体,形成RNA聚合酶Ⅱ、NF-κB、C/EBP β复合物结合到IL- 6、IL- 8基因的κB增强子位点上,促进炎症因子在活化巨噬细胞中的表达增多,导致AE细胞增殖及气道慢性炎症,BRD4特异性抑制剂阻断复合物与启动子区结合发挥抑制其分泌作用,最终抑制气道异常结构变化。Clifford等[44]发现哮喘患者AE细胞内IL- 6、IL- 8组蛋白H3乙酰化较健康者增多,特别是组蛋白H3K18乙酰化。而Khan等[45]同样在IL- 1β刺激的AE细胞内发现IL- 6和IL- 8启动子区组蛋白H3乙酰化增多,并与NF-κB/p65和BRD4蛋白的募集有关。

哮喘患者气道组织中BRD4过度表达可引起IL- 8分泌增多,导致激素抵抗型气道炎症及气道上皮细胞向间质细胞转化[46];而且引起NF-κB活化增多、表达增高,NF-κB被认为是AE细胞表型变化的关键因子,最终也可导致气道上皮细胞向间质细胞转化[47]。这都表明BRD4不仅能维持哮喘患者气道处于持续炎症状态,还能抑制上游调控因子表达使得自身表达增多,促进下游NF-κB活化,导致气道结构重塑[48]。有研究观察到,AE细胞在TGF-β诱导下NF-κB/RelA通路相关基因、蛋白表达增多,且BRD4抑制剂具有抑制作用,上述结果提示BRD4作为NF-κB的激活剂,在炎症因子刺激信号作用下,第276位磷酸化丝氨酸的NF-κB/RelA诱导BRD4从染色质分离并募集活化的CDK9或者细胞周期蛋白T1(cyclinT1),构成1个正性转录延伸因子-b(positive transcription elongation factor,P-TEFb)。BRD4与P-TEFb复合体相互作用,促进活化后P-TEFb复合体结合到启动子区,引起RNA PolⅡ羧基端第2位丝氨酸磷酸化,RNA PolⅡ拼接,促进EMT相关基因的转录起始、转录延伸和蛋白翻译过程,对EMT进行调控,促进哮喘气道重塑[49- 53]。并且气道组织BRD4的表达增多除引起IL- 8分泌增多维持气道慢性炎症外,也会导致RNA聚合酶Ⅱ的C末端结构域上P-TEFb依赖性磷酸化增多,并刺激EMT相关基因启动子的转录[54- 55];但BRD4表达降低并不影响RelA mRNA水平,表明BRD4是在蛋白水平调控RelA而非mRNA水平[56]。

气道重塑是复杂的细胞形态变化和细胞间相互作用的共同产物,且上皮细胞损伤是主要诱发因素。气道炎症导致的急性氧化损伤可使上皮屏障功能下降,激发气道重塑相关的生长因子和细胞因子释放,导致气道重塑。呼吸道合胞病毒(respiratory syncytial virus,RSV)感染是小儿哮喘发病的主要病因之一,Brasier等[57]通过对RSV诱导的上皮转化过程炎症基因表达发现,RelA 276丝氨酸磷酸化与310赖氨酸乙酰化可促P-TEFb复合物激活和NF-κB通路下游基因表达,且细胞内BRD4和CDK9明显增加。Tian等[58]同样在RSV刺激的气道上皮细胞内发现CDK9水平增多,并且可以诱导RNA聚合酶Ⅱ第2丝氨酸磷酸化增多,促进EMT过程相关基因Snail、Twist、ZEB- 1等表达。关于BRD4调控NF-κB依赖的EMT过程和肺纤维化研究显示,TGF-β刺激支气管上皮细胞细胞可激活NF-κB/RelA信号通路相关的调控炎症基因,在细胞处于间充质状态下,276位丝氨酸磷酸化的NF-κB/RelA结合至BRD4转录延长复合物上,激活休眠的RNA聚合酶Ⅱ,促进哮喘气道重塑;而且BRD4抑制剂可恢复TGF-β刺激的支气管上皮细胞种E-钙黏蛋白并减少间质细胞表型蛋白(vimentin)水平,这证实BRD4通过调控NF-κB信号通路中分子表达或修饰参与哮喘气道重塑过程[59]。

综上,气道慢性炎症和气道重塑是支气管哮喘最重要的病理生理特征。BRD4是溴结构域蛋白家族中较为重要的与癌症细胞增殖、炎症有关的转录调节因子,而BRD4在哮喘发病过程中,不仅可以通过与炎症因子启动子结合促进炎症因子释放,维持气道长期炎症状态;而且作为NF-κB/RelA信号通路的激活剂,可以通过募集活化的CDK9或cyclinT1并形成P-TEFb复合体,结合至DNA启动子区,启动Snail、Twist等相关基因的转录起始、延伸和蛋白翻译;抑制气道上皮细胞表型基因表达的同时,诱导间质细胞表型基因表达,最终发生气道EMT而参与气道重塑过程。BRD4特异性抑制剂在抑制哮喘患者AE细胞或TGFβ刺激的AE细胞炎症因子基因表达、NF-κB/RelA通路相关基因表达以及EMT过程基因、蛋白表达方面发挥相当重要作用,使其能够作为哮喘治疗的新方向。但目前对于BRD4在哮喘发病过程中作用的具体分子机制研究尚不完全明确,仍需更多的基础实验研究证实BRD4是否可以通过调控其他信号通路促进哮喘气道炎症和重塑过程,继续发掘BRD4特异性拮抗剂以应用于哮喘的治疗,提高哮喘患者的治愈率。

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ZHENG Yan1,WANG Jun2,LI Qiugen2

1Medical Department of Nanchang University,Nanchang 330006,China

2Department of Respiratory Medicine,Jiangxi Province People’s Hospital,Nanchang 330006,ChinaCorresponding author:LI Qiugen Tel:0791- 86895508,E-mail:liqiugen6787@126.com

Asthma is a chronic airway disease characterized by airway inflammation and airway remodeling. Chronic airway inflammation can be involved in airway remodeling in asthmatic patients by incuding epithelial-mesenchymal transition (EMT).Bromodomain-containing protein 4 (BRD4) is a key transcriptional regulator in mammals,and many evidences have shown that BRD4 plays a pivotal role in airway remodeling via nuclear factor-κB/RelA signaling pathway. This review summarizes the recent advances in the role of BRD4 in regulating EMT,with an attempt to elucidate the molecular mechanisms of asthma and inform the prevention and control of asthma.

epithelial-mesenchymal transition;asthma;airway remodeling;bromodomain-containing protein 4;nuclear factor-κB/RelA signal pathway

国家自然科学基金(30960143)和江西省科技厅重大项目(20151BBB70267)Supported by the National Natural Sciences Foundation of China (30960143) and the Major Projects of Jiangxi Provincial Science and Technology Department (20151BBB70267)

李秋根 电话:0791- 86895508,电子邮件:liqiugen6787@126.com

R562.2+5

A

1000- 503X(2017)03- 0425- 07

10.3881/j.issn.1000- 503X.2017.03.022

2016- 10- 18)

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