CN115624561A - 纤细薯蓣皂苷在制备治疗肺纤维化药物中的应用 - Google Patents
纤细薯蓣皂苷在制备治疗肺纤维化药物中的应用 Download PDFInfo
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Abstract
本发明提供了一种纤细薯蓣皂苷在制备治疗肺纤维化药物中的应用,该纤细薯蓣皂苷用于减轻肺纤维化的病死率,改善肺部结构的破坏和肺部胶原纤维的沉积,降低肺部炎症、纤维化水平、肺部水肿程度,可以作为一种有潜力的抑制肺纤维化的药物。
Description
技术领域
本发明属于生物医药领域,具体涉及一种纤细薯蓣皂苷在制备治疗肺纤维化药物中的应用。
背景技术
肺纤维化(pulmonary fibrosis)是一种非常严重的疾病症状,可以由多种致病因素导致,伴随成纤维细胞和细胞外基质聚集,通常伴有炎症损伤和组织结构破坏,其特点是进行性呼吸困难和肺功能下降,最后可因为呼吸衰竭而死亡。肺纤维化的发生有许多不同原因,包括自身免疫性疾病、环境或职业暴露、某些药物的副作用等,还有一些发病原因是未知的,称为特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)。据统计,近年来,随着大气污染越来越严重,再加上吸烟等不良的生活习惯,肺纤维化的发病率逐年升高且趋于年轻化,中位生存期为3-5年,5年死亡率为60-80%,高于大多数肿瘤,被称为一种“类肿瘤疾病”。
目前治疗肺纤维化常用的药物是吡非尼酮和尼达尼布,虽然这两种药物可以缓解患者的肺部纤维化症状,但是只能在纤维化早期起作用,并不能诱导损伤组织的再生,对阻止肺纤维化发展和改善其预后的效果并不理想,不能从根本上治愈肺纤维化。因此,开发一种治疗肺纤维化安全、有效的药物,将为降低肺纤维化病死率提供更为有效的帮助,具有重要的科学意义和临床价值。
随着近些年分离纯化和化学合成技术的发展,许多具有抗肺纤维化活性的天然小分子化合物得以被分离或合成。纤细薯蓣皂苷(gracillin)是一种三萜类化合物,广泛存在于重楼属、薯蓣属等植物的根茎中(图1A),其化学结构式见图1B,其水解后的产物,特别是薯蓣皂苷元具有广泛的生物活性和应用价值。
有研究发现薯蕷皂苷具有免疫调节的作用,例如台湾薯蓣宁C可以有效增强人外周血细胞丝裂原的反应性,并增强自然杀伤细胞的活性。穿山龙总皂苷含药血清在小鼠体内可过抑制LPS诱导的B淋巴细胞增殖,从而抑制小鼠的免疫功能。这说明许多薯蓣皂苷可通过不同途径调节机体免疫力。
薯蓣皂苷还能通过不同的途径对心血管系统起作用。有研究通过建立大鼠H9c2心肌细胞缺氧模型,并用薯蓣皂苷处理细胞后发现,薯蓣皂苷可以有效减少心肌细胞在缺氧后复氧后的细胞存活率,而且薯蓣皂苷可通过抗氧化作用保护缺氧后复氧的心肌细胞受到的损伤。也有研究发现,薯蓣皂苷对缺氧心肌细胞具有的保护作用是因为其可通过增强肌浆网上钙泵SERCA2的表达从而减轻缺氧心肌细胞的钙超负荷。
另一个对薯蓣皂苷研究较多的药理活性是它的抗肿瘤活性。有研究发现薯蓣皂苷对人宫颈癌HeLa细胞的生长有显著的抑制效果,并且能诱导癌细胞发生凋亡。而且还证实了薯蓣皂苷可将HeLa细胞的生长抑制在细胞周期中的S期。有研究利用人工合成的薯蓣皂苷类似物,发现它们可以有效抑制人乳腺癌MDA-MB-231细胞的生长。还有研究发现薯蓣皂苷对M-07e、HL-60和K562这三种白血病细胞的生长都有显著的抑制作用。
虽然有不少对薯蓣皂苷药理活性的研究,但对纤细薯蓣皂苷这种化合物的研究相对较少。既往研究已报道纤细薯蓣皂苷具有抗肿瘤活性,但其对肺纤维化的生物学功能影响及价值仍不清楚。
发明内容
本发明所要解决的技术问题是提供一种纤细薯蓣皂苷在药物制备中的应用,从而为肺纤维化的治疗提供更多的选择。
一种纤细薯蓣皂苷在药物制备中的应用,所述药物以纤细薯蓣皂苷作为活性成分;
所述的药物用于预防或者治疗肺纤维化。
作为优选,所述的肺纤维化是由博来霉素诱导的。
作为优选,所述纤细薯蓣皂苷用于减轻肺纤维化的病死率,并且不影响体重。
作为优选,所述的纤细薯蓣皂苷用于改善肺部结构的破坏和肺部胶原纤维的沉积。
作为优选,所述的纤细薯蓣皂苷用于降低肺部炎症、纤维化水平、肺部水肿程度。
作为优选,所述的纤细薯蓣皂苷用于降低炎症因子IL-1β、IL-6、TNF-α和CXCL1/IL-8的渗出。
作为优选,所述的纤细薯蓣皂苷用于降低肺纤维化标志物Collagen I、Fibronectin和α-SMA的表达水平。
附图说明
图1为纤细薯蓣皂苷的天然来源和化学结构式;
图2为实施例1中纤细薯蓣皂苷对肺纤维化小鼠体重和病死率的影响;
图3为实施例2中纤细薯蓣皂苷对肺纤维化小鼠肺部病理改变的影响;
图4为实施例3中纤细薯蓣皂苷对肺纤维化小鼠肺部炎症及纤维化水平、水肿程度和胶原含量的影响;
图5为实施例4中纤细薯蓣皂苷对肺纤维化小鼠肺泡灌洗液的影响;
图6为实施例5中纤细薯蓣皂苷对肺纤维化小鼠肺功能的影响;
图7为实施例6中纤细薯蓣皂苷对小鼠肺纤维化标志物的影响;
图8为实施例7中纤细薯蓣皂苷对NIH-3T3细胞活力及TGF-β1刺激后细胞外基质沉积标志物的影响;
图9为实施例8中纤细薯蓣皂苷对NIH-3T3细胞迁移能力的影响。
具体实施方式
下面结合附图和具体实施例对本发明进行进一步的说明。
实施例1
采用单次气管内滴注博来霉素(3mg/Kg)建立小鼠肺纤维化模型,造模后一天进行腹腔注射纤细薯蓣皂苷治疗,剂量分别为1mg/kg、2mg/kg,每两天注射一次,并于造模前及每次给药前记录小鼠体重。造模28天后处死,进行肺组织收集以及各项指标的测定。结果见图2,图2中,BLM表示仅注射博来霉素不加注射纤细薯蓣皂苷组,CON为正常对照组。通过体重曲线可以发现纤细薯蓣皂苷对小鼠体重没有影响(图2A);通过生存曲线发现纤细薯蓣皂苷可以减轻肺纤维化的病死率(图2B)。
上述结果证明了纤细薯蓣皂苷可以减轻博来霉素诱导的小鼠肺纤维化。
实施例2
各组小鼠造模结束后,取右肺中间叶置于4%多聚甲醛中固定48小时后进行石蜡包埋、切片、脱蜡、水化、苏木素-伊红染色、脱水、封片等步骤后,通过HE染色发现纤细薯蓣皂苷可以改善肺纤维化小鼠肺部结构的破坏(图3A);同样取右肺中间叶置于4%多聚甲醛中固定48小时后进行石蜡包埋、切片、脱蜡、水化、重铬酸钾铬化处理、丽春红染色、磷钼酸处理、苯胺蓝染色、1%冰醋酸分化、脱水、封片等步骤后,通过Masson染色发现纤细薯蓣皂苷可以改善肺纤维化小鼠肺部胶原纤维的沉积(图3B)。
实施例3
通过普通光学显微镜200倍视野下对HE染色切片进行拍照获取每个肺组织病理学图像,采用半定量评分系统进行Ashcroft评分。评分如下:肺部正常,没有纤维化的出现=0分;肺泡部分扩大,伴轻微的、孤立的纤维化改变=1分;肺泡部分扩大,有较明显的纤维化改变,有类似结节状形成=2分;肺泡部分扩大,相邻连续的纤维化壁=3分;出现单个的纤维化肿块(≤10%的显微镜视野)=4分;融合性的纤维化肿块(>10%且≤50%的显微镜视野)=5分;大块连续状的纤维化肿块(>50%的显微镜视野)=6分;肺组织结构严重变形,肺泡几乎完全消失,即蜂窝肺=7分;肺部全部区域的纤维化肿块闭塞=8分。每个载玻片的10个随机的显微镜下观察区域被评分。通过Ashcroft评分发现纤细薯蓣皂苷可以降低肺纤维化小鼠肺部炎症和纤维化水平(图4A)。取完肺泡灌洗液后,取出肺组织,小心剪去心脏和周围其他脂肪组织,将肺置于预冷的PBS中漂洗血液,吸干残余液体后,取右肺上叶和左肺下叶置于空锡纸盒中称量肺湿重后,于60℃烘箱放置48小时后称量肺干重,用于肺湿/干重比测量。通过肺湿/干重比发现纤细薯蓣皂苷可以降低肺纤维化小鼠肺部水肿程度(图4B)。取肺组织30-100mg,采用碱性水解法测定肺组织羟脯氨酸含量,操作步骤按试剂盒说明书进行。通过肺组织羟脯氨酸含量测定发现纤细薯蓣皂苷可以降低肺纤维化小鼠肺部胶原纤维沉积(图4C)。
实施例4
收集各组小鼠肺泡灌洗液(BALF),4℃,3000rpm,离心10min,吸取上清液测定BALF中总蛋白浓度,发现纤细薯蓣皂苷可以降低肺纤维化小鼠BALF中总蛋白浓度(图5A);将沉淀重悬于50ul PBS中,用细胞计数仪进行细胞计数,发现纤细薯蓣皂苷可以降低肺纤维化小鼠BALF中活细胞数/总细胞数比率(图5B)。将BALF上清液进行ELISA检测,发现纤细薯蓣皂苷可以降低肺纤维化小鼠BALF中炎症因子IL-1β(图5C)、IL-6(图5D)、TNF-α(图5E)、CXCL1/IL-8(图5F)的渗出,且高浓度组的效果更明显。以上实验均证明了纤细薯蓣皂苷可以改善小鼠肺纤维化过程中伴随的炎症表现。
实施例5
造模后28天对各组小鼠进行了肺功能实验,评估各组小鼠的肺功能状况,结果发现纤细薯蓣皂苷可以改善小鼠肺纤维化过程中发生的肺功能障碍,降低弹性阻力(图6A)和呼吸阻力(图6B),提高肺顺应性(图6C)。
实施例6
同时对各组肺组织样本进行免疫组化实验发现纤细薯蓣皂苷可以降低肺纤维化标志物α-SMA的表达水平(图7A),WB检测发现纤细薯蓣皂苷可以降低肺纤维化标志物Collagen I、Fibronectin和α-SMA的表达水平(图7B)。以上实验均证明了纤细薯蓣皂苷可以减轻博来霉素诱导的小鼠肺纤维化。
实施例7
为检测药物对细胞活力的影响,取生长状态良好、同时处于在对数生长期的小鼠成纤维化(NIH-3T3)细胞,对细胞进行消化,并用完全培养基对细胞进行重悬,配成3×104个/ml细胞悬液。设置5个复孔,每孔取100μl铺于96孔板中,周围加一圈PBS,在37℃、5%CO2恒温培养箱中培养24小时。显微镜下观察贴壁后细胞密度,等到细胞密度达到60-80%时,更换200μL的新鲜培养基。以DMSO为溶剂配制所需浓度梯度的药物溶液(0.5、1、1.5、2、2.5、3μM),于96孔板内加药干预(设置阴性对照组只加入DMSO),置于37℃、5%CO2恒温培养箱中培养24小时。药物干预结束后,取出96孔板,吸去各孔上清液,用PBS洗2次。避光条件下,配置CCK8反应液(DMEM基础培养基:CCK8反应液=10:1),每孔加入110μl CCK8反应液。加入反应液后,用锡纸包裹96孔板于培养箱中孵育1小时。孵育结束后,用酶标仪在450nm波长下测定OD值。本实施例通过CCK8实验在小鼠成纤维细胞(NIH-3T3)中筛选出不影响细胞活力的药物浓度(图8A),将1.5μM作为后续细胞实验的作用浓度。通过WB检测发现纤细薯蓣皂苷可以降低TGF-β1刺激后NIH-3T3细胞中细胞外基质沉积标志物Collagen I、Fibronectin和α-SMA的表达水平(图8B)。
实施例8
Transwell实验取对数生长期的NIH-3T3细胞,对细胞进行消化,加入完全培养基重悬细胞;采用Corning 8.0μm 24孔板小室,将100μl 3×104个/ml细胞悬液加入Transwell小室上室,贴壁培养12-18小时;分组为正常组(CON)、药物组(0.5μM G)、造模组(10ng/ml TGF-β1)、治疗组(10ng/ml TGF-β1+0.5μM G),下室缓慢加入600μl对应的反应液,上室补充100μl基础培养基;置入培养箱中培养24h;造模结束后,吸出小室内的液体,放入4%多聚甲醛中固定30min;将小室取出,风干后置于结晶紫中染色30min,棉签去除多余的结晶紫;使用普通光学显微镜100倍视野进行观察和拍照,使用Image J软件对图像进行定量统计分析。划痕实验先用marker笔在6孔板背后均匀地划横线,大约每隔1-1.5cm一道,横穿过孔,每孔穿过3条线;在孔中加入1ml 5×105个/ml细胞悬液,分组与干预的方式如前所述,待细胞长满后,用200μl枪头尽量垂直于背后的横线划痕,每孔划3-5条线;用PBS洗3次,去除划下的细胞,加入新鲜的完全培养基,分组与干预的方式如前所述;放入37℃、5%CO2恒温培养箱中培养24小时;使用普通光学显微镜100倍视野在0、24小时进行观察和拍照,使用Image J软件对图像进行定量统计分析。通过transwell(图9A)和划痕实验(图9B)发现纤细薯蓣皂苷可以降低TGF-β1刺激后NIH-3T3细胞的迁移能力。以上实验分别证明了纤细薯蓣皂苷可以在细胞层面降低细胞外基质沉积和细胞迁移能力。
基于上述实验结果,我们认为纤细薯蓣皂苷是一种抑制肺纤维化的药物。
Claims (7)
1.一种纤细薯蓣皂苷在药物制备中的应用,其特征在于,所述药物以纤细薯蓣皂苷作为活性成分;
所述的药物用于预防或者治疗肺纤维化。
2.根据权利要求1所述的纤细薯蓣皂苷在药物制备中的应用,其特征在于,所述的肺纤维化是由博来霉素诱导的肺纤维化。
3.根据权利要求1所述的纤细薯蓣皂苷在药物制备中的应用,其特征在于,所述纤细薯蓣皂苷用于减轻肺纤维化的病死率,并且不影响体重。
4.根据权利要求1所述的纤细薯蓣皂苷在药物制备中的应用,其特征在于,所述的纤细薯蓣皂苷用于改善肺部结构的破坏和肺部胶原纤维的沉积。
5.根据权利要求1所述的纤细薯蓣皂苷在药物制备中的应用,其特征在于,所述的纤细薯蓣皂苷用于降低肺部炎症、纤维化水平、肺部水肿程度。
6.根据权利要求1或5所述的纤细薯蓣皂苷在药物制备中的应用,其特征在于,所述的纤细薯蓣皂苷用于降低炎症因子IL-1β、IL-6、TNF-α和CXCL1/IL-8的渗出。
7.根据权利要求1或5所述的纤细薯蓣皂苷在药物制备中的应用,其特征在于,所述的纤细薯蓣皂苷用于降低肺纤维化标志物Collagen I、Fibronectin和α-SMA的表达水平。
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