CN117385022A - Il-17a作为靶点在制备筛选治疗或预防心脏骤停的药物中的应用 - Google Patents
Il-17a作为靶点在制备筛选治疗或预防心脏骤停的药物中的应用 Download PDFInfo
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Abstract
本发明提供了IL‑17A作为靶点在制备筛选治疗或预防心脏骤停的药物中的应用。本发明还提供了IL‑17A作为靶点在制备用于筛选治疗或预防心脏骤停的单克隆抗体药物中的应用。本发明还提供了抗IL‑17A单克隆抗体在制备改善心脏骤停后综合征的药物中的用途。本发明提供了抗IL‑17A单克隆抗体在制备心脏骤停早期干预的药物中的用途。本发明还提供了抗IL‑17A单克隆抗体在制备改善心脏骤停引起的心肌损伤、心功能障碍、脑损伤或神经功能障碍的药物中的用途。本发明还提供了检测血清中IL‑17A水平的试剂在制备检测心肌梗死合并心脏骤停患者的试剂盒中的用途。本发明通过实验证明，心脏骤停后心、脑组织IL‑17相关通路显著活化，血清中IL‑17A显著上调，利用IL‑17A单克隆抗体在复苏后早期拮抗IL‑17A可以改善心脏骤停后心肌损伤、心功能障碍(收缩和舒张功能障碍)、脑组织损伤或者神经功能障碍，并提高心脏骤停后生存率。
Description
技术领域
本发明属于生物医药领域，涉及一种治疗靶点和心血管药物，尤其涉及IL-17A作为靶点在制备筛选治疗或预防心脏骤停的药物中的应用以及抗IL-17A单克隆抗体在制备改善心脏骤停预后的药物中的用途。
背景技术
据统计，中国平均每年有55万人经历心脏骤停(Cardiac Arrest，CA)，人数之多居各国之首。尽管现在广泛推行的心肺复苏(Cardiopulmonary Resuscitation，CPR)及自动体外除颤器(Automated External Defibrillator，AED)可以一定程度挽救心脏骤停患者，但其存活率仍不到10％。这些触目惊心的数据表明，我们对于该疾病的认知仍然极度匮乏，因此，积极寻找全新的研究突破口是当务之急。
心脏骤停后综合征(post–cardiac arrest syndrome，PCAS)是导致患者早期死亡的关键因素，其中包括4个相互作用的组成部分：全身缺血/再灌注反应、脑损伤、心肌功能障碍和心脏骤停的持续诱发因素。在心脏骤停期间，患者处于全身缺血状态，而在自主循环恢复后，机体发生再灌注损伤。早期的缺血和再灌注损伤都会触发炎症级联反应，导致全身炎症瀑布样反应或败血症样综合征，并导致后续多器官功能障碍。因此，早期干预心脏骤停后的炎症反应从而打破PCAS的相互作用，对心脏骤停的预后具有重要临床意义。然而截至目前，针对心脏骤停的干预手段主要包括靶向温度管理、维持血流动力学稳态等，尚无针对心脏骤停后早期炎症瀑布阶段的特效药物治疗。
白细胞介素17A(interleukin-17A，IL-17A)由辅助T17(Th17)细胞、γδT细胞和自然杀伤T(NKT)细胞等细胞产生，已被证明在宿主防御、过敏性疾病和自身免疫性疾病中发挥着关键作用。IL-17A作为一种促炎细胞因子，可诱导趋化因子的表达，促进中性粒细胞靶器官浸润。近年来，有证据表明IL-17A可以直接介导心脏缺血/再灌注损伤中的心肌细胞凋亡，并加重缺血性脑损伤。利用IL-17A单克隆抗体可以改善脑卒中预后。然而，IL-17A在CA中的作用以及干预IL-17A对是否能影响心脏骤停的预后转归仍不完全清楚。
已有研究表明，血清中的一些炎性细胞因子例如IL-6、IL-23等是评价心脏骤停预后的重要生物学指标，早期升高的IL-6及IL-23与心脏骤停的不良预后显著相关。但一项针对院外心脏骤停患者的单中心临床队列研究显示，通过输注IL-6受体拮抗剂Tocilizumab虽能改善心脏骤停后的心肌损伤，其对心脏骤停后的脑损伤或者生存率并没有显著影响[15]。并且，目前尚无证据显示拮抗IL-23对心脏骤停预后的作用。这些结果表明，现阶段发现的心脏骤停后早期炎症瀑布生物学指标难以成为干预靶点，或具有组织倾向性，普适性差，不适用于PCAS的治疗。
苏金单抗(Secukinumab)是一种重组、高亲和性、全人源化抗IL-17A单克隆免疫球蛋白G1K抗体，2015年1月先后获欧盟和美国FDA批准用于治疗中重度斑块状银屑病。该药可选择性和IL-17A结合，从而很大程度阻断银屑病患者的炎症级联反应，且对其他的机体免疫功能影响较小。
发明内容
针对现有技术中的上述技术问题，本发明提供了IL-17A作为靶点在制备筛选治疗或预防心脏骤停药物中的应用，所述的这种IL-17A作为靶点在制备筛选治疗或预防心脏骤停的药物中的应用要解决现有技术中的药物对于心脏骤停后早期炎症瀑布阶段的治疗效果不佳的技术问题。
本发明提供了IL-17A作为靶点在制备筛选治疗或预防心脏骤停的药物的应用。
本发明还提供了IL-17A作为靶点在制备用于筛选治疗或预防心脏骤停的单克隆抗体药物中的应用。
本发明还提供了抗IL-17A单克隆抗体在制备改善心脏骤停后综合征的药物中的用途。
本发明还提供了抗IL-17A单克隆抗体在制备心脏骤停早期干预的药物中的用途。
本发明还提供了抗IL-17A单克隆抗体在制备改善心脏骤停引起的心肌损伤、心功能障碍(收缩和舒张功能障碍)、脑组织损伤或者神经功能障碍的药物中的用途。
进一步的，所述的抗IL-17A单克隆抗体为苏金单抗。
本发明还提供了检测血清中IL-17A水平的试剂在制备检测心肌梗死合并心脏骤停患者的试剂盒中的用途。
本发明通过实验证明，心脏骤停后心、脑组织IL-17相关通路显著活化，血清中IL-17A显著上调，利用IL-17A单克隆抗体在复苏后早期拮抗IL-17A可以改善心脏骤停后心肌损伤、心功能障碍(收缩和舒张功能障碍)、脑组织损伤或者神经功能障碍，并提高心脏骤停后生存率。
本发明提供了IL-17A这一细胞因子作为一种心脏骤停复苏后早期多器官炎症瀑布反应的核心靶标，其在治疗或预防心脏骤停的新用途。本发明通过动物实验探究及临床标本观察实验佐证，阐明了IL-17A在制备心脏骤停这一临床危重症疾病早期干预治疗药物的可行性。
本发明和已有技术相比，其技术效果是积极和明显的。本发明通过动物及临床数据首次证明IL-17A在影响心脏骤停预后转归中的核心作用，而利用单克隆中和抗体早期拮抗IL-17A可显著改善心脏骤停复苏后多器官系统炎症及功能障碍，对临床心脏骤停后的药物干预具有积极的指导意义，为临床上心脏骤停的防治提供新的策略。
附图说明
图1显示了心脏组织转录组学揭示心脏骤停诱导心肌炎症反应。
图2显示了脑组织转录组学揭示心脏骤停诱导大脑炎症反应。
图3显示了心脏骤停后IL-17家族在血清中的表达变化。
图4显示了早期拮抗IL-17A改善心脏骤停后心肌炎症反应及心功能障碍。
图5显示了早期拮抗IL-17A改善心脏骤停后脑组织炎症反应、神经功能障碍及生存率。
具体实施方式
以下是结合附图对本发明的优选实施例进行说明，此处所述的优选实施例是用来描述和解释本发明，而不是限制本发明。
实施例中未注明具体条件的实验方法，通常按照常规条件，例如教科书和实验指南中所述的条件，或按照制造厂商提供的建议条件。
实施例1心脏骤停后心肌组织转录组学检测。
1.小鼠心脏骤停模型建立：
①麻醉：6-8周C57BL/6小鼠(购买自江苏集萃药康生物科技股份有限公司)禁食过夜，利用异氟烷进行诱导麻醉。
②气管插管：麻醉后的小鼠仰卧位固定，连接心电遥测系统。颈部皮肤清洁消毒，用剪刀剪开后迅速分离气管周围肌肉和结缔组织以充分暴露气管。将大小合适的气管插管经小鼠口腔插入并顺势送入气道，固定插管后连接至小动物呼吸机通气(潮气量：200μL，呼吸频率：150次/分)并维持异氟烷麻醉。
③颈静脉置管：游离小鼠右侧颈静脉，远心端用丝线结扎，近心端用丝线吊起以阻断血流。利用显微剪于血管中段剪出一小口，顺势将静脉留置管经缺口插入并用丝线固定，推入少量生理盐水冲刷管道内回流的血液防止血栓形成。
2.心脏骤停诱导与心肺复苏
①心脏骤停：将高浓度KCl溶液(0.08mg/g)经颈静脉置管迅速推入颈静脉并实时观察心电变化直至心脏丧失电活动，骤停时长9min。
②心肺复苏：心脏骤停持续9min后，开始实施心肺复苏术，由机械通气结合机械胸外按压实现。机械通气参数如上，机械按压频率约350次/分。复苏期间经颈静脉推注盐酸肾上腺素共三次(复苏起始、复苏1min，复苏2min)以刺激心脏恢复自主心率。当小鼠恢复自主循环或心肺复苏持续时间达5min时停止心肺复苏，出现下列任一指征可认为自主循环恢复：1)心电图显示恢复自主心跳，频率＞200次/分；2)平均动脉压＞40mmHg。
3.术后管理
小鼠恢复自主循环后撤去动静脉置管，缝合颈部皮肤。继续观察小鼠心电图改变及呼吸状况，至30min后移至32℃恒温加热台，期间腹腔注射葡萄糖生理盐水补充丢失的电解质和水分。
术后3h收集心脏骤停组(CA/CPR)及假手术组(Sham)的心脏组织，提取总RNA并进行转录组测序，结果显示心脏骤停可明显诱导心肌炎症反应，其中IL-17信号通路改变最为明显(排位第一，图1A-C)，其中趋化因子相关基因在心脏骤停后显著上调(图1D)。
A图：PCA分析揭示CA/CPR组及Sham组心肌组织的基因表达在转录组水平差异明显。
B图：火山图揭示了CA/CPR组及Sham组心肌组织的差异基因上下调情况。
C图：针对心肌组织差异基因的KEGG通路富集分析显示，心脏骤停前后的差异通路主要与炎症反应相关，其中，IL-17信号通路改变最为明显。
D图：热图显示心脏骤停前后IL-17通路基因表达水平变化。
实施例2
心脏骤停后脑组织转录组学检测。
按照实施例1中的方案建立小鼠心脏骤停模型，术后3h收集心脏骤停组(CA/CPR)及假手术组(Sham)的脑组织，提取总RNA并进行转录组测序，结果显示心脏骤停可明显诱导脑组织炎症反应，其中IL-17信号通路改变排位第二(图2A-C)，其中趋化因子相关基因在心脏骤停后显著上调(图2D)。
A图：PCA分析揭示CA/CPR组及Sham组脑组织的基因表达在转录组水平差异明显。
B图：火山图揭示了CA/CPR组及Sham组脑组织的差异基因上下调情况。
C图：针对脑组织差异基因的KEGG通路富集分析显示，心脏骤停前后的差异通路主要与炎症反应相关，其中，IL-17信号通路改变排位第二。
D图：热图显示心脏骤停前后IL-17通路基因表达水平变化。
实施例3
心脏骤停后血清中IL-17家族表达水平检测。
按照实施例1中的方案建立小鼠心脏骤停模型，术后3h收集心脏骤停组(CA/CPR)及假手术组(Sham)的血样。另外，同时收集心肌梗死并发CA的临床患者血样及未发生CA的心肌梗死患者血样。以上采集的血样置于室温放置1h以充分凝固，3000rpm 4℃离心10min，收集血清并分装至1.5mL EP管防止反复冻融，用于后续IL-17家族血清含量水平检测。通过检测小鼠血清中所有IL-17家族成员(IL-17A、IL-17B、IL-17C、IL-17D、IL-17E和IL-17F)在心脏骤停后的表达变化，我们发现IL-17A是其中改变最为显著的成员(图3A)。另外，在心肌梗死并发CA的临床患者血清中，相较于未发生CA的心肌梗死患者，我们检测到了更高的IL-17A表达水平(图3B)。这些结果提示，IL-17家族尤其是IL-17A在CA/CPR后早期的表达改变，可能是调控多器官功能的关键节点。
A图：小鼠在CA/CPR及假手术(Sham)早期(3h)IL-17家族的血清学改变。
B图：心肌梗死合并心脏骤停患者(CA)及心肌梗死未合并心脏骤停患者(Non-CA)血清中IL-17A的表达改变。
实施例4
早期应用抗IL-17A单克隆中和抗体secukinumab(苏金单抗(secukinumab)是一种人白介素-17A拮抗剂，购买自瑞士诺华制药公司)对心脏骤停后心肌损伤及心功能障碍的改善作用。
通过实施例1的方式建立心脏骤停模型后，在复苏起始阶段(即早期干预阶段)分别给予抗IL-17A单克隆中和抗体secukinumab及其同种型对照抗体isotype(人IgG1κ抗体的同型对照，购买自selleck)，给药方式为经颈静脉给药，与肾上腺素配伍使用，抗体给药剂量为10mg/kg，以达到早期拮抗IL-17A的目的。
通过提取复苏后3h心脏组织的总RNA以检测心脏骤停后secukinumab组及isotype组心肌炎症水平改变，评估心肌损伤情况。利用Vevo2100超声成像系统检测心脏骤停后secukinumab组及isotype组的心脏收缩及舒张功能变化。具体为：采集心脏长轴、短轴画面，测量M mode模式下心脏的射血分数(Ejection Fraction，EF)与缩短分数(FractionalShortening，FS)数值，分析心脏收缩功能；采集心脏四腔心画面，测量PW doppler模式下的血流参数，分析心脏舒张功能。每个测量指标数值为5个心动周期的平均值。
结果显示，相较于isotype组，早期拮抗IL-17A能够显著减少心肌组织中趋化因子的表达，减轻心肌细胞损伤(图4A)；显著改善心脏骤停引起的心脏收缩功能(图4B)及舒张功能障碍(图4C)。
A图：早期拮抗IL-17A显著降低心肌组织中趋化因子的表达，证明心肌损伤显著降低。
B图：心超结果显示，早期拮抗IL-17A显著提高左心室EF及FS值，证明心脏收缩功能显著改善。
C图：心超结果显示，早期拮抗IL-17A显著提高左心室E/A比值并降低等容舒张时间(Isovolumic Relaxation Time，IVRT)，证明心脏舒张功能显著改善。
实施例5
早期应用抗IL-17A单克隆中和抗体secukinumab对心脏骤停后脑组织损伤、神经功能障碍及生存率的改善作用。
通过实施例4中描述的模型建立及IL-17A干预方案，在复苏后3h提取脑组织的总RNA以检测心脏骤停后secukinumab组及isotype组脑组织炎症水平改变，评估脑组织损伤情况。在复苏后24h评估两组小鼠神经功能。术后生存率的统计截至术后72h，期间每3h观察两组小鼠存活情况，并绘制各组生存曲线。
结果显示，相较于isotype组，早期拮抗IL-17A能够显著减少脑组织中趋化因子的表达，减轻脑组织损伤(图5A)；显著改善心脏骤停引起的神经功能障碍(图5B)并提高复苏后生存率(图5C)。
A图：早期拮抗IL-17A显著降低脑组织中趋化因子的表达，证明脑组织损伤显著降低。
B图：早期拮抗IL-17A显著提高复苏后24h神经功能评分，证明神经功能改善。
C图：早期拮抗IL-17A显著提高心脏骤停后72h生存率。
Claims (7)
1.IL-17A作为靶点在制备筛选治疗或预防心脏骤停的药物中的应用。
2.IL-17A作为靶点在制备用于筛选治疗或预防心脏骤停的单克隆抗体药物中的应用。
3.抗IL-17A单克隆抗体在制备改善心脏骤停后综合征的药物中的用途。
4.抗IL-17A单克隆抗体在制备心脏骤停早期干预的药物中的用途。
5.抗IL-17A单克隆抗体在制备改善心脏骤停引起的心肌损伤、心功能障碍、脑组织损伤或者神经功能障碍的药物中的用途。
6.根据权利要求3-5中任一所述的用途，其特征在于，所述的抗IL-17A单克隆抗体为苏金单抗。
7.检测血清中IL-17A水平的试剂在制备检测心肌梗死合并心脏骤停患者的试剂盒中的用途。
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