CN116350629A - 前列腺素e2受体ep4拮抗剂在制备预防和/或治疗肺动脉高压疾病的药物中的应用 - Google Patents
前列腺素e2受体ep4拮抗剂在制备预防和/或治疗肺动脉高压疾病的药物中的应用 Download PDFInfo
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Abstract
本发明提供前列腺素E2受体EP4拮抗剂在制备预防和/或治疗肺动脉高压疾病的药物中的应用。本发明首次验证EP4拮抗剂能够缓解肺动脉高压，本发明提供了Grapiprant作为EP4拮抗剂，具有应用于预防和治疗肺动脉高压的重要价值，本发明提供了EP4作为肺动脉高压药物研发潜在靶点的证据。
Description
技术领域
本发明涉及前列腺素E2受体EP4拮抗剂在制备预防和/或治疗肺动脉高压疾病的药物中的应用，属于生物医药领域。
背景技术
肺动脉高压(pulmonary artery hypertension，PAH)是指由各种原因导致肺动脉压力增高，超过一定界值(其血流动力学诊断标准为：海平面静息状态下，右心导管检测肺动脉平均压≥25mmHg)的一种慢性进行性疾病。其发病率在心血管疾病中仅次于冠心病和高血压，由于PAH临床症状不明显，并且确诊该病需要右心室漂浮导管检测，导致实际发病率远高于临床检出率，使得其致残、致死率非常高。
PAH的病理特征主要是早期血管内皮细胞功能障碍导致血管收缩，随后内皮损伤和血管平滑肌细胞增殖、迁移、肥大，导致微动脉肌化、肺动脉内膜及中膜增厚、细胞外基质沉积，造成血管硬化甚至狭窄、阻塞，即肺血管重构。PAH的临床治疗目前主要使用前列环素、内皮素受体阻滞剂、磷酸二酯酶抑制剂、一氧化氮(NO)吸入或其供体L-精氨酸、钙通道阻滞剂等，但这些药物主要是减轻症状，对疾病的整体预后帮助欠佳，并没有改善血管重构等病理变化，因此这些药物的疗效并不理想。
前列腺素简称PG，是一种重要的生理活性物质。其中，PGE2广泛存在于动物和人体中，以花生四烯酸为原料经过多种酶的作用合成，其化学结构是一个含有20个碳的不饱和脂肪酸。PGE2在病理学和生理学上发挥着非常重要的作用，其生物学功能广泛，对于生殖、胃肠、免疫、心血管以及神经系统等多个组织和系统均有重要影响。
前期研究显示，花生四烯酸的代谢产物及其下游通路在PAH中具有重要的作用。花生四烯酸COX代谢通路涉及多种合酶和代谢产物，并通过不同受体发挥生物学作用。简而言之，花生四烯酸是由磷脂酶A2(PLA2)将其从细胞膜磷脂中解离出来的，之后进入COX代谢通路，经环氧酶-1(COX-1)和环氧酶-2(COX-2)催化，生成中间产物PGG2和PGH2，再经不同终末合酶生成不同类型的前列腺素。这些前列腺素通过结合并激动各自不同的G蛋白偶联受体(GPCR)而发挥其生物学功能。PGE2 是由PGES(mPGES-1、mPGES-2和cPGES)催化合成的，其生物学作用由四种EP 受体介导。EP受体分为EP1、EP2、EP3和EP4四种亚型，其生物学功能各异。其中EP1受体主要通过偶联Gq蛋白使胞内Ca2+水平升高；EP3通常与Gi蛋白偶联，使胞内cAMP水平和PKA活性降低；而EP2和EP4受体则通过偶联Gs蛋白使胞内cAMP水平升高，激活PKA通路。在高血压的研究中，PGE2是一个强大的降血压物质，这种降血压作用是四种EP受体综合作用的结果。
花生四烯酸环氧酶(COX)代谢产物前列环素(PGI2)是研究较早的舒血管物质，使用PGI2能通过舒张肺动脉使肺动脉压力降低，临床上以PGI2为基础的治疗是目前治疗PAH的主要手段。PGI2是PGIS催化合成的，PGI2的受体是IP，其通过激动IP 受体，导致腺苷酸环化酶(AC)激活，使细胞内cAMP水平升高，从而达到降低血压作用。因此，利用PGI2类似物(如iloprost，treprostinil和berapros等)激动IP受体，可缓解PAH，但因其与其他前列腺素受体的非特异性结合，因而会产生副作用而影响临床疗效。
PGE2和PGI2都具有降血压的作用，但迄今为止PGE2因其受体的多样性而没有应用于PAH的治疗。如前所述，PGE2四种受体中EP4具有显著血管活性，且在血管重构中发挥重要作用。EP4受体广泛分布在各种组织和器官中，如巨噬细胞、单核细胞、血小板、感觉神经元等组织，以及胃肠道、肾、胸腺、心脏、肺和子宫等器官中。大量证据表明EP4作为PGE2的重要受体在骨关节炎的发生和发展中起着十分重要的作用，因而EP4受体拮抗剂已经成为治疗骨关节炎的一个重要靶点。EP4也组成型的表达在肺动脉血管组织，但EP4受体拮抗剂能否用于预防和治疗肺动脉高压疾病还未见报道。
发明内容
本发明的目的是提供EP4拮抗剂的一种药物新用途。
本发明所提供的EP4拮抗剂的药物新用途，为：EP4拮抗剂在制备预防和/或治疗肺脏疾病的药物中的应用。
优选的，所述EP4拮抗剂为Grapiprant。
优选的，所述肺脏疾病为肺动脉高压。
更优选的，所述药物为具有如下任一项功能的药物：
1)改善右心室压力和肺动脉压力升高的药物；
2)改善肺血管重构的药物；
3)改善右心室肥厚的药物；
4)抑制肺动脉平滑肌细胞增殖的药物；
5)抑制PASMC缺氧24小时HIF1α蛋白表达的药物。
优选的，所述药物以EP4拮抗剂作为活性成分，还可包括药学上可接受的辅料。
优选的，所述药物的剂型包括：散剂、糊剂、颗粒剂、丸剂、片剂、胶囊剂、冲剂、膏滋、汤剂、喷雾剂或注射剂。
在符合本领域常识的基础上，上述各优选条件可任意组合，而不超出本发明的构思与保护范围。
本发明验证了EP4拮抗剂Grapiprant能够预防和治疗急性肺损伤，具体研究方案为利用SD大鼠证实Grapiprant能够缓解肺动脉高压和肺动脉重塑。
本发明首次验证EP4拮抗剂能够缓解肺动脉高压；本发明提供了Grapiprant作为EP4拮抗剂，具有应用于预防和治疗肺动脉高压的重要价值；本发明提供了EP4作为肺动脉高压药物研发潜在靶点的证据。
附图说明
图1为本发明中EP4拮抗剂(Grapiprant,简写G)显著降低MCT诱导的SD大鼠右心室收缩压和肺动脉压力升高的结果示意图(其中：A.右心室收缩压；B.肺动脉血流频谱多普勒超声代表图；C.肺动脉血流频谱多普勒超声分析：肺动脉血流加速时间 PAT/肺动脉血流射血时间PET。每组6只大鼠，结果表示为平均值±标准误，*表示 p<0.05,**表示p<0.01,***表示p<0.001)。
图2为本发明中EP4拮抗剂(Grapiprant,简写G)显著改善MCT诱导的肺血管重构的结果示意图(其中：A.左肺组织切片H&E染色直径大于50um中动脉血管厚度结果；B.左肺组织切片H&E染色直径大于50um中动脉血管厚度统计结果；C.左肺组织切片H&E染色直径小于50um小动脉血管厚度结果；D.左肺组织切片H&E染色直径小于50um小动脉血管厚度统计结果。每组6只大鼠，每个动物取一张切片统计所有血管，大于50um的血管数目为6-17个，小于50um的血管数目为59-75个，结果表示为平均值±标准误，***表示p<0.001)。
图3为本发明中EP4拮抗剂(Grapiprant,简写G)显著改善MCT诱导的右心室肥厚的结果示意图(其中：A.多普勒超声显示右心室游离壁厚度；B.右心室游离壁厚度统计图；C&D.右心肥厚指数。每组6只大鼠，结果表示为平均值±标准误，*表示p<0.05, **表示p<0.01,***表示p<0.001)。
图4.为本发明中EP4拮抗剂(Grapiprant,简写G)改善MCT诱导的血管平滑肌细胞增殖(A.Western Blot检测肺动脉蛋白增殖相关蛋白PCNA(增殖细胞核抗原，Proliferating Cell Nuclear Antigen，简称PCNA)的表达水平代表图；B.PCNA的WesternBlot半定量统计结果。每组6个样品，结果表示为平均值±标准误，*表示p<0.05)。
图5为本发明中血管平滑肌特异性EP4敲除能改善低氧联合血管内皮生长因子抑制剂(SU5416)诱导的肺动脉高压小鼠模型右心室压力升高和肺血管重构的结果示意图(A.常氧和低氧状态下野生型小鼠(EP4f/f小鼠)和血管平滑肌细胞特异性EP4受体特异性敲除小鼠(VSMC-EP4-/-小鼠)的右心室压力；B.常氧和低氧状态下EP4f/f小鼠和VSMC-EP4-/-小鼠肺组织切片H&E染色大于50um的中动脉血管厚度；C.常氧和低氧状态下EP4f/f小鼠和VSMC-EP4-/-小鼠肺组织切片H&E染色大于50um的中动脉血管厚度统计图；D.常氧和低氧状态下EP4f/f小鼠和VSMC-EP4-/-小鼠肺组织切片H&E染色小于50um的中动脉血管厚度；E.常氧和低氧状态下EP4f/f小鼠和 VSMC-EP4-/-小鼠肺组织切片H&E染色小于50um的中动脉血管厚度统计图。每组3-7 只小鼠，每个小鼠取一张切片统计所有血管，直径大于50um血管数目为5-16个，直径小于50um血管数目为25-49个，结果表示为平均值±标准误，*表示p<0.05,**表示p<0.01,***表示p<0.001)。
图6为本发明中EP4拮抗剂(Grapiprant，简写G)能抑制PDGF-BB(血小板衍生生长因子-BB，Platelet derived growth factor-BB，简称PDGF-BB，下同)(10ng/ml) 6h处理诱导的肺动脉平滑肌细胞增殖的结果示意图(Western Blot检测细胞增殖相关蛋白PCNA的表达水平。实验重复3次，结果表示为平均值±标准误，*表示p<0.05,** 表示p<0.01)。
图7为本发明中EP4拮抗剂(Grapiprant，简写G)能抑制PDGF-BB(10ng/ml) 12h处理诱导的肺动脉平滑肌细胞增殖的结果示意图(Western Blot检测细胞增殖相关蛋白Cyclin D1的表达水平。实验重复4次，结果表示为平均值±标准误，***表示 p<0.001)。
图8为本发明中EP4拮抗剂(Grapiprant，简写G)能抑制肺动脉平滑肌细胞缺氧(3％O2)24小时HIF1α(缺氧诱导因子-1α，hypoxia inducible factor-1α，简称HIF1α) 蛋白的表达的结果示意图(Western Blot检测细胞缺氧转录因子HIF1α的表达水平。实验重复3次，结果表示为平均值±标准误，**表示p<0.01)。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下面结合附图和实施例对本发明的技术方案进行详细描述，但并不因此将本发明限制在所述的实施例范围之中。
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。本发明所用试剂和原料均市售可得。
采用的具体技术方案如下：
野百合碱(MCT)诱导的肺动脉高压(PAH)模型：给予200-250g SD大鼠单次皮下注射60mg/kg野百合碱，21天后诱导大鼠肺动脉高压模型。
肺动脉压力测定：在浓度为20g/L三溴乙醇麻醉下，通过插入导管至右心室，使用多导电生理仪测量右心室压力。
超声分析肺动脉血流速度检测测定肺动脉压力：使用超高分辨率超声进行二维和脉冲多普勒(PWD)超声。在胸骨旁主动脉瓣右心室流出视图中，在主动脉瓣的水平上获得肺血流的PWD，测量PAT(从血流开始到峰值速度的时间)、ET(从肺血流开始到结束的时间)。根据回归公式RVSP＝64.5-(83.5*PAT/ET)计算右心室收缩期压力 PVSP。
形态学检测技术：H&E染色对大鼠肺动脉中小血管进行检测，并用Image J软件进行量化分析，用Prism 6.0进行统计分析。
分子生物学实验：用Western Blot，Real-time PCR技术等进行检测分析。
实施例1
本实施例发现EP4拮抗剂(Grapiprant,简写G)能够缓解野百合碱(MCT)诱导的肺动脉高压所致的右心室收缩压和肺动脉压力升高。
肺动脉高压是指由各种原因导致肺动脉压力升高，超过一定界值(其血流动力学诊断标准为：海平面静息状态下，右心导管检测肺动脉平均压≥25mmHg)的一种慢性进行性疾病，因此肺动脉压力是诊断肺动脉高压的指标。本研究将实验大鼠分为三组，即对照(Control)组、模型(MCT)组和模型给药(MCT+G)组。
进行模型给药组的每天灌胃给予EP4拮抗剂(Grapiprant)3mg/kg(溶于玉米油)，进行对照组和模型组口服给予玉米油，共给予22天；在给予EP4拮抗剂第二天给予模型组和模型给药组MCT 60mg/kg(溶于无水乙醇：生理盐水＝1：4)单次皮下注射， 22天后完成肺动脉高压模型构建。
随后做如下分析：1)超声分析肺动脉血流速度间接测定肺动脉压力：使用超高分辨率超声进行二维和脉冲多普勒超声，在胸骨旁主动脉瓣右心室流出视图中，在主动脉瓣的水平上获得肺血流的PWD，测量PA T(从血流开始到峰值速度的时间)、PET (从肺血流开始到结束的时间)。根据PAT/PET比值计算肺动脉压力；2)肺动脉压力直接测定：在三溴乙醇麻醉下，通过颈外静脉插入导管至右心室，使用多导电生理仪测量右心室压力(RVSP)；3)检测RVSP后取大鼠右心室、左心室和室间隔、肺动脉、肺脏组织。结果表明，MCT组RVSP(图1A)显著升高，肺动脉血流频谱图(图1B) 和PAT/PET(图1C)显著降低，而EP4拮抗剂能显著改善MCT诱导的右心室压力和肺动脉压力升高。
实施例2
本实施例研究EP4拮抗剂(Grapiprant,简写G)能够缓解野百合碱(MCT)诱导的肺动脉高压所致的肺血管重构。
大鼠肺脏组织石蜡切片进行苏木素-伊红(H&E)染色，我们发现无论是直径大于50um的中动脉(图2A&B)还是直径小于50um的小动脉(图2C&D)，在MCT组肺动脉中都发生明显的血管重构，而给予EP4拮抗剂可以明显改善肺血管重构。
实施例3
本实施例研究EP4拮抗剂(Grapiprant,简写G)能够缓解野百合碱(MCT)诱导的肺动脉高压所致的右心室肥厚。
超声分析大鼠右心室游离壁厚度(图3A)并对该厚度进行统计(图3B)，右心室重量/体重(图3C)，右心室重量/左心室加室间隔重量(图3D)计算右心肥厚指数，结果显示MCT组右心室游离壁厚度明显增加，给予EP4拮抗剂可以明显改善右心室肥厚。
实施例4
本实施例研究EP4拮抗剂(Grapiprant,简写G)能够缓解野百合碱(MCT)诱导的肺动脉高压所致的肺动脉异常增殖。
利用Western Blot检测肺脏组织中增殖指标PCNA的蛋白表达水平，结果发现EP4拮抗剂可以抑制MCT组中PCNA的表达升高(图4A和图4B)。
实施例5
本实施例研究血管平滑肌细胞特异性敲除EP4基因(VSMC-EP4-/-)可以缓解低氧联合血管内皮生长抑制剂SU5416诱导的肺动脉高压所致的右心室压力升高和肺血管重构。
本实验取8-10周龄雄性VSMC-EP4-/-和其同窝出生的EP4f/f小鼠(作为野生型对照小鼠)各16只，分为对照组和肺动脉高压模型组(HySu组)(每种基因型小鼠各8只)。对照组与模型组用同样的灯光和饮水饮食控制(即12小时白天，12小时黑夜，自由饮水饮食)，模型诱导完后行颈外静脉插管于右心室直接检测肺动脉压力，结果显示HySu组小鼠肺动脉压力明显升高，而VSMC-EP4-/-可以明显降低低氧引起的肺动脉压力升高。随后取肺组织，取部分肺脏组织石蜡切片进行苏木素-伊红(H&E) 染色，结果显示无论是直径大于50um的中动脉(图5B&C)还是直径小于50um的小动脉(图5D&E)，在HySu组肺动脉中都发生明显的血管重构，而VSMC-EP4-/-可以明显改善肺血管重构。
实施例6
本实施例研究EP4拮抗剂能抑制PDGF-BB(10ng/ml)6h处理诱导的肺动脉平滑肌细胞增殖。
取大鼠肺动脉培养大鼠肺动脉平滑肌细胞(PASMC)，待细胞长至30％-40％左右，给予EP4拮抗剂预处理半小时后给予PDGF-BB诱导平滑肌细胞增殖，6小时后提取细胞蛋白，利用Western Blot检测PASMC增殖指标PCNA的蛋白表达水平，结果发现EP4拮抗剂能抑制PDGF-BB 6h处理诱导的PASMC增殖(图6)。
实施例7
本实施例研究EP4拮抗剂能抑制PDGF-BB(10ng/ml)12h处理诱导的肺动脉平滑肌细胞增殖。
取大鼠肺动脉培养大鼠肺动脉平滑肌细胞(PASMC)，待细胞长至30％-40％左右，给予EP4拮抗剂预处理半小时后给予PDGF-BB诱导平滑肌细胞增殖，12小时后提取细胞蛋白，利用Western Blot检测PASMC增殖指标CyclinD1的蛋白表达水平，结果发现EP4拮抗剂能抑制PDGF-BB 12h处理诱导的PASMC增殖(图7)。
实施例8
本实施例研究EP4拮抗剂能抑制PASMC缺氧(3％O2)24小时HIF1α蛋白的表达。
取大鼠肺动脉培养大鼠肺动脉平滑肌细胞(PASMC)，待细胞长至30％-40％左右，给予EP4拮抗剂预处理半小时后给予低氧(3％O2)处理，24小时后提取细胞蛋白，利用Western Blot检测缺氧诱导因子HIF1α的蛋白表达水平，结果发现EP4拮抗剂能抑制PASMC缺氧24小时HIF1α蛋白的表达(图8)。
Claims (6)
1.EP4拮抗剂在制备预防和/或治疗肺脏疾病的药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述EP4拮抗剂为Grapiprant。
3.根据权利要求1或2所述的应用，其特征在于：所述肺脏疾病为肺动脉高压。
4.根据权利要求1-3中任一项所述的应用，其特征在于：所述药物为具有如下任一项功能的药物：
1)改善右心室压力和肺动脉压力升高的药物；
2)改善肺血管重构的药物；
3)改善右心室肥厚的药物；
4)抑制肺动脉平滑肌细胞增殖的药物；
5)抑制PASMC缺氧24小时HIF1α蛋白表达的药物。
5.一种预防和/或治疗肺脏疾病的药物，所述药物以EP4拮抗剂作为活性成分，还包括药学上可接受的辅料。
6.根据权利要求5所述的药物，其特征在于：所述药物的剂型包括：散剂、糊剂、颗粒剂、丸剂、片剂、胶囊剂、冲剂、膏滋、汤剂、喷雾剂或注射剂。
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