Association of aging with pulmonary fibrosis and chronic obstructive pulmonary disease and treatment with mesenchymal stem cells

doi:10.3969/j.issn.2095-4344.1714

Abstract

Abstract:

BACKGROUND: Aging is closely related to the occurrence and development of pulmonary fibrosis and chronic obstructive pulmonary disease, and mesenchymal stem cells may have therapeutic effects on senile pulmonary fibrosis and chronic obstructive pulmonary disease due to their characteristics.
OBJECTIVE: To review the relationship between aging and pulmonary fibrosis and chronic obstructive pulmonary disease, as well as the therapeutic effect and mechanism of mesenchymal stem cells.
METHODS: PubMed and CNKI database were searched for articles published from June 2005 to October 2018 on pulmonary fibrosis, the relationship between chronic obstructive pulmonary disease and aging, as well as the relationship between mesenchymal stem cells for the treatment of chronic obstructive pulmonary disease and pulmonary fibrosis. The key words in Chinese were “pulmonary fibrosis, chronic obstructive pulmonary disease, aging, mesenchymal stem cells”, and the English terms were “pulmonary fibrosis, COPD, aging, MSCs.” Obsolete and unrelated studies were excluded, and finally 64 articles were reviewed.
RESULTS AND CONCLUSION: Length of the telomere, cell and immunosenescence, oxidative stress and many anti-aging molecules and changes in the extracellular matrix are closely related to pulmonary fibrosis and chronic obstructive pulmonary disease. Mesenchymal stem cells are pluripotent cells that have self-renewal, multilineage differentiation and secretion activity, adjust the aging molecules from oxidation stress, and reduce cell senescence and apoptosis, to treat pulmonary fibrosis associated with aging and chronic obstructive pulmonary disease.

Key words: mesenchymal stem cells, chronic obstructive pulmonary disease, pulmonary fibrosis, cell senescence, cell apoptosis, anti-oxidative stress, telomere length, extracellular matrix

CLC Number:

Yang Yukun, Zhu Xiangqing, Ruan Guangping, Wang Yanying, Kan Xiaoli, Zhang Xuejuan, Yu Qianqian, Wang Mao, He Huanyu,Pan Xinghua. Association of aging with pulmonary fibrosis and chronic obstructive pulmonary disease and treatment with mesenchymal stem cells[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(17): 2746-2752.

Figures/Tables 3

2.1 衰老与肺纤维化、慢性阻塞性肺疾病的关系衰老是一个自然老化的过程，其表现为进行性功能障碍和对环境刺激及损伤作出适当反应的能力降低[6]。像任何其他器官一样，肺也会衰老。生理性肺衰老包括组织学变化(肺泡增大、肺泡壁破坏、气道交换表面积减少，气道阻塞或闭塞减少、肺血管减少)和功能改变(弹性反冲减少、残余气体增加以及气体交换障碍)导致的肺通气与换气功能减退[7]。另一方面，根据流行病学报道，衰老与多种慢性疾病的发病率有关，如动脉粥样硬化、骨质疏松症、2型糖尿病、癌症等[2]。肺也不例外，调查发现许多慢性肺部疾病的发病率均随年龄的增加而增加，如肺气肿、肺纤维化等[8]。当前认为，端粒长度调节、细胞和免疫衰老、氧化应激以及许多抗衰老分子和细胞外基质变化是衰老的关键[9]，且在肺纤维化、慢性阻塞性肺疾病的发生发展中起重要作用[10]。 2.1.1 端粒长度的调节端粒是染色体末端的区域，含有1-5 kb(TTAGGG)一段重复序列，可使DNA免于降解和重组，保护染色体的稳定性[11]。在大多数体细胞中，该区域DNA聚合酶难以合成DNA，端粒会随着细胞周期的增加而缩短，而过短的端粒会导致细胞周期永久性停滞，使细胞进入衰老状态。同时，在体内所有循环的体细胞迟早都会永久停止分裂，进入衰老状态，有研究表明衰老细胞的积累是造成衰老和与衰老有关疾病的重要原因[12]。因此，迄今为止端粒长度已成为描述老化的重要标志之一，已有报道称端粒长度的异常存在于某些肺疾病中。Moela等[13]发现慢性阻塞性肺疾病患者的端粒长度和正常人相比明显缩短。另有研究表明，这种缩短在有肺气肿改变的患者中更加严重[14]。同时，端粒长度的调节与肺纤维化也密切相关，据报道几乎全部的特发性肺纤维化患者均有端粒的异常缩短，并且在家族性特发性肺纤维化中有20%发生了端粒基因的突变[15-17]。 2.1.2 氧化应激氧化应激意味着氧化剂和抗氧化剂之间的不平衡且有利于氧化。人类的有氧生活增加了细胞和组织成分过度氧化的危险，这可能会损害细胞功能和生存能力。氧化产物的形成和积累在各种病理和正常衰老过程中都有观察到，并被认为在衰老过程中起关键作用[18]。慢性阻塞性肺疾病发生和发展的一个重要原因是肺部加速衰老，这个进程可能与高水平的氧化应激对肺部功能和结构的影响有关。研究发现，在慢性阻塞性肺疾病患者的肺部、血液以及骨骼肌中均发现有高水平氧化应激的证据，这可能是线粒体功能紊乱产生过多的活性氧和线粒体氧化损伤导致的结果[19]。另外，Malli等[20]发现在肺纤维化患者的肺泡灌洗液中氧化应激因子8-异前列烷水平显著升高，这表明在肺纤维化患者的肺部存在着较高的氧化应激水平，而衰老的进程与氧化应激水平呈正相关。 2.1.3 细胞衰老和干细胞耗竭细胞衰老是一种细胞周期停滞、趋向凋亡的细胞状态。正常情况下，衰老细胞可被免疫系统清除，但随着年龄的增加，衰老细胞数量在组织中逐渐增加。衰老细胞能分泌多种炎症因子，而且由于其增殖能力和正常生理功能丧失而干扰正常组织的稳态和修复[21]。根据以往研究来看，细胞衰老可通过至少两种非互斥的机制促成慢性阻塞性肺疾病。首先，在慢性阻塞性肺疾病中上皮细胞和内皮细胞凋亡增多，这造成了肺泡壁中细胞的损失，此时应该发生涉及细胞增殖的补偿机制，以消除肺泡细胞的丢失[22]。然而，当细胞衰老发生时，其增殖能力丧失，平衡倾向于细胞凋亡并由此形成慢性阻塞性肺疾病；其次，有证据表明细胞衰老与炎症之间存在密切关系。衰老细胞可表现出NF-κB的活化，以及释放各种炎性细胞因子，导致炎症增强[23]。这些与衰老相关的促炎机制在人肺组织中得到了证实，例如有研究发现在p16阳性的Ⅱ型肺泡上皮中，肿瘤坏死因子α表达量与对照组相比明显增加，并且这种p16阳性细胞的衰老程度与慢性阻塞性肺疾病炎症严重程度之间也存在着正相关性[24]。另外，细胞衰老也被证明与特发性肺纤维化的发病密切相关。Hecker等[25]发现，老年肺纤维化小鼠模型的肺部存在着异于正常数量的衰老和抗凋亡的肌成纤维细胞，并且还证明了这些细胞在持续肺纤维化中起关键作用。还有研究表明，支气管上皮衰老也是特发性肺纤维化进程的关键因素，其与患者支气管上皮的再上皮化密切相关，并且这种再上皮化可被SIRT6拮抗[26]。衰老过程中也伴随着干细胞的衰老和耗竭，而这种干细胞耗竭现象对组织和器官的修复存在着严重不利影响，这也使得老年动物肺部在内外刺激的作用下更容易发生纤维化[27]。 2.1.4 衰老和抗衰老分子的改变衰老过程中，伴随着许多分子的变化，已有多项报道证实这些衰老分子的变化和肺疾病关系密切。已知衰老会伴随着DNA和RNA变化，年龄相关的DNA甲基化改变被称为“表观遗传时钟”。众所周知，香烟是慢性阻塞性肺疾病的主要危险因素，在香烟所致的慢性阻塞性肺疾病模型中，存在DNA的过度甲基化，并且这类改变与肺功能和疾病的严重程度相关[10]。另外，肺纤维化的发生与DNA的甲基化也密切相关，Dakhlallah等[28]发现在衰老过程中miR-17-92的减少可致使DNA甲基转移酶增加，导致肺纤维化的发生；再者，组蛋白去乙酰化酶可以减少组蛋白的乙酰化，其活性也与衰老密切相关。组蛋白去乙酰化酶参与了慢性阻塞性肺疾病的发病机制，导致炎性基因的表达增强。患有慢性阻塞性肺疾病人群的肺部巨噬细胞和支气管组织中均能观察到组蛋白去乙酰化酶活性的降低，并且这种降低与慢性阻塞性肺疾病严重程度呈正相关。同样，Sirtuins家族NAD+依赖的Ⅲ类蛋白质脱乙酰酶是一类抗衰老酶，其中具有抗衰老活性的SIRT1、SIRT6水平在慢性阻塞性肺疾病患者的外周血和肺组织中明显减低[29]。另外，Baker等[30]还发现Sirtuins的表达受microRNA MiR-34a调节，在慢性阻塞性肺疾病患者中高度表达的microRNA MiR-34a导致Sirtuins表达显著减少。 2.1.5 免疫失调衰老可引起先天性和适应性免疫改变，这些改变使细胞对病原体和环境损害的防御机制下调，如衰老可使Toll样受体识别细菌抗原的先天免疫应答被钝化、巨噬细胞吞噬能力降低，从而使肺部更容易受外界病原体的感染[31]。同时，衰老可以导致炎症调控的异常，使某些肺疾病的发展进一步加剧。John-Schuster等[32]发现，暴露于香烟烟雾的老年小鼠比年轻小鼠具有更高的炎症水平，并且更容易患肺气肿。这种老年动物肺部炎症细胞和炎症递质的较高水平，可能导致更低水平的修复，从而更容易患肺气肿。2015年的两项研究表明，由于氧化应激、炎症和细胞凋亡，Klotho这种具有抗炎特性的抗衰老蛋白在肺泡巨噬细胞和慢性阻塞性肺疾病患者气道上皮细胞中显著减少[33-34]。根据上述案例，作者可以分析，衰老可使肺部对内外刺激反应发生异常，产生较高的炎症水平，进而加速肺部衰老，形成恶性循环；同时，衰老涉及的免疫失调还可以在没有抗原攻击的情况下通过非特异性炎症形式出现，这通常与循环细胞因子如肿瘤坏死因子α、白细胞介素β和白细胞介素6的增加有关，并且被描述为炎症衰老。炎症衰老可能代表衰老相关表型谱的一部分，对邻近细胞产生深远影响[35]。在慢性阻塞性肺疾病的进程中，也发现了肺部在没有外界因素的刺激下，产生了与炎症衰老相似的无菌性非特异性炎症[36]。作者推断，衰老与慢性阻塞性肺疾病的进展可能是相辅相成的关系。另外，慢性阻塞性肺疾病中miR-125a和miR-125b水平的增加导致NF-κB活化和病毒清除率的降低也与衰老相关炎症和免疫应答受损密不可分[37]。 2.1.6 细胞外基质的变化已知衰老涉及几乎所有器官中细胞外基质的变化。研究表明，大多数慢性肺病，特别是慢性阻塞性肺疾病和特发性肺纤维化，与细胞外基质的表达、周转、沉积、降解的改变有关。现在认为细胞外基质的变化发生在肺损伤早期，并且能抑制修复，促进疾病的发展[38]。老化肺的特征在于较高水平的胶原沉积与弹性蛋白表达减少，老化啮齿动物肺组织中胶原蛋白、纤连蛋白和基质金属蛋白酶的表达均发生了变化[39]。同样，在慢性阻塞性肺疾病和肺纤维化患者中也观察到了类似的变化，如在肺纤维化患者肺部发现有过多胶原蛋白的累积，在慢性阻塞性肺疾病患者的肺部观察到核心蛋白聚糖和双糖链蛋白多糖的减少[40]。综上所述，衰老与肺纤维化、慢性阻塞性肺疾病的发生发展密切相关，但当前的各种治疗手段各有弊端，并不能很好地治疗和预防上述与衰老有关的肺疾病[3，41]。从衰老与肺纤维化、慢性阻塞性肺疾病关联的机制角度出发，探究肺纤维化、慢性阻塞性肺疾病的治疗方法，或许可能成为治疗这类疾病的新道路。 2.2 间充质干细胞治疗肺纤维化、慢性阻塞性肺疾病的疗效与机制间充质干细胞，也被称为多能基质细胞或间充质基质细胞，其最早于骨髓中被发现，富含CD105，CD73和CD90，而缺乏CD45，CD34，CD14或CD11b，CD79a或CD19和HLA-DR表面分子，并具有自我更新能力和多项分化潜能。迄今为止，间充质干细胞已能从多种不同的结缔组织中(如脂肪组织、肌肉、胎盘、脐带基质、血液、肝脏和牙髓等)分离获得。目前认为，间充质干细胞不仅具有自我更新和分化能力，并且能够在衰老损伤部位分泌多种具有生物活性的因子(如神经生长因子、血管内皮生长因子、血管内皮生长因子受体2、碱性成纤维生长因子等)、与其他细胞相接触传导信号、将自身具有良好功能的结构转移到受损细胞(如线粒体的转移)等方式，起到免疫调节、抗凋亡、血管生成、促进局部干/祖细胞的生长和分化等作用。因此间充质干细胞可能是治疗衰老相关慢性阻塞性肺疾病、肺纤维化的有效手段[5]。从目前已有的研究来看，间充质干细胞主要从5个方面对肺纤维化、慢性阻塞性肺疾病起作用。 2.2.1 端粒的调节衰老与端粒的改变关系密切，某些肺疾病伴随着端粒的改变。研究表明，特发性肺纤维化患者通过药物治疗可减少其端粒的损耗，并改善患者的病情[42]。间充质干细胞可以改善受损老化细胞中端粒的磨损[43]。由此推断，间充质干细胞可能通过减少衰老肺泡上皮细胞、成纤维细胞等端粒的磨损，来延缓肺部疾病的进展，改善肺功能。 2.2.2 减少氧化应激衰老过程中逐渐增强的氧化应激是导致肺疾病的重要因素。减轻氧化应激，可以改善组织的衰老、减少肺疾病的发生、延缓慢性肺病的进展。研究发现，间充质干细胞对组织的过度氧化应激有明显的改善作用。活性氧是细胞活动中消耗氧气而产生的物质，其与氧化应激密切相关。Liu等[44]发现骨髓间充质干细胞可有效减少肺损伤大鼠肺组织中的活性氧，减轻肺部损伤。同时，超氧化物歧化酶是广泛分布于原核和真核细胞中的金属酶，其作为氧自由基的天敌，能对抗和阻断氧自由基对细胞造成的损害，并及时修复受损细胞，对人体不断补充超氧化物歧化酶具有抗衰老的特殊效果[45]。Huang等[46]研究发现骨髓间充质干细胞植入的肺纤维化小鼠模型肺组织中超氧化物歧化酶活性和总抗氧化活力显著增加，表明间充质干细胞可减轻肺组织氧化应激。另外，丙二醛和血红素氧合酶1是两种相拮抗的物质，前者具有增强氧化应激的作用，而后者则具有抗氧化应激和保护细胞的功能。Fredenblibgh等[47]发现间充质干细胞可在降低肺部丙二醛水平的同时增加血红素氧合酶1的合成。 2.2.3 补充耗竭的干细胞，调节衰老相关分子，改善细胞凋亡和衰老，修复肺组织间充质干细胞可作为已耗竭干细胞的一种补充，通过抗衰老和凋亡的作用，治疗肺纤维化、慢性阻塞性肺疾病。目前，已有报道称骨髓间充质干细胞在体内外都可分化为肺泡上皮细胞，且能在肺部定植，例如Huang等[46]通过静脉植入骨髓间充质干细胞能减轻肺纤维化大鼠肺纤维化的程度，并且能定植在模型大鼠肺部，分化为Ⅱ型肺泡上皮。Liu等[48]发现，植入小鼠肺损伤模型的人脐带间充质干细胞能发挥抑制细胞衰老和凋亡的作用，肺组织中有间充质干细胞定植。另外，间充质干细胞还可在特定部位分泌各种因子来抑制衰老，修复肺组织，见图2。肝细胞生长因子是一种能刺激肝细胞增殖的物质，现在认为其有诱导肺上皮细胞增殖、迁移的作用，并具有抑制肺上皮细胞凋亡及抗纤维化的特性。研究发现，大鼠骨髓间充质干细胞可以分泌肝细胞生长因子来修复肺泡上皮细胞损伤，同时减少博来霉素诱导的大鼠肺纤维化[49]。同样，血管内皮生长因子是最有效的促血管生长因子，其能促进肺泡上皮增殖和肺损伤后毛细血管的形成[50]。Guan等[51]报道脐带间充质干细胞可通过上调血管内皮生长因子减少细胞凋亡，改善慢性阻塞性肺疾病大鼠肺部损害。然而，血管内皮生长因子的表达有很多不良反应，例如提高肝癌发病率等，为了避免与血管内皮生长因子表达相关的并发症，研究人员通过用c-白藜芦醇下调间充质干细胞的热休克蛋白70启动子，实现了血管内皮生长因子的条件表达，而且这种经过诱导的间充质干细胞在香烟提取物攻击中，表现出比对照组更高的存活率，与弹性蛋白酶诱导的肺气肿模拟对照相比，条件表达血管内皮生长因子的间充质干细胞具有更好的治疗效果[52]。除了以上机制外，间充质干细胞还可调节一些与凋亡、衰老相关的分子来修复肺组织。前文中已经概述了衰老与DNA的甲基化密切相关，有研究表明，间充质干细胞可通过miR-29b介导的Dnmt1下调来减低DNA的甲基化，改善细胞衰老[53]；Yuan等[54]发现间充质干细胞还能上调抗衰老相关分子SIRT1来调节线粒体的功能，从而改善氧化应激。另外在脐带间充质干细胞治疗衰老小鼠肺部也发现了衰老相关蛋白(p16、p53)表达减少[55]。"

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