CN115400201A - Ss-31在制备预防和/或治疗香烟诱导的气道炎症及慢性阻塞性肺疾病的药物中的用途 - Google Patents
Ss-31在制备预防和/或治疗香烟诱导的气道炎症及慢性阻塞性肺疾病的药物中的用途 Download PDFInfo
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Abstract
本发明提供了SS‑31在制备预防和/或治疗香烟诱导的气道炎症及慢性阻塞性肺疾病的药物中的用途,属于制药领域。实验结果表明,SS‑31能够有效改善香烟烟雾提取物诱导的气道炎症反应,能够有效降低香烟烟雾诱导的慢性阻塞性肺疾病气道炎症小鼠模型的炎症因子IL‑6、TNF‑α、MMP9浓度,能够用来制备预防和/或治疗慢性阻塞性肺疾病,特别是慢性阻塞性肺疾病引起的气道炎症的药物,应用前景广阔。
Description
技术领域
本发明属于制药领域,具体涉及SS-31在制备预防和/或治疗香烟诱导的气道炎症及慢性阻塞性肺疾病的药物中的用途。
背景技术
慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是一种具有气流阻塞为特征的慢性支气管炎和/或肺气肿,其以持续性气流受限为特征,是呼吸系统的常见病、多发病。COPD发病率高,吸烟是COPD最主要的危险因素,我国40岁以上人群的发病率达8.2%;COPD死亡率高,其目前是世界上第四大死亡原因。COPD临床症状主要表现为慢性咳嗽、咳痰、气短或呼吸困难、喘息和胸闷,随着疾病的进展还会发生气道炎症反应等,严重影响患者的生活质量,其高发病率、高致残率和高病死率也给患者及社会带来巨大的经济负担。因此,开发出能够有效防治COPD的药物具有重要意义。
虽然COPD一直受到广泛重视,但目前仍缺乏有效的防治方法。现普遍认为COPD是具有气流阻塞为特征的慢性支气管炎和/或肺气肿,而气道炎症尤其是小气道炎症是COPD的主要病变及发病的主要原因。
目前,COPD临床治疗存在如下问题:单纯戒烟后COPD气道慢性炎症不会停止或逆转,而是持续性发展;单纯吸入糖皮质激素(ICS)虽然能缓解COPD患者的症状,延缓肺功能下降速度,但达不到理想的抗炎效果,不能阻止或逆转COPD的发展进程。因此,抑制气道炎症是治疗COPD的关键。
线粒体靶向抗氧化肽SS-31是一种新型的线粒体靶向肽,它可以穿透血脑屏障,定位于线粒体内膜。当细胞稳态受到干扰时,SS-31会作为抗氧化剂来消除过量的活性氧(ROS)。已有研究表明,SS-31对脓毒血症引起的急性肺损伤(ALI)有保护性作用。但是,目前还未见将SS-31用来防治慢性阻塞性肺疾病的报道。
发明内容
本发明的目的在于提供SS-31或其药学上可接受的盐在制备预防和/或治疗香烟诱导的慢性阻塞性肺疾病和气道炎症的药物中的新用途。
具体的,本发明提供了SS-31或其药学上可接受的盐在制备预防和/或治疗阻塞性肺疾病的药物中的用途。
进一步地,所述阻塞性肺疾病为慢性阻塞性肺疾病。
进一步地,所述慢性阻塞性肺疾病为香烟烟雾或香烟烟雾提取物诱导的慢性阻塞性肺疾病。
本发明还提供了SS-31或其药学上可接受的盐在制备预防和/或治疗气道炎症的药物中的用途。
进一步地,所述气道炎症为慢性气道炎症。
进一步地,所述慢性气道炎症为香烟烟雾或香烟烟雾提取物诱导的慢性气道炎症。
进一步地,所述气道炎症为慢性阻塞性肺疾病引起的气道炎症。
进一步地,所述药物能够降低炎症因子的表达。
进一步地,所述炎症因子为IL-6、TNF-α、MMP9。
进一步地,所述炎症因子为肺泡灌洗液和/或气道上皮细胞中的炎症因子。
进一步地,所述气道上皮细胞为支气管上皮细胞。
进一步地,所述药物为以SS-31为活性成分,加上药学上可接受的辅料制得的制剂。
进一步地,所述制剂为口服制剂或注射制剂。
进一步地,所述口服制剂为汤剂、口服液、颗粒剂、胶囊剂、散剂、丸剂或片剂。
实验结果表明,SS-31能够有效改善香烟烟雾提取物诱导的气道炎症反应,能够有效降低香烟烟雾诱导的慢性阻塞性肺疾病气道炎症小鼠模型的炎症因子IL-6、TNF-α、MMP9浓度,能够用来制备预防和/或治疗慢性阻塞性肺疾病,特别是慢性阻塞性肺疾病引起的气道炎症的药物,应用前景广阔。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为各组细胞上清中炎症因子浓度的变化:与CON组相比,****P<0.0001;
与CSE组相比,#P<0.05,###P<0.001,####P<0.0001。
图2为各组小鼠BALF中炎症因子浓度的变化:与CON组相比,****P<0.0001;
与CS组相比,##P<0.01,####P<0.0001;与SS-31(L)+CS组相比,&&P<0.01,&&&P<0.001。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
本发明实施例采用的SS-31 TFA购买于TOPSCIENCE(陶素生化),产品编号:TP1096,CAS:1606994-55-1;别名:MTP-131(TFA),RX-31(TFA),Elamipretide TFA。
实施例1 SS-31减轻气道炎症反应
1、实验方法
实验细胞:人正常支气管上皮细胞BEAS-2B。本实施例利用香烟烟雾提取物(CSE)诱导构建气道上皮细胞炎症模型。
具体操作如下:
首先分成3组进行细胞干预,每组3次生物学重复:
(1)实验组(SS-31+CSE组):SS-31 TFA干预细胞1h后加入8%CSE刺激24h;
(2)模型组(CSE组):8%CSE刺激24h;
(3)对照组(CON组):给予相同体积的培养基干预24h。
分组干预后,用酶联免疫吸附法(ELISA)测定各组细胞上清中炎症因子IL-6、TNF-α、MMP9的浓度。
2、实验结果
表1各组细胞上清中炎症因子浓度的变化(平均值±SD)
实验结果如表1和图1所示。可以看出,与对照组相比,模型组细胞上清中炎症因子IL-6、TNF-α、MMP9的浓度均显著升高(P<0.0001),说明气道上皮细胞炎症模型构建成功。
与模型组相比,SS-31干预后细胞上清中炎症因子IL-6、TNF-α、MMP9的浓度均显著降低(P<0.0001,P<0.05,P<0.001),说明SS-31能够显著降低气道上皮细胞炎症模型的炎症因子浓度,改善气道炎症反应。
上述实验结果表明,SS-31能够有效改善香烟烟雾提取物(CSE)诱导的气道炎症反应,能够用来制备治疗气道炎症的药物。
实施例2 SS-31治疗慢性阻塞性肺疾病
1、实验方法
实验动物:SPF级雄性C57BL/6J小鼠,体重20–22g,9-10周龄大。本实施例利用香烟烟雾(CS)诱导构建慢性阻塞性肺疾病气道炎症小鼠模型。
具体操作如下:
首先将小鼠随机分成4组分别进行干预,每组5~7只:
(1)高剂量实验组(SS-31(H)+CS组):CS熏烟前1h进行SS-31 TFA干预(腹腔注射5mg/kg SS-31 TFA),后连续经鼻熏烟75min,休息1h后再连续熏烟75min;
(2)低剂量实验组(SS-31(L)+CS组):CS熏烟前1h进行SS-31 TFA干预(腹腔注射2.5mg/kg SS-31 TFA),后连续经鼻熏烟75min,休息1h后再连续熏烟75min;
(3)模型组(CS组):连续经鼻熏烟75min,休息1h后再连续熏烟75min;
(4)对照组(CON组):自由呼吸空气。
分组干预后,用酶联免疫吸附法(ELISA)测定各组小鼠肺泡灌洗液(BALF)中炎症因子IL-6、TNF-α、MMP9的浓度。
2、实验结果
表2各组小鼠BALF中炎症因子浓度的变化(平均值±SD)
实验结果如表2和图2所示。可以看出,与对照组相比,模型组小鼠BALF中炎症因子IL-6、TNF-α、MMP9的浓度均显著升高(P<0.0001),说明慢性阻塞性肺疾病气道炎症小鼠模型构建成功。
与模型组相比,低剂量SS-31干预后小鼠BALF中的炎症因子IL-6、MMP9的浓度显著降低((P<0.0001),炎症因子TNF-α的浓度也明显降低;与模型组相比,高剂量SS-31干预后小鼠BALF中的炎症因子IL-6、MMP9的浓度显著降低(P<0.0001),炎症因子TNF-α的浓度也显著降低(P<0.01)。说明SS-31能够有效降低慢性阻塞性肺疾病气道炎症小鼠模型的炎症因子浓度,有效治疗慢性阻塞性肺疾病气道炎症。
与低剂量SS-31干预相比,高低剂量SS-31干预后小鼠BALF中的炎症因子IL-6、MMP9的浓度显著降低(P<0.01,P<0.001),炎症因子TNF-α的浓度也明显降低。说明SS-31对慢性阻塞性肺疾病气道炎症的治疗效果呈浓度依赖趋势。
上述实验结果表明,SS-31能够有效降低香烟烟雾(CS)诱导的慢性阻塞性肺疾病气道炎症模型小鼠BALF中的炎症因子IL-6、TNF-α、MMP9的浓度,能够用来制备治疗慢性阻塞性肺疾病气道炎症的药物。
综上,本发明提供了SS-31在制备预防和/或治疗香烟诱导的气道炎症及慢性阻塞性肺疾病的药物中的用途。实验结果表明,SS-31能够有效改善香烟烟雾提取物诱导的气道炎症反应,能够有效降低香烟烟雾诱导的慢性阻塞性肺疾病气道炎症小鼠模型的炎症因子IL-6、TNF-α、MMP9浓度,能够用来制备预防和/或治疗慢性阻塞性肺疾病,特别是慢性阻塞性肺疾病引起的气道炎症的药物,应用前景广阔。
Claims (10)
1.SS-31或其药学上可接受的盐在制备预防和/或治疗阻塞性肺疾病的药物中的用途。
2.根据权利要求1所述的用途,其特征在于:所述阻塞性肺疾病为慢性阻塞性肺疾病。
3.根据权利要求2所述的用途,其特征在于:所述慢性阻塞性肺疾病为香烟烟雾或香烟烟雾提取物诱导的慢性阻塞性肺疾病。
4.SS-31或其药学上可接受的盐在制备预防和/或治疗气道炎症的药物中的用途。
5.根据权利要求4所述的用途,其特征在于:所述气道炎症为慢性气道炎症。
6.根据权利要求5所述的用途,其特征在于:所述慢性气道炎症为香烟烟雾或香烟烟雾提取物诱导的慢性气道炎症。
7.根据权利要求4~6任一项所述的用途,其特征在于:所述气道炎症为慢性阻塞性肺疾病引起的气道炎症。
8.根据权利要求1~7任一项所述的用途,其特征在于:所述药物能够降低炎症因子的表达。
9.根据权利要求8所述的用途,其特征在于:所述炎症因子为IL-6、TNF-α、MMP9。
10.根据权利要求8或9所述的用途,其特征在于:所述炎症因子为肺泡灌洗液和/或气道上皮细胞中的炎症因子。
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