CN104997775B - 长春西汀在制备抗肺纤维化药物中的应用 - Google Patents
长春西汀在制备抗肺纤维化药物中的应用 Download PDFInfo
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Abstract
本发明公开了长春西汀在制备抗肺纤维化药物中的应用。本发明经过研究表明，长春西汀对肺纤维化动物模型TGFβ有明显的抑制作用，可用于制备抗肺纤维化药物。本发明开拓了长春西汀有利于肺纤维化机制及治疗药物的研究，为新的治疗肺纤维化的药物提供了实验基础。
Description
技术领域
本发明涉及长春西汀在制备抗肺纤维化药物中的应用。
背景技术
肺纤维化(pulmonary fibrosis,PF)是一种原因不明、以弥漫性肺泡炎和肺泡结构紊乱最终导致肺间质纤维化为特征的疾病。是许多肺间质疾病的最终结局。主要病理特点为肺间质和肺泡腔内纤维化和炎细胞浸润混合存在。就其解剖部位来说，虽发生在肺间质系统，但影响常常肺泡及支气管。就其病因而言，它是炎症、感染、变态反应、免疫、肉芽肿、肿瘤、增生、阻塞等多种因素所致肺疾病。目前的治疗药物以糖皮质激素、免疫抑制剂、免疫调节剂为主，但尚无特效药。
长春西汀(别名：卡兰,长春西丁,阿扑长春胺酸乙酯,长春乙酯；外文名：Vinpocetine,Calan)是从夹竹桃科小蔓长春花中提取的吲哚生物碱长春胺经结构改造所得衍生物，能抑制磷酸二酯酶活性、增加血管平滑肌松弛信使C-GMP的作用，是一种优良的脑血管疾病药物。
长春西汀有增加红细胞变形能力，能提高血液流动性并改善微循环，降低血黏度及抑制血小板凝聚作用，并具有增进和改善大脑氧的供给，能选择性的增加脑部血流量，改善血液流动性和微循环促进脑组织摄取葡萄糖、增加脑耗氧量、改善脑部新陈代谢。
目前长春西汀临床用于治疗由于大脑血液循环障碍而引起的精神性或神经性症状，如因脑栓塞、脑出血后遗症、脑动脉硬化症等引起的眩晕、头沉、头昏、头痛、记忆力减退、行动障碍、语言障碍等。此外，还可应用于高血压脑病、脑血管痉挛、脑动脉内膜炎、进行性脑血管硬化。在眼科方面，用于视网膜和脉络膜血管硬化及血管痉挛。在耳科方面，用于治疗老年性耳聋、眩晕等。
长春西汀的药理作用复杂多样，有的还未得到很好的证实，作用机制也还不明确。已有报道其具有脑血管扩张和加强代谢活性的作用。目前还没有一个作用机制能解释该药在临床应用中所有的好处。体内试验表明，在正常情况下或动脉缺氧时，长春西汀能增加脑部血流，而对外周血流没有明显的影响，因此说明长春西汀具有选择性血管扩张作用。但是，这种选择性作用在离体试验中并未得到证实，其他研究者的体内试验也没有证实这种脑血管扩张效应。在动物研究中报道长春西汀具有脑代谢刺激活性，在缺氧和三烷基锡引起脑水肿时能延长生存率。抗缺氧的活性也在窒息性缺氧和低比重性或贫血性缺氧模型中有报道。
发明内容
本发明的技术目的是提供一种抗肺纤维化的药物。
本发明采用的技术方案是：
长春西汀在制备抗肺纤维化药物中的应用。
本发明经过研究表明，长春西汀有对抗博莱霉素诱导的肺纤维化小鼠模型的肺纤维化病作用，能够预防和治疗上述模型的肺纤维化，因此可将长春西汀用于制备抗肺纤维化药物。
本发明提供了一种长春西汀治疗肺纤维化疾病的应用，所述应用的方法一般是，将长春西汀用冰醋酸溶解，再用生理盐水稀释后注射给药；或将长春西汀与其他人体可接受的药用辅料制成片剂、胶囊等口服剂型给药，用于治疗肺纤维化。
本发明采用博莱霉素诱导的肺纤维化小鼠模型，研究了不同浓度长春西汀的作用，发现长春西汀具有明显的治疗肺纤维化的作用，对肺纤维化动物模型胶原的生成有明显的抑制作用。
通常推荐的剂量用量是：1-10mg/kg。
本发明经过研究表明，长春西汀对肺纤维化动物模型TGFβ有明显的抑制作用，可用于制备抗肺纤维化药物。本发明开拓了长春西汀有利于肺纤维化机制及治疗药物的研究，为新的治疗肺纤维化的药物提供了实验基础。
附图说明
图1模型组、对照组、预防组对博莱霉素诱导肺纤维化损伤的Masson染色照片，20X镜拍照，标尺＝10μm，图1中，A组：BLM模型组；B组：正常对照组；C组:DEX阳性对照组；D组:长春西汀预防低剂量1mg/kg组；E:组长春西汀预防中剂量3mg/kg组；F组:长春西汀预防高剂量10mg/kg组。
图2模型组、对照组、治疗组对博莱霉素诱导肺纤维化损伤的Masson染色照片，20X镜拍照，标尺＝10μm，图2中，A组：BLM模型组；B组：正常对照组；C组:DEX阳性对照组；D组:长春西汀治疗低剂量1mg/kg组；E:组长春西汀治疗中剂量3mg/kg组；F组:长春西汀治疗高剂量10mg/kg组。
图3长春西汀预防组和治疗组对肺组织胶原含量的影响柱状图。数据以均值±SEM表示，n＝6-8,*表示P<0.05,***表示P<0.001，均是与BLM模型组进行比较。
图4长春西汀预防组和治疗组对肺组织MPO活性的影响柱状图，数据以均值±SEM表示，n＝6-8，*表示P<0.05,***表示P<0.001，均与BLM模型组进行比较。
图5长春西汀预防组和治疗组的ashcroft评分柱状图。数据以均值±SEM表示，n＝6-8，*P<0.05，均与BLM模型组进行比较。
具体实施方式
下面以具体实验来对本发明的技术方案进行说明，但本发明的保护范围不限于此。
实施例1
1材料与方法
1.1实验动物、药品、试剂和仪器
药品：
长春西汀(sigma,V6383)批号Lot 118H46803V；辅料为：(0.25-2.5％)乙酸、生理盐水。博莱霉素(简称BLM)：日本化药株式会社，批号：410102；地塞米松磷酸钠注射液(浙江省仙琚制药股份公司)；
动物：
C57小鼠，雄性，8周，体重在20-22g，由浙江大学动物实验中心提供，动物合格证号：2007000526749。动物饲养及操作过程均遵守浙江大学《实验动物管理条例》要求。
试剂:
胶原测定试剂盒：Biocolor；小鼠TGF-β1ELISA试剂盒：R&D公司；MPO测定试剂：sigma公司；荧光定量PCR仪CFX96型：Bio-Rad；垂直电泳槽、电泳仪：Biorad公司。
1.2模型建立与实验分组
根据本实验室建立的小鼠肺纤维化造模方法，对小鼠进行4％水合氯醛麻醉(280mg/kg)，然后有创气道给药法滴入生理盐水配制的博莱霉素(2.5g/L)，剂量为2.5mg/kg，记为模型组(简称BLM)。空白对照组滴入同等体积的生理盐水，记为对照组(简称Con)。地塞米松组腹腔注射：2mg/kg，记为阳性对照组(简称Dex)。
长春西汀溶液配制方法：溶液配制方法：称量100mg长春西汀，加入1ml冰醋酸溶解，作为原液，使用时取原液进行稀释，取25ul原液，加入975ul生理盐水稀释39倍，得到高剂量药物(1)，取(1)300ul，加入700ul生理盐水，得到中剂量药物(2)；取(1)100ul，加入900ul生理盐水，得到低剂量药物(3)。腹腔注射给药剂量分别为100ul/25g体重小鼠：低剂量1mg/kg、中剂量3mg/kg、高剂量10mg/kg。冰醋酸的终浓度分别是0.25％、0.75％、2.5％。采用腹腔注射用药。
实验方案：预防组采用了BLM用药后1-8天早期连续给药一周方案，希望能明确其对早期炎症的作用。治疗组采用了BLM用药后14-21天后期连续给药一周方案，希望能明确对后期纤维化进展的影响。预防组14天处理、治疗组21天处理，进行支气管肺泡灌洗及留取肺组织进行病理学、蛋白及分子生物学检测等。
1.3肺组织病理学观察
小鼠股动脉放血处死后，留取肺组织用福尔马林固定，制备石蜡切片，进行Masson染色，观察肺组织纤维化改变。
1.4 BALF收集和处理
取1ml生理盐水灌洗肺组织得到肺泡灌洗液。混匀取50μl用于白细胞计数，余下以3000rpm/min离心5min，取上清液进行分装冻存于-80℃，用于BALF中细胞因子测定。
1.5 BALF中炎症因子的ELISA测定
取BALF上清液按照小鼠TGF-β1ELISA试剂盒说明书进行TGF-β1的ELISA含量测定。
1.6肺组织胶原含量及髓过氧化物酶(MPO)活性测定
取右肺，用生理盐水制备10％的组织匀浆，取450μL用MPO试剂盒进行MPO活性测定，剩余匀浆于12000g/min离心10分钟，取上清液按胶原试剂盒说明书上说明进行胶原含量测定，并取5μL上清液根据DC蛋白含量测定说明书进行上清液总蛋白含量测定。MPO与胶原含量测定结果皆为每毫克上清液总蛋白中的MPO活性单位与胶原含量。
1.7肺纤维化评分标准(Ashcroft评分标准)：
0分：正常；1分：肺泡壁或支气管壁轻度增厚；2分，3分：肺泡壁或支气管壁中度增厚，但无肺结构损毁；4分，5分:纤维组织明显增多，伴明显肺结构损害，有纤维组织条索或小的纤维组织团块形成；6分，7分:严重肺结构损毁，大片纤维化区域，蜂窝肺。；8分:满视野纤维组织。
1.8统计学分析
数据以平均数±标准差表示，用SPSS 10.0 for Window统计软件做单因素方差分析和t检验，P<0.05为差异有统计学意义。
2结果
1长春西汀对博莱霉素诱导肺组织纤维化的病理变化的影响
博莱霉素(BLM)气道滴入，能成功诱导了肺组织纤维化病变。用药后第一周即可出现强烈的炎症和水肿、及细胞因子如肿瘤坏死因子α(TNF-α)，白细胞介素1β(IL-1β)增加；第二周，促纤维化表达细胞因子转化生长因子β(TGF-β)达峰值；第二和第三周后，形成胶原沉积，类似于纤维化，Masson染色呈蓝色的即沉积的胶原纤维，细胞外基质成分沉积，包括纤连蛋白和胶原蛋白-1。因此本研究分了二部分对长春西汀的抗肺纤维化作用进行了研究，预防组采用了BLM用药后1-8天早期给药方案，希望能明确其对早期炎症的作用。治疗组采用了BLM用药后14-21天后期给药方案，希望能明确对后期纤维化进展的影响。
(1)预防作用：
模型组、对照组、预防组对博莱霉素诱导肺纤维化损伤的Masson染色照片见图1，20X镜拍照，标尺＝10μm，图1中，A组：BLM模型组；B组：正常对照组；C组:DEX阳性对照组；D组:长春西汀预防低剂量1mg/kg组；E:组长春西汀预防中剂量3mg/kg组；F组:长春西汀预防高剂量10mg/kg组。
图1可以看出，用药模型组气道附近胶原沉积明显，肺泡组织结构被严重破坏，间隔消失形成空洞。正常对照组的肺组织肺泡结构清晰且完整，无炎症细胞浸润。而地塞米松阳性对照组对抗博莱霉素诱导的肺纤维化病变作用不明显。长春西汀对此纤维化病变的抑制作用呈现出剂量依赖性，低剂量组效果不明显，高剂量对此纤维化有明显抑制作用。
(2)治疗作用
模型组、对照组、治疗组对博莱霉素诱导肺纤维化损伤的Masson染色照片见图2，20X镜拍照，标尺＝10μm，图2中，A组：BLM模型组；B组：正常对照组；C组:DEX阳性对照组；D组:长春西汀治疗低剂量1mg/kg组；E:组长春西汀治疗中剂量3mg/kg组；F组:长春西汀治疗高剂量10mg/kg组。
图2可见，在造模14天后进行长春西丁药物治疗一周，我们发现用药组也有明显的剂量依赖性减轻肺纤维化的作用。尤其是高剂量组，能明显减少肺纤维化的程度。
2长春西汀对博莱霉素诱导纤维化肺组织胶原含量的影响
长春西汀预防组和治疗组对肺组织胶原含量的影响柱状图见图3，肺组织中胶原含量在博莱霉素气道滴入后14d即快速上升，与正常对照组比较即有极显著性差异(P<0.01)。阳性对照组胶原含量有抑制趋势，但与模型组比较无显著性差异。预防组和治疗组中，低、中剂量长春西丁对胶原的影响也不明显，但高剂量组下降较明显，达统计学显著性(P<0.05与模型组比较)。提示长春西汀高剂量最有较好的抑制肺纤维化的作用。
3长春西汀对博莱霉素诱导肺纤维化小鼠肺组织中MPO活性的影响
长春西汀预防组和治疗组对肺组织MPO活性的影响柱状图见图4，由图4可知，治疗组的MPO各组差异不是很大，低、中、高浓度依次降低。但空白组的含量也较高。预防组、治疗组中，空白对照组的MPO含量与模型组的MPO相当。提示MPO不是肺纤维化模型的敏感指标。而长春西汀对MPO活性的影响不明显，预防组略有下降趋势。
4 Ashcroft评分
长春西汀预防及治疗组的ashcroft评分柱状图见图5，从Ashcroft评分可以发现，无论是治疗组或者是预防组，空白对照组都是分数很低的，几乎是0。模型组的评分最高，而预防组的程度轻于治疗组。在预防组中，高剂量组评分最低，地塞米松组次之，其中高剂量组相比阳性对照组有显著性差异(P<0.05)，优于地塞米松组；在治疗组中，地塞米松组，低剂量组、高剂量组相当，其中，高剂量组和低剂量组与模型组比较有显著性差异(P<0.05)。
3.讨论
磷酸二酯酶(Phosphodiesterases，PDEs)是细胞内第二信使cAMP和cGMP的水解酶，负责维持细胞内第二信使浓度平衡，在信号传递过程中扮演着重要作用。PDEs作为一个有11个家族成员的蛋白酶超家族，拥有非常多的变异体。对细胞的生长、增殖、及细胞代谢都起着重要作用。
长春西汀的作用机制目前尚不清楚，已有国外文献报道认为长春西汀为PDE1抑制剂，IC50为21μM。我们实验室前期的研究工作中，发现PDE1在肺纤维化过程中是明显有表达上调的，所以我们就想研究如果抑制PDE1是否能对肺纤维化过程产生作用。
通过长春西汀的预防和治疗研究，我们发现长春西汀预防和治疗对博莱霉素诱导的肺纤维化模型均有效，预防组高剂量的效果更明显，而治疗组低剂量的效果也较好，同时治疗组的肺纤维化评分下降更明显，提示该药对于肺纤维化的预防和治疗均有一定作用。对于肺纤维化病人，长期用药可能有益于纤维化病变的逆转。
Claims (2)
1.长春西汀在制备抗肺纤维化药物中的应用。
2.如权利要求1所述的应用，其特征在于所述应用的方法为：将长春西汀用冰醋酸溶解，再用生理盐水稀释后注射给药；或将长春西汀与其他人体可接受的药用辅料制成片剂或胶囊，口服给药。
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