CN111297854A - 雷帕霉素在制备自然流产保胎药物中的应用 - Google Patents
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Abstract
本发明涉及医药技术领域,具体是雷帕霉素在制备自然流产保胎药物中的应用。相对正常妊娠,反复自然流产患者蜕膜组织中驻留的巨噬细胞减少,黏附分子表达较低;且流产患者蜕膜巨噬细胞自噬低水平。实验结果表明:雷帕霉素可显著促进巨噬细胞对蜕膜基质细胞的黏附。而后构建正常孕鼠和流产孕鼠模型并经体内实验证实,应用雷帕霉素可通过挽救自噬障碍所致的蜕膜巨噬细胞驻留减少,维持蜕膜免疫成分稳态,并显著降低孕鼠胚胎吸收率,从而改善不良妊娠结局。因此,雷帕霉素有望作为自然流产的保胎药物,这为反复自然流产这类患者提供了新的治疗方案,减轻了该类患者的心里负担,可很好的应用于临床上。
Description
技术领域
本发明涉及医药技术领域,具体地说,是雷帕霉素在制备自然流产保胎药物中的应用。
相对正常妊娠,反复自然流产患者蜕膜组织中驻留的巨噬细胞减少,黏附分子表达较低;且流产患者蜕膜巨噬细胞自噬低水平。雷帕霉素可显著促进巨噬细胞对蜕膜基质细胞的黏附。而后构建正常孕鼠和流产孕鼠模型并经体内实验证实,应用雷帕霉素可通过挽救自噬障碍所致的蜕膜巨噬细胞驻留减少,维持蜕膜免疫成分稳态,并显著降低孕鼠胚胎吸收率,从而改善不良妊娠结局。因此,雷帕霉素有望作为自然流产的保胎药物。
背景技术
成功妊娠是一个复杂的生理过程,需要母体对父亲来源的同种异体抗原的免疫耐受。在正常妊娠过程中,绒毛外滋养细胞侵袭进入蜕膜化的母体子宫内膜及基底膜下,参与之后的血管重铸,从而为胎儿的生长发育提供充足的营养物质。除胚胎来源的滋养细胞外,还有母体来源的蜕膜基质细胞和蜕膜免疫细胞参与母-胎界面的形成及其相关妊娠过程。这三类细胞互相作用,共同构成了母-胎界面独特的微环境,其中各类细胞复杂的交互对话是正常妊娠的前提,母-胎免疫耐受则是交互对话的核心。近年统计资料表明,自然流产发病率高达15%。即便是在辅助生育技术飞速发展的今天,仍不能克服因母-胎免疫调节紊乱造成的妊娠失败。咎其原因,在于对母-胎免疫耐受的形成机制和母-胎免疫调节紊乱的致病机制不甚了解。母婴健康水平对于一个民族和国家具有深远而广泛的社会影响,也是生命科学领域的重大科学问题。因此解析母-胎免疫耐受机制有重要的理论和临床意义。
正常妊娠是促炎与抗炎动态平衡的过程,有大量蜕膜免疫细胞的参与。母-胎界面存在多种免疫细胞,其中自然杀伤细胞约占50%-70%、巨噬细胞占近20%,T细胞约占10%,其他细胞则为树突状细胞等。蜕膜及螺旋动脉有选择素等黏附分子表达,有利于囊胚的黏附及种植。蜕膜免疫细胞在蜕膜化和母-胎免疫调节中扮演主要角色,因此研究占蜕膜细胞中30-40%的免疫细胞在母-胎界面募集和驻留的机制也是进一步阐明蜕膜化机制的关键之一。它们在母-胎界面募集和驻留的调控机制以及分化和发育的分子机制是母-胎免疫调节和耐受的研究重点,有着重要的理论和临床意义。
蜕膜巨噬细胞主要参与胚胎植入、螺旋动脉重塑、胎盘发育、宫颈成熟和分娩等妊娠生理过程。早孕期蜕膜巨噬细胞,一方面,对胎儿产生特异性免疫耐受;另一方面,可清除外来病原体以免引起宫内感染,在两者之间达到平衡状态。因此,在一次成功的生理性妊娠过程中,蜕膜巨噬细胞的功能受到严密调控,可能受到生殖内分泌激素和局部细胞因子格局所形成的复杂网络的直接和间接调控。人类蜕膜化进程中CD14+蜕膜巨噬细胞的数量已被证实是增加或相对恒定的。耗竭孕鼠巨噬细胞导致孕鼠胚胎吸收率增加,表明母-胎界面局部蜕膜巨噬细胞的密度异常及驻留不良可导致不良妊娠结局。
自噬是溶酶体介导的细胞内蛋白质及细胞器降解并回收降解产物重新利用的过程,这种保守的代谢过程广泛存在于真核生物中,是细胞成分更新、发育、分化的重要调节机制。自噬过程主要由吞噬泡形成、囊泡延伸包绕、自噬小体成熟、自噬溶酶体形成、内容物降解以及产物回收等几个步骤,从而维持蛋白代谢平衡及细胞内环境稳定。多项研究均证实,自噬在胚胎发生、着床和妊娠维持中起重要作用。
雷帕霉素属于大环内酯类抗生素,是一种新型高效的免疫抑制剂,临床上用于器官移植的抗排斥反应和自身免疫性疾病的治疗,目前也已被临床批准用于某些癌症适应症。雷帕霉素是mTOR的变构抑制剂,它与FK506结合蛋白12形成复合物,变构结合TOR以抑制TORC1活性。mTOR是一种非典型的蛋白激酶,可响应营养、生长因子和细胞能量水平控制生长和代谢,其在癌症和代谢紊乱中经常表达失常。mTORC1在细胞分解代谢程序中起着重要作用,尤其是通过直接调节自噬机制和溶酶体的生物发生。mTORC1直接磷酸化并抑制自噬引发激酶ULK1;直接磷酸化自噬小体成核和成熟所必需的PIK3C3复合物的成分以抑制其活性;同时在溶酶体生物发生的水平上间接影响自噬。因此雷帕霉素可通过抑制mTORC1及其下游信号,解除mTORC1对自噬相关蛋白及信号的抑制,从而有效诱导细胞自噬。
基于现有技术,本申请的发明人拟通过检测自然流产和正常妊娠蜕膜巨噬细胞的黏附状态和自噬水平,进一步通过构建自然流产小鼠模型来评价雷帕霉素在调节蜕膜巨噬细胞驻留和改善胚胎吸收率中的潜在价值,提供了雷帕霉素用于自然流产保胎治疗的用途和方法,为自然流产的临床治疗提供新方法和新思路。关于本发明雷帕霉素在制备自然流产保胎药物中的应用目前还未见报道。
发明内容
本发明的目的是针对现有技术的不足,提供一种雷帕霉素的新用途。
为实现上述目的,本发明采取的技术方案是:
雷帕霉素在制备治疗自然流产保胎药物中的应用。
雷帕霉素在制备提高蜕膜巨噬细胞在蜕膜组织部的驻留的药物中的应用。
雷帕霉素在制备促进巨噬细胞对蜕膜基质细胞的粘附的药物中的应用。
雷帕霉素在制备提高蜕膜组织CD14+巨噬细胞的绝对数量、提高蜕膜组织CD14+巨噬细胞占CD45+免疫细胞的比例的药物中的应用。
雷帕霉素在制备增加蜕膜巨噬细胞自噬溶酶体含量、促进自噬基因LC3B和BECN1表达、抑制MTOR表达的药物中的应用。
雷帕霉素在制备促进检测CD45+、CD14+蜕膜巨噬细胞上黏附分子E-钙粘蛋白(E-Cadherin)、VE-钙粘蛋白(VE-Cadherin)、血管细胞黏附分子1(VCAM-1)及L-选择素(L-Selectin)表达的药物中的应用。
雷帕霉素在制备治疗母-胎免疫耐受障碍的保胎药物中的应用。
优选地,所述的雷帕霉素按照药物常规制备方法制备成临床上可接受的药物制剂。
优选地,所述的药物制剂包括口服剂、注射剂、胶囊剂或膏剂。
优选地,所述的药物包括临床治疗药物、预防药物和/或保健食品。
本发明比较正常妊娠和自然流产患者蜕膜巨噬细胞黏附状态及自噬水平,进一步通过构建自然流产小鼠模型来评价自噬诱导剂雷帕霉素在调节孕鼠蜕膜巨噬细胞的驻留和改善胚胎吸收率中的潜在价值;提供了雷帕霉素作为自然流产保胎治疗药物的一种新用途。结果显示:1)在自然流产患者蜕膜免疫细胞中,蜕膜驻留的巨噬细胞数量及占比显著低于正常妊娠妇女,且巨噬细胞表面黏附分子普遍低表达,呈现低黏附状态;2)自然流产患者蜕膜巨噬细胞自噬溶酶体含量较正常妊娠组低,自噬相关基因LC3B和BECN1表达下降,而MTOR表达高水平;3)体外经外源性雷帕霉素处理的巨噬细胞表现出对蜕膜基质细胞的强黏附力;4)体内应用雷帕霉素可挽救自然流产小鼠模型的胚胎丢失,逆转自然流产小鼠子宫的巨噬细胞的低占比和数量低水平。这些结果提示自噬诱导剂雷帕霉素可用于子宫蜕膜驻留不良所致的自然流产的保胎治疗。
具体而言,本发明公开了一种通过应用雷帕霉素可通过诱导蜕膜巨噬细胞自噬、促进其在蜕膜局部的黏附和驻留,进而改善孕鼠胚胎吸收,可用于制备治疗自然流产的药物。
本发明通过收集正常早孕和自然流产(流产次数≥3次,术后绒毛染色体检测无异常、孕前内分泌激素检查无异常)患者的蜕膜组织,分离收集蜕膜免疫细胞,流式检测CD14+巨噬细胞的数量及其所占CD45+免疫细胞的比例,并检测CD45+、CD14+蜕膜巨噬细胞上黏附分子E-钙粘蛋白(E-Cadherin)、VE-钙粘蛋白(VE-Cadherin)、血管细胞黏附分子1(VCAM-1)及L-选择素(L-Selectin)的水平。结果显示,与正常妊娠妇女相比,自然流产患者蜕膜组织CD14+巨噬细胞的绝对数量下降且占CD45+免疫细胞的比例下降,上述黏附分子的表达普遍下降(如图1所示)。磁珠分离富集蜕膜免疫细胞中蜕膜巨噬细胞,自噬溶酶体染料评估其自噬水平,发现自然流产患者蜕膜巨噬细胞的平均荧光密度显著低于正常妊娠妇女蜕膜巨噬细胞;提取RNA并进行realtime-PCR后,发现自噬相关基因LC3B及BECN1在自然流产患者蜕膜巨噬细胞中表达低于正常妊娠组,而自噬抑制分子MTOR表达高于对照组(如图2所示)。而后体外对经佛波酯(50ng/mL)诱导的巨噬细胞给予雷帕霉素(2uM)处理,与贴壁的蜕膜基质细胞进行黏附实验,结果显示雷帕霉素可显著促进巨噬细胞对蜕膜基质细胞层面的黏附(如图3所示)。最后通过构建对照孕鼠(CBA/J♀×BALB/c♂)和自然流产孕鼠(CBA/J♀×DBA/2♂)模型,腹腔注射1%DMSO或者雷帕霉素(40ug/kg,从阴栓D0天开始,每两天腹腔注射100ul,连续13天)。雷帕霉素可改善自然流产孕鼠的胚胎丢失,使其高胚胎吸收率显著降低;与对照孕鼠相比,自然流产孕鼠子宫CD11b+F4/80+巨噬细胞在免疫细胞中占比下降,给予雷帕霉素后,孕鼠子宫巨噬细胞的数量得以回复,驻留巨噬细胞占比显著上调,绝对数量明显回升(如图4所示)。
本发明优点在于:
本发明提供了雷帕霉素用于自然流产保胎治疗的用途和方法;尤其是经动物实验证实,补充雷帕霉素可通过改善蜕膜巨噬细胞在组织局部的驻留、促进巨噬细胞对蜕膜基质细胞的粘附,进而改善孕鼠胚胎丢失。得到结论:所述的雷帕霉素可用于自然流产的保胎治疗。这为反复自然流产这类患者提供了新的治疗方案,减轻了该类患者的心里负担,可广泛应用于临床上,具有很好的应用前景。
附图说明
附图1是自然流产患者蜕膜巨噬细胞驻留减少且黏附分子表达下降,
其中,NP:正常妊娠,
SA:自然流产,
DICs:蜕膜免疫细胞,
Macrophage% of DICs:蜕膜免疫细胞中巨噬细胞占比,
E-Cadherin:E-钙粘蛋白;
VE-Cadherin:VE-钙粘蛋白;
VCAM-1:血管细胞黏附分子1;
L-Selectin:L-选择素。
*P<0.05,**P<0.01。
附图2是自然流产患者蜕膜巨噬细胞自噬低水平,
其中,NP:正常妊娠,
SA:自然流产,
MFI:平均荧光密度,
LC3B,BECN1,MTOR:自噬相关基因,
ACTB:内参基因,
*P<0.05,**P<0.01,***P<0.001。
附图3是雷帕霉素促进巨噬细胞对蜕膜基质细胞的黏附,
其中,DSC:蜕膜基质细胞(红光),
Merge:重叠,
Ctrl:对照组,
Rapa/Rapamycin:雷帕霉素组,
**P<0.01。
附图4是应用雷帕霉素挽救自然流产孕鼠胚胎吸收和蜕膜巨噬细胞丢失,其中,CBA/J♀×BALB/c♂(DMSO):对照孕鼠模型,
×BALB/c♂:对照孕鼠组,
CBA/J♀×DBA/2♂(DMSO):流产孕鼠模型,
×DBA/2♂:流产孕鼠组,
CBA/J♀×DBA/2♂(Rapa):流产孕鼠给予雷帕霉素处理,
×DBA/2♂+Rapa:流产孕鼠雷帕霉素处理组,
Embryo resorption rate(%):胚胎吸收率,
Macrophage% of DICs:蜕膜免疫细胞中巨噬细胞占比,
*P<0.05,***P<0.001,****P<0.0001,NS无显著差异。
其中,吸收胚胎因伴有缺血、出血和坏死,其体积明显小于正常存活胚胎,此外吸收胚胎与存活胚胎的色泽表现亦有明显差别,前者为黑褐色(如图箭头所示)而后者为粉红色。据此计数吸收胚胎数和存活胚胎数。胚胎吸收率R:R=Re/(Re+F)×100%。Re为吸收胚胎数,F为存活胚胎数。
具体实施方式
下面结合具体实施方式,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明记载的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1分析正常早孕和自然流产妇女蜕膜巨噬细胞驻留比例和黏附分子水平
1实验方法
取正常早孕和自然流产妇女蜕膜组织,剪碎消化后,分离获得蜕膜免疫细胞,流式细胞术(所有流式抗体来自BioLegend)对其分析。
2实验结果
相对于正常早孕组,自然流产妇女CD45+、CD14+蜕膜巨噬细胞在组织内数量下降(如图1A所示,P=0.0173),且占CD45+蜕膜免疫细胞的比例降低(如图1B所示,P=0.0048)。而后通过流式细胞术检测CD14+蜕膜巨噬细胞上黏附分子的比例,包括E-钙粘蛋白、VE-钙粘蛋白、血管细胞黏附分子1和L-选择素。自然流产蜕膜巨噬表面上述黏附分子低表达,黏附能力显著弱于正常蜕膜巨噬细胞(如图1C所示)。
实施例2分析正常早孕和自然流产妇女蜕膜巨噬细胞自噬水平
1实验方法
取正常早孕和自然流产妇女蜕膜组织,剪碎消化分离获得蜕膜免疫细胞后,磁珠分选(CD14磁珠和分析相关试剂购于美天旎公司)CD14+蜕膜巨噬细胞。使用自噬溶酶体绿色荧光染料(购于上海东仁化学科技有限公司)并经流式细胞术分析FITC通道的平均荧光密度。
2实验结果
发现自然流产蜕膜巨噬细胞的自噬溶酶体荧光密度低于对照组(如图2A所示,P=0.0286)。获得富集的蜕膜巨噬细胞后,提取RNA并利用real time-RCR(所有试剂均购于Takara公司)分析后发现,自噬相关蛋白的编码基因LC3B(P=0.04)和BECN1(P=0.0025)mRNA的水平在自然流产蜕膜巨噬细胞中显著低于对照组,而MTOR(P=0.0002)mRNA水平在自然流产组较高(如图2B所示)。
3结论
结果表明,相对于正常早孕组,自然流产妇女蜕膜巨噬细胞自噬状态呈现显著低水平。
实施例3体外实验验证雷帕霉素促进巨噬细胞对蜕膜基质细胞的黏附
1实验方法
从正常早孕蜕膜组织中分离原代蜕膜基质细胞,纯化培养后经活细胞红色染料(购于sigma公司)处理后以适当密度接种于孔板,培养过夜待其贴壁。人外周血单核细胞系U937细胞经佛波酯(购于sigma公司,100ng/mL)处理24小时以诱导巨噬细胞,用带有绿色荧光的空载慢病毒(购于上海吉凯基因)感染巨噬细胞,经雷帕霉素(购于MCE公司)或对照溶剂处理后,进行体外黏附实验。
2实验结果
结果显示,雷帕霉素处理使黏附的巨噬细胞相对数量增多,提示雷帕霉素可显著提高巨噬细胞对蜕膜巨噬细胞的黏附能力(如图3所示)。
实施例4体内实验证实雷帕霉素改善流产孕鼠胚胎吸收和蜕膜巨噬细胞丢失
1实验方法
通过构建对照孕鼠(CBA/J♀×BALB/c♂)和自然流产孕鼠(CBA/J♀×DBA/2♂)模型(所有实验动物均购于北京华阜康公司),腹腔注射1%DMSO(来自sigma公司)或者雷帕霉素(40ug/kg,从阴栓D0天开始,每两天腹腔注射100ul,连续13天)。
2实验结果
流产孕鼠存在显著的胚胎吸收丢失,吸收胚胎因伴有缺血、出血和坏死,其体积明显小于正常存活胚胎,此外吸收胚胎与存活胚胎的色泽表现亦有明显差别,前者为黑褐色(如图4A中箭头所示)而后者为粉红色。雷帕霉素可改善自然流产孕鼠的胚胎丢失,使其高胚胎吸收率显著降低(如图4B所示);与对照孕鼠相比,自然流产孕鼠子宫CD11b+F4/80+巨噬细胞在免疫细胞中占比下降,给予雷帕霉素后,巨噬细胞的丢失被回复,驻留巨噬细胞占比显著上调且数量回升(如图4C和4D所示)。
3结论
这些结果表明,雷帕霉素可通过挽救自噬障碍所致的蜕膜巨噬细胞丢失,从而维持蜕膜免疫成分稳态,改善胚胎吸收。
本发明经体外和体内试验结果证实,自然流产患者早孕期子宫蜕膜免疫细胞中巨噬细胞驻留比例和能力降低,且自噬呈现低水平。自噬诱导剂雷帕霉素补充可明显提高巨噬细胞的黏附能力,挽救蜕膜巨噬细胞驻留不良,并显著改善孕鼠胚胎丢失。首次发现了将雷帕霉素与FK506结合蛋白12形成复合物,变构结合TOR以抑制TORC1活性及其下游信号,解除mTORC1对自噬相关蛋白及信号的抑制,从而有效诱导细胞自噬。这些结果提示了雷帕霉素可用于蜕膜巨噬细胞驻留降低所致自然流产的保胎治疗,为反复自然流产这类患者提供了新的治疗方案,可很好的应用于临床上。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员,在不脱离本发明原理的前提下,还可以做出若干改进和补充,这些改进和补充也应视为本发明的保护范围。
Claims (10)
1.雷帕霉素在制备治疗自然流产保胎药物中的应用。
2.雷帕霉素在制备提高蜕膜巨噬细胞在蜕膜组织部的驻留的药物中的应用。
3.雷帕霉素在制备促进巨噬细胞对蜕膜基质细胞的粘附的药物中的应用。
4.雷帕霉素在制备提高蜕膜组织CD14+巨噬细胞的绝对数量、提高蜕膜组织CD14+巨噬细胞占CD45+免疫细胞的比例的药物中的应用。
5.雷帕霉素在制备增加蜕膜巨噬细胞自噬溶酶体含量、促进自噬基因LC3B和BECN1表达、抑制MTOR表达的药物中的应用。
6.雷帕霉素在制备促进检测CD45+、CD14+蜕膜巨噬细胞上黏附分子E-钙粘蛋白(E-Cadherin)、VE-钙粘蛋白(VE-Cadherin)、血管细胞黏附分子1(VCAM-1)及L-选择素(L-Selectin)表达的药物中的应用。
7.雷帕霉素在制备治疗母-胎免疫耐受障碍的保胎药物中的应用。
8.根据权利要求1-7任一所述的应用,其特征在于,所述的雷帕霉素按照药物常规制备方法制备成临床上可接受的药物制剂。
9.根据权利要求8所述的应用,其特征在于,所述的药物制剂包括口服剂、注射剂、胶囊剂或膏剂。
10.根据权利要求1-7任一所述的应用,其特征在于,所述的药物包括临床治疗药物、预防药物和/或保健食品。
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