CN114404597A - 治疗肺损伤或急性呼吸窘迫综合征的药物及药物组合物 - Google Patents
治疗肺损伤或急性呼吸窘迫综合征的药物及药物组合物 Download PDFInfo
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Abstract
本发明涉及药物领域,具体涉及一种治疗肺损伤或急性呼吸窘迫综合征的药物,以及含有该药物的药物组合物。本发明首次发现GPR116通过抑制中性粒细胞胞外诱捕网(急性肺损伤或急性呼吸窘迫综合征的关键致病机制)来缓解了肺损伤小鼠肺组织的病理学损伤、炎症反应并显著改善肺损伤小鼠的生存率。相应地,GPR116的激动剂就能够用于作为治疗肺损伤或急性呼吸窘迫综合征的药物应用,例如可以作为新的药物干预靶点与药学上可接受的载体和/或辅料配合后,对肺损伤或急性呼吸窘迫综合征患者进行给药来为急性肺损伤或急性呼吸窘迫综合征提供潜在的治疗方法。
Description
技术领域
本发明涉及药物领域,具体涉及一种治疗肺损伤或急性呼吸窘迫综合征的药物,以及含有该药物的药物组合物。
背景技术
肺连接了呼吸和循环两个重要系统,而健康成人平均呼吸膜总面积高达70平方米,易受各种病原微生物的入侵,发生急性肺损伤(Acute lung injury,ALI)。若治疗不及时或治疗不当,则易致病情进一步发展,出现急性呼吸窘迫综合征(Acute respiratorydistress syndrome,ARDS)。ALI或ARDS每年感染约300万人,病死率高达40%,其主要的病理表现为毛细血管弥漫性损伤、血气屏障破坏、透明膜形成,临床表现为进行性呼吸窘迫和难治性低氧血症。临床实践中,新的柏林定义取缔原用的肺损伤概念,转由轻度的急性呼吸窘迫综合征代替,但模拟临床急性呼吸窘迫综合征的动物研究模型仍称为急性肺损伤。临床上,AL或ARDS的治疗以抗炎、呼吸支持为主,其治疗效果有限。事实上,现有技术中,至今仍缺乏针对ALI的更深层次,即分子层面发病机制的有效治疗药物。
发明内容
作为人类最大的膜蛋白家族,G蛋白偶联受体(GPCRs)是目前研究最广泛的药物靶点。其中,G蛋白偶联受体116(GPR116)已经被发现与多种疾病相关,其激动剂也已经被发现可以应用于肥胖症、糖尿病的治疗中(参见CN101123964A)。
本发明的发明人发现,除了上述已经被发现的作用,GPR116还对LPS所致的小鼠急性肺损伤具有保护作用,因此,GPR116的激动剂可以作为治疗肺损伤或急性呼吸窘迫综合征的药物应用。
基于上述发现,本发明提供了一种治疗肺损伤或急性呼吸窘迫综合征的药物,其特征在于,包括G蛋白偶联受体116的激动剂。
进一步,本发明提供的治疗肺损伤或急性呼吸窘迫综合征的药物,还具有这样的特征,该药物通过抑制急性肺损伤中中性粒细胞外诱捕网释放,从而抑制急性肺损伤中的肺组织及全身炎症反应并显著改善肺损伤小鼠的生存率。
另外,本发明还提供了一种药物组合物,其特征在于,包括如上任一项所述的治疗肺损伤或急性呼吸窘迫综合征的药物。
进一步,上述药物组合物,还可以包括药学上可接受的载体或辅料,或药学上可接受的载体和辅料的组合。
发明的作用与效果
由于GPR116具有抑制肺部炎症反应、抑制中性粒细胞胞外诱捕网释放的作用,并且能够增加肺损伤小鼠的存活率,因此,GPR116的激动剂能够用于作为治疗肺损伤或急性呼吸窘迫综合征的药物应用,起到相应的治疗作用。
附图说明
图1是本发明实施例1的GPR116对小鼠肺损伤的影响考察的肺组织切片显微镜照片;
图2是本发明实施例3的GPR116对急性肺损伤小鼠肺组织中中性粒细胞外捕获网形成影响的荧光显微镜照片;
图3是GPR116在影响肺损伤小鼠存活率中作用的存活比例图。
具体实施方式
本发明的发明人对GPR116的作用的发现过程主要采用GPR116髓系细胞特异性敲除小鼠(以下简称KO小鼠)及野生型小鼠(以下简称WT小鼠)进行,在急性肺损伤动物模型中证实GPR116对急性肺损伤或急性呼吸窘迫综合征的保护作用及其相关的保护机制。其中,本课题组委托上海南方模式生物研究中心培育GPR116髓系细胞特异性敲除的小鼠,KO及WT小鼠均由该研究中心提供。具体构建方法如下:将具有C57BL或6遗传背景的GPR116 flox或flox小鼠与Lyz-cre小鼠杂交,产生髓系细胞特异性敲除的KO小鼠。以下涉及基因工程鼠的所有实验,均将与KO小鼠同窝的WT小鼠设为严格的实验对照鼠,以排除小鼠品系不同对实验结果造成的干扰。此外,下述各实施例中,未提及来源的试剂和材料的来源均为常规市售。
<实施例1>
本实施例考察GPR116对急性肺损伤或急性呼吸窘迫综合征的保护作用,其中急性肺损伤模型采用脂多糖(即LPS)气管内注射进行建模。
本实施例中,采用KO小鼠、WT小鼠各10只,各分为对照组(记为control组)和建模组(记为LPS组)两组,每组5只,然后按照以下过程进行操作。
分别对各小鼠实施麻醉后,向实验组小鼠气管内按10mg或kg注射LPS,诱导急性肺损伤;对照组小鼠气管内给与同样体积的生理盐水。各小鼠均完成处理后,8小时后处死小鼠,取肺组织以及支气管肺泡灌洗液,将肺组织切片行苏木精伊红染色,支气管肺泡灌洗液以BCA法测量蛋白质浓度并用流式细胞仪检测气管灌洗液中细胞计数。
图1是本发明实施例1的GPR116对小鼠肺损伤的影响考察的肺组织切片显微镜照片。对图1中各组实验小鼠的肺损伤情况按照表一的损伤评分标准进行病理评分后,结果如下表2所示,各组数值取组中5只小鼠的平均分值作为结果。
表1.肺组织损伤评分标准
评分 | 切片特征 |
0 | 肺组织结构正常 |
1 | 轻度肺组织水肿、损伤 |
2 | 炎症细胞浸润少、中度肺组织水肿 |
3 | 炎症细胞浸润明显、肺间隔充血增厚 |
4 | 较严重的组织水肿、间隔增厚、炎症细胞浸润 |
5 | 整个视野肺组织严重水肿破坏 |
表2.GPR116对小鼠肺损伤病理评分的影响
各组小鼠中支气管肺泡灌洗液中细胞计数如下表3所示,蛋白质浓度测定结果如下表4所示。表3、表4中,各组数值取自组中5只小鼠的平均值。
表3.GPR116对ALI小鼠支气管肺泡灌洗液中中性粒细胞计数的影响
表4.GPR116对ALI小鼠支气管肺泡灌洗液蛋白质浓度的影响
如图1以及表2-表4所示,与WT小鼠相比,KO小鼠在LPS致肺损伤后,其肺损伤分级、支气管肺泡灌洗液蛋白质浓度、中性粒细胞数量均有明显升高,表明GPR116可以减轻LPS诱导的肺损伤,抑制支气管肺泡灌洗液中的蛋白质渗出及中性粒细胞浸润。
<实施例2>
本实施例考察GPR116在抑制急性肺损伤小鼠肺部炎症反应中的作用。采用KO小鼠和WT小鼠各10只,各分为对照组(记为control组)、建模组(记为LPS组)两组,每组5只,然后按照以下过程进行操作。
实施麻醉后,向LPS组各小鼠的气管内按10mg或kg注射LPS诱导急性肺损伤;对照组小鼠气管内给与同样体积的生理盐水。处理完成8小时后处死小鼠,取各小鼠的气管肺泡灌洗液及血液,采用ELISA试剂盒检测细胞因子TNF-α、IL-6水平,检测结果如下表5、表6所示。
表5.GPR116对ALI小鼠气管肺泡灌洗液TNF-α、IL-6水平的影响。
表6.GPR116对ALI小鼠血浆TNF-α、IL-6水平的影响。
如上表5、表6所示,与WT组相比,KO组的小鼠气管肺泡灌洗液及血浆中TNF-α、IL-6水平均明显升高,表明GPR116可抑制急性肺损伤小鼠肺部的肺局部炎症反应及全身炎症反应。
<实施例3>
本实施例考察GPR116在抑制急性肺损伤小鼠肺部中性粒细胞胞外诱捕网释放的作用。采用KO小鼠、WT小鼠各10只,各分为对照组(记为control组)和建模组(记为LPS组)两组,每组5只,然后按照以下过程进行操作。
实施麻醉后,向LPS组各小鼠的气管内按10mg或kg注射LPS诱导急性肺损伤;对照组小鼠气管内给与同样体积的生理盐水。处理完成8小时后处死小鼠,取肺组织行免疫荧光检测,在荧光显微镜下观察中性粒细胞胞外诱捕网的形成(组蛋白histone H3和髓过氧化物酶MPO共染色的情况)。
图2是本发明实施例3的GPR116对急性肺损伤小鼠肺组织中中性粒细胞外捕获网形成影响的荧光显微镜照片。
如图2所示,与WT组相比,KO组小鼠肺组织中histone H3和MPO共染色的强度明显增强,表明GPR116可抑制急性肺损伤小鼠肺组织中中性粒细胞胞外诱捕网的释放,能够实现肺保护作用。
<实施例4>
本实施例考察GPR116对致死剂量LPS诱导肺损伤小鼠生存率的影响。采用KO小鼠、WT小鼠各12只,各分为对照组(记为control组,n=4)和建模组(记为LPS组,n=8)两组,然后按照以下过程进行操作。
实施麻醉后,向LPS组各小鼠的气管内按40mg或kg注射LPS诱导急性肺损伤;对照组小鼠气管内给与同样体积的生理盐水。处理完成后,每4h观察一次小鼠存活情况,持续总共80h,记录小鼠存活数量。
图3是GPR116在影响肺损伤小鼠存活率中作用的存活比例图。图3中,纵坐标为存活率(死亡小鼠占该组小鼠总数的百分比),横坐标为LPS的刺激时间。另外,图3中Control-WT与Control-KO两组在80h内存活率保持为100%,因此对应的两条曲线重合。
如图3所示,与WT小鼠相比,KO小鼠在给予致死剂量的LPS后,其存活率显著下降,说明GPR116具有改善小鼠在肺损伤后存活率的作用。
实施例的作用与效果
根据上述实施例,可以看出,与WT组相比,KO组小鼠在LPS处理后,肺损伤分级、支气管肺泡灌洗液蛋白质浓度、支气管肺泡灌洗液中性粒细胞数量、支气管肺泡灌洗液及血浆中TNF-α和IL-6水平均有明显升高,肺组织中histone H3和MPO共染色的强度明显增强,且存活率显著下降,这些结果表明GPR116具有抑制肺部炎症反应、抑制中性粒细胞胞外诱捕网释放的作用,并且能够改善肺损伤小鼠的存活率。相应地,GPR116的激动剂就能够用于作为治疗肺损伤或急性呼吸窘迫综合征的药物应用,例如可以与药学上可接受的载体和/或辅料配合后,对肺损伤或急性呼吸窘迫综合征患者进行给药。
Claims (4)
1.一种治疗肺损伤或急性呼吸窘迫综合征的药物,其特征在于,包括G蛋白偶联受体116的激动剂。
2.根据权利要求1所述的治疗肺损伤或急性呼吸窘迫综合征的药物,其特征在于:
其中,所述药物通过抑制急性肺损伤或急性呼吸窘迫综合征中中性粒细胞外诱捕网释放,从而抑制急性肺损伤中的肺组织及全身炎症反应。
3.一种药物组合物,其特征在于,包括如权利要求1或2所述的治疗肺损伤或急性呼吸窘迫综合征的药物。
4.根据权利要求3所述的药物组合物,其特征在于,还包括药学上可接受的载体或辅料,或药学上可接受的载体和辅料的组合。
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WO2024032527A1 (zh) * | 2022-08-08 | 2024-02-15 | 石药集团中奇制药技术(石家庄)有限公司 | 一种含有三环杂芳基的化合物的用途 |
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