脂肪干細胞治療急性肺損傷研究進展

佟昌慈， 柳云恩， 張玉彪， 施 琳， 叢培芳， 劉 穎， 史秀云， 毛 舜， 金紅旭， 侯明曉

沈陽軍區(qū)總醫(yī)院 急診醫(yī)學部 全軍重癥(戰(zhàn))創(chuàng)傷救治中心實驗室 遼寧省重癥創(chuàng)傷和器官保護重點實驗室，遼寧 沈陽 110016

·干細胞研究·

脂肪干細胞治療急性肺損傷研究進展

佟昌慈， 柳云恩， 張玉彪， 施 琳， 叢培芳， 劉 穎， 史秀云， 毛 舜， 金紅旭， 侯明曉

沈陽軍區(qū)總醫(yī)院 急診醫(yī)學部 全軍重癥(戰(zhàn))創(chuàng)傷救治中心實驗室 遼寧省重癥創(chuàng)傷和器官保護重點實驗室，遼寧 沈陽 110016

急性肺損傷； 炎癥反應； 脂肪干細胞

Acute lung injury； Inflammatory reaction； Adipose stem cells

在多發(fā)傷患者中，胸外傷是較為常見的[1-2]，而胸部創(chuàng)傷的危重患者具有極高的彌散性血管內(nèi)凝血、肺炎、急性肺損傷(acute lung injury，ALI)或急性呼吸窘迫綜合征(acute respiratory distress syndrome，ARDS)等并發(fā)癥發(fā)生率[3-4]，嚴重影響患者的存活率[5-7]。胸部創(chuàng)傷主要是由鈍性機制和肋骨骨折引起的，常出現(xiàn)氣胸和肺挫傷(pulmonary contusion，PC)[8]，50%患者在病程中出現(xiàn)肺炎或ARDS等并發(fā)癥[9-10]。此外，胸外傷是嚴重創(chuàng)傷患者發(fā)生ARDS的獨立危險因素[11]。胸部創(chuàng)傷引起肺損傷的原因是多方面的。首先，機械損傷本身會對肺部組織造成直接損傷；其次，炎癥反應可損傷肺泡毛細血管膜，引起肺通透性增加，進而導致肺水腫和肺泡充盈，隨后，炎癥級聯(lián)反應和凝血激活可引起ALI[12-13]。在其他呼吸道疾病中，ALI和ARDS的損傷機制與中性粒細胞浸潤肺壁有關(guān)。因此，肺組織損傷與由蛋白水解酶和氧化劑釋放引起的微血管損傷密切相關(guān)。直接或間接的胸部外傷通過Toll樣受體(Toll-like receptor，TLR)介導激活NF-κB通路，激活炎癥反應[14]。在炎癥反應發(fā)生過程中，中性粒細胞被招募到損傷部位。雖然ALI的具體病理生理機制尚不清楚，但中性粒細胞在肺組織中的積聚似乎是嚴重創(chuàng)傷后發(fā)生急性呼吸窘迫綜合征的主要機制之一。細菌性或病毒性肺炎、毒性吸入、溺水或PC可直接誘導ARDS的發(fā)生，而膿毒癥、胰腺炎、大量輸血和嚴重創(chuàng)傷可間接導致[15]。目前，可用的治療方法僅限于支持性治療，包括肺保護性通氣、高頻振蕩通氣、保守的液體策略和易于定位的緩解癥狀的治療方法等[16-17]。

除了ALI外，肺部炎癥性疾病還包括哮喘、慢性阻塞性肺病(chronic obstructive pulmonary disease，COPD)。全球有將近3億人患有哮喘[18]。哮喘是一種慢性炎癥性疾病，患者出現(xiàn)陣發(fā)性癥狀，如哮鳴音、咳嗽、胸悶、氣短。到目前為止，吸入具有抑炎作用的糖皮質(zhì)激素和長效β2激動劑仍然是該病的主要治療方法。雖然大多數(shù)哮喘患者對激素的治療反應良好，但仍有5%～10%患者的治療是無效的[19]。此外，長期使用類固醇激素會產(chǎn)生許多不良反應[20-21]。COPD也是一種慢性肺部炎癥性疾病，其特征是持續(xù)及進行性發(fā)展的氣流受限，同時伴有增強的炎癥反應，是一種具有氣流阻塞特征的肺氣腫和(或)慢性支氣管炎[4]。COPD是全球第4大死因，預計到2020年將達到第3位[4,22]。然而，其治療方法僅有有限數(shù)量的藥理學療法可供選擇[23-26]。令人驚訝的是，類固醇作為哮喘的強效抗炎劑，被發(fā)現(xiàn)在控制COPD相關(guān)炎癥方面效果較差[27-29]。到目前為止，還沒有真正改變這種疾病進展性的藥物。因此，尋找確定有效的ALI、哮喘和COPD等的治療方法具有重要意義。

干細胞包括胚胎干細胞(embryonic stem cells，ESCs)、誘導多能干細胞(induced pluripotent stem cells，iPSCs)和出生后的成體干細胞。ESCs能夠自我更新并分化成體內(nèi)任何一種細胞類型；iPSCs是遺傳基因重新編輯的體細胞，并具有ESCs的特征，但ESCs和iPSCs之間的區(qū)別尚不清楚[30-31]。由于倫理問題，在臨床研究和實踐中應用ESCs是很困難的，但iPSCs和成體干細胞沒有這樣的問題。近年來，從脂肪組織中分離得到了一種具有多向分化潛能的干細胞，即脂肪干細胞(adipose-derived stem cells，ADSCs)，是成體干細胞的一種。ADSCs能夠在體外穩(wěn)定增殖且衰亡率低，同時，ADSCs可以容易地從脂肪抽吸物或皮下脂肪組織碎片中提取獲得，并可在體外擴增。因此，其具有取材容易，少量組織即可獲取大量干細胞，適宜大規(guī)模培養(yǎng)，對機體損傷小等優(yōu)點，而且其來源廣泛，體內(nèi)儲備量大，適宜自體移植，另外，沒有倫理問題，適用于多種臨床應用[32-36]。ADSCs逐漸成為近年來新的研究熱點之一。

ADSCs被發(fā)現(xiàn)存在于任何類型的白色脂肪組織中，包括皮下和網(wǎng)膜脂肪，為了獲得分離ADSCs的脂肪組織，吸脂是一個安全且并發(fā)癥發(fā)生率較低方法[37-38]。來自吸脂的脂肪細胞的90%～100%是完整的，分離的ADSCs可以大力擴增，直到其進入特定細胞譜系的分化過程。ADSCs能夠在長期培養(yǎng)中體外分化成脂肪細胞、成骨細胞、軟骨細胞、肌細胞等[36]。由于ADSCs的多能性，其可廣泛應用于臨床，主要功能為修復組織細胞，促進細胞的再生等，適用于再生醫(yī)學。

ADSCs不但具有多功能的轉(zhuǎn)分化潛能，還表現(xiàn)出廣泛的分泌譜，可分泌促炎細胞因子、抗炎細胞因子、趨化因子和生長因子[39-41]。ADSCs分泌的旁分泌調(diào)節(jié)劑可通過調(diào)節(jié)同期性組織中的血分泌或營養(yǎng)性旁分泌作用以改善組織損傷關(guān)鍵活性[42-43]。 ADSCs的獨特分泌特征表明其特異性影響組織再生[44-45]，血管生成[46-47]和淋巴管生成[48]，同時，抑制局部免疫/炎癥反應[39,49]并減少纖維發(fā)生[50-51]。另外，ADSCs在缺氧條件下對非血管細胞具有保護作用，具有抗凋亡作用和抗氧化應激作用[52]。

肺損傷的治療修復主要集中在兩個方面，即調(diào)節(jié)炎癥反應和修復受損的肺組織細胞。因此，治療肺損傷的方法需要兼顧抗炎和損傷修復兩方面。ADSCs具有增強血管發(fā)生和驅(qū)動組織再生的性質(zhì)，同時，還具有介導抗炎、抗凋亡、抗纖維化、抗氧化和免疫調(diào)節(jié)性質(zhì)，這使ADSCs用以治療肺損傷具有可行性。

目前，關(guān)于ADSCs在肺損傷修復中的研究主要集中在基礎(chǔ)性實驗模擬階段。2011年，Schweitzer等[53]證明ADSCs對香煙煙霧引起的肺和全身損傷都具有積極的治療作用，通過減輕香煙煙霧對骨髓造血祖細胞功能的抑制作用，緩解香煙煙霧暴露期間小鼠持續(xù)的體質(zhì)量減輕和保護肺血管。同年，Sun等[54]通過大鼠肺缺血再灌注模型證明，ADSCs可通過抑制氧化應激和炎癥反應減少缺血再灌注肺損傷。接著，Yip等[55]在2013年證明褪黑素聯(lián)合ADSCs治療可有效抑制炎癥蛋白血管細胞黏附因子1、細胞間黏附分子1、腫瘤壞死因子α、NF-κB、血小板衍生因子和血管緊張素Ⅱ受體，氧化應激因子半胱天冬酶3和聚腺苷二磷酸核糖聚合酶，凋亡蛋白Bax的表達，保護肺部免于急性缺血再灌注損傷。Zhang等[56]比較人源性脂肪干細胞(human adipose-derived stem cells，hASCs)和小鼠源性脂肪干細胞(mouseadipose-derived stem cells，mASCs)在脂多糖誘導ALI動物模型中的療效，結(jié)果顯示兩種療法均可降低白細胞(如嗜中性粒細胞)的水平，降低肺泡灌洗液中的總蛋白和白蛋白濃度以及ALI誘導的過氧化物酶活性；另外，兩種細胞類型的細胞治療均有效地抑制了促炎細胞因子的表達，促進了抗炎細胞因子白細胞介素(interleukin,IL)-10的表達，但在該模型中的同基因的mASCs治療比異種hASCs治療更有效[56]。Liang等[57]研究發(fā)現(xiàn)，ADSCs治療可有效減輕肺水腫、組織學肺損傷指數(shù)、支氣管肺泡灌洗液中的嗜中性粒細胞數(shù)、腫瘤壞死因子-α、IL-1β、IL-6、IL-10和轉(zhuǎn)化生長因子-β1的含量，改善大鼠呼吸機誘導的肺損傷(ventilator-induced lung injury，VILI)。Sung等[58]在盲腸結(jié)扎穿孔引起的大鼠膿毒癥肺和腎損傷模型中驗證了凋亡脂肪干細胞(apoptotic adipose-derived stem cells，A-ADSCs)的治療效果優(yōu)于健康的hADSCs。2014年，Zhang等[59]研究ADSCs調(diào)節(jié)肺炎癥的機制，hASCs和mASCs治療的基因表達分析結(jié)果顯示，hASCs和mASCs在抗炎分子的表達之間存在顯著差異；hASCs和mASCs在ALI中的有益作用可能是由于不同旁分泌因子的產(chǎn)生；與hASCs處理相比，mASCs處理的肺中的IL-6表達顯著升高，通過RNA干擾敲除mASCs中的IL-6后消除了其大部分治療效果，表明ALI中mASCs的抗炎性質(zhì)至少是部分地通過激活I(lǐng)L-6的分泌來誘導的。同年，Zheng等[60]對同種異體ADSCs治療ARDS的不良事件及療效進行臨床研究，結(jié)果發(fā)現(xiàn)同種異體ADSCs施用在ARDS的治療中無不良反應發(fā)生，是安全可行的，但臨床療效較弱，需要進一步優(yōu)化ADSCs的劑量和應用策略來達到減少ARDS中肺泡上皮損傷的目的。在Chen等[61]的研究中發(fā)現(xiàn)，褪黑素可增強A-ADSCs治療盲腸結(jié)扎和穿刺引起的膿毒癥ALI。Jiang等[62]于2015年的研究顯示，大鼠尾靜脈輸送脂肪來源的間充質(zhì)基質(zhì)細胞(adipose-derived mesenchymal stemcell，Ad-MSC)減弱放射性肺損傷(radiation induced lung injury，RILI)，具有抗炎和抗纖維化作用，并維持肺上皮完整性，抑制促炎細胞因子IL-1、IL-6和腫瘤壞死因子α的血清水平，促進抗炎細胞因子IL-10水平升高，并且在照射的肺組織中下調(diào)轉(zhuǎn)化生長因子-β1、α-平滑肌肌動蛋白和Ⅰ型膠原水平，Ad-MSC還調(diào)節(jié)抗凋亡介質(zhì)(Bcl-2、Bax和Caspase-3)的表達，以保護肺細胞免于細胞凋亡。Tashiro等[63]研究表明，老年小鼠中博萊霉素誘導的肺纖維化可被年輕供體ADSCs阻斷，其機制涉及膠原周轉(zhuǎn)和炎癥標志物的變化。同時，Uji等[64]研究也顯示，氣管內(nèi)注射ADSCs在博萊霉素誘導的大鼠肺損傷模型中可發(fā)揮長期預防肺損傷持續(xù)惡化的作用。Aboul-Fotouh等[65]證明ADSCs與阿托伐他汀改善胺碘酮所致雄性大鼠的肺損傷，對肺組織的退行性、炎癥、凋亡和纖維化變化具有明顯的改善作用。2016年，Lu等[66-67]在金黃色葡萄球菌誘導的小鼠ALI模型中驗證了ADSCs主要通過Reg Ⅲγ的TLR2-MyD88-JAK2/STAT3依賴性分泌直接抗微生物活性。2017年，Ihara等[68]在羊吸入煙霧導致ARDS的模型中驗證了靜脈內(nèi)ADSCs可有效調(diào)節(jié)肺微血管超敏性，改善肺氣交換，阻止ARDS的發(fā)生。

在動物模型方面，ADSCs治療肺損傷的療效研究已經(jīng)取得的可喜的進展，ADSCs以其良好的抗炎、抗凋亡、抗纖維化、抗氧化和免疫調(diào)節(jié)性質(zhì)及優(yōu)異的增強血管發(fā)生和驅(qū)動組織再生的性質(zhì)，極大地改善了不同因素誘導的肺損傷，同時，ADSCs的自體移植十分方便，不存在移植排斥反應和道德倫理問題。

綜上所述，ADSCs用于治療肺損傷具有極大的可行性。但是，目前關(guān)于ADSCs的研究仍集中在動物模型中，且其具體的保護機制也尚不明確。ADSCs能否真正應用于臨床治療肺損傷患者，仍需進一步的深入研究，不過，隨著科研工作者研究的不斷深入，相信ADSCs移植治療肺損傷會具有十分廣闊的臨床應用前景。

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全軍十二五面上項目(CSY12J002)；全軍重大新藥創(chuàng)制項目(2013ZX09J13109-02B)；全軍十二五面上項目(CSY13J002)；總后衛(wèi)生部重大新上(ASM14L008)

佟昌慈(1988-)，女，遼寧撫順人，技師，碩士

侯明曉，E-mail：houmingxiao188@163.com

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

2017-09-05