CN102961656B - 一种治疗肺纤维化病的中药组合物及其应用 - Google Patents
一种治疗肺纤维化病的中药组合物及其应用 Download PDFInfo
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Abstract
本发明公开了一种治疗肺纤维化病的中药组合物及其应用。所述中药组合物由下列重量份的组分组成:白芨3.6~4份、五倍子0.9~1.2份、僵蚕1~1.2份、焦术4~4.5份、沙参4~5份、百部4~4.5份、桔梗1~1.2份、党参7~8份。本发明经过研究表明中药组合物的水提物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。本发明开拓了中药组合物的新用途及其治疗机制,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
一、技术领域
本发明涉及一种治疗肺纤维化病的中药组合物及其应用。
二、背景技术
肺纤维化(pulmonary fibrosis,IPF)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。而中成药中有些品种比如养阴益肺通络丸、仙芪扶阳固本丸等对肺纤维化有一定疗效。养阴益肺通络丸的成分有:麦冬、桃仁、西洋参、丹参、赤芍、白术、黄芪、防风、蛤蚧、川贝母、橘红、女贞子、玄参、甘草等。仙芪扶阳固本丸的成分有:人参(白)、淫羊藿、蛤蚧、黄芪、白术、茯苓等。
白芨具有止血生肌、化痰敛肺的作用,临床多用于大咯血、肺结核少量咯血等的治疗,效果较显著。白芨水提物中的主成分为白芨多糖,有研究表明其具有抗菌、抗氧化、抑制大鼠皮肤成纤维细胞VEGF的mRNA表达等作用。中药治疗矽肺的记载中提及白芨对矽肺症状有治疗作用,但对X光胸片无改善。
沙参具有祛痰作用,有研究报道其对博莱霉素诱导的实验性肺纤维化有明显改善作用,能降低肺组织纤维连接素、层粘蛋白的含量。对博莱霉素诱导的肺纤维化小鼠也有明显改善作用,能降低肺组织羟脯氨酸含量。
百部生物碱具有止咳、化痰、平喘、抗菌等作用。Liao JF等研究发现百部水提取物对Carbacol、组织胺、KCl所致的离体豚鼠支气管平滑肌痉挛有松弛作用。
党参为中国常用的传统补益药,具有补中益气,健脾益肺之功效。党参含多种糖类、酚类、甾醇、挥发油、黄芩素葡萄糖甙、皂甙及微量生物碱,具有增强免疫力、扩张血管、降压、改善微循环、增强造血功能等作用。
五倍子具有敛肺、止汗、涩肠、固精、止血、解毒之功效。主治肺虚久咳、自汗盗汗、久痢久泻、脱肛、遗精、白浊、各种出血、痈肿疮疖。
焦术又名焦白术、白术炭,具收敛止泻作用。桔梗是我国传统常用中药材,功效具有宣肺、祛痰、利咽、排脓等功能,主治咳嗽痰多、咽喉肿痛等症状。
三、发明内容
本发明采用博莱霉素诱导的肺纤维化小鼠模型,研究了不同组方的药物组合,最终精选出本发明的药物组方,对肺纤维化动物模型TGFβ有明显的抑制作用。
本发明提供一种治疗肺纤维化病的中药组合物,所述中药组合物由下列重量份的组分组成:
进一步,本发明所述中药组合物优选由下列重量份的组分组成:
本发明还提供所述中药组合物在制备抗肺纤维化药物中的应用。
所述应用的方法可以是将所述中药组合物与其他人体可接受的药用辅料制成片剂、散剂、汤剂或胶囊。
本发明研究了上述中药组合物对肺纤维化病理改变的影响、检测代表性的炎症因子如TGF-β1的分泌,肺组织中羟脯氨酸的含量等,并从mRNA表达水平进行了相关机制研究,研究表明中药组合物对肺纤维化动物模型TGFβ有明显的抑制作用。
本发明的研究机理在于: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。最近的研究提示。PDE8家族是保持cAMP稳态的调节者之一,在淋巴细胞中高表达,提示其在调节免疫和炎症中起作用,但目前对其抗炎作用的研究尚无。目前已知哺乳动物PDE8家族包括2个基因PDE8A、PDE8B。两种异构体都对cAMP有特异性且对底物有着很高的亲和力。PDE8A mRNA的表达十分广泛并在许多组织被检测到,PDE8已被证实与淋巴细胞趋化相关,通过干预淋巴细胞内cAMP信号通路可以阻止淋巴细胞透过毛细血管向炎症病灶区聚集。抑制剂实验证明抑制PDE8可以弥补单独抑制PDE4的不足,阻止炎症病灶区对淋巴细胞的募集作用。
本发明经过研究表明,本发明提供的中药组合物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。本发明开拓了提供的中药组合物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。
四、附图说明
图1博莱霉素诱导的肺纤维化模型的肺组织纤维病变的Masson染色照片。
图2博莱霉素诱导的肺纤维化模型的肺组织中羟脯氨酸含量对比图。
图3博莱霉素诱导的肺纤维化模型的肺泡灌洗液中TGF-β1水平对比图。
图4博莱霉素诱导的肺纤维化模型的PDE8AmRNA表达的PCR产物检测扫描对比图片。
图5博莱霉素诱导肺纤维化模型的PDE8AmRNA表达的PCR产物的吸光度比值对比图。
五、具体实施方式:
实施例1
1.1实验动物、药品、试剂和仪器
ICR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。博莱霉素:Sigma,批号:9041-93-4;地塞米松磷酸钠注射液(浙江省仙琚制药股份公司);Real time PCR相关试剂(包括dNTP Mixture,Oligo(dt)18primer,RNase Inhibitor,M-MLV Reverse Transcriptase):宝生物工程(大连)有限公司;羟脯氨酸测定试剂盒:凯基,KGT030-2;小鼠TGF-β1ELISA试剂盒:武汉博士德生物工程有限公司;小鼠β-actin、PDE8A引物由上海生工生物工程有限公司合成;PCR仪:Eppendoff公司;水平电泳仪:英国CLP公司。
中药组合物:按照白芨3.6份,五倍子1份,僵蚕1份,焦术4份,沙4份,百部4份,桔梗1份,党参7份的重量份数称量各组分,混合均匀。
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(Bleomycin)。空白对照组滴入同等体积的生理盐水,记为控制组(control)。地塞米松组腹腔注射:2mg/kg,记为阳性对照组(Dex)。中药组合物提取液配制方法:将中药组分按上述比例称量好后,粉碎研磨后称重,5倍重量的蒸馏水浸泡过夜,5000g离心取上清,然后70℃水浴浓缩至生药含量1g/ml的水提液,并依次稀释成生药含量0.2g/ml、生药含量0.04g/ml。灌胃给药剂量分别为:低剂量0.4g/kg、中剂量2g/kg、高剂量10g/kg,分别记为低剂量组(L)、中剂量组(M)、高剂量组(H)。博莱霉素给药后14d处死,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。结果见附图1,Masson染色,胶原蓝染,放大倍数×10,标尺50μm胶原蓝染,放大倍数×10,标尺50μm。
1.4肺组织中羟脯氨酸含量测定
取右肺称重,加入1ml羟脯氨酸试剂盒水解液匀浆后100℃水浴(电磁炉保温档)水解20min,调PH值至6.0-6.8,然后加入蒸馏水10ml,混匀,3500rpm离心10min,取1ml上清,60℃水浴15min,冷却后,550nm波长读取数值。计算公式:
结果见附图2,结果采用均数±标准误表示,n=6~8,*P<0.05,**P<0.01与模型组比较。
1.5BALF中TGF-β1的ELISA测定
取1ml生理盐水灌洗肺组织得到肺泡灌洗液。以2000rpm/min离心10min,留取上清液。按照小鼠TGF-β1ELISA试剂盒说明书进行TGF-β1的ELISA含量测定,结果见附图3,结果采用均数±标准误表示,n=6~8,*P<0.05,***P<0.001与模型组比较。
1.6-PCR测定肺组织中磷酸二酯酶8亚型的mRNA的表达
取液氮固定的左肺组织加入1ml trizol于冰浴中匀浆,提取RNA,逆转录合成cDNA,于-20℃保存。以cDNA为模板,用目的基因PDE8A引物进行半定量PCR扩增,内参为β-actin。引物序列如下:小鼠β-actin上游(5’-3’):GAT TAC TGC TCT GGC TCC TAG C;小鼠β-actin下游(5’-3’):GAC TCA TCG TAC TCC TGC TTG C。扩增条件为:95℃10s,60℃30s,72℃45s,25个循环。小鼠PDE8A上游(5’-3’):CCA TCA CCA AGG TAA TCA;小鼠PDE8A下游(5’-3’):TCC GTGGTG GGA CAT CAT。扩增条件为:95℃10s,48.9℃30s,72℃45s,40个循环。PCR产物检测采用1.5%琼脂糖凝胶水平电泳,采用UVP凝胶成像分析系统对条带进行扫描分析,其中代表照片如图4所示。以β-actin为内参,以吸光度比值进行半定量分析,所得结果见图5,结果采用均数±标准误表示,n=6,*P<0.05,**P<0.01与模型组比较。
1.7统计学分析
数据以平均数±标准误表示,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
2.1中药组合物水提物对博莱霉素诱导肺组织纤维化的病理变化的影响
博莱霉素气道滴入后14d,成功诱导了肺组织纤维化病变。Masson染色呈蓝色的即沉积的胶原纤维,如图1所示。。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。中药组合物水提物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。
2.2中药组合物水提物对博莱霉素诱导纤维化肺组织羟脯氨酸含量的影响
肺组织中羟脯氨酸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),如图2所示。阳性对照组羟脯氨酸含量有抑制趋势,但与模型组比较无显著性差异。低、中剂量中药组合物水提物对羟脯氨酸的影响也不明显,但高剂量组下降较明显,达统计学显著性(P<0.01与模型组比较)。
2.3中药组合物水提物对博莱霉素诱导肺纤维化小鼠BALF中TGF-β1含量的影响
在博莱霉素刺激后14d,TGF-β上升迅速,达325pg/ml(P<0.001vs正常对照组),如图3所示。而中药组合物的水提物各剂量对TGF-β1的分泌均有明显抑制作用,尤以高剂量组为显著,与模型组比较,差异极显著(P<0.001vs模型组)。而地塞米松组也能明显抑制TGF-β1的分泌(P<0.001vs模型组)。
2.4中药组合物的水提物对博莱霉素诱导纤维化肺组织中PDE8AmRNA表达的影响
根据半定量PCR结果,博莱霉素刺激后肺组织中PDE8A的mRNA表达量明显增加,这与肺纤维化的趋势相符。与正常对照组比较,14d的PDE8A mRNA表达即有显著性差异(P<0.01vs正常对照组),相对表达量比值为0.49;中药组合物的水提物各剂量组PDE8AmRNA的相对表达量均有明显下降(P<0.05vs模型组)。地塞米松组PDE8A的表达也有下降,但差异无显著性。
2.5中药组合物的水提物对博莱霉素诱导纤维化肺组织中PDE8AmRNA表达与TGF-β1分泌量的相关分析
将上述结果中的TGF-β1含量与PDE8A mRNA表达进行了相关分析,结果显示TGF-β1含量的变化趋势与PDE8AmRNA表达量间的相关系数为0.541,P<0.05。提示PDE8A与肺纤维化间存在相关性,可能是中药组合物的水提物的作用靶点,也提示PDE8A可能是肺纤维化的治疗靶点。
3、优点和效果:
本研究发现了本发明组方的中药组合物的水提物对肺纤维化有较好的效果,且发现其机制可能涉及PDE8A。这些结果目前尚无研究报道。提示以这些成分入药的组合药物对肺纤维化疾病的治疗有益,且通过对PDE8A的影响可能对肺纤维化的治疗有益。
Claims (2)
1.一种治疗肺纤维化病的中药组合物在制备抗肺纤维化药物中的应用,其特征在于所述中药组合物由下列重量份的组分组成:
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,将所述中药组合物与其他人体可接受的药用辅料制成片剂、散剂、汤剂或胶囊。
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