CN112294961A - Acp5抑制剂及其在预防和治疗纤维化疾病中的用途 - Google Patents
Acp5抑制剂及其在预防和治疗纤维化疾病中的用途 Download PDFInfo
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Abstract
本发明公开了一种ACP5抑制剂及其在预防和治疗纤维化疾病中的用途,属于生物医药技术领域。本领域技术人员研究发现ACP5抑制剂能够有效的减轻纤维化疾病,进而提供了ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,为纤维化疾病的预防和治疗提供了新选择。
Description
技术领域
本发明涉及具有预防或治疗各种纤维化疾病及病状的药物,属于生物医药技术领域,具体地涉及一种ACP5抑制剂及其在预防和治疗纤维化疾病中的用途。
背景技术
抗酒石酸酸性磷酸酶,又称acid phosphatase 5,tartrate resistant-ACP5,是一种糖基化的含金属蛋白酶。ACP5有a、b两种亚型,其中前者ACP5a为一种单体多肽,具有环状结构域,去磷酸化的活性被其环状结构所抑制,更多表现为一种生长因子的活性,主要来源于巨噬细胞,可分泌到血液中。ACP5b为二聚体,不含环状结构域,因而磷酸酶的活性不受抑制,其与细胞迁移有关,并可由成骨细胞分泌到血液中。虽然已有大量研究结果表明,ACP5可影响肿瘤细胞如非小细胞肺癌细胞的增殖、迁移、凋亡以及上皮细胞间质化转化但尚不清楚ACP5在纤维化疾病的发病进程中发挥的作用。
纤维化定义为器官内成纤维细胞过度增殖,并伴有大量沉积细胞外基质聚集,破坏组织结构。在多种疾病,如病毒性肝炎、慢性肾炎、硬皮病、冠心病等的病程晚期,器官均会发生纤维化,并最终导致器官衰竭。常见的纤维化疾病包括肺纤维化、肾纤维化、肝纤维化、心肌纤维化和皮肤纤维化。大量研究表明,在纤维化进程中,相关组织内转化生长因子-β,如TGF-β表达量上调。在纤维化进程中,TGF-β可诱导成纤维细胞分化为肌成纤维细胞(Suet al.,2015,Nature communications 6:8523)。而成纤维细胞向肌成纤维细胞的分化在纤维化过程中发挥重要的作用(Chen et al.,2016,Nature communications 7:12564;Hung et al.,2013,American journal of respiratory and critical care medicine188:820-830)。肌成纤维细胞分泌过量的纤维状ECM蛋白,包括I型胶原蛋白和纤连蛋白,导致肺间质中基质硬度增加和病理基质沉积(Chen et al.,2016,Nature communications7:12564;Pedroza et al.,,2016,FASEB journal:official publication of theFederation of American Societies for Experimental Biology 30:129-140)。尽管目前研究表明TGF-β在肺纤维化进程中发挥着重要的作用,但是目前仍缺少可以临床应用的有效阻断TGF-β信号通路,进而阻止或逆转肺纤维化进程的药物。
目前,纤维化疾病的治疗手段主要包括药物治疗及器官移植。器官移植作为纤维化疾病患者仅能选择的最终治疗手段,其应用推广受限于供体获取困难、手术风险高、手术费用昂贵。而现有药物无法逆转纤维化病程,其临床治疗效果和安全性均无法满足治疗需求。因此,亟需深入研究纤维化疾病发生机制,寻找新的治疗靶点,充分结合创新的医药发展趋势,开发新型的可有效治疗纤维化疾病且安全性高的药物。
发明内容
为解决上述技术问题,本发明公开了一种ACP5抑制剂及其在预防和治疗纤维化疾病中的用途。其中,包含ACP5抑制剂的药物可以抑制成纤维细胞的增殖和活化,从病理学的主要发病机制上发挥作用从而用于治疗纤维化疾病。
为实现上述技术目的,本发明公开了一种ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,其中,所述纤维化疾病包括肺纤维化、肾纤维化、心肌纤维化、肝纤维化或皮肤纤维化中的一种或两种及两种以上。
进一步地,所述纤维化疾病为肺纤维化。
进一步地,所述纤维化疾病为心肌纤维化。
进一步地,所述纤维化疾病为肾纤维化。
进一步地,所述纤维化疾病为肝纤维化。
进一步地,所述纤维化疾病为皮肤纤维化。
进一步地,所述药物为RNAi药物。
进一步地,所述ACP5抑制剂是以ACP5为靶标的siRNA、shRNA或miRNA中的至少一种。
进一步地,所述个体为哺乳动物。
进一步地,所述个体包括人或小鼠。
此外,为更好的实现本发明技术目的,本发明还公开了一种包括ACP5抑制剂的药物组合物,它包括上述ACP5抑制剂及药学上可接受的载体。
有益效果:
1、本发明研究的ACP5抑制剂针对目前缺乏有效治疗方法的纤维化疾病,提供了一种新的治疗策略;
2、本发明研究的ACP5抑制剂可以用于治疗多种纤维化疾病,包括肺、肝、肾、心肌以及皮肤纤维化。
附图说明
图1为ACP5-/-小鼠和野生型小鼠肺组织的H&E、天狼星红、马松三色法染色结果图;
图2为ACP5-/-小鼠和野生型小鼠的纤维化的阿什克罗夫特评分示意图,其中,**p<0.01;
图3为ACP5-/-小鼠和野生型小鼠中纤连蛋白、I型胶原和α-SMA的western blot结果示意图,其中,*p<0.05;**p<0.01,且图3a为测试结果显示图,图3b为图3a的柱状图;
图4为经博来霉素诱导纤维化后,ACP5-/-小鼠和野生型小鼠中纤连蛋白、I型胶原和α-SMA的定量RT-PCR结果示意图,其中,*p<0.05;
图5为经博来霉素诱导纤维化后,ACP5-/-小鼠和野生型小鼠中羟脯氨酸的定量结果示意图,其中,***p<0.001;
图6为TGF-β刺激后0、12、24、48h,ACP5-/-小鼠和野生型小鼠肺成纤维细胞中纤连蛋白、I型胶原和ACP5的western blot结果示意图,其中,**p<0.01,***p<0.001;其中,图6a为采用小鼠原代肺成纤维细胞的测试结果显示图,图6b为图6a的柱状列表图,图6c为采用人原代肺成纤维细胞的测试结果显示图,图6d为图6c的柱状图;
图7为ACP5-/-小鼠和野生型小鼠的成纤维细胞Transwell实验结果示意图;其中,图7a、图7b分别为野生型小鼠、ACP5-/-小鼠原代肺成纤维细胞的测试结果显示图,图7c为图7a和图7b的柱状图;图7d、图7e分别为对照siRNA、ACP5siRNA在人原代肺成纤维细胞中的测试结果显示图,图7f为图7d和图7e的柱状图;
图8为ACP5-/-小鼠和野生型小鼠的成纤维细胞Edu染色实验结果示意图;其中,图8a、图8b分别为野生型小鼠、ACP5-/-小鼠的原代肺成纤维细胞测试结果显示图,图8c为图8a和图8b的柱状图;图8d、图8e分别为对照siRNA、ACP5siRNA在人原代肺成纤维细胞中的测试结果显示图,图8f为图8d和图8e的柱状图。
具体实施方式
目前,纤维化疾病的治疗手段主要包括药物治疗及器官移植。器官移植作为纤维化疾病患者仅能选择的最终治疗手段,其应用推广受限于供体获取困难、手术风险高、手术费用昂贵。而现有药物无法逆转纤维化病程,其临床治疗效果和安全性均无法满足治疗需求。因此,亟需深入研究纤维化疾病发生机制,寻找新的治疗靶点,充分结合创新的医药发展趋势,开发新型的可有效治疗纤维化疾病且安全性高的药物。
术语的定义和使用
纤维化疾病:在本发明中,纤维化疾病包括肺纤维化、肾纤维化、心肌纤维化、肝纤维化和皮肤纤维化。其中,肝纤维化是指由各种致病因子所致肝脏内结缔组织异常增生,肝脏内弥漫性细胞外基质过度沉淀的病理过程。多种因素均可引起肝纤维化,如病毒感染、炎症反应、氧化应激和酗酒等。肝纤维化的病理特点为汇管区和肝小叶内有大量纤维组织增生和沉积,但尚未形成小叶内间隔,肝硬化则有假小叶形成,中心静脉区和汇管区出现间隔,肝的正常结构遭到破坏,肝纤维化进一步发展即为肝硬化。我国的慢性肝病以病毒性肝炎为主,慢性病毒性肝炎引起的肝组织纤维化与肝内炎症、坏死、病毒复制等有关,该病程在早期是可逆的。因此,将抗病毒、调节机体免疫功能等治疗方案有机结合,可在一定程度上控制肝纤维化进程。
肺纤维化主要病理特点包括肺组织间充质细胞增殖、细胞外基质增生沉积及肺实质的重构等。目前主要采用抗炎、抗氧化、抗成纤维细胞增殖和胶原沉积及肺移植等措施治疗肺纤维化。
肾纤维化表现为大量细胞外基质和结缔组织在肾脏聚集,导致肾脏结构改变和功能受损的病理过程。几乎所有肾疾病进展到终末期均会伴有肾纤维化的发生,并最终导致肾脏衰竭。肾纤维化过程涉及炎症反应,肾小管上皮细胞的凋亡以及多种可调控纤维化的细胞因子失衡等,故可通过抗炎症、抗凋亡和针对纤维化细胞因子治疗等途径防治肾纤维化。
心肌纤维化以成纤维细胞的增殖和细胞外基质在心肌正常组织结构中沉积为主要特征。目前认为主要由高血压性心脏病、缺血性心肌病、扩张性心肌病、病毒性心肌炎、糖尿病心肌病等所致。心肌纤维化引起心脏硬度增加,顺应性降低,影响心脏的正常舒张和收缩功能,是心血管疾病预后的关键性因素。
皮肤纤维化形成瘢痕组织。瘢痕组织是肉芽组织经改建成熟形成的老化阶段的纤维结缔组织。创伤等情况下,成纤维细胞分裂、增殖,向受损部位迁移,产生细胞外基质,形成瘢痕组织,修复创伤。
ACP5抑制剂:在本发明中,ACP5抑制剂是指:1)抑制ACP5表达的物质,其可以包括能够抑制ACP5表达的siRNA、shRNA和miRNA,含有上述siRNA、shRNA和/或miRNA的载体以及含有上述载体的宿主细胞,但本发明不限于此;
2)使ACP5活性降低或失活的物质;
3)促使ACP5降解的物质,诸如引起降解的ACP5抗体。
个体:在本发明中,术语“个体”指哺乳动物,包括但不限于大鼠、小鼠、非人灵长类、人、犬、猫、马、牛、绵羊、猪、山羊。优选为人或小鼠。
预防和治疗:
本发明所述“预防”是指在可能的促纤维因素的存在下,使用后防止或降低纤维化的产生。本发明所述“治疗”是指降低纤维化的程度,或者治愈纤维化使之正常化,或者减缓纤维化的进程。
本发明通过以下实施例证实了通过抑制成纤维细胞中ACP5表达,可显著减少成纤维细胞向肌成纤维细胞的分化。其中,成纤维细胞向肌成纤维细胞的分化在包括肝纤维化、肺纤维化、肾纤维化和皮肤纤维化等纤维化疾病的发病中发挥了极其重要的作用。
本发明还公开了一种包括ACP5抑制剂的药物组合物,它包括上述的ACP5抑制剂及药学上可接受的载体,该药物组合物可为注射型、胶囊、片剂、喷鼻剂或气雾剂等,以个体可接受的方式,如注射、口服、喷鼻等各种方式给与受试个体。
本发明还保护一种药盒,它包括上述的ACP5抑制剂和使用说明书。
为更好的解释本发明,以下结合具体实施例进行详细说明。
实施例1 ACP5缺陷对纤维化程度的影响;
实验动物及材料:
1、实验动物:
来源、种系、品系:从上海南方模式生物研究中心订购的ACP5-/-小鼠(C57BL/6背景),繁育于同济医学院动物房的野生型小鼠(WT,C57BL/6);
育龄:8~10周龄;
2、实验材料:
博来霉素:购自辉瑞制药有限公司;
戊巴比妥钠:上海斯信生物科技有限公司
生理盐水:上海百特医疗用品有限公司
3、实验方法:
采用戊巴比妥钠(70mg/kg)腹腔注射麻醉野生型小鼠和ACP5-/-小鼠,随后通过气道注射终浓度2U/kg的博来霉素,该博来霉素溶于40μL的生理盐水中,使用气道注射相同体积生理盐水的小鼠用作对照。施用博来霉素或生理盐水21天后处死小鼠,分析各小鼠肺部纤维化程度。由两位病理学家使用阿什克罗夫特评分系统以盲评的方式对每个连续区域的间质纤维化严重程度进行独立评估。
4、实验结果:
具体的,ACP5-/-小鼠和野生型小鼠的肺组织的H&E、天狼星红、马松三色法染色结果如图1所示,结合图1可知,经博来霉素刺激诱导后,相较于野生型小鼠,ACP5-/-小鼠中肺损伤和纤维化明显减轻。
阿什克罗夫特评分结果如图2所示,由图2可知,ACP5-/-小鼠的阿什克罗夫得分较野生型更低,这说明其肺纤维化的程度大大减轻。
实施例2 ACP5缺陷对纤连蛋白、I型胶原和α-SMA的蛋白及mRNA的水平的影响;
为进一步评价各小鼠经博来霉素注射后的纤维化程度,本发明分别通过westernblot及RT-PCR方式检测了各小鼠肺组织中纤连蛋白、I型胶原和α-SMA的蛋白及mRNA水平。
具体是收集实施例1实验后小鼠肺组织,通过RIPA裂解液提取组织中的蛋白,并通过Western blot检测目的蛋白,如纤连蛋白、I型胶原和α-SMA的表达量,结果如图3所示。其中,所述Western blot为参考Wang et al.,2017,Journal of Allergy and ClinicalImmunology 40:1550-1561。
同时,使用SYBR Premix Ex Taq(TaKaRa)进行荧光定量RT-PCR,并以β-肌动蛋白作为内参,标准化每个目的基因的相对表达,结果如图4所示。而每个目的基因所对应的引物列于下表1中。其中,具体测试测试表达方法如Chen et al.,2015,Internationaljournal of clinical and experimental pathology 8:6700-6707中记载。
表1 目的基因所对应的引物列表
结合图3和图4可知,相对于野生型小鼠而言,ACP5-/-小鼠的纤连蛋白、I型胶原和α-SMA的转录水平及蛋白表达水平均降低,这说明ACP5-/-小鼠纤维化得到较大程度的减轻。
实施例3 ACP5缺陷对羟脯氨酸水平的影响;
1、实验材料:
羟脯胺酸检测试剂盒:南京建成生物科技有限公司。
2、实验方法:
采用羟脯胺酸检测试剂盒对实施例1中各组小鼠肺组织中的羟脯氨酸的表达水平进行测定。
测定结果如图5所示,结合图5可知,如上述实施例2的表达结果一致,相较于ACP5-/-小鼠,野生型小鼠经博来霉素诱导后,其纤维化程度更为严重,肺组织中羟脯氨酸水平显著上调。
实施例4 ACP5敲除对成纤维细胞向肌成纤维细胞分化、成纤维细胞的增殖以及成纤维细胞的迁移的影响;
通过实验,越来越多的证据表明,成纤维细胞分化为肌成纤维细胞这一过程,对于维持肺纤维化是必须的。因此本发明进一步检测了ACP5对于经TGF-β刺激后的成纤维细胞向肌成纤维细胞分化的影响。
如上述实施例2的western blot结果表明,相较于野生型小鼠的肺成纤维细胞,采用10ng/ml的TGF-β刺激后的ACP5-/-小鼠肺成纤维细胞中纤连蛋白、α-肌动蛋白及I型胶原的表达显著降低。
紧接着,本发明通过ACP5 siRNA在人原代肺成纤维细胞中验证敲减ACP5对成纤维细胞分化为肌成纤维细胞的影响。结果如图6所示,与对照组相比,敲减ACP5后,纤连蛋白、α-肌动蛋白及I型胶原的表达显著降低。
进一步地,本发明通过Transwell实验和Edu染色进一步检测了ACP5敲除对成纤维细胞迁移和增殖的影响。如图7、图8所示,ACP5敲除后的成纤维细胞与野生型成纤维细胞相比,能明显减轻成纤维细胞的迁移和增殖。
综上,上述实验数据表明ACP5可通过抑制成纤维细胞向肌成纤维细胞细胞分化、成纤维细胞的增殖以及成纤维细胞的迁移,进而减缓纤维化进程。
因此,本发明研究的ACP5抑制剂针对目前缺乏有效治疗方法的纤维化疾病,提供了一种新的治疗策略。
Claims (10)
1.一种ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,其中,所述纤维化疾病包括肺纤维化、肾纤维化、心肌纤维化、肝纤维化或皮肤纤维化中的一种或两种及两种以上。
2.根据权利要求1所述ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,其特征在于,所述纤维化疾病为肺纤维化。
3.根据权利要求1所述ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,其特征在于,所述纤维化疾病为肾纤维化。
4.根据权利要求1所述ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,其特征在于,所述纤维化疾病为肝纤维化。
5.根据权利要求1所述ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,其特征在于,所述纤维化疾病为皮肤纤维化。
6.根据权利要求1~5中任意一项所述ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,其特征在于,所述药物为RNAi药物。
7.根据权利要求1~5中任意一项所述ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,其特征在于,所述ACP5抑制剂是以ACP5为靶标的siRNA、shRNA或miRNA中的至少一种。
8.根据权利要求1~5中任意一项所述ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,其特征在于,所述个体为哺乳动物。
9.根据权利要求8所述ACP5抑制剂在制备用于预防和/或治疗个体纤维化疾病的药物中的用途,其特征在于,所述个体包括人或小鼠。
10.一种包括ACP5抑制剂的药物组合物,它包括权利要求1所述的ACP5抑制剂及药学上可接受的载体。
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