CN114796273A - Tlr4激动的外泌体或外泌体制剂在制备防治放射性肺损伤药物中的应用 - Google Patents
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Abstract
本发明涉及TLR4激动的外泌体或外泌体制剂在制备防治放射性肺损伤药物中的应用，属于医药技术领域。本发明提供了TLR4激动的外泌体或外泌体制剂在制备防治放射性肺损伤药物中的应用，所述TLR4激动的外泌体或外泌体制剂由激动剂激活巨噬细胞TLR4后产生，属人体自身产生的外泌体，无组织毒性。经试验证实，本发明所述TLR4激动的外泌体或外泌体制剂能够显著减轻辐射诱导的肺上皮细胞的增殖活力降低，减少辐射后肺上皮细胞的凋亡及DNA的损伤程度，显示出TLR4激动的外泌体或外泌体制剂在防护电离辐射致放射性肺损伤中的独特之处，具有极高的临床应用价值。
Description
技术领域
本发明涉及医药技术领域，特别是涉及TLR4激动的外泌体或外泌体制剂在制备防治放射性肺损伤药物中的应用。
背景技术
正常肺组织是电离辐射最敏感的组织之一。人体在进行核能领域操作及胸部放疗等情形下极容易造成放射性肺损伤。放射性肺损伤包括早期放射性肺炎和晚期放射性肺纤维化，其发病机制仍不能完全明确。目前认为电离辐射可直接造成肺组织细胞DNA等生物大分子损伤、间接造成自由基大量产生，二者通过促进氧化应激、血管损伤、炎症反应等导致多种细胞因子、生长因子的释放，破坏细胞外基质，募集并促进炎症细胞分泌促纤维化细胞因子，从而造成肺间质增生实变，形成放射性肺损伤。目前对于放射性肺损伤的发生发展机制不能完全明确，因此对于放射性肺损伤的临床治疗非常局限。当前临床上主要以运用糖皮质激素为主，合并使用抗生素、止咳化痰平喘等对症治疗药物，但均非特效治疗。因此，寻找有效的防治药物对放射性肺损伤患者的治疗和预后具有极其重要的医学意义。
国内外研究表明，Toll 样受体（Toll-like receptors，TLRs）在辐射损伤防护领域中可能发挥重要作用。TLRs是一类参与天然免疫的重要蛋白分子，可以通过激活下游多种分子蛋白调控免疫应答，从而发挥生物作用。近年来研究表明，尽管TLR2、TLR5、TLR9等Toll 样家族的受体均能起到辐射防护作用，TLR4可能在辐射损伤防护领域中扮演最关键的角色。但是目前研究不能明确TLR4激动剂发挥辐射防护作用的具体机制，严重制约了TLR4激动剂在临床中的实际应用。而现有技术中未见有TLR4激动的外泌体制剂具有放射性肺损伤防治作用的相关报道。
发明内容
本发明的目的在于提供TLR4激动的外泌体或外泌体制剂在制备防治放射性肺损伤药物中的应用，能够显著减轻辐射诱导的肺上皮细胞的增殖活力降低，减少辐射后肺上皮细胞的凋亡及DNA的损伤程度。
为解决上述技术问题，本发明提供了以下技术方案：
本发明提供了TLR4激动的外泌体或外泌体制剂在制备防治放射性肺损伤药物中的应用，所述TLR4激动的外泌体或外泌体制剂是由TLR4激动巨噬细胞产生的。
优选的，通过激动剂激动巨噬细胞TLR4产生的外泌体或外泌体制剂防治放射性肺损伤。
更优选的，所述激动剂为MPLA。
更优选的，所述MPLA的给药剂量为0.5-5µg/mL。
优选的，所述放射性肺损伤由电离辐射所致，所述电离辐射为60Co γ射线。
优选的，所述TLR4激动的外泌体或外泌体制剂在药物中的百分含量为0.1%~99.9%。
优选的，所述TLR4激动的外泌体或外泌体制剂为药物中的单一活性成分。
本发明的有益效果：
本发明提供了TLR4激动的外泌体或外泌体制剂在制备防治放射性肺损伤药物中的应用，所述TLR4激动的外泌体或外泌体制剂由激动剂激活巨噬细胞TLR4后产生，属人体自身产生的外泌体，无组织毒性。经试验证实，本发明所述TLR4激动的外泌体或外泌体制剂能够显著减轻辐射诱导的肺上皮细胞的增殖活力降低，减少辐射后肺上皮细胞的凋亡及DNA的损伤程度，显示出TLR4激动的外泌体或外泌体制剂在防护电离辐射致放射性肺损伤中的独特之处，具有极高的临床应用价值。
附图说明
图1为小鼠肺上皮细胞MLE-12经不同处理后，辐射后的克隆形成情况。
图2为小鼠肺上皮细胞MLE-12经不同处理后，辐射后的克隆形成能力相应细胞存活率对比图。
图3为小鼠肺上皮细胞MLE-12经不同处理后，辐射后的凋亡情况。
图4为小鼠肺上皮细胞MLE-12经不同处理后，辐射后的凋亡比例对比图。
图5为体外小鼠肺上皮细胞MLE-12经不同处理后，辐射后不同时间点的γ-H2AX表达情况。
图6为体外小鼠肺上皮细胞MLE-12经不同处理后，辐射后不同时间点的γ-H2AX表达量对比图。
具体实施方式
本发明提供了TLR4激动的外泌体或外泌体制剂在制备防治放射性肺损伤药物中的应用，所述TLR4激动的外泌体或外泌体制剂是由TLR4激动巨噬细胞产生的。
本发明中，通过激动剂激动巨噬细胞TLR4产生的外泌体或外泌体制剂防治放射性肺损伤；所述激动剂优选为MPLA。本发明中，所述MPLA的给药剂量优选为0.5-5µg/mL，更优选为1µg/mL；所述MPLA的给药时间优选为遭受放射线辐射前12h。
本发明中，所述放射性肺损伤优选的由电离辐射所致，所述电离辐射优选为60Coγ射线。
本发明中，所述TLR4激动的外泌体或外泌体制剂在药物中的百分含量优选为0.1%~99.9%，更优选为1%-99%；所述TLR4激动的外泌体或外泌体制剂优选为药物中的单一活性成分。
在本发明的具体实施例中，细胞株和细胞培养具体如下：将小鼠肺上皮细胞MLE-12细胞（美国细胞收藏中心）在含有10％胎牛血清的DMEM培养基于37℃、5％CO2培养箱中培养。
药物与主要试剂来源如下：DMEM培养基、胎牛血清、胰酶购自Gibco公司；AnnexinV-FITC及PI购自Invitrogen公司；结晶紫、蛋白电泳所需试剂均购自江苏碧云天生物技术研究所；抗r-H2AX、β-actin抗体购自abcam公司。
在本发明的具体实施例中，照射条件为辐射中心（军事医学研究院）的60Co γ射线照射，剂量率为61.75cGy/min。
本发明中，如无特殊说明，所用的化学试剂均为常规市售试剂，所用的技术手段均为本领域技术人员所熟知的常规技术手段。
为了进一步说明本发明，下面结合实施例对本发明提供的技术方案进行详细地描述，但不能将它们理解为对本发明保护范围的限定。
实施例1
克隆形成实验
（1）分组及相应的处理方式：
选取小鼠巨噬细胞RAW264.7，于细胞培养箱培养12小时后，收集培养基，离心收集作为RAWsup处理组培养基；
选取小鼠巨噬细胞RAW264.7，培养基中加MPLA（1µg/mL），培养12小时后，收集培养基，离心收集作为（MPLA+RAW）sup处理组培养基；
培养基加MPLA（1µg/mL）作为MPLA处理组培养基；
正常对照组（NC）为未作处理的正常培养基（DMEM培养基）。
（2）实验步骤：
培养四组不同数目的MLE-12细胞（400个，800个，1600个，3200个）12小时，然后在每一种数目MLE-12细胞培养基分别进行（1）中所示四种不同处理，继续培养12小时后分别进行0Gy，2Gy，4Gy，8Gy 60Co γ射线照射。对照射后的不同组MLE-12细胞更换正常培养基（DMEM培养基），进行克隆形成实验，得到结果如图1和图2所示。
可以看出，（MPLA+RAW）sup处理组克隆形成能力明显优于另外三组，表明MPLA通过激动巨噬细胞TLR4刺激巨噬细胞分泌的外泌体制剂促进了照射后的MLE-12细胞增殖。
实施例2
（1）对MLE-12细胞的不同处理同实施例1（1）。
（2）对培养的MLE-12细胞分别进行以上四种处理，12个小时后进行0Gy、8Gy照射，照射后更换正常培养基（DMEM培养基），继续培养48小时进行流式细胞术凋亡检测，结果如图3和图4。
可以看出，（MPLA+RAW）sup处理组较另外三组显著减轻了细胞照射后的凋亡，表明MPLA通过激动巨噬细胞TLR4刺激巨噬细胞分泌的外泌体制剂减少了照射后的MLE-12细胞凋亡。
实施例3
（1）对MLE-12细胞的不同处理同实施例1（1）。
（2）对培养的MLE-12细胞分别进行以上四种处理，12个小时后进行8Gy照射，并在照射第0小时、1小时、8小时收集细胞进行γ-H2AX Western Blot检测，得到结果如图5和图6。
可以看出，激活巨噬细胞TLR4后产生的外泌体制剂减轻了照射MLE-12细胞DNA双链断裂。
本发明实施例1-3的所有实验均重复3次以上，结果采用±S表示。采用SPSS25.0软件统计软件对相关数据进行t检验，以P<0.05为有显著性差异。
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是利用本发明说明书内容所作的等效结构或等效流程变换，或直接或间接运用在其他相关的技术领域，均同理包括在本发明的专利保护范围内。
Claims (7)
1.TLR4激动的外泌体或外泌体制剂在制备防治放射性肺损伤药物中的应用，其特征在于，所述TLR4激动的外泌体或外泌体制剂是由TLR4激动巨噬细胞产生的。
2.根据权利要求1所述的应用，其特征在于，通过激动剂激动巨噬细胞TLR4产生的外泌体或外泌体制剂防治放射性肺损伤。
3.根据权利要求2所述的应用，其特征在于，所述激动剂为MPLA。
4.根据权利要求3所述的应用，其特征在于，所述MPLA的给药剂量为0.5-5µg/mL。
5.根据权利要求1或2所述的应用，其特征在于，所述放射性肺损伤由电离辐射所致，所述电离辐射为60Co γ射线。
6.根据权利要求1所述的应用，其特征在于，所述TLR4激动的外泌体或外泌体制剂在药物中的百分含量为0.1%~99.9%。
7.根据权利要求1所述的应用，其特征在于，所述TLR4激动的外泌体或外泌体制剂为药物中的单一活性成分。
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