脂肪干细胞治疗急性肺损伤研究进展

佟昌慈， 柳云恩， 张玉彪， 施 琳， 丛培芳， 刘 颖， 史秀云， 毛 舜， 金红旭， 侯明晓

沈阳军区总医院 急诊医学部 全军重症(战)创伤救治中心实验室 辽宁省重症创伤和器官保护重点实验室，辽宁 沈阳 110016

·干细胞研究·

脂肪干细胞治疗急性肺损伤研究进展

佟昌慈， 柳云恩， 张玉彪， 施 琳， 丛培芳， 刘 颖， 史秀云， 毛 舜， 金红旭， 侯明晓

沈阳军区总医院 急诊医学部 全军重症(战)创伤救治中心实验室 辽宁省重症创伤和器官保护重点实验室，辽宁 沈阳 110016

急性肺损伤； 炎症反应； 脂肪干细胞

Acute lung injury； Inflammatory reaction； Adipose stem cells

在多发伤患者中，胸外伤是较为常见的[1-2]，而胸部创伤的危重患者具有极高的弥散性血管内凝血、肺炎、急性肺损伤(acute lung injury，ALI)或急性呼吸窘迫综合征(acute respiratory distress syndrome，ARDS)等并发症发生率[3-4]，严重影响患者的存活率[5-7]。胸部创伤主要是由钝性机制和肋骨骨折引起的，常出现气胸和肺挫伤(pulmonary contusion，PC)[8]，50%患者在病程中出现肺炎或ARDS等并发症[9-10]。此外，胸外伤是严重创伤患者发生ARDS的独立危险因素[11]。胸部创伤引起肺损伤的原因是多方面的。首先，机械损伤本身会对肺部组织造成直接损伤；其次，炎症反应可损伤肺泡毛细血管膜，引起肺通透性增加，进而导致肺水肿和肺泡充盈，随后，炎症级联反应和凝血激活可引起ALI[12-13]。在其他呼吸道疾病中，ALI和ARDS的损伤机制与中性粒细胞浸润肺壁有关。因此，肺组织损伤与由蛋白水解酶和氧化剂释放引起的微血管损伤密切相关。直接或间接的胸部外伤通过Toll样受体(Toll-like receptor，TLR)介导激活NF-κB通路，激活炎症反应[14]。在炎症反应发生过程中，中性粒细胞被招募到损伤部位。虽然ALI的具体病理生理机制尚不清楚，但中性粒细胞在肺组织中的积聚似乎是严重创伤后发生急性呼吸窘迫综合征的主要机制之一。细菌性或病毒性肺炎、毒性吸入、溺水或PC可直接诱导ARDS的发生，而脓毒症、胰腺炎、大量输血和严重创伤可间接导致[15]。目前，可用的治疗方法仅限于支持性治疗，包括肺保护性通气、高频振荡通气、保守的液体策略和易于定位的缓解症状的治疗方法等[16-17]。

除了ALI外，肺部炎症性疾病还包括哮喘、慢性阻塞性肺病(chronic obstructive pulmonary disease，COPD)。全球有将近3亿人患有哮喘[18]。哮喘是一种慢性炎症性疾病，患者出现阵发性症状，如哮鸣音、咳嗽、胸闷、气短。到目前为止，吸入具有抑炎作用的糖皮质激素和长效β2激动剂仍然是该病的主要治疗方法。虽然大多数哮喘患者对激素的治疗反应良好，但仍有5%～10%患者的治疗是无效的[19]。此外，长期使用类固醇激素会产生许多不良反应[20-21]。COPD也是一种慢性肺部炎症性疾病，其特征是持续及进行性发展的气流受限，同时伴有增强的炎症反应，是一种具有气流阻塞特征的肺气肿和(或)慢性支气管炎[4]。COPD是全球第4大死因，预计到2020年将达到第3位[4,22]。然而，其治疗方法仅有有限数量的药理学疗法可供选择[23-26]。令人惊讶的是，类固醇作为哮喘的强效抗炎剂，被发现在控制COPD相关炎症方面效果较差[27-29]。到目前为止，还没有真正改变这种疾病进展性的药物。因此，寻找确定有效的ALI、哮喘和COPD等的治疗方法具有重要意义。

干细胞包括胚胎干细胞(embryonic stem cells，ESCs)、诱导多能干细胞(induced pluripotent stem cells，iPSCs)和出生后的成体干细胞。ESCs能够自我更新并分化成体内任何一种细胞类型；iPSCs是遗传基因重新编辑的体细胞，并具有ESCs的特征，但ESCs和iPSCs之间的区别尚不清楚[30-31]。由于伦理问题，在临床研究和实践中应用ESCs是很困难的，但iPSCs和成体干细胞没有这样的问题。近年来，从脂肪组织中分离得到了一种具有多向分化潜能的干细胞，即脂肪干细胞(adipose-derived stem cells，ADSCs)，是成体干细胞的一种。ADSCs能够在体外稳定增殖且衰亡率低，同时，ADSCs可以容易地从脂肪抽吸物或皮下脂肪组织碎片中提取获得，并可在体外扩增。因此，其具有取材容易，少量组织即可获取大量干细胞，适宜大规模培养，对机体损伤小等优点，而且其来源广泛，体内储备量大，适宜自体移植，另外，没有伦理问题，适用于多种临床应用[32-36]。ADSCs逐渐成为近年来新的研究热点之一。

ADSCs被发现存在于任何类型的白色脂肪组织中，包括皮下和网膜脂肪，为了获得分离ADSCs的脂肪组织，吸脂是一个安全且并发症发生率较低方法[37-38]。来自吸脂的脂肪细胞的90%～100%是完整的，分离的ADSCs可以大力扩增，直到其进入特定细胞谱系的分化过程。ADSCs能够在长期培养中体外分化成脂肪细胞、成骨细胞、软骨细胞、肌细胞等[36]。由于ADSCs的多能性，其可广泛应用于临床，主要功能为修复组织细胞，促进细胞的再生等，适用于再生医学。

ADSCs不但具有多功能的转分化潜能，还表现出广泛的分泌谱，可分泌促炎细胞因子、抗炎细胞因子、趋化因子和生长因子[39-41]。ADSCs分泌的旁分泌调节剂可通过调节同期性组织中的血分泌或营养性旁分泌作用以改善组织损伤关键活性[42-43]。 ADSCs的独特分泌特征表明其特异性影响组织再生[44-45]，血管生成[46-47]和淋巴管生成[48]，同时，抑制局部免疫/炎症反应[39,49]并减少纤维发生[50-51]。另外，ADSCs在缺氧条件下对非血管细胞具有保护作用，具有抗凋亡作用和抗氧化应激作用[52]。

肺损伤的治疗修复主要集中在两个方面，即调节炎症反应和修复受损的肺组织细胞。因此，治疗肺损伤的方法需要兼顾抗炎和损伤修复两方面。ADSCs具有增强血管发生和驱动组织再生的性质，同时，还具有介导抗炎、抗凋亡、抗纤维化、抗氧化和免疫调节性质，这使ADSCs用以治疗肺损伤具有可行性。

目前，关于ADSCs在肺损伤修复中的研究主要集中在基础性实验模拟阶段。2011年，Schweitzer等[53]证明ADSCs对香烟烟雾引起的肺和全身损伤都具有积极的治疗作用，通过减轻香烟烟雾对骨髓造血祖细胞功能的抑制作用，缓解香烟烟雾暴露期间小鼠持续的体质量减轻和保护肺血管。同年，Sun等[54]通过大鼠肺缺血再灌注模型证明，ADSCs可通过抑制氧化应激和炎症反应减少缺血再灌注肺损伤。接着，Yip等[55]在2013年证明褪黑素联合ADSCs治疗可有效抑制炎症蛋白血管细胞黏附因子1、细胞间黏附分子1、肿瘤坏死因子α、NF-κB、血小板衍生因子和血管紧张素Ⅱ受体，氧化应激因子半胱天冬酶3和聚腺苷二磷酸核糖聚合酶，凋亡蛋白Bax的表达，保护肺部免于急性缺血再灌注损伤。Zhang等[56]比较人源性脂肪干细胞(human adipose-derived stem cells，hASCs)和小鼠源性脂肪干细胞(mouseadipose-derived stem cells，mASCs)在脂多糖诱导ALI动物模型中的疗效，结果显示两种疗法均可降低白细胞(如嗜中性粒细胞)的水平，降低肺泡灌洗液中的总蛋白和白蛋白浓度以及ALI诱导的过氧化物酶活性；另外，两种细胞类型的细胞治疗均有效地抑制了促炎细胞因子的表达，促进了抗炎细胞因子白细胞介素(interleukin,IL)-10的表达，但在该模型中的同基因的mASCs治疗比异种hASCs治疗更有效[56]。Liang等[57]研究发现，ADSCs治疗可有效减轻肺水肿、组织学肺损伤指数、支气管肺泡灌洗液中的嗜中性粒细胞数、肿瘤坏死因子-α、IL-1β、IL-6、IL-10和转化生长因子-β1的含量，改善大鼠呼吸机诱导的肺损伤(ventilator-induced lung injury，VILI)。Sung等[58]在盲肠结扎穿孔引起的大鼠脓毒症肺和肾损伤模型中验证了凋亡脂肪干细胞(apoptotic adipose-derived stem cells，A-ADSCs)的治疗效果优于健康的hADSCs。2014年，Zhang等[59]研究ADSCs调节肺炎症的机制，hASCs和mASCs治疗的基因表达分析结果显示，hASCs和mASCs在抗炎分子的表达之间存在显著差异；hASCs和mASCs在ALI中的有益作用可能是由于不同旁分泌因子的产生；与hASCs处理相比，mASCs处理的肺中的IL-6表达显著升高，通过RNA干扰敲除mASCs中的IL-6后消除了其大部分治疗效果，表明ALI中mASCs的抗炎性质至少是部分地通过激活IL-6的分泌来诱导的。同年，Zheng等[60]对同种异体ADSCs治疗ARDS的不良事件及疗效进行临床研究，结果发现同种异体ADSCs施用在ARDS的治疗中无不良反应发生，是安全可行的，但临床疗效较弱，需要进一步优化ADSCs的剂量和应用策略来达到减少ARDS中肺泡上皮损伤的目的。在Chen等[61]的研究中发现，褪黑素可增强A-ADSCs治疗盲肠结扎和穿刺引起的脓毒症ALI。Jiang等[62]于2015年的研究显示，大鼠尾静脉输送脂肪来源的间充质基质细胞(adipose-derived mesenchymal stemcell，Ad-MSC)减弱放射性肺损伤(radiation induced lung injury，RILI)，具有抗炎和抗纤维化作用，并维持肺上皮完整性，抑制促炎细胞因子IL-1、IL-6和肿瘤坏死因子α的血清水平，促进抗炎细胞因子IL-10水平升高，并且在照射的肺组织中下调转化生长因子-β1、α-平滑肌肌动蛋白和Ⅰ型胶原水平，Ad-MSC还调节抗凋亡介质(Bcl-2、Bax和Caspase-3)的表达，以保护肺细胞免于细胞凋亡。Tashiro等[63]研究表明，老年小鼠中博莱霉素诱导的肺纤维化可被年轻供体ADSCs阻断，其机制涉及胶原周转和炎症标志物的变化。同时，Uji等[64]研究也显示，气管内注射ADSCs在博莱霉素诱导的大鼠肺损伤模型中可发挥长期预防肺损伤持续恶化的作用。Aboul-Fotouh等[65]证明ADSCs与阿托伐他汀改善胺碘酮所致雄性大鼠的肺损伤，对肺组织的退行性、炎症、凋亡和纤维化变化具有明显的改善作用。2016年，Lu等[66-67]在金黄色葡萄球菌诱导的小鼠ALI模型中验证了ADSCs主要通过Reg Ⅲγ的TLR2-MyD88-JAK2/STAT3依赖性分泌直接抗微生物活性。2017年，Ihara等[68]在羊吸入烟雾导致ARDS的模型中验证了静脉内ADSCs可有效调节肺微血管超敏性，改善肺气交换，阻止ARDS的发生。

在动物模型方面，ADSCs治疗肺损伤的疗效研究已经取得的可喜的进展，ADSCs以其良好的抗炎、抗凋亡、抗纤维化、抗氧化和免疫调节性质及优异的增强血管发生和驱动组织再生的性质，极大地改善了不同因素诱导的肺损伤，同时，ADSCs的自体移植十分方便，不存在移植排斥反应和道德伦理问题。

综上所述，ADSCs用于治疗肺损伤具有极大的可行性。但是，目前关于ADSCs的研究仍集中在动物模型中，且其具体的保护机制也尚不明确。ADSCs能否真正应用于临床治疗肺损伤患者，仍需进一步的深入研究，不过，随着科研工作者研究的不断深入，相信ADSCs移植治疗肺损伤会具有十分广阔的临床应用前景。

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全军十二五面上项目(CSY12J002)；全军重大新药创制项目(2013ZX09J13109-02B)；全军十二五面上项目(CSY13J002)；总后卫生部重大新上(ASM14L008)

佟昌慈(1988-)，女，辽宁抚顺人，技师，硕士

侯明晓，E-mail：houmingxiao188@163.com

2095-5561(2017)05-0292-06DOI∶10.16048/j.issn.2095-5561.2017.05.09

2017-09-05