CN116602943A - 香芹酚在制备预防或治疗脓毒症药物中的应用及药物组合物 - Google Patents
香芹酚在制备预防或治疗脓毒症药物中的应用及药物组合物 Download PDFInfo
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Abstract
本发明属于中医药学技术领域,具体涉及香芹酚在制备预防或治疗脓毒症药物中的应用及药物组合物。本发明首次创新提出了香芹酚可以应用在制备脓毒症药物中,香芹酚可通过抑制巨噬细胞活化负向调节炎症细胞因子风暴,可以为脓毒症的预防或治疗策略开辟新的途径,具有重要的临床价值。
Description
技术领域
本发明属于中医药学技术领域,具体涉及香芹酚在制备预防或治疗脓毒症药物中的应用及药物组合物。
背景技术
脓毒症是宿主对感染反应失调引起的危及生命的器官功能障碍,其特征是过度炎症反应与高死亡率相关。脓毒症可能是由微生物产物引起的,如病原体相关分子模式(PAMPs)和损伤相关性分子模式(DAMPs),它们会导致多器官损伤,例如,内毒素LPS诱导的脓毒症,导致患者出现肾损伤,小鼠肺组织出现严重水肿等。虽然近年来对脓毒症发病机制的认识和治疗手段不断提高,但内毒素LPS诱导的脓毒症脓毒症患者院内死亡率依旧居高不下,迫切需要开发新的药物来有效预防或治疗内毒素LPS诱导的脓毒症脓毒症。系统评价更多预防或治疗脓毒症的潜在药物具有重要的临床意义。
脓毒症作为一种众所周知的异质性疾病,在不同个体中疾病进程差异较大,其潜在的分子机制,特别是疾病早期的宿主反应和发病机制,一直是研究热点。许多研究都集中在脓毒症早期可用于确定有效治疗的预测和预后标志物上。最新研究表明,凝血因子蛋白水平预测了脓毒症期间出现的纤溶和抗凝血活性失调。此外,一项研究表明,肠道真菌在脓毒症的发病机制中起着保护作用,使用抗真菌药物可以促进脓毒症的发生。另一项研究发现,6-姜酚通过调节细胞因子平衡和减少淋巴细胞凋亡来改善脓毒症诱导的免疫功能障碍。更好地了解脓毒症的病理学和开发新的预防或治疗方法对于有效缓解内毒素LPS诱导的脓毒症脓毒症症状至关重要。
发明内容
本发明的目的是解决现有技术的不足,提供一种香芹酚在制备预防或治疗脓毒症药物中的应用及药物组合物,具体采用以下的技术方案:
根据本发明的第一方面,本发明提供了一种香芹酚在制备预防或治疗内毒素LPS诱导的脓毒症药物中的应用。
本发明通过研究药物中香芹酚在内毒素LPS(Lipopolysaccharides, 脂多糖)诱导的脓毒症中多器官损伤和巨噬细胞活化中具有特殊的作用,香芹酚通过抑制LPS激活的巨噬细胞ERK1/2信号通路,减弱巨噬细胞炎症反应,降低血清中炎症因子IL-6的释放,减弱器官功能损伤从而达到缓解脓毒症的目的。具体机制为:香芹酚可通过细胞外调节蛋白激酶(ERK1/2)信号通路所介导的巨噬细胞炎症反应,抑制巨噬细胞活化负向调节炎症细胞因子风暴。该研究可以为脓毒症的预防或治疗策略开辟新的途径,并证明香芹酚在药理学研究中的潜在应用。
上述脓毒症包括脓毒症的急性炎性反应综合征、单纯脓毒症、重症脓毒症或脓毒症休克中的一种或多种。
上述药物为通过减弱巨噬细胞炎症反应,从而降低血清中炎症因子IL-6的释放,减弱器官功能损伤,从而预防或治疗脓毒症的药物。
根据本发明的第二方面,还提供了一种用于预防或治疗脓毒症的药物组合物,该药物组合物包括香芹酚为主要有效成分。
作为进一步优选的实施方式,香芹酚的有效浓度为1mg/kg-100mg/kg。更优选地,香芹酚的有效浓度为40mg/kg-80mg/kg。
作为进一步优选的实施方式,上述药物组合物包含药学上可接受的辅料或辅助性成分制备而成的药物。上述药物为口服制剂、外用制剂或注射剂;上述口服制剂为片剂、丸剂、粉剂、悬浮液、乳膏、颗粒剂、胶囊、凝胶剂、丸剂;上述外用制剂为栓剂;上述注射制剂为针剂。
本发明的有益效果为:本发明提供香芹酚在制备预防或治疗脓毒症药物的新用途,香芹酚通过巨噬细胞ERK1/2信号通路显著抑制炎症细胞因子Il-6的产生,可以广泛的应用于制备脓毒症预防或治疗药物中,具有重要的临床价值。
附图说明
图1所示为香芹酚对小鼠存活率的影响;
图2A所示为香芹酚减轻LPS诱导脓毒症中小鼠的肝、肺和心脏损伤(用苏木精-伊红染色(H&E)对石蜡包埋的肝脏切片进行染色图,右侧为肝脏组织的损伤统计图;
图2B所示为香芹酚减轻LPS诱导脓毒症中小鼠的肝、肺和心脏损伤(用苏木精-伊红染色(H&E)对石蜡包埋的肺切片进行染色图,右侧为肺组织的损伤统计图;
图2C所示为香芹酚减轻LPS诱导脓毒症中小鼠的肝、肺和心脏损伤(用苏木精-伊红染色(H&E)对石蜡包埋的心脏切片进行染色,右侧为心脏组织的损伤统计图;
图2D所示为每组的代表性超声心动图图像;
图2E所示为使用D中的图像测量心脏的射血分数和分数缩短;
图3A所示为香芹酚在体内抑制LPS诱导的巨噬细胞活化和促炎反应:流式细胞术分析巨噬细胞的细胞数量和百分比;
图3B所示为流式细胞术分析脾脏巨噬细胞中CD86和CD40的水平以及CD86和CD40的平均荧光强度;
图3C所示为CELISA分析小鼠血清中IL-6和TNF-α水平;
图3D所示为腹腔灌洗液中IL-6和TNF-α水平;
图3E所示为qRT-PCR测定小鼠腹腔细胞中IL-6和TNF-αmRNA的表达;
图4A所示为香芹酚抑制LPS激活的巨噬细胞ERK1/2信号通路:用所示抗体对细胞裂解物进行免疫印迹分析;
图4B所示为体外用ERK1/2信号通路抑制剂U0126可抑制香芹酚对LPS的拮抗作用;
图4C所示为体内用ERK1/2信号通路抑制剂U0126可抑制香芹酚对LPS的拮抗作用。
具体实施方式
以下将结合实施例和附图对本发明的构思、具体结构及产生的技术效果进行清楚、完整的描述,以充分地理解本发明的目的、方案和效果。
本发明提供了一种香芹酚在制备预防或治疗内毒素LPS诱导的脓毒症药物中的应用,通过给药浓度40mg/kg-80mg/kg,或0.2%吐温80预处理2小时,最后腹膜内注射LPS25mg/kg,并观察小鼠的死亡。其结果如图1所示,与LPS处理的给予PBS的小鼠相比,给予香芹酚的LPS处理的小鼠具有显著更长的存活时间和更好的存活率。本发明首次提出了香芹酚在制备预防或治疗内毒素LPS诱导的脓毒症药物中的应用,揭示了香芹酚抗抗脓毒症的作用机理,通过实验结果数据显示,香芹酚的使用能够显著降低脓毒症的死亡率。
图1所示为用香芹酚40mg/kg或80mg/kg或0.2%吐温80处理C57BL/6小鼠,然后用LPS刺激。LPS(25mg/kg体重)刺激后观察到的小鼠存活率(n=10只小鼠/组)。数据通过双向方差分析和Bonferroni后验进行分析。
实施例1
本实施例香芹酚缓解内毒素LPS引起的脓毒症症状的验证实验:
分别用香芹酚(80mg/kg体重)和0.2%吐温80处理C57BL/6小鼠2小时,然后使用LPS(10mg/kg体重)进行刺激,在LPS注射后12小时采集肺、肝和心脏样品并用4%多聚甲醛固定。用苏木精-伊红染色(H&E)对石蜡包埋的肝脏、肺和心脏切片(5μm)进行染色,并对急性肝损伤进行组织学分析(箭头标记细胞质褪色、空泡化、核浓缩、核褪色),肺损伤(箭头标记出血、肺水肿、炎性细胞浸润)和心脏损伤(箭头指示心肌细胞结构和炎性细胞渗透)(n=3/组);肺损伤的程度在以下领域中从0到3分37:出血、肺水肿、炎症细胞浸润、透明膜和肺不张(0:“无”、1:“轻度”、2:“中度”和3:“严重”),肝损伤程度根据以下参数从0到3进行评分:细胞质褪色、空泡化、核浓缩、核碎裂、核褪色和红细胞停滞(0:“无”、1:“轻度”、2:“中度”和3:“严重”)。在包含右心室和左心室的切片中,心脏损伤的程度从0到4分,如下:0:“无损伤或无炎症浸润”,1:“孤立性心肌细胞损伤”,2:“一个局部损伤区域”,3:“两个或多个损伤区域”和4:“损害50%以上心肌的弥漫性损伤区域”。然后通过将所有参数的得分相加来计算总损伤得分;对所有样品进行盲分析。我们观察到香芹酚预处理后,LPS导致的小鼠肝脏、肺部和心脏损伤要小得多(图2A-C);肺组织中炎症细胞浸润、出血和水肿的水平降低;肝细胞的细胞质褪色、空泡化、核浓缩和核褪色显著减少;心肌细胞结构变化和炎症细胞浸润水平也有所降低。为了进一步研究香芹酚是否改善内毒素休克小鼠的心功能,LPS给药12小时后,用2%异氟烷麻醉小鼠;使用超高分辨率小动物超声(Visual Sonics,Canada,VEVO2100) 进行超声心动图检查;在M模式图像上测量心功能参数,并收集射血分数(EF)和缩短分数(FS)数据(图2D-E);数据显示,LPS处理的小鼠表现出比对照组小鼠显著更低的EF和FS,而用香芹酚预处理的小鼠比LPS组小鼠表现出更高的EF和FS;这些结果表明,香芹酚在暴露于LPS下提供了重要的的器官保护功能。
图2A-E所示为香芹酚减轻LPS诱导脓毒症中小鼠的肝、肺和心脏损伤结果,A,B为用香芹酚(80mg/kg体重)或0.2%吐温80处理C57BL/6小鼠2小时,然后使用LPS(10mg/kg体重)进行刺激。在LPS注射后12小时采集肺、肝和心脏样品并用4%多聚甲醛固定。用苏木精-伊红染色(H&E)对石蜡包埋的肝脏(图2A)、肺(图2B)和心脏(图2C)切片进行染色,并对急性肝损伤进行组织学分析(箭头标记细胞质褪色、空泡化、核浓缩、核褪色),肺损伤(箭头标记出血、肺水肿、炎性细胞浸润)和心脏损伤(箭头指示心肌细胞结构和炎性细胞渗透)(n=3/组);(图2D)每组的代表性超声心动图图像;(图2E)使用(图2D)中的图像测量心脏的射血分数和分数缩短。数据采用单因素方差分析和Tukey多重比较检验进行分析。
实施例2
本实施例探究香芹酚对脓毒症小鼠巨噬细胞促炎反应的影响:
首先测量了脾脏巨噬细胞的百分比和数量。分别用香芹酚(80mg/g体重)和0.2%吐温80处理C57BL/6小鼠2小时,然后用LPS(10mg/kg体重)刺激;12h后,将小鼠脾脏放入含有DMEM的塑料培养皿中,并用剪刀切成几段。将脾脏置于70µm的滤网上,并用5 ml注射器的柱塞研磨。为了裂解红细胞,收集脾细胞并用3ml1x裂解缓冲液孵育2分钟,并用洗涤缓冲液(含有2%FBS和5mM EDTA的PBS)洗涤两次。然后,用7-AAD活力染色溶液对细胞染色10分钟,然后用抗小鼠CD16/CD32、APC偶联的抗小鼠CD11b和PE偶联的抗鼠F4/80的混合物在冰上染色30分钟。用流式细胞术分析脾脏中CD11b+F4/80+巨噬细胞的细胞数量和百分比(n=4/组)及脾脏巨噬细胞中CD86和CD40的水平以及CD86和CD40的平均荧光强度。结果显示,施用香芹酚的小鼠在暴露于LPS后,脾脏巨噬细胞的百分比和数量显著减少(图3A)。给予香芹酚的小鼠巨噬细胞中CD40的表达显著低于给予0.2%吐温80的小鼠,表明香芹酚可抑制巨噬细胞的活化。相反,在相同条件下,CD86的表达没有显示出显著差异(图3B)。为了进一步阐明香芹酚在巨噬细胞功能中的作用,利用小鼠ELISA试剂盒(赛默飞,美国)根据制造商推荐的方案测量小鼠血清、腹膜灌洗液中促炎细胞因子的水平。我们发现,在注射LPS 6小时或24小时后,使用香芹酚给药,血清IL-6而非TNF-α的水平显著降低(图3C)。值得注意的是,腹膜灌洗的实验结果与血清类似(图3D)。qPCR分析显示,香芹酚可以显著降低了LPS刺激的小鼠腹膜细胞中的IL-6 mRNA水平(图3E)。香芹酚和0.2%吐温80处理组在TNF-α的蛋白质水平和mRNA水平方面均未显示出任何显著差异。一般来说,这些观察结果表明,在LPS诱导的内毒素休克下,香芹酚对巨噬细胞的促炎反应具有负调控作用。
图3A-E所示为香芹酚在体内抑制LPS诱导的巨噬细胞活化和促炎反应结果,香芹酚(80mg/g体重)或0.2%吐温80处理C57BL/6小鼠2小时,然后用LPS(10mg/kg体重)刺激。(图3A)用LPS或PBS刺激12小时后脾脏中CD11b+F4/80+巨噬细胞的细胞数量和百分比的流式细胞术分析(n=4/组);(图3B)脾脏巨噬细胞中CD86和CD40的水平以及CD86和CD40的平均荧光强度的代表性流式细胞术分析,如(图3A)所示。LPS暴露6或24小时后,香芹酚或0.2%吐温80处理小鼠血清(图3C)或腹腔灌洗液(图3D)中IL-6和TNF-α的ELISA分析(n≥3/组);(图3E)用qRT-PCR法测定小鼠腹腔细胞中IL-6和TNF-αmRNA的表达(n=3/组);数据采用Bonferroni后验的双向方差分析或Tukey多重比较检验的单向方差分析进行分析。
实施例3
本实施例分析ERK1/2信号通路在香芹酚缓解脓毒症过程中的作用:
为了进一步探索香芹酚抑制LPS诱导的炎症的机制,我们从C57BL/6小鼠的胫骨和股骨分离骨髓(BM)细胞,并在补充有M-CSF(10ng/mL)的 DMEM 培养基中培养。每隔一天用补充有M-CSF(10ng/mL)的新鲜DMEM代替一半的培养基。在培养的第5天,收获骨髓源性巨噬细胞(BMDM),并以1×106个细胞/mL的密度接种在新鲜的完全DMEM中进行实验。用香芹酚(5μg/ml或10μg/ml)处理这些BMDM 2小时,然后在不同时间用LPS(1μg/ml)刺激;在LPS刺激后10分钟,30分钟和24小时利用蛋白质印迹法 (Western Blot) 检测BMDM p38、ERK1/2、JNK和p65的磷酸化。观察到,在LPS刺激15分钟后,香芹酚仅抑制ERK1/2的磷酸化,而不抑制p65、JNK和p38的磷酸化。此外,香芹酚在LPS刺激24小时后抑制ERK1/2的磷酸化(图4A)。使用MAPK特异性抑制剂(U0126)预处理BMDMs,并评估香芹酚对LPS诱导的炎症的影响。发现U0126抑制LPS处理的BMDMs中IL-6和TNF-α的产生。当用U0126(10μM)预处理BMDM 1小时,然后用香芹酚(10μg/mL)预处理2小时,然后给药LPS(1μg/mL)24小时。测量培养基中IL-6和TNF-α的水平,香芹酚对IL-6产生的抑制作用显著降低(图4B)。我们还用该抑制剂进行了体内实验,用香芹酚(80mg/kg)预处理小鼠2小时,然后用LPS(5mg/kg体重)刺激小鼠。1小时后,腹膜内注射U0126(20μL 20mM,i.p.)(n=4),香芹酚对LPS诱导的IL-6产生的抑制作用显著降低(图4C)。这些数据表明,香芹酚主要负调控ERK1/2信号传导,随后抑制LPS刺激后炎症因子的产生和组织损伤。
图4A-C所示为香芹酚抑制LPS激活的ERK1/2信号通路结果,图4A为不同剂量的香芹酚(0、5和10μg/mL)预处理BMDMs 2小时,然后用LPS(1μg/mL)处理这些细胞10分钟、15分钟或24小时。用所示抗体对细胞裂解物进行免疫印迹分析。使用Tubulin作为对照。B为U0126(10μM)预处理 BMDM 1小时,然后用香芹酚(10μg/mL)预处理2小时,然后给药LPS(1μg/mL)24小时。测量培养基中IL-6和TNF-α的水平;图4B为用香芹酚(80mg/kg)预处理小鼠2小时,然后用LPS(5mg/kg体重)刺激小鼠。1小时后,腹膜内注射U0126(20μL 20mM,i.p.)(n=4)。数据通过双向方差分析和Bonferroni后验(B-C)进行分析。
尽管本发明的描述已经相当详尽且特别对几个所述实施例进行了描述,但其并非旨在局限于任何这些细节或实施例或任何特殊实施例,而是应当将其视作是通过参考所附权利要求考虑到现有技术为这些权利要求提供广义的可能性解释,从而有效地涵盖本发明的预定范围。此外,上文以发明人可预见的实施例对本发明进行描述,其目的是为了提供有用的描述,而那些目前尚未预见的对本发明的非实质性改动仍可代表本发明的等效改动。
Claims (10)
1.香芹酚在制备预防或治疗内毒素LPS诱导的脓毒症药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述脓毒症包括脓毒症的急性炎性反应综合征、单纯脓毒症、重症脓毒症或脓毒症休克中的一种或多种。
3.根据权利要求1所述的应用,其特征在于,所述药物为通过减弱巨噬细胞炎症反应,从而降低血清中炎症因子IL-6的释放,减弱器官功能损伤,从而预防或治疗脓毒症的药物。
4.一种用于预防或治疗脓毒症的药物组合物,其特征在于,所述药物组合物包括权利要求1所述的香芹酚为主要活性成分。
5.根据权利要求4所述的药物组合物,其特征在于,香芹酚的有效浓度为1mg/kg-100mg/kg。
6.根据权利要求5所述的药物组合物,其特征在于,香芹酚的有效浓度为40mg/kg-80mg/kg。
7.根据权利要求4所述的药物组合物,其特征在于,其特征在于,所述药物组合物包含药学上可接受的辅料或辅助性成分制备而成的药物。
8.根据权利要求7所述的药物组合物,其特征在于,所述药物为口服制剂、外用制剂或注射剂。
9.根据权利要求8所述的药物组合物,其特征在于,所述口服制剂为片剂、丸剂、粉剂、悬浮液、乳膏、颗粒剂、胶囊、凝胶剂。
10.根据权利要求8所述的药物组合物,其特征在于,所述外用制剂为栓剂;所述注射制剂为针剂。
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