J Extracell Vesicles:瞿介明教授采用同种异体脂肪间充质细胞来源细胞外囊泡治疗ARDS的临床前研究

2021-09-19 网络 网络

急性呼吸窘迫综合征 (ARDS) 的特征是弥漫性肺泡损伤,占重症监护病房 (ICU) 入院人数的 10%,并存在于 25% 的机械通气患者中。 多种临床疾病可导致 ARDS,例如严重外伤、肺炎、败血症

急性呼吸窘迫综合征 (ARDS) 的特征是弥漫性肺泡损伤,占重症监护病房 (ICU) 入院人数的 10%,并存在于 25% 的机械通气患者中。 多种临床疾病可导致 ARDS,例如严重外伤、肺炎、败血症和胰腺炎。尽管管理主要基于支持性措施,例如保护性机械通气、神经肌肉阻滞剂或俯卧位,但全球 ARDS 死亡率仍然很高,约为30%。大量的研究表明间充质细胞来源的细胞外囊泡在组织损伤修复、免疫调节等方面发挥着重要的作用,但间充质细胞来源的细胞外囊泡对ARDS临床治疗的有效性和安全性还有待进一步确认。

近日,来自上海交通大学医学院附属瑞金医院的瞿介明教授团队发表了最新研究成果,介绍了同种异体脂肪间充质细胞来源细胞外囊泡用于雾化吸入治疗ARDS的有效性和安全性评价结果。相关论文以“Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derivedextracellular vesicles”为题,发表在Journal of Extracellular Vesicles上。

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间充质基质细胞在静息或诸如缺氧应激、辐射、氧化损伤或血清饥饿等不同刺激下均会释放的细胞外囊泡 (EVs)。 EVs 是细胞间通讯的重要信号介质,它们能够运输特定的蛋白质、mRNA 和 microRNA。多项临床前研究支持 MSC-EVs 在包括 LPS刺激、烟雾吸入、烧伤和创伤等不同类型的非传染性因素引起的急性肺损伤中具有潜在治疗价值。此外,还有大量证据表明气管接种活大肠杆菌和铜绿假单胞菌 (PA)引起的肺部炎症能够被 MSCs和 MSC来源的EV所缓解。巨噬细胞吞噬作用、细菌杀伤和最终预后结果得到改善,这些证据表明 MSC-EVs 给药与 MSCs 治疗对接种性肺炎的益处相似。

MSC-EVs 与MSCs对肺损伤模型的治疗特性相似,而MSC-EV更易于制备、储存和输送到临床病人身边,同时避免某些细胞治疗限制,例如肺栓塞和肿瘤形成的风险。目前已有的几项临床研究表明,施用 MSC(高达 10^7 个细胞/公斤体重的剂量)可能是 ARDS 的一种治疗方法。多项临床试验表明,静脉输注 MSCs 和 MSC-EVs 对 SARS-CoV-2 引起的严重肺损伤是安全有效的。但是,迄今为止,已发表的关于 MSCs 和 MSC-EVs 治疗ARDS 的临床试验大多数都是采用静脉注射给药策略。虽然,在这些研究中 MSCs 和 MSC-EVs 治疗的安全性得到了肯定,但治疗效果并不显著,这可能是由于静脉给药的策略造成的。鉴于其在递送至肺部的药物生物利用度方面的优异性能,雾化途径构成了肺损伤背景下理想的给药策略。

该研究通过DiR标记MSC-EVs,观察了雾化吸入后的MSC-EV在体内的生物分布。证实了雾化吸入后EV在肺部的积累在24小时达到峰值,然后逐渐降低,持续时间约28天。在铜绿假单胞菌造成的小鼠肺损伤模型研究中发现,雾化吸入MSC-EVs可降低小鼠肺部炎症水平,减轻肺损伤,显著提高小鼠生存率。剂量-反应效应研究发现:在2×10^5至2×10^6细胞外囊泡数量范围内,随着剂量的提升,治疗效果会更好。而超过2×10^6细胞外囊泡数量后,剂量与治疗效果则呈现负相关。这一结果提示适当剂量是雾化吸入MSC-EV发挥治疗效果的前提。同时,该研究招募了健康志愿者(24人)进行雾化吸入MSC-EVs的安全性评价(MEXVT study, NCT04313647)。临床试验研究表明所有志愿者均表现出对雾化吸入MSC-EVs的良好耐受性,生命体征、血常规、凝血功能、IgE等指标未见显著异常,均为出现严重不良反应。

该研究证实雾化吸入MSC-EVs治疗策略有效性和安全性,提示通过雾化吸入MSC-EVs的给药途径具有优越的性能,为进一步推进雾化吸入MSC-EVs在急性呼吸窘迫综合征中的临床应用提供有力证据。

据悉,上海交通大学医学院附属瑞金医院呼吸与危重症医学科瞿介明主任医师、复旦大学附属华东医院朱迎钢副主任医师为论文的通讯作者,上海交通大学医学院附属瑞金医院呼吸与危重症医学科石萌萌医师、杨清源博士研究生、法国巴黎索邦大学Antoine Monsel教授、呼吸与危重症医学科颜佳扬博士研究生及西比曼生物科技(上海)有限公司的戴成祥为论文的共同第一作者。

参考文献:

Shi MM, Yang QY, Monsel A, Yan JY, Dai CX, Zhao JY, Shi GC, Zhou M, Zhu XM, Li SK, Li P, Wang J, Li M, Lei JG, Xu D, Zhu YG, Qu JM.Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles.J Extracell Vesicles. 2021 Aug;10(10):e12134. doi: 10.1002/jev2.12134

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createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sat Dec 18 22:24:48 CST 2021, time=2021-12-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1218086, encodeId=6fde1218086c0, content=<a href='/topic/show?id=b0082e3590' target=_blank style='color:#2F92EE;'>#ARDS#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2735, encryptionId=b0082e3590, topicName=ARDS)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=病毒猎手, createdTime=Mon May 09 11:18:59 CST 2022, time=2022-05-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1656071, encodeId=ac4016560e14e, content=<a href='/topic/show?id=2a011829d7' target=_blank style='color:#2F92EE;'>#ACE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1829, encryptionId=2a011829d7, topicName=ACE)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=635024767990, createdName=shanyongle, createdTime=Mon Nov 22 20:24:48 CST 2021, time=2021-11-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1053185, encodeId=d6121053185de, content=申请明年的<a href='/topic/show?id=ca2e4095eaf' target=_blank style='color:#2F92EE;'>#国家自然科学基金#</a>的同仁们,一定要学习的。<a href='/topic/show?id=c030421865b' target=_blank style='color:#2F92EE;'>#基金#</a>,这是热点领域, beContent=null, objectType=article, channel=null, level=null, likeNumber=375, replyNumber=1, topicName=null, topicId=null, topicList=[TopicDto(id=40957, encryptionId=ca2e4095eaf, topicName=国家自然科学基金), TopicDto(id=42186, encryptionId=c030421865b, topicName=基金)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=病毒猎手, createdTime=Mon Sep 20 08:39:45 CST 2021, time=2021-09-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962599, encodeId=e6311962599e5, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Sat Dec 25 05:24:48 CST 2021, time=2021-12-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1657557, encodeId=951b165e5579a, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Mon Feb 07 01:24:48 CST 2022, time=2022-02-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2040274, encodeId=313f20402e482, content=<a href='/topic/show?id=cb0b1520365' target=_blank style='color:#2F92EE;'>#RDS#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=56, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15203, encryptionId=cb0b1520365, topicName=RDS)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=08e964, createdName=drwjr, createdTime=Mon Mar 21 17:24:48 CST 2022, time=2022-03-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1493594, encodeId=2439149359486, content=<a href='/topic/show?id=36dfe7869dd' target=_blank style='color:#2F92EE;'>#细胞外囊泡#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77869, encryptionId=36dfe7869dd, topicName=细胞外囊泡)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a12645, createdName=智智灵药, createdTime=Tue Sep 21 09:24:48 CST 2021, time=2021-09-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1544101, encodeId=ab60154410137, content=<a href='/topic/show?id=610d266582b' target=_blank style='color:#2F92EE;'>#体脂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=26658, encryptionId=610d266582b, topicName=体脂)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e74a13632472, createdName=ms4964546379600229, createdTime=Tue Sep 21 09:24:48 CST 2021, time=2021-09-21, status=1, ipAttribution=)]
    2022-05-09 病毒猎手
  4. [GetPortalCommentsPageByObjectIdResponse(id=1688000, encodeId=00eb168800061, content=<a href='/topic/show?id=b3e73898423' target=_blank style='color:#2F92EE;'>#同种异体#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=38984, encryptionId=b3e73898423, topicName=同种异体)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=23b928427427, createdName=12498768m22(暂无昵称), createdTime=Wed Nov 24 08:24:48 CST 2021, time=2021-11-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1872283, encodeId=28d718e2283db, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, 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href='/topic/show?id=36dfe7869dd' target=_blank style='color:#2F92EE;'>#细胞外囊泡#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77869, encryptionId=36dfe7869dd, topicName=细胞外囊泡)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a12645, createdName=智智灵药, createdTime=Tue Sep 21 09:24:48 CST 2021, time=2021-09-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1544101, encodeId=ab60154410137, content=<a href='/topic/show?id=610d266582b' target=_blank style='color:#2F92EE;'>#体脂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=26658, encryptionId=610d266582b, topicName=体脂)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e74a13632472, createdName=ms4964546379600229, createdTime=Tue Sep 21 09:24:48 CST 2021, time=2021-09-21, status=1, ipAttribution=)]
    2021-11-22 shanyongle
  5. 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href='/topic/show?id=36dfe7869dd' target=_blank style='color:#2F92EE;'>#细胞外囊泡#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77869, encryptionId=36dfe7869dd, topicName=细胞外囊泡)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a12645, createdName=智智灵药, createdTime=Tue Sep 21 09:24:48 CST 2021, time=2021-09-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1544101, encodeId=ab60154410137, content=<a href='/topic/show?id=610d266582b' target=_blank style='color:#2F92EE;'>#体脂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=26658, encryptionId=610d266582b, topicName=体脂)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e74a13632472, createdName=ms4964546379600229, createdTime=Tue Sep 21 09:24:48 CST 2021, time=2021-09-21, status=1, ipAttribution=)]
    2021-09-20 病毒猎手

    申请明年的#国家自然科学基金#的同仁们,一定要学习的。#基金#,这是热点领域

    1

    展开1条回复
  6. 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level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1829, encryptionId=2a011829d7, topicName=ACE)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=635024767990, createdName=shanyongle, createdTime=Mon Nov 22 20:24:48 CST 2021, time=2021-11-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1053185, encodeId=d6121053185de, content=申请明年的<a href='/topic/show?id=ca2e4095eaf' target=_blank style='color:#2F92EE;'>#国家自然科学基金#</a>的同仁们,一定要学习的。<a href='/topic/show?id=c030421865b' target=_blank style='color:#2F92EE;'>#基金#</a>,这是热点领域, beContent=null, objectType=article, channel=null, level=null, likeNumber=375, replyNumber=1, topicName=null, topicId=null, topicList=[TopicDto(id=40957, encryptionId=ca2e4095eaf, topicName=国家自然科学基金), TopicDto(id=42186, encryptionId=c030421865b, topicName=基金)], attachment=null, authenticateStatus=null, 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level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Mon Feb 07 01:24:48 CST 2022, time=2022-02-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2040274, encodeId=313f20402e482, content=<a href='/topic/show?id=cb0b1520365' target=_blank style='color:#2F92EE;'>#RDS#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=56, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15203, encryptionId=cb0b1520365, topicName=RDS)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=08e964, createdName=drwjr, createdTime=Mon Mar 21 17:24:48 CST 2022, time=2022-03-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1493594, encodeId=2439149359486, content=<a 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status=1, ipAttribution=)]
    2021-12-25 维他命
  7. 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status=1, ipAttribution=)]
    2022-02-07 bsmagic9140
  8. 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status=1, ipAttribution=)]
    2022-03-21 drwjr
  9. 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