药学学报

Type	Name	Expression	Function	Reference
miRNA	let-7d	Downregulation	Inhibit	[15, 16]
miR-26a	Downregulation	Inhibit	[17, 18]
miR-221	Downregulation	Inhibit	[19]
miR-200, miR-200b/c	Downregulation	Inhibit	[20, 21]
miR-1343	Downregulation	Inhibit	[22]
miR-338*(miR-338-5p)	Downregulation	Inhibit	[23]
miR-497	Downregulation	Inhibit	[24]
miR-448-5p	Downregulation	Inhibit	[25]
miR-106b-5p	Downregulation	Inhibit	[26]
miR-495-3p	Downregulation	Inhibit	[27]
miR-30	Downregulation	Inhibit	[28]
miR-155-5p	Downregulation	Inhibit	[29]
miR-184	Downregulation	Inhibit	[30]
miR-320a-3p	Downregulation	Inhibit	[31]
miR-140	Downregulation	Inhibit	[32]
miR-34a-5p	Downregulation	Inhibit	[33]
miR-182-5p, miR-23a-3p	Upregulation	Inhibit	[34]
miR-15b, miR-25, let-7d	Upregulation	Promote	[35]
miR-210	Upregulation	Promote	[36]
miR-4417	Upregulation	Promote	[37]
miR-21	Upregulation	Promote	[38, 39]
miR-34a	Upregulation	Promote	[40, 41]
miR-483-5p	Upregulation	Promote	[42]
miR-424	Upregulation	Promote	[43]
lncRNA	lncRNA uc.77, 05RiK	Upregulation	Promote	[44]
lncRNA HOTAIR, CARLo-5, CD99P1	Upregulation	Inhibit	[45]
lncRNA MALAT1	Upregulation	Promote	[46]
lncRNA-ATB	Upregulation	Promote	[47]
lncRNA ZEB1-AS1	Upregulation	Promote	[48]
lncRNA sirt1 NAT	Downregulation	Inhibit	[49]
lncRNA MEG3	Downregulation	Inhibit	[50]
lncRNA CHRF	Upregulation	Promote	[51]
lncRNA DLEU2	Upregulation	Promote	[52]
lncRNA NEAT1	Upregulation	Promote	[53, 54]
lncRNA CDR1as	Upregulation	Promote	[55]
circRNA	hsa_circ_0044226	Upregulation	Promote	[56]
circRNA-ZC3H4	Upregulation	Inhibit	[57]
mmu_circ_0000981	Upregulation	Promote	[58]

Type	Name	Expression	Function	Reference
miRNA	let-7d	Downregulation	Inhibit	[15, 16]
miR-26a	Downregulation	Inhibit	[17, 18]
miR-221	Downregulation	Inhibit	[19]
miR-200, miR-200b/c	Downregulation	Inhibit	[20, 21]
miR-1343	Downregulation	Inhibit	[22]
miR-338*(miR-338-5p)	Downregulation	Inhibit	[23]
miR-497	Downregulation	Inhibit	[24]
miR-448-5p	Downregulation	Inhibit	[25]
miR-106b-5p	Downregulation	Inhibit	[26]
miR-495-3p	Downregulation	Inhibit	[27]
miR-30	Downregulation	Inhibit	[28]
miR-155-5p	Downregulation	Inhibit	[29]
miR-184	Downregulation	Inhibit	[30]
miR-320a-3p	Downregulation	Inhibit	[31]
miR-140	Downregulation	Inhibit	[32]
miR-34a-5p	Downregulation	Inhibit	[33]
miR-182-5p, miR-23a-3p	Upregulation	Inhibit	[34]
miR-15b, miR-25, let-7d	Upregulation	Promote	[35]
miR-210	Upregulation	Promote	[36]
miR-4417	Upregulation	Promote	[37]
miR-21	Upregulation	Promote	[38, 39]
miR-34a	Upregulation	Promote	[40, 41]
miR-483-5p	Upregulation	Promote	[42]
miR-424	Upregulation	Promote	[43]
lncRNA	lncRNA uc.77, 05RiK	Upregulation	Promote	[44]
lncRNA HOTAIR, CARLo-5, CD99P1	Upregulation	Inhibit	[45]
lncRNA MALAT1	Upregulation	Promote	[46]
lncRNA-ATB	Upregulation	Promote	[47]
lncRNA ZEB1-AS1	Upregulation	Promote	[48]
lncRNA sirt1 NAT	Downregulation	Inhibit	[49]
lncRNA MEG3	Downregulation	Inhibit	[50]
lncRNA CHRF	Upregulation	Promote	[51]
lncRNA DLEU2	Upregulation	Promote	[52]
lncRNA NEAT1	Upregulation	Promote	[53, 54]
lncRNA CDR1as	Upregulation	Promote	[55]
circRNA	hsa_circ_0044226	Upregulation	Promote	[56]
circRNA-ZC3H4	Upregulation	Inhibit	[57]
mmu_circ_0000981	Upregulation	Promote	[58]

Drug	ncRNA	Effect	Reference
ASV	lncRNA sirt1 NAT (sirt1 AS)	Up-regulate	[49]
PTX	miR-140	Up-regulate	[32]
Sulindac	miR-21	Down-regulate	[39]
PG	miR-410	Down-regulate	[61]
Atr	mmu_circ_0000981	Down-regulate	[58]
BaP	linc00673	Up-regulate	[62]

Drug	ncRNA	Effect	Reference
ASV	lncRNA sirt1 NAT (sirt1 AS)	Up-regulate	[49]
PTX	miR-140	Up-regulate	[32]
Sulindac	miR-21	Down-regulate	[39]
PG	miR-410	Down-regulate	[61]
Atr	mmu_circ_0000981	Down-regulate	[58]
BaP	linc00673	Up-regulate	[62]

非编码RNA介导肺纤维化的EMT进程及天然药物干预的研究进展

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朱德伟 , 余群 , 沈云辉 ^*

药学学报 | 专题报道：脏器纤维化疾病与抗纤维化药物研究 2021,56(11): 2934-2942

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药学学报 | 专题报道：脏器纤维化疾病与抗纤维化药物研究 2021, 56(11): 2934-2942

非编码RNA介导肺纤维化的EMT进程及天然药物干预的研究进展

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朱德伟, 余群, 沈云辉^*

作者信息

上海中医药大学中药学院, 上海 201203

通讯作者:

*沈云辉, Tel: 86-21-51323146, E-mail: bravesyh@163.com

Research advances of EMT progression of pulmonary fibrosis mediated by non-coding RNAs and natural medicines interventions

De-wei ZHU, Qun YU, Yun-hui SHEN^*

Affiliations

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

出版时间: 2021-11-12 doi: 10.16438/j.0513-4870.2021-0971

文章导航

摘要

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上皮间质转化（epithelial mesenchymal transition，EMT）是上皮细胞向间充质细胞转变的重编程过程。在这一过程中，上皮细胞失去其细胞极性和细胞间的黏附作用，获得类似于间充质细胞的更强的迁移和侵袭能力。在肺纤维化发病过程中，EMT是非常关键的步骤。部分肺上皮细胞通过EMT过程向肌成纤维细胞分化，促进肺纤维化发展。近年来，有大量研究表明非编码RNA（non-coding RNA，ncRNA）参与了肺上皮细胞的EMT过程，同时一些天然药物可以通过干预肺纤维化相关ncRNA的方式，对肺纤维化起到预防和治疗作用。本文总结了肺纤维化EMT过程中ncRNA的表达情况、发挥的生物学功能以及天然药物介导EMT相关ncRNA影响肺纤维化的研究进展，旨在为ncRNA的研究与天然药物新作用靶点探究提供新的思路。

关键词

肺纤维化 / 上皮间质转化 / 非编码RNA / 天然药物 / 作用机制

Abstract

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Epithelial mesenchymal transition (EMT) is a reprogramming process of epithelial to mesenchymal transition, in which epithelial cells lose polarity and intercellular adhesion and acquire stronger migration and invasion ability similar to mesenchymal cells. EMT is a critical step during the pathogenesis of pulmonary fibrosis. Lung epithelial cells can differentiate into myofibroblasts through EMT, which accelerates the fibrosis process. In recent years, a large number of studies have shown that non-coding RNAs (ncRNAs) are involved in the EMT process of lung epithelial cells, at the same time, some natural medicines were found to prevent and treat pulmonary fibrosis by intervening in ncRNAs related to pulmonary fibrosis. In this review, we summarize the expression change and biological function of vital ncRNAs in EMT progression during pulmonary fibrosis, as well as the research progress of EMT related ncRNA mediated by natural medicines on pulmonary fibrosis, aiming to provide new insights into the research of ncRNAs and the exploration of new pharmacological targets of natural medicine.

Key words

pulmonary fibrosis / epithelial mesenchymal transition / non-coding RNA / natural medicine / mechanism

引用本文

朱德伟, 余群, 沈云辉. 非编码RNA介导肺纤维化的EMT进程及天然药物干预的研究进展. 药学学报, 2021 , 56 (11) : 2934 -2942 . DOI: 10.16438/j.0513-4870.2021-0971

De-wei ZHU, Qun YU, Yun-hui SHEN. Research advances of EMT progression of pulmonary fibrosis mediated by non-coding RNAs and natural medicines interventions[J]. Acta Pharmaceutica Sinica, 2021 , 56 (11) : 2934 -2942 . DOI: 10.16438/j.0513-4870.2021-0971

正文

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组织器官纤维化是许多慢性疾病久治不愈的根本原因, 也是矽肺、病毒性心肌炎以及病毒性肝炎等疾病致残、致死的主要原因^[1]。肺纤维化将导致肺实质结构破坏和功能丧失, 目前无法完全治愈, 且患者确诊后中位生存期仅为3~5年^[2]。肺纤维化也是严重急性呼吸系统综合征(severe acute respiratory syndrome, SARS) 与新型冠状病毒肺炎“COVID-19”患者的临床表现和后遗症之一^[3]。肺纤维化增加了患者的病症负担, 且影响治疗的预后效果。

早期观点认为, 肺泡上皮重复性损伤形成的慢性炎症, 是导致纤维化的主要原因, 然而抑制炎症的免疫抑制药物在临床中并没有取得良好的效果。近年来的研究表明, 慢性损伤引起的上皮干细胞[如肺泡Ⅱ型上皮细胞(alveolar type Ⅱ epithelial cells, AEC Ⅱ)] 功能的异常或缺失, 才是导致纤维化的关键因素。功能受损的上皮干细胞, 一方面可以分泌细胞因子促进纤维母细胞的病变发展, 另一方面还能通过上皮间质转化(epithelial mesenchymal transition, EMT) 过程, 转化成具有干性特征的间充质样细胞, 促进纤维化发展^[4]。

1 肺纤维化与EMT进程

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EMT参与各组织器官生理病理活动, 在肺部早期创伤修复以及纤维化进程中主要发生与损伤修复、组织再生和器官纤维化相关的EMT进程, 即Ⅱ型EMT。同时巨噬细胞和淋巴细胞亚群释放促炎因子、纤维化生长因子, 上皮细胞和成纤维细胞分化为表达α-平滑肌肌动蛋白(α-SMA) 的肌成纤维细胞, 细胞外基质(extracellular matrix, ECM) 与胶原蛋白沉积, 导致肺功能受损并最终产生肺衰竭^[5]。至少1/3的肺纤维化中肌成纤维细胞通过肺上皮细胞的EMT转化得到^[6], 肌成纤维细胞具有与癌细胞类似特征, 如表观遗传和遗传异常以及不受控制的增殖、抗凋亡和高迁移率^[7]。

肺泡上皮细胞分为Ⅰ型(AEC Ⅰ) 和Ⅱ型(AEC Ⅱ), Ⅱ型AEC约占肺泡上皮细胞的60%和所有肺细胞的10%~15%, 占肺泡表面积的4%^{[8, 9]}, AEC Ⅱ能够自身增殖, 也能分化为AEC Ⅰ。在炎症或损伤时, 发生EMT的上皮细胞失去细胞极性并下调钙黏蛋白介导的细胞间黏附, 上皮表型丧失如E-cadherin和α-catenin表达降低, 而间充质标志物如成纤维细胞特异性蛋白1 (FSP-1)、N-cadherin、波形蛋白、纤连蛋白和α-SMA的表达增加, AEC Ⅱ最终转化为具有间质表型的细胞。EMT受源自基质细胞和周围微环境的各种信号通路的调节, 其中包括各种细胞因子、生长因子与纤维化的关键因子, 如多效性生长因子TGF-β1 (transforming growth factor-β1)、血小板源性生长因子(PDGF) 以及白介素1β (IL-1β) 等, 也会被机械应力或缺氧等损伤激发。

2 非编码RNA (non-coding RNA, ncRNA) 介导肺纤维化的EMT进程

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随着高通量测序技术的发展, 人类基因组计划逐渐完成, 基因组中除1%~2%编码蛋白质的基因外, 其余大部分皆可转录不编码蛋白质的ncRNA。根据长度和加工机制的不同, ncRNA可分为微小RNA (microRNA, miRNA)、长链非编码RNA (long noncoding RNA, lncRNA) 及环状RNA (circular RNA, circRNA) 等。1976年circRNA作为某些高等植物的类病毒首次被发现^[10], 2013年《Nature》首次报道circRNA具有miRNA海绵功能^[11]; 1991年lncRNA由小鼠Xist基因首次分离与鉴定, 并证明其具有生物学功能, 此前它一直被认为是基因转录的副产物^[12]; 1993年miRNA作为秀丽隐杆线虫lin-4的转录物首次被发现^[13], 通过对let-7的研究也证实miRNA能与mRNA结合从而抑制基因表达^[14]。同时, 更多研究发现ncRNA广泛参与生理病理过程, 因此, 了解ncRNA在EMT中的作用将有助于启发并建立新的研究思路和途径, 以进一步揭示肺纤维化的发病机制并确定预防和治疗目标, ncRNA的种类及作用如表 1^[15-58]和图 1所示。

2.1 miRNA参与肺纤维化的EMT进程

2.1.1 miRNA在肺纤维化的EMT中发挥抑制作用

miRNA与一个或多个下游靶基因mRNA非编码区域序列(3'UTR) 互补结合, 导致mRNA翻译抑制或降解, 在肺纤维化的EMT中可以与Snail、Smad3等的3'UTR靶向结合, 抑制EMT进程。let-7家族是最早发现、研究最广泛的miRNA之一。Pandit等^[15]单独抑制let-7d后, 发现A549、RLE-6TN和NHBE细胞发生EMT变化, 间充质标记物N-cadherin-2、波形蛋白、α-SMA、高迁移率族蛋白A2 (high mobility group AT-hook 2, HMGA2) 以及let-7的其他纤维化相关指标(如RAS、胰岛素样生长因子) 上调; 特发性肺纤维化(idiopathic pulmonary fibrosis, IPF) 小鼠的肺泡间隔增厚, 胶原蛋白、α-SMA和S100钙结合蛋白A4 (S100 calcium binding protein A4, S100A4) 表达增加。此团队在人胎肺成纤维细胞(FLF)、正常人肺成纤维细胞(NHLF) 和人包皮成纤维细胞(HFF-1) 中转染let-7d发现, 细胞间充质基因和蛋白质表达水平降低, 增殖与迁移能力减弱, 可能是其通过HMGA2和Snail家族转录因子-2 (snail homolog 2, SLUG)轴防止α-SMA表达, 从而介导成纤维细胞向肌成纤维细胞的分化, 抑制EMT进程^[16]。HMGA2是一种转录因子, 能够通过激活TGF-β1/Smad3信号通路诱导EMT, Liang等^[17]发现miR-26a能直接靶向结合HMGA2的3'UTR并减弱EMT。Liang等^[18]后来研究证明Lin28B可以通过抑制let-7d来诱导EMT的过程, Lin28B是miR-26a的直接靶点之一, miR-26a能部分介导Lin28B/let-7d轴来抑制EMT。miR-221导致E-cadherin的上调和N-cadherin、波形蛋白和α-SMA的下调, 机制可能为miR-221直接靶向HMGA2的3'UTR, 通过TGF-β1/Smad3信号通路抑制EMT^[19]。

人miR-200家族分别编码于人染色体1和12, 家族成员包括miR-200a/200b/429和miR-200c/141。miR-200家族成员增强了E-cadherin的表达并下调α-SMA与纤连蛋白的表达, 抑制TGF-β1诱导的大鼠肺泡上皮细胞的EMT^[20]。脂多糖(lipopolysaccharide, LPS) 是一种炎症诱导因子, 可引起急性肺损伤(ALI) 与急性呼吸窘迫综合征(ARDS), 促进AEC等多种类型细胞的EMT^[59]。RLE-6TN细胞被LPS或LPS+TGF-β刺激后, miR-200b/c和E-cadherin蛋白表达下降, 而ZEB1/2上调, miR-200b/c过表达能降低p38和Smad3磷酸化, 降低波形蛋白和α-SMA蛋白水平^[21]。miR-1343通过靶向1型TGF-β受体(TGF-β receptor 1, TGFBR1) 和TGFBR2的3'UTR来显著抑制其表达, 减少TGF-β诱导的纤维化标志物并抑制EMT^[22]。Hedgehog (Hh) 信号通路的重新激活与器官纤维化有关, Smoothened (SMO) 与G蛋白偶联受体相关, 是Hh信号通路的关键下游分子, miR-338^* (miR-338-5p) 可能靶向SMO的3'UTR, 干扰EMT来调节肺纤维化的病理过程^[23]。真核翻译起始因子3亚基A (EIF3A) 可以调节mRNA翻译, 影响细胞周期、细胞增殖以及促进肺泡上皮细胞EMT, miR-497通过靶向抑制EIF3A的基因表达来抑制TGF-β1诱导的肺泡上皮细胞中的EMT和肺成纤维细胞中的ECM水平^[24]。Sine oculis homeobox homolog 1 (Six1) 属于Sine oculis homeobox基因家族, 是TGF-β诱导基因, miR-448-5p可直接靶向Six1的3'UTR影响TGF-β1刺激下p-Smad3的表达, 从而调节16HBE细胞中的EMT^[25]。Liu等^[26]发现E2F转录因子1 (E2F1) 促进TGF-β1诱导的纤维化, 敲除E2F1和Six1可阻断BEAS-2B细胞中TGF-β1诱导的纤维化和EMT, miR-106b-5p通过靶向结合E2F1的3'UTR负调节Six1, 抑制EMT。鞘氨醇1磷酸受体3 (S1PR3) 是纤维化的关键分子, miR-495-3p可以靶向S1PR3基因抑制S1PR3/Smad2/3通路从而抑制EMT进程^[27]。

镉(Cd) 暴露的人肺上皮细胞中上皮标志物E-cadherin水平降低, 间充质标志物ZEB1和波形蛋白水平增加, 从而发生EMT。miR-30家族成员在EMT细胞中下调, EMT主调节器Snail是miR-30靶标基因中上调最多的, Cd可能通过下调miR-30, 上调Snail从而诱导EMT^[28]。miR-155-5p可以靶向糖原合酶激酶-3β (GSK-3β)基因, 抑制电离辐射诱导的肺上皮细胞EMT并增强p65 (NF-κB的亚基) 的磷酸化^[29]。TGF-β1刺激肺上皮细胞, 显著增加肿瘤蛋白p63 (TP63) 的表达, miR-184可通过靶向TP63的3'UTR抑制EMT减缓肺纤维化^[30]。miR-320a-3p降低STAT3磷酸化表达水平、降低p-Smad3蛋白水平从而抑制EMT^[31]。miR-140在EMT中表达下调, 通过与AEC中的Smad3-3'UTR结合负向调节Smad3表达^[32]。Smad4被确定为miR-34a的靶标, miR-34a-5p可以通过靶向Smad4-3'UTR, 从而减弱二氧化硅(SiO₂) 诱导的肺纤维化中的EMT^[33]。间充质干细胞(MSC) 有助于改善急性肺损伤和肺纤维化, MSC通过外泌体可将miRNA转移到急性肺损伤模型细胞中, 调节急性肺损伤模型细胞功能。Xiao等^[34]研究发现, LPS处理的MLE-12细胞与MSC共培养后, 其EMT过程被逆转。原因可能为MSC分泌的外泌体中含有较高水平的miR-182-5p和miR-23a-3p, 两种miRNA被递送到LPS诱导的MLE-12细胞中后, 一方面miR-182-5p靶向Ikbkb mRNA, 另一方面miR-23a-3p靶向抑制与IKKβ互作的泛素特异性肽酶5 (USP5) 的基因表达, 通过下调Ikbkb mRNA并促进IKKβ的泛素化, 最终使得NF-κB和Hh通路失活, 从而抑制EMT过程。

2.1.2 miRNA在肺纤维化的EMT中发挥促进作用

部分miRNA在肺纤维化EMT组织或细胞中高表达, 与EMT上游调控基因RUNX3、PTEN等结合, 促进EMT进展。Kuhn等^[35]在弹性膜(elastic membranes) 上对大鼠Ⅱ型肺泡(alveolar type II, ATII) 细胞和成纤维细胞使用较高振幅模式(“非生理”) 拉伸, 发现肺细胞的非生理性机械拉伸会显著加速EMT, 伴随let-7d、miR-15b以及miR-25高表达, 胶原蛋白Ⅰ和Ⅳ的蛋白质水平升高, 波形蛋白增加, 细胞角蛋白表达减少。脯氨酰羟化酶结构域蛋白2 (PHD2) 是促进HIF-1α降解的关键酶, Runt相关转录因子-3 (RUNX3) 能增加PHD2的羟基化能力, Zhu等^[36]观察到百草枯(PQ) 处理的大鼠肺组织中HIF-1α与miR-210表达显著增加, 伴随EMT的发生, 可能是RUNX3基因可以被miR-210直接靶向, 降低了PHD2的羟基化能力, 增强HIF-1α的稳定性, 加重PQ诱导的EMT和加速肺纤维化。镍化合物可诱导肺上皮细胞系发生EMT, 转化生长因子β活化激酶结合蛋白2 [TGF-beta activated kinase 1 (MAP3K7) binding protein 2, TAB 2] 属于IL-1信号通路中的转化生长因子β活化激酶1 (transforming growth factor beta-activated kinase 1, TAK1) 与肿瘤坏死因子受体相关因子6 (TNF receptor associated factor 6, TRAF6) 的连接蛋白, 介导TAK1的激活, 是NF-κB通路的关键分子, 在镍化合物诱导的肺上皮细胞系EMT中, miR-4417与纤连蛋白上升, TAB 2表达降低^[37]。胸部放疗可引发放射诱发肺纤维化(radiation-induced pulmonary fibrosis, RIPF), Liu等^[38]发现受照射小鼠肺中的EMT进展同时伴随miR-21表达增加, PTEN是miR-21的靶基因, 可负向调节Akt激活, miR-21可能通过下调PTEN表达而上调Akt磷酸化, 促进EMT进展。另一项研究也证实肺纤维化的EMT中, STAT3通路激活后miR-21过表达, 表明miR-21可能促进肺纤维化的EMT进展^[39]。

Yamamoto等^[40]将人类基因ABCA3 (accession No. NM_001089) 转染进入A549细胞, 并用博来霉素(bleomycin, BLM) 和甲氨蝶呤(methotrexate, MTX) 诱导A549/ABCA3细胞建立EMT模型, 发现miR-34a及其诱导剂p53都被上调, 机制可能为诱导药物上调磷酸化p53中Ser15的水平, 诱导EMT发生。miR-34a在TGF-β1诱导的RLE/ABCA3 (一种具有肺泡Ⅱ型细胞样表型的细胞系) 细胞中高表达, 其可能通过降低细胞角蛋白19与促进α-SMA表达参与EMT^[41]。Rho GDP解离抑制剂1 (RhoGDI1) 作为miR-483-5p靶基因, 可调节GDP/GTP交换周期对Rho小GTP酶家族的成员Rac1进行负调节。Rac1-GTP能激活PI3K/Akt通路, 促进肺纤维化的EMT。Huang等^[42]发现miR-483-5p可抑制RhoGDI1来改善TGF-β1诱导的EMT, 其机制可能为激活Rac1/PI3K/Akt通路。miR-424的过表达增加了α-SMA的表达, 降低Smurf2 (TGF-β信号传导的负调节因子) 的蛋白水平, 其可能通过增强TGF-β信号通路调节EMT期间的肌成纤维细胞分化^[43]。

2.2 lncRNA参与肺纤维化的EMT进程

lncRNA是一大类长度大于200 nt且缺乏蛋白质编码能力的RNA, 主要作用包括X染色体沉默、基因修饰、转录激活或干扰、核内运输等。Sun等^[44]在纤维化肺组织中鉴定了513个上调和204个下调的lncRNA, 其中uc.77和05Rik预测分别靶向Zeb2和Hoxa3, 能降低上皮标志物E-cadherin, 上调波形蛋白和α-SMA在内的间充质标志物等, 促进EMT。Yildirim等^[45]实验发现lncRNA HOTAIR、CARLo-5和CD99P1可以通过与EMT和PF相关的蛋白质和miRNA (如miR-148b、miR-218-1、miR-7-1) 的相互作用来调节EMT介导的肌成纤维细胞分化。Yan等^[46]使用SiO₂诱导两种细胞系(HBE和A549) 发生EMT, 发现lncRNA MALAT1的表达增强, 其竞争性结合并抑制miR-503表达, 导致miR-503的靶基因PI3K p85被释放, 加剧EMT过程。Liu等^[47]使用TGF-β1诱导肺上皮细胞EMT, 发现lncRNA-ATB大量表达, 通过结合miR-200c并释放ZEB1, 促进EMT。

lncRNA中存在一类天然反义转录本(NATs), 一般是指从其他转录本的反义链转录, 与含有蛋白质编码或非编码基因的正义转录本的区域互补的RNA产物, 其也具有促进细胞增殖等生物功能, 是调节肺中纤维化表型和TGF-β信号传导的有力候选者^[60]。lncRNA ZEB1反义RNA 1 (ZEB1-AS1)^[48]作为一种新的促纤维化分子, 竞争性结合miR-141-3p, 释放ZEB1表达, 诱导肺泡Ⅱ型上皮细胞的EMT。研究者^[49]发现sirt1 NAT, 也称为lncRNA sirt1反义(sirt1 AS) 能直接结合sirt1 mRNA, 增强其稳定性, 抑制EMT进展。lncRNA MEG3通过阻碍氧化镍纳米颗粒(NiO NPs) 诱导的A549细胞EMT和胶原沉积过程, 缓解肺纤维化进程^[50]。lncRNA CHRF与IPF的发展有关, 能竞争性结合miR-146a, 上调L1细胞黏附分子(L1CAM), 促进EMT^[51]。三结构域蛋白2 (tripartite motif-containing protein 2, TRIM2) 能通过EMT增强结直肠癌细胞侵袭性, 在BLM诱导的纤维化小鼠的肺组织和TGF-β1刺激的A549细胞中, TRIM2表达增加而miR-369-3p表达降低, lncRNA DLEU2能结合并下调miR-369-3p, 进而上调TRIM2促进肺上皮细胞EMT^[52]。在TGF-β1诱导的细胞中, lncRNA-NEAT1显著上调而miR-9-5p下调, 同时NEAT1敲低可以降低p-Smad2、N-cadherin、collagen I、collagen III等表达, 表明lncRNA NEAT1通过靶向miR-9-5p和调节TGF-β信号传导促进肺上皮细胞EMT^[53], 另外lncRNA NEAT1还可以通过调节miR‑455‑3p/Smad3信号轴促进EMT^[54]。

2.3 circRNA介导肺纤维化的EMT进程

circRNA具有无5'端帽子和3'端多聚腺苷酸尾巴的环状闭合结构, 相比线性RNA分子更稳定、更丰富、更保守, 是基因表达的重要调节剂和修饰剂, 主要功能包括“miRNA海绵”, 与蛋白互作、翻译多肽等作用。circRNA CDR1as在SiO₂刺激的肺上皮细胞中表达增加, 而miR-7表达减少, 生物信息学表明circRNA CDR1as具有多个miR-7结合位点, 过表达circRNA CDR1as后, 其通过海绵性结合miR-7, 释放TGFBR2, 促进EMT^[55]。后期促进复合物/环状体(APC/C) 主要调节细胞周期中染色体分离和有丝分裂的完成, CDC27是其核心亚基, 可被TGF-β激活促进EMT, Qi等^[56]发现hsa_circ_0044226敲低后, CDC27表达显著降低, EMT被抑制。CCCH型锌指蛋白4 (ZC3H4) 与circZC3H4在SiO₂诱导的EMT中上调, ZC3H4介导细胞间充质表型的获得, circRNA-ZC3H4作为miR-212海绵能下调miR-212与ZC3H4表达, 抑制EMT^[57]。mmu_circ_0000981在TGF-β1诱导小鼠肺上皮细胞TC-1的EMT模型中表达上调, 竞争性结合miR-211-5p, 从而能调节TGFBR2表达促进EMT^[58]。

3 中医药、天然药物通过ncRNA干预肺纤维化的EMT进程

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从天然药物中寻找新的生物活性化合物已成为新药开发的重要途径, 并且从中寻找药物新的适应症, 从而扩大药物应用范围都是目前研究的热点, 天然药物也可以调控ncRNA表达, 从而介导肺纤维化EMT (表 2^{[32, 39, 49, 58, 61, 62]})。Sirt1 AS是EMT的负调节因子, 具有抗纤维化功能。黄芪甲苷(astragaloside IV, ASV) 是黄芪的活性成分之一, 可以抑制Akt介导的Foxo3下调以逆转IPF中的EMT。Qian等^[49]发现ASV可上调RLE-6TN细胞中的sirt1 AS表达, 敲除sirt1 AS不仅减少ASV诱导的sirt1, 而且增加磷酸化的Akt, 从而降低BLM处理的肺组织中Foxo3的表达。紫杉醇(paclitaxel, PTX) 抑制胶原诱导的关节炎和纤维化相关的系统性硬化症, 改善肝和肾纤维化; 低剂量紫杉醇上调miR-140和减少Smad3/p-Smad3, 使得EMT表型逆转并改善肺纤维化^[32]。舒林酸(sulindac) 属于芳基链烷酸类, 研究发现其可以改善胰腺和肺部炎症和纤维化, miR-21作为STAT3相关因子, 可下调E-cadherin和上调α-SMA促进EMT, 舒林酸通过阻断STAT3相关的miR-21表达, 逆转EMT并改善肺纤维化^[39]。灵菌红素(prodigiosin, PG) 是一系列具有甲氧基吡咯环的红色素, 其抑制miR-410和TGF-β1的表达, 上调具有血小板反应蛋白基序的去整合素和金属蛋白酶1 (A disintegrin and metalloproteinase with a thrombospondin type 1 motif, ADAMTS1), 减少纤维化蛋白积累, 减缓EMT^[61]。苍术酮(atractylon, Atr) 具有抗炎作用, Zeng等^[58]研究发现其通过抑制mmu_circ_0000981和TGFBR2的表达来抑制TGF-β1诱导的EMT和纤维化相关蛋白的表达, 表明苍术酮也通过调节circRNA而具有抗肺纤维化作用。

苯并芘[benzo(a)pyrene, BaP] 是肺癌的强致癌物, 在烟草中含量丰富, 苯并芘显著提高linc00673的表达水平, 以时间和剂量依赖的方式促进间充质生物标志物表达并抑制上皮生物标志物E-cadherin, 敲除芳烃受体(AHR) 后, 苯并芘对linc00673的上调作用被逆转, 沉默linc00673可显著抑制此过程, 表明苯并芘以AHR依赖性方式上调linc00673的表达来促进A549的EMT^[62]。

4 问题与展望

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4.1 肺纤维化EMT研究机制尚未完全阐明

现代EMT模型大多采用TGF-β、LPS等单一造模剂与上皮细胞共培养进行EMT模型构建, 然而最新研究已提出可塑性和过渡态的概念, 细胞并不总是在完整的上皮和完全间充质状态之间转化, 而是更加灵活, 存在着一系列中间阶段, 具体而言, 细胞可能处于中间状态徘徊, 即经常发生部分的EMT过程。但大多数实验仅选择过度简化的EMT模型, 倾向于关注上皮和间充质标志物的显著变化以确认EMT, 造成了一定的结论差异, 比如miR-34a在不同EMT模型中存在差异, 可能是由于不同的细胞类型和疾病阶段的异质性造成^[63]。若需在器官、组织、细胞中更好地研究EMT, 需要开发更好的动物、细胞模型。

4.2 ncRNA研究较为单一

越来越多的证据表明, ncRNA作为信号分子参与肺纤维化EMT的进程。但其中对于circRNA与lncRNA介导此病理过程的机制研究有限。lncRNA/circRNA-miRNA-mRNA调控网络都是通过相关基因数据库预测下游靶分子, 数据繁复, 此外, 非编码RNA的研究往往比较单一, 基本是线性的研究, 未充分考虑其在肺部炎性环境或纤维化过程其他效应细胞中的表达和功能, 因此还需整体性研究。

4.3 中医药介导非编码RNA干预肺纤维化EMT研究较少

药物介导EMT中ncRNA途径的研究空白较多, 肺纤维化的常规治疗药物包括广谱抗炎/抑制免疫力的药物, 诸如细胞毒药物、糖皮质激素类、环孢素A等, 均不能从根本上延缓纤维化进程, 效果有限; 美国FDA批准上市的吡非尼酮与尼达尼布作为有条件推荐应用于IPF, 虽然能部分延缓肺纤维化进展、改善患者生活质量, 但其不良反应和高昂的治疗费用限制了其推广使用^[64]。中医药作为巨大宝库, 对于开发安全有效且价格低廉的肺纤维化治疗药物有着广阔的前景, 目前发现清热解毒类中药具有广泛的应用, 对于肺纤维化或者EMT具有较好的治疗效果, 如灯盏花乙素(scutellarin)^[65]、高良姜素(galangin)^[66]、隐丹参酮(cryptotanshinone)^[67]等都通过EMT在体内和体外改善肺纤维化。但是中医药介导的非编码RNA调节肺纤维化EMT进程的研究较少。

综上所述, ncRNA广泛参与肺纤维化EMT进程, 对其作用及机制并对于疾病进程调控的研究具有广大的应用前景, 但目前大多仅停留在机制研究并且分子机制研究较为线性单一, 未从整体进行系统研究, 同时药物的干预调控研究存在较多空白, ncRNA影响EMT以及药物参与的机制还有待深入研究, 为抗肺纤维化新药的研发提供基础研究支撑。

作者贡献: 朱德伟负责文献检索、文章撰写和绘制插图; 余群负责协助文献检索并负责核对参考文献; 沈云辉负责文章的构思、设计框架和文章修改。

利益冲突: 本论文所有作者均声明无利益冲突。

基金

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国家中医药管理局中医药国际合作专项中医药国际化发展研究中心项目(GZYYGJ2020003)
上海中医药大学预算内项目(2019GJ170)

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2021年第56卷第11期

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doi: 10.16438/j.0513-4870.2021-0971

接收时间：2021-06-30
首发时间：2025-12-18
出版时间：2021-11-12

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收稿日期：2021-06-30
修回日期：2021-08-01

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国家中医药管理局中医药国际合作专项中医药国际化发展研究中心项目(GZYYGJ2020003)

上海中医药大学预算内项目(2019GJ170)

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上海中医药大学中药学院, 上海 201203

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*沈云辉, Tel: 86-21-51323146, E-mail: bravesyh@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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RefWorks
TxT

Type	Name	Expression	Function	Reference
miRNA	let-7d	Downregulation	Inhibit	[15, 16]
miR-26a	Downregulation	Inhibit	[17, 18]
miR-221	Downregulation	Inhibit	[19]
miR-200, miR-200b/c	Downregulation	Inhibit	[20, 21]
miR-1343	Downregulation	Inhibit	[22]
miR-338*(miR-338-5p)	Downregulation	Inhibit	[23]
miR-497	Downregulation	Inhibit	[24]
miR-448-5p	Downregulation	Inhibit	[25]
miR-106b-5p	Downregulation	Inhibit	[26]
miR-495-3p	Downregulation	Inhibit	[27]
miR-30	Downregulation	Inhibit	[28]
miR-155-5p	Downregulation	Inhibit	[29]
miR-184	Downregulation	Inhibit	[30]
miR-320a-3p	Downregulation	Inhibit	[31]
miR-140	Downregulation	Inhibit	[32]
miR-34a-5p	Downregulation	Inhibit	[33]
miR-182-5p, miR-23a-3p	Upregulation	Inhibit	[34]
miR-15b, miR-25, let-7d	Upregulation	Promote	[35]
miR-210	Upregulation	Promote	[36]
miR-4417	Upregulation	Promote	[37]
miR-21	Upregulation	Promote	[38, 39]
miR-34a	Upregulation	Promote	[40, 41]
miR-483-5p	Upregulation	Promote	[42]
miR-424	Upregulation	Promote	[43]
lncRNA	lncRNA uc.77, 05RiK	Upregulation	Promote	[44]
lncRNA HOTAIR, CARLo-5, CD99P1	Upregulation	Inhibit	[45]
lncRNA MALAT1	Upregulation	Promote	[46]
lncRNA-ATB	Upregulation	Promote	[47]
lncRNA ZEB1-AS1	Upregulation	Promote	[48]
lncRNA sirt1 NAT	Downregulation	Inhibit	[49]
lncRNA MEG3	Downregulation	Inhibit	[50]
lncRNA CHRF	Upregulation	Promote	[51]
lncRNA DLEU2	Upregulation	Promote	[52]
lncRNA NEAT1	Upregulation	Promote	[53, 54]
lncRNA CDR1as	Upregulation	Promote	[55]
circRNA	hsa_circ_0044226	Upregulation	Promote	[56]
circRNA-ZC3H4	Upregulation	Inhibit	[57]
mmu_circ_0000981	Upregulation	Promote	[58]

Type

Name

Expression

Function

Reference

miRNA

let-7d

Downregulation

Inhibit

[15, 16]

miR-26a

Downregulation

Inhibit

[17, 18]

miR-221

Downregulation

Inhibit

[19]

miR-200, miR-200b/c

Downregulation

Inhibit

[20, 21]

miR-1343

Downregulation

Inhibit

[22]

miR-338*(miR-338-5p)

Downregulation

Inhibit

[23]

miR-497

Downregulation

Inhibit

[24]

miR-448-5p

Downregulation

Inhibit

[25]

miR-106b-5p

Downregulation

Inhibit

[26]

miR-495-3p

Downregulation

Inhibit

[27]

miR-30

Downregulation

Inhibit

[28]

miR-155-5p

Downregulation

Inhibit

[29]

miR-184

Downregulation

Inhibit

[30]

miR-320a-3p

Downregulation

Inhibit

[31]

miR-140

Downregulation

Inhibit

[32]

miR-34a-5p

Downregulation

Inhibit

[33]

miR-182-5p, miR-23a-3p

Upregulation

Inhibit

[34]

miR-15b, miR-25, let-7d

Upregulation

Promote

[35]

miR-210

Upregulation

Promote

[36]

miR-4417

Upregulation

Promote

[37]

miR-21

Upregulation

Promote

[38, 39]

miR-34a

Upregulation

Promote

[40, 41]

miR-483-5p

Upregulation

Promote

[42]

miR-424

Upregulation

Promote

[43]

lncRNA

lncRNA uc.77, 05RiK

Upregulation

Promote

[44]

lncRNA
HOTAIR, CARLo-5, CD99P1

Upregulation

Inhibit

[45]

lncRNA MALAT1

Upregulation

Promote

[46]

lncRNA-ATB

Upregulation

Promote

[47]

lncRNA
ZEB1-AS1

Upregulation

Promote

[48]

lncRNA sirt1
NAT

Downregulation

Inhibit

[49]

lncRNA MEG3

Downregulation

Inhibit

[50]

lncRNA CHRF

Upregulation

Promote

[51]

lncRNA DLEU2

Upregulation

Promote

[52]

lncRNA NEAT1

Upregulation

Promote

[53, 54]

lncRNA CDR1as

Upregulation

Promote

[55]

circRNA

hsa_circ_0044226

Upregulation

Promote

[56]

circRNA-ZC3H4

Upregulation

Inhibit

[57]

mmu_circ_0000981

Upregulation

Promote

[58]

Drug	ncRNA	Effect	Reference
ASV	lncRNA sirt1 NAT (sirt1 AS)	Up-regulate	[49]
PTX	miR-140	Up-regulate	[32]
Sulindac	miR-21	Down-regulate	[39]
PG	miR-410	Down-regulate	[61]
Atr	mmu_circ_0000981	Down-regulate	[58]
BaP	linc00673	Up-regulate	[62]

Drug

ncRNA

Effect

Reference

ASV

lncRNA sirt1
NAT (sirt1 AS)

Up-regulate

[49]

PTX

miR-140

Up-regulate

[32]