CN116327745A - 一种蓝萼甲素在制备治疗内毒素血症的药物中的应用 - Google Patents
一种蓝萼甲素在制备治疗内毒素血症的药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种蓝萼甲素在制备治疗内毒素血症的药物中的应用，属于医疗技术领域，本发明药物至少存在以下作用之一：在细胞层面，可以缓解LPS导致的细胞死亡；下调炎症相关基因IL‑6、TNF‑a、COX‑2和iNOS的表达，下调RIP1、p‑RIP1、RIP3、p‑RIP3、MLKL和p‑MLKL的表达；通过抑制RIP1‑RIP3‑MLKL通路抑制LPS导致的细胞坏死。本发明的蓝萼甲素可以缓解LPS导致的急性肺损伤、可以缓解LPS导致的细胞死亡、没有毒副作用、适合治疗革兰氏阴性菌引起的内毒素血症。
Description
技术领域
本发明属于医疗技术领域，尤其涉及一种蓝萼甲素在制备治疗内毒素血症的药物中的应用。
背景技术
内毒素或称脂多糖(Iipopolysaccharide，LPS)是革兰氏阴性菌细胞壁的主要组成成分之一，具有很强的致炎作用。当机体受到创伤感染，革兰氏阴性菌侵入血循环并生长繁殖时，产生的内毒素形成内毒素血症，其临床表现为发烧、心动过速、血压下降、呼吸急促和白细胞增多。内毒素激活炎症细胞释放炎症介质，导致全身炎症反应综合征(SIRS)、多器官功能不全综合征(MOPS)甚至多脏器功能衰竭(MOF)，进而危害生命。目前内毒素血症的病理生理过程和发病机制仍然不清楚，缺乏有效的治疗措施。面临这一严重迫境，科学家的共识和挑战是如何确立新的靶点和建立新的干预途径。显然，充分阐明革兰氏阴性细菌及其表面脂多糖与宿主蛋白之间的相互作用，已成为目前亟待解决的关键问题，这一问题的解决对于认识内毒素血症的发病机理，建立有效的新的靶向预防和治疗措施，从而挽救人类生命，具有极其重要的临床意义。在过去30年的各种临床试验中，不管是针对早期急性炎症反应使用抑制剂靶向调节炎症因子，还是使用糖皮质激素或非甾体类抗炎药等产生广谱的抑制免疫反应，均未能有效控制内毒素血症。
血液中LPS不存在游离形式。已知机体具有LPS清除机制，包括LBP，sCD14，CTBP及其它脂蛋白，它们与LPS的结合将其递呈给肝脏的三种细胞(包括枯否细胞、肝细胞及星状细胞)，通过细胞内的降解排入胆汁，而被解毒。虽然目前对机体清除LPS的机制有了一定的认识，但是脓毒症患者血液中LPS仍然处于高水平。因此认识LPS如何利用宿主蛋白逃逸机体的清除机制，从而维持其循环水平具有重要意义。
唇形科香茶菜属蓝萼香茶菜味苦、甘、性寒，具有清热利尿，活血散瘀，解毒消肿的功效。作为一种传统草药，蓝萼香茶菜具有较好的抗炎作用，广泛用于治疗各种炎症性疾病，如肝炎、胃炎等。已知蓝萼甲素(Glaucocalyxin A，GLA)是蓝萼香茶菜中主要的抗炎活性成分之一，但其抗炎作用机制尚不明确。尽管蓝萼甲素被发现有多重功效，但其对小鼠内毒素血症的保护作用仍不确定。
发明内容
为解决上述技术问题，本发明提供了一种蓝萼甲素在制备治疗内毒素血症的药物中的应用。
本发明的第一个目的是提供一种蓝萼甲素在制备治疗内毒素血症的药物中的应用。
在本发明的一个实施例中，所述药物至少存在以下作用之一：在细胞层面，可以缓解LPS导致的细胞死亡；下调炎症相关基因IL-6、TNF-a、COX-2和iNOS的表达，下调RIP1、p-RIP1、RIP3、p-RIP3、MLKL和p-MLKL的表达；通过抑制RIP1-RIP3-MLKL通路抑制LPS导致的细胞坏死。
在本发明的另一个实施例中，还提供了一种药物组合物，包括蓝萼甲素和常规药用辅料。
在本发明的一个实施例中，所述常规药用辅料包括pH调节剂、渗透压调节剂、增溶剂、助溶剂、乳化剂、稳定剂、防腐剂、填充剂、崩解剂、粘合剂、矫味剂、矫嗅剂和润滑剂中的一种或多种。
在本发明的一个实施例中，所述药物组合可以通过注射给药、鼻腔给药、肺部给药、透皮给药和口服药的方式施用于患者。
在本发明的一个实施例中，所述蓝萼甲素可以作为单独的药效活性物质。
在本发明的一个实施例中，所述蓝萼甲素可以与抗炎药物联用。
在本发明的一个实施例中，所述抗炎药物包括但不限于头孢类抗生素和喹诺酮类抗生素。
在本发明的一个实施例中，所述头孢类抗生素为头孢曲松、头孢他啶、头孢哌酮和头孢噻肟中的任意一种，喹诺酮类抗生素为氧氟沙星、环丙沙星和氟罗沙星中的任意一种。
综上所述，由于采用了上述技术方案，本发明的有益效果是：
1、本发明的蓝萼甲素无细胞毒性。
2、经腹腔注射蓝萼甲素后，可降低小鼠由LPS导致的内毒素血症的死亡率，并且抑制炎症因子的产生。
3、本发明的蓝萼甲素可以缓解LPS导致的急性肺损伤。
4、本发明的蓝萼甲素可以缓解LPS导致的细胞死亡，下调炎症相关基因IL-6、TNF-a、COX-2和iNOS等的表达，下调RIP1，p-RIP1、RIP3、p-RIP3、MLKL和p-MLKL的表达，通过抑制RIP1-RIP3-MLKL通路抑制LPS导致的细胞坏死。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1为一种蓝萼甲素的化学结构图。
图2为CCK-8试剂盒测定不同浓度(0，0.625，1.25，2.5，5，10uM)的蓝萼甲素对巨噬细胞作用24h后的细胞毒性图。
图3为GLA对50ng/ml LPS处理巨噬细胞的活力影响图。
图4为GLA对LPS刺激的巨噬细胞坏死通路的影响图。
图5为GLA对小鼠内毒素血症的保护作用的生存率图。
图6为GLA下调白细胞中炎症因子mRNA水平验证图。
图7为血浆中炎症因子的检测图。
图8为LPS小鼠的肺组织HE染色图。
图9为肺泡灌洗液中细胞数验证图。
图10为肺泡灌洗液中蛋白含量验证图。
图11为肺泡灌洗液中过氧化物酶验证图。
图12为小鼠在注射LPS或LPS+GLA后血浆中LPS的浓度变化图。
图13为小鼠在注射LPS或LPS+GLA 48小时后血浆LPS浓度动力学水平图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
实验流程：
图2-3为本发明GLA对巨噬细胞活力的影响，采用CCK-8法，筛查了LPS感染的THP-1巨噬细胞(THP-1-Mφ)活力的保护效应。结果显示，图2为CCK-8试剂盒测定不同浓度(0，0.625，1.25，2.5，5，10uM)的蓝萼甲素对巨噬细胞作用24h后的细胞毒性。不同浓度的GLA对细胞均没有任何毒性。图3为50ng/ml LPS处理巨噬细胞，同时加入不同浓度的GLA，可以显著改善LPS导致的细胞死亡。
CCK-8实验检测细胞活性的具体操作如下：
a)接种细胞：THP1巨噬细胞接种2×105/孔于24孔板；
b)对细胞进行相应实验需要所做的处理；
c)MOI＝2/5感染MTB标准毒株H37Rv；
d)培养至实验观察时间点，吸取细胞上清，PBS洗涤两次，向培养板中加入20μL的CCK-8和180μL的DMEM完全培养基；
e)细胞在培养箱中培养2-4h；
f)检测：使用酶标仪在450nm条件下检测每孔0D值。
图4是GLA通过抑制RIP1-RIP3-MLKL通路抑制LPS导致的细胞坏死的验证结果。50ng/ml LPS处理巨噬细胞24h，可导致RIP1-RIP3-MLKL通路激活进而导致细胞坏死，具体表现为RIP1，RIP3，MLKL磷酸化增强，加入5uM GLA后，可以显著降低LPS导致的RIP1，RIP3，MLKL磷酸化，说明GLA通过抑制RIP1-RIP3-MLKL通路抑制LPS导致的细胞坏死。
图5-图7为本发明GLA对小鼠内毒素血症的保护作用的验证结果。图5为生存率实验，20mg/kg LPS导致小鼠在200h内死亡80％，而注射10mg/kg GLA后可以缓解LPS导致的小鼠死亡。图6为小鼠在注射5mg/kg LPS 8h后，与对照小鼠相比，GLA治疗组小鼠白细胞中炎症因子的mRNA水平显著降低，提示GLA下调白细胞中炎症因子mRNA水平。图7为血浆中炎症因子的检测，小鼠腹腔注射5mg/kg LPS，8h后血浆中主要炎症因子都显著升高，GLA治疗组小鼠血浆中主要炎症因子都显著降低。
图8-图11为GLA对LPS所致死亡的组织器官保护机制的验证结果。取出小鼠肺组织，进行HE染色，观察肺组织的病变程度。如图8所示，LPS导致小鼠的肺组织间质增生明显，纤维细胞增多，炎性细胞浸润明显，血管扩张，提示炎症程度较强，GLA治疗组小鼠LPS导致的肺损伤明显改善。在LPS引起肺的急性炎症反应中，LPS损伤肺血管内皮细胞，激活白细胞，使其释放氧自由基及多种炎症介质等，是诱发肺损伤发生的主要病理环节。临床研究表明，肺泡中自细胞是炎症因子的主要来源。炎症细胞(中性粒细胞和巨噬细胞)在急性肺损伤的发病过程中发挥重要作用，其胞内髓过氧化物酶在细胞活化过程中被释放，其浓度反映了中性粒细胞和巨噬细胞渗出程度。因此9-11图我们检测肺泡灌洗液中细胞数和蛋白含量，以及肺泡髓过氧化物酶。如图9-10所示，小鼠注射5mg/kg LPS 8h后，GLA治疗组小鼠肺泡灌洗液中总蛋白和细胞数都明显减少，同时，小鼠肺泡髓过氧化物酶活性也有明显的降低。以上结果GLA显著改善内毒素所导致的炎性细胞浸润和急性肺损伤。
图12-图13为GLA导致的小鼠的表型是否与其血浆中内毒素水平相关的验证结果，我们检测小鼠在注射LPS后血浆中LPS的浓度变化。如图12-13所示，与对照组小鼠相比，GLA治疗组小鼠在注射LPS后0，3，6，12，24，48小时血浆中LPS浓度明显降低，提示GLA导致小鼠血浆中LPS清除明显增加，缓解小鼠炎症反应。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围之内。
Claims (10)
1.一种蓝萼甲素在制备治疗内毒素血症的药物中的应用。
2.根据权利要求1所述的一种蓝萼甲素在制备治疗内毒素血症的药物中的应用，其特征在于，所述药物至少存在以下作用之一：在细胞层面，可以缓解LPS导致的细胞死亡；下调炎症相关基因IL-6、TNF-a、COX-2和iNOS的表达，下调RIP1、p-RIP1、RIP3、p-RIP3、MLKL和p-MLKL的表达；通过抑制RIP1-RIP3-MLKL通路抑制LPS导致的细胞坏死。
3.一种药物组合物，其特征在于，包括权利要求1-2任一一项所述的药物。
4.根据权利要求3所述的一种药物组合物，其特征在于，包括蓝萼甲素和常规药用辅料。
5.根据权利要求4所述的一种药物组合物，其特征在于，所述常规药用辅料包括pH调节剂、渗透压调节剂、增溶剂、助溶剂、乳化剂、稳定剂、防腐剂、填充剂、崩解剂、粘合剂、矫味剂、矫嗅剂和润滑剂中的一种或多种。
6.根据权利要求4所述的一种药物组合物，其特征在于，所述药物组合可以通过注射给药、鼻腔给药、肺部给药、透皮给药和口服药的方式施用于患者。
7.根据权利要求4所述的一种药物组合物，其特征在于，所述蓝萼甲素可以作为单独的药效活性物质。
8.根据权利要求4所述的一种药物组合物，其特征在于，所述蓝萼甲素可以与抗炎药物联用。
9.根据权利要求8所述的一种药物组合物，其特征在于，所述抗炎药物包括但不限于头孢类抗生素和喹诺酮类抗生素。
10.根据权利要求9所述的一种药物组合物，其特征在于，所述头孢类抗生素为头孢曲松、头孢他啶、头孢哌酮和头孢噻肟中的任意一种，喹诺酮类抗生素为氧氟沙星、环丙沙星和氟罗沙星中的任意一种。
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