CN109464453B - 芦荟纯酰素在制备防治肺纤维化药物中的应用 - Google Patents
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Abstract
本发明公开了芦荟纯酰素在制备防治肺纤维化药物中的应用,属于芦荟纯酰素作为治疗肺纤维化的新用途。本发明芦荟纯酰素能够明显改善枸橼酸溶液诱发的豚鼠咳嗽;显著抑制博来霉素所致大鼠的肺胶原纤维沉积导致的肺纤维化,对肺纤维化治疗具有确切的疗效,同时芦荟纯酰素具有安全性高的特点。
Description
技术领域
本发明涉及药物技术领域,具体来说是芦荟纯酰素在制备防治肺纤维化药物中的应用。
背景技术
肺纤维化(pulmonary fibrosis,PF)属于一种慢性、进展性间质型肺炎的一种特殊类型。发病人群男性多发于女性,多为50~70岁。肺纤维化是由多种诱因引起的肺部 炎症反应、肺泡持续性损伤以及胞外基质反复被破坏、修复、重建,从而导致基质过度 沉积,最终造成肺组织结构的改变和肺功能丧失的一类疾病。临床表现为干咳、进行性 呼吸困难,经数月或数年逐渐恶化至衰竭或死亡。肺纤维化患者的生存率较低,但早期 症状不明显,目前治疗主要是以缓解病情为主。
肺组织分实质和间质两部分,实质是进行气体交换的场所,而间质则是肺纤维化的 发生部位。过敏反应、环境颗粒、感染或机械性的损伤均可导致正常组织结构的破坏。急性受损的内皮细胞会释放炎症因子和启动抗纤溶系统凝集。同时血小板在受损部位大量聚集,形成富含纤维的凝块。在炎症阶段,趋化因子梯度会招募大量的炎症细胞如中 性粒细胞、嗜酸性粒细胞等,它们分泌大量的细胞因子,如白介素IL-4、IL-6、IL-10、 TGF-β等,促进上皮细胞向成纤维细胞以及成纤维细胞向肌成纤维细胞的转化,最终产 生大量的细胞外基质。在纤维化阶段,细胞外基质如胶原、纤连蛋白通过整合素等细胞 表面受体,介导下游信号的发生,导致肺组织的正常结构被增厚的纤维组织所填充,气 体交换功能丧失和呼吸衰竭。
迄今为止,肺纤维化的药物治疗方法主要是应用糖皮质激素。糖皮质激素可以改善 炎症反应、抑制免疫反应过程,对以肺泡炎症为主的肺纤维化有着一定的疗效;但是对弥漫性肺纤维化病人疗效甚差,且长期使用糖皮质激素副作用太大。目前化药中吡啡尼 酮是一种新的抗纤维化治疗的口服药物,但因其价格昂贵,临床应用受限。
随着中药研究的深入,近年来发现许多中药单体成分或复方在肺纤维化治疗上具有 显著的疗效,中药治疗肺纤维化得到广泛关注,因此从中药中寻找新型的低毒高效抗肺纤维化药物成为研究热点。
芦荟是一种百合科草本植物,原产于非洲,属多年生百合科肉质草本植物。含有丰富的多糖、蛋白质、氨基酸、维生素、活性酶及对人体十分有益的微量元素。它的特征 成分是芦荟蒽醌等,芦荟由于含有多种生物活性物质,在中国民间就被作为美容、护发 和治疗皮肤疾病的天然药物。
纯酰素(PMAS)是从芦荟多糖中提取的乙酰化甘露聚糖再纯化人体最易吸收的活细 胞多糖物质精华,活细胞纯酰素(PMAS)凭借优于动物活性肽抗衰老的逆生长年轻态功效以及抑制艾滋病病毒、抗肿瘤功效而备受医学界关注。活细胞纯酰素(PMAS)通过毛 细血管迅速抵达人的皮下组织,刺激皮肤细胞的分裂,对于皮肤粗糙、暗晦、色斑、粉 刺等都有很大的改善,使皮肤变得光滑、润泽并富有弹性,不过这种变化首先是基于人 体机能的全面提高,使得细胞更新的速度加快,内分泌得到平衡、自身免疫力提高,新 陈代谢旺盛。
目前尚未有芦荟纯酰素在制备防治肺纤维化药物及其应用的报道。
发明内容
本发明的目的在于提供芦荟纯酰素在制备防治肺纤维化药物中的应用,是芦荟纯酰 素的一种新用途,目前没有任何报道涉及芦荟纯酰素用于肺纤维化疾病的治疗。
其中,所述芦荟纯酰素从植物芦荟中提纯得到。
具体地,所述植物芦荟为库拉索芦荟(Aloe barbadebsis Miller)、木立芦荟(Aloe arboresecens Miller)、元江芦荟(Aloe yuan-jiangensis)和中华芦荟(Aloechinenesis)的任意一种或上述植物芦荟的其他近缘芦荟植物。
提取芦荟纯酰素的方法可以采用常规多糖提取、精制方法得到,在一种实施方式中, 所述芦荟纯酰素通过如下方法制备得到:采摘芦荟鲜叶以备用;芦荟鲜叶依次进行清洗、 消毒、去皮,制取芦荟凝胶片;将芦荟凝胶片依次粉碎研磨、离心分离,制取芦荟凝胶原汁;按200~300g/T芦荟凝胶原汁的添加量加入果胶酶,然后依次粉碎研磨、离心分 离,制取芦荟浊汁,依次经活性炭脱色过滤、硅藻土过滤,制取芦荟清汁,后经反渗透 膜进行浓缩,然后再常温浓缩,制取低倍芦荟浓缩汁,加入乙醇至酒精度数为55°,将 析出物过滤后取清液,再加乙醇至酒精度数为85°,过滤得析出物,超滤或不超滤,喷 雾干燥、冻干、或烘干中的一种方式干燥,即得芦荟多糖。
优选地,所述芦荟纯酰素的重均分子量在1000-300000之间。
其中,所述芦荟纯酰素在使用时按照常规方法制备成片剂、散剂、胶囊剂、颗粒剂、糖浆剂、口服液、乳剂、脂质体和注射剂。
本发明研究发现芦荟纯酰素可显著减轻由博来霉素导致的大鼠肺胶原的沉积形成肺 纤维化,表现明显的预防肺纤维化的形成和治疗肺纤维化作用。
附图说明
图1为芦荟纯酰素对博来霉素致大鼠肺纤维化影响的肉眼观察图,其中:
A:正常组;B:模型组;C:芦荟提取物低剂量;D:芦荟提取物高剂量;
图2为H&E染色图(指示肺脏的病变情况),其中:
A:正常组;B:模型组;C:芦荟提取物低剂量;D:芦荟提取物高剂量;
图3为Masson染色图,指示肺脏纤维化的程度(呈亮绿色部分为纤维化组织),其中:
G:正常组;H:模型组;I:芦荟提取物低剂量;J:芦荟提取物高剂量;
图4为制备的芦荟多糖的红外图谱。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
实施例1:本发明芦荟纯酰素防治肺纤维化的作用
1.材料与方法
1.1动物:雌性SD大鼠,220-250g左右,由南京医科大学实验动物中心提供,合格证号:SCXK(苏)2013-0005。
1.2受试品与试剂
芦荟多糖,大鼠两给药剂量分别为0.24g/kg和0.48g/kg;豚鼠两给药剂量分别为0.22 g/kg和0.44g/kg。
博来霉素,15mg/瓶,海正辉瑞制药有限公司
芦荟纯酰素的制备:采摘芦荟鲜叶以备用;芦荟鲜叶依次进行清洗、消毒、去皮,制取芦荟凝胶片;依次粉碎研磨、离心分离,制取芦荟凝胶原汁;,按200~300g/T 芦荟原汁物料的添加量加入果胶酶,依次3道粉碎研磨、离心分离,制取芦荟浊汁, 依次经活性炭脱色过滤、硅藻土过滤,制取芦荟清汁经反渗透膜进行浓缩,然后再常温 浓缩,制取低倍芦荟浓缩汁,加入乙醇至55°(酒精度数),将析出物过滤后取清液, 再加乙醇至85°(酒精度数),过滤得析出物,超滤或不超滤,并用适宜条件干燥得芦 荟多糖。其主要成份为乙酰化的甘露聚糖,红外光谱如下,和甘露糖红外光谱相近,并 在1750cm-1、1250cm-1左右有强吸收(酯键),在870cm-1左右处有吸收(β-D-吡喃环), 其红外图如图4所示。
2.实验方法
2.1.博来霉素致大鼠肺纤维化模型。
取SD雌性大鼠70只,体重250-280g。大鼠戊巴比妥钠(30mg/kg)麻醉后仰位固 定在鼠板上。大鼠头部垫高,剪开颈部皮肤,钝性分离肌肉,暴露气管。使用4号小针 头朝肺部方向缓慢均匀注入博来霉素溶液(5mg/kg),注射完毕后缝合颈部创口。常规 饲养两周后,剩余存活模型大鼠进行分组,分别为模型组(NS)、芦荟多糖高剂量组(0.48 g/kg)、芦荟多糖低剂量组(0.24g/kg)。分组按相应剂量进行给药,每天一次,持续 两周,最后一次给药后1h脱椎处死大鼠,剖取大鼠肺进行肉眼观察,并且固定在甲醛 中,进行H&E染色检验和Massion染。
3.实验结果
3.1.芦荟纯酰素对博来霉素致大鼠肺纤维化的影响
图1结果显示,博来霉素直接作用大鼠肺部可引起明显的变化,肉眼观察肺部相较于正常肺部(A),模型大鼠肺脏(B)颜色变淡白,表面有较多斑点出现,质地变硬。 而用芦荟纯酰素或芦荟浓缩汁干预之后,大鼠肺脏出现了较为明显区别于模型组大鼠肺 脏的变化。芦荟纯酰素(C,D)干预后,大鼠肺脏出现较为明显变化,肺脏表面斑点减 少,肺脏的色泽、质地均与模型组肺脏有较为明显的区别,提示芦荟纯酰素的干预可以 改善大鼠肺脏的纤维化状况。
肺纤维化评分结果
表1.芦荟纯酰素对肺纤维化大鼠影响的病理检验评分结果
图2为H&E染色结果,结果显示显示正常肺组织由肺泡、肺内支气管分支及间质组成,结构清晰可见(A)。
模型组大鼠肺脏肺泡壁有轻度充血、炎细胞浸润为主,且致肺泡壁增厚,间质中可见轻度或中度纤维组织增生,尤其以支气管和血管周围较明显(B)。
芦荟纯酰素给药组(C,D):大鼠肺脏出现的病变与模型组基本类似,但程度上较轻, 从表1的HE评分结果可看出,该两剂量组平均HE分值均低于模型组。
图3为Masson染色结果。结果表明:模型组(H)大鼠肺脏肺内支气管和血管分支 周围和肺泡壁增厚部位可见亮绿色的染色反应,显示纤维化形成。
芦荟纯酰素给药组(I,J):大鼠肺脏出现的纤维化病变与模型组基本类似,但程度上较 轻,从表1的Masson评分结果可看出,该两剂量组平均Masson分值均低于模型组,经统计检验芦荟多糖高剂量有显著意义(p<0.05)。
综上所述,博来霉素致大鼠肺纤维化实验中,芦荟纯酰素给药后肉眼观察发现大鼠 的病变肺脏与模型组比较有一定的改善;HE染色结果也支持肉眼观察结果,芦荟纯酰素可改善大鼠肺脏的病变状况,减轻充血及炎证反应;Masson染色显示高剂量作用大鼠可 明显减少大鼠的肺纤维化行成,低剂量呈现同样的趋势。以上结果说明芦荟纯酰素对博 来霉素导致的大鼠肺纤维化有改善作用,可逆转肺纤维化形成,体现抗纤维化作用。
Claims (6)
1.芦荟纯酰素在制备防治肺纤维化药物中的应用,其特征在于:所述芦荟纯酰素通过如下方法制备得到:采摘芦荟鲜叶以备用;芦荟鲜叶依次进行清洗、消毒、去皮,制取芦荟凝胶片;将芦荟凝胶片依次粉碎研磨、离心分离,制取芦荟凝胶原汁;按200~300g/T芦荟凝胶原汁的添加量加入果胶酶,然后依次粉碎研磨、离心分离,制取芦荟浊汁,依次经活性炭脱色过滤、硅藻土过滤,制取芦荟清汁,后经反渗透膜进行浓缩,然后再常温浓缩,制取低倍芦荟浓缩汁,加入乙醇至酒精度数为55°,将析出物过滤后取清液,再加乙醇至酒精度数为85°,过滤得析出物,超滤或不超滤,干燥,即得芦荟纯酰素。
2.根据权利要求1所述的应用,其特征在于,所述芦荟为库拉索芦荟、木立芦荟、元江芦荟或中华芦荟中的任意一种。
3.根据权利要求1所述的应用,其特征在于,所述干燥为喷雾干燥、冻干、或烘干中的任意一种。
4.根据权利要求1所述的应用,其特征在于,所述芦荟纯酰素的重均分子量在1000-300000之间。
5.根据权利要求1所述的应用,其特征在于,所述芦荟纯酰素在使用时按照常规方法制备成片剂、散剂、胶囊剂、颗粒剂、糖浆剂、口服液、乳剂和注射剂。
6.根据权利要求1所述的应用,其特征在于,所述芦荟纯酰素在使用时按照常规方法制备成脂质体。
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