CN114469960A - 丹参酮iia磺酸钠在制备治疗肺动脉重塑病症药物中的应用 - Google Patents
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Abstract
本发明提供丹参酮IIA磺酸钠在制备治疗肺动脉重塑病症药物中的应用，本发明主要从肺高压相关发病相关机制通过减轻肺高压进程、缓解右心室和抑制肺动脉重塑来改善患者的肺高压状态，提供了丹参酮IIA磺酸钠在用于制备治疗肺高压和/或相关的肺动脉重塑药物中的新应用。
Description
技术领域
本发明涉及丹参酮IIA磺酸钠在制备治疗肺动脉重塑症状药物中的应用，属于医学技术领域。
背景技术
肺高压指的就是肺动脉高压，是由于多种原因引起的肺动脉的压力持续的增高，超过正常的极限。正常情况下肺动脉的压力在人体的静息状态时，为2.4-4kPa，平均压力为1.7-2.3kPa。肺动脉高压见于很多疾病，临床上最常见的是迁延不愈的慢性支气管炎、慢性阻塞性肺气肿，以及慢性肺源性心脏病而引起。肺动脉高压出现有呼气性呼吸困难，进行性加重。这种呼吸困难不可逆转，随时可能伴随有心功能不全，而导致心力衰竭。
丹参酮IIA磺酸钠注射液(STS)性状为红色澄明液体，主要成份为丹参酮ⅡA磺酸钠，主要用于冠心病、心绞痛、心肌梗死的医治，也可用于室性早搏。目前也未见丹参酮IIA磺酸钠在用于制备治疗肺高压药物中的应用。
发明内容
针对现有技术存在的不足，本发明的目的在于提供丹参酮IIA磺酸钠在制备治疗肺动脉重塑症状药物中的应用。
优选的，所述的肺动脉重塑病症为肺高压引起的肺动脉重塑病症。
优选的，所述的肺高压为MCT诱导和/或SuHx诱导的肺高压。
优选的，所述的丹参酮IIA磺酸钠加入药学上辅料制备成注射液。
优选的，所述丹参酮IIA磺酸钠的推荐剂量为40-80mg/次。
本发明的有益效果：
本发明提出的丹参酮IIA磺酸钠注射液(STS)可有效的减轻肺高压进程、缓解右心室、抑制肺小动脉的重塑。
附图说明
图1为本发明试验例1中Control组、MCT诱导肺高压模型组、低剂量丹参酮IIA磺酸钠干预组和高剂量丹参酮IIA磺酸钠干预组的大鼠右心室收缩压检测结果图；
图2为本发明试验例1中Control组、MCT诱导肺高压模型组、低剂量丹参酮IIA磺酸钠干预组和高剂量丹参酮IIA磺酸钠干预组的大鼠右心室比重检测结果图；
图3为本发明试验例1中Control组、MCT诱导肺高压模型组、低剂量丹参酮IIA磺酸钠干预组和高剂量丹参酮IIA磺酸钠干预组的大鼠肺小动脉中膜厚度检测结果图；
图4为本发明试验例1中Control组、MCT诱导肺高压模型组、低剂量丹参酮IIA磺酸钠干预组和高剂量丹参酮IIA磺酸钠干预组的大鼠的肌化率检测结果图；
图5为本发明试验例1中通过Real Time Q-PCR分析Control组、MCT诱导肺高压模型组、低剂量丹参酮IIA磺酸钠干预组和高剂量丹参酮IIA磺酸钠干预组中Coll1mRNA的含量结果图；
图6为本发明试验例1中通过Real Time Q-PCR分析Control组、MCT诱导肺高压模型组、低剂量丹参酮IIA磺酸钠干预组和高剂量丹参酮IIA磺酸钠干预组中Coll3 mRNA的含量结果图；
图7为本发明试验例1中通过Real Time Q-PCR分析Control组、MCT诱导肺高压模型组、低剂量丹参酮IIA磺酸钠干预组和高剂量丹参酮IIA磺酸钠干预组中FN mRNA的含量结果图；
图8为本发明试验例2中N组、N+STS组、SuHx组和SuHx+STS组的小鼠右心室收缩压检测结果图；
图9为本发明试验例2中N组、N+STS组、SuHx组和SuHx+STS组的小鼠右心室比重检测结果图；
图10为本发明试验例2中N组、N+STS组、SuHx组和SuHx+STS组的小鼠肺小动脉中膜厚度检测结果图；
图11为本发明试验例2中N组、N+STS组、SuHx组和SuHx+STS组的小鼠的肌化率检测结果图；
图12为本发明试验例2中N组、N+STS组、SuHx组和SuHx+STS组中Coll1mRNA的含量结果图；
图13为本发明试验例2中N组、N+STS组、SuHx组和SuHx+STS组中Coll3 mRNA的含量结果图；
图14为本发明试验例2中N组、N+STS组、SuHx组和SuHx+STS组中FN mRNA的含量结果图；
图15为本发明试验例3中不同剂量的STS对PASMCs活性的影响；
图16为本发明试验例3中TGF-β刺激和STS用药干预24h的WB分析图。
具体实施方式
为使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施方式，进一步阐述本发明。
本发明主要通过减轻肺高压进程、缓解右心室和肺动脉重塑来改善患者的肺高压状态，提供了丹参酮IIA磺酸钠在用于制备治疗肺高压和/或相关的肺动脉重塑药物中的新应用。
试验例1 STS对野百合碱(MCT)诱导肺高压大鼠肺动脉重塑的影响
(1)实验分组及给药
24只5周龄SD雄性大鼠，适应性喂养3天后，随机分为四组，分别为：正常对照组(Control组，n＝6)、MCT诱导肺高压模型组(MCT组，n＝6)、低剂量丹参酮IIA磺酸钠干预组(MCT+L-STS组，n＝6)和高剂量丹参酮IIA磺酸钠干预组(MCT+H-STS组，n＝6)。模型组及干预组单次腹腔注射MCT60 mg/kg，对照组予相应无菌生理盐水。在MCT注射7天后MCT+L-STS组腹腔注射STS注射液3.6mg/kg/d，MCT+H-STS组腹腔注射STS7.2mg/kg/d，Control组和MCT模型组的大鼠每天腹腔注射相应体积的无菌生理盐水，连续注射14d，进行后续检测。
(2)血流动力学检测
给药14天后，采用微创闭合胸部法检测大鼠右心室收缩压。
(3)组织病理学检测和Real Time Q-PCR分析
检测右心室收缩压后，使用冰生理盐水冲洗心脏和肺组组织，取出心脏，分离出右心室组织，计算右心室比重。
将鼠肺组织取出，冰生理盐水冲洗。
分离右肺下叶，4％多聚甲醛固定，后续进行HE染色和弹力染色，计算肺小动脉中膜厚度及机化率。
分离右肺中叶锡箔纸包裹装于冻存管中，液氮速冻，后转移至-80℃冰箱保存，进行后续Real Time Q-PCR分析。
(4)结果
如图1-图4所示，MCT造模3周后，与Control组比较，MCT组大鼠的右心室收缩压、右心室比重、肺小动脉中膜厚度、肺小动脉半肌化(Partoal)比例、肺小动脉全肌化(Full)比例明显升高，说明造模成功；经过低剂量或高剂量STS干预后，大鼠的右心室收缩压、右心室比重、肺小动脉中膜厚度、肺小动脉半肌化比例、肺小动脉全肌化比例下降。
如图5-图7所示，Real Time Q-PCR对大鼠的肺组织Coll1mRNA、Coll3mRNA、FNmRNA含量进行检测，与Control组比较，MCT组的Coll1mRNA、Coll3mRNA、FN mRNA含量明显升高，经过低剂量或高剂量STS干预后，Coll1mRNA、Coll3mRNA、FN mRNA的含量明显下降。
综上，STS可减轻MCT诱导肺高压大鼠肺高压进程、缓解右心室、抑制肺小动脉的重塑。
说明：
(1)肺小动脉中膜厚度检测：计算15-20条来自每个肺的直径为20-50μm的肌动脉内侧壁厚度，中膜厚度表示为内侧面积与横截面积的比率。
(2)肺小动脉肌化率：将每只鼠中大小在20至50μm之间的40至60条腺泡内血管分为非肌层(仅有一层弹力层而无明显的平滑肌层)、部分肌层(即具有完整的外弹力层，但平滑肌层和内弹力层不完整)或肌层(即具有完整的内外弹力层及完整的平滑肌层)。
(3)**与Control比较，P<0.01；##与MCT组比较，P<0.01；#与MCT组比较，P<0.05。
试验例2 STS对SuHx诱导肺高压小鼠肺动脉重塑的影响
(1)实验分组及给药
24只C57BL/6J小鼠，随机分为四组，分别为：常氧对照组(N组，n＝6)、常氧给药组(N+STS组，n＝6)、Su5416+低氧诱导肺高压模型组(SuHx组，n＝6)和丹参酮IIA磺酸钠干预组(SuHx+STS组，n＝6)。SuHx组及SuHx+STS组低氧(10％O2、90％N2)条件下每周一次腹腔注射Su5416(20mg/kg)，即第0d、7d、14d，N组及N+STS组常氧(21％O2)条件下予相应无菌生理盐水腹腔注射。第14d开始N+STS组、SuHx+STS组每日腹腔注射STS 10.4mg/kg，N组和SuHx组大鼠每天腹腔注射相应体积的无菌生理盐水，连续注射14d，进行后续检测。
(2)血流动力学检测
给药14天后，采用开胸方法检测右心室收缩压。
(3)组织病理学检测和Real Time Q-PCR分析
同试验例1。
(4)结果
如图8-图11所示，SuHx造模4周后，与N组、N+STS组比较，SuHx组小鼠的右心室收缩压、右心室比重、肺小动脉中膜厚度、肺小动脉半肌化比例、肺小动脉全肌化比例明显升高，经过STS干预后，SuHx+STS组小鼠的右心室收缩压、右心室比重、肺小动脉中膜厚度、肺小动脉半肌化比例、肺小动脉全肌化比例下降。
如图12-图14所示，通过Real Time Q-PCR对小鼠肺组织的Coll1mRNA、Coll3mRNA、FN mRNA含量进行检测，与N组、N+STS组比较，SuHx组小鼠的Coll1mRNA、Coll3mRNA、FN mRNA含量明显升高，经过STS干预后，Coll1mRNA、Coll3mRNA、FN mRNA含量明显下降。
综上，STS可减轻SuHx诱导肺高压小鼠肺高压进程、缓解右心室、抑制肺小动脉的重塑。
说明：
(1)肺小动脉中膜厚度检测：同试验例1。
(2)肺小动脉肌化率：同试验例1。
(3)**与N组、N+STS组比较，P<0.01；*与N组、N+STS组比较，P<0.05；##与SuHx组比较，P<0.01；#与SuHx组比较，P<0.05。
试验例3 STS抑制TGF-beta诱导肺动脉平滑肌细胞表型转换
(1)细胞活性检测
采用CCK8检测STS对PASMCs细胞毒性。
将传至第3代PASMCs用胰酶消化、离心后，加入4ml含1％双抗、10％胎牛血清的DMEM/F2培养基重悬液后，以6×103/孔接种至96孔板，待PASMCs融合60％时，将含1％双抗、10％胎牛血清的DMEM/F2培养基更换为含1％双抗、无胎牛血清的DMEM/F2培养基对PASMCs同步化12h，分别加入含有0μg/ml、5μg/ml、10μg/ml、20μg/ml、40μg/ml、60μg/ml、80μg/mlSTS的1％双抗、1％胎牛血清的DMEM/F2培养基。给药处理后24h，PBS漂洗2次，加入含10％CCK8的DMEM/F2培养基100μl 37℃孵育30分钟后，酶标仪设置吸光度450nm，检测OD。
结果如图15所示，用药干预24h时80μg/mlSTS剂量组对PASMCs产生了明显的毒性。为避免STS对PASMCs毒性，采用40μg/ml的STS浓度进行后续实验。
(2)PASMCsWB检测
将传至第4-5代PASMCs用胰酶消化、离心后，加入4ml含1％双抗、10％胎牛血清的DMEM/F2培养基重悬液后，细胞均匀接种至10cm培养皿，铺板后，随机分为四组，正常对照组(Control组)、正常给药组(C+STS组)、TGF-β模型组(M组)和STS干预组(M+STS组)。待PASMCs融合50％-80％时，将含1％双抗、10％胎牛血清的DMEM/F2培养基更换为含1％双抗、无胎牛血清的DMEM/F2培养基对PASMCs同步化12h。12h后将1％双抗、无胎牛血清的DMEM/F2培养基更换为1％双抗、1％牛血清的DMEM/F2培养基，M组、M+STS组分别予TGF-β10ng/ml，C+STS组和M+STS组分别予STS 40μg/ml，分别继续培养24h后收取细胞。
收取细胞时，每皿细胞吸除培养基后，加入预冷的PBS漂洗2次，移除剩余液体后每个样品加入蛋白酶抑制剂4ul、磷酸酶抑制剂4ul、RIPA裂解液200ul，用移液枪反复吹打，充分裂解后，转移至1.5mlEP管，4℃离心，12000转/分，10min。将上清移至新的1.5ml EP管中。进行后续实验或存放于-80℃冰箱。后续蛋白定量、电泳。
采用TGF-β作为PASMCs表型转换刺激剂。TGF-β刺激和STS用药干预24h收取蛋白进行WB分析。图16显示，PASMCs在TGF-β刺激24h时Smad2/3磷酸化水平、FN蛋白表达明显增高，给药干预24h时Smad2/3磷酸化水平、FN蛋白表示无明显下降，综上，STS可调控TGF-β-smad2/3通路抑制PASMCs表型转换。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点，对于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。
Claims (5)
1.丹参酮IIA磺酸钠在制备治疗肺动脉重塑病症药物中的应用。
2.如权利要求1所述的应用，其特征在于，所述的肺动脉重塑病症为肺高压引起的肺动脉重塑病症。
3.如权利要求1所述的应用，其特征在于，所述的肺高压为MCT诱导和/或SuHx诱导的肺高压。
4.如权利要求1-3任意一项所述的应用，其特征在于，所述的丹参酮IIA磺酸钠加入药学上辅料制备成注射液。
5.如权利要求4所述的应用，其特征在于，所述丹参酮IIA磺酸钠的推荐剂量为40-80mg/次。
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