CN105362263B - 化合物Isomeranzin在治疗炎症性疾病中的应用 - Google Patents
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Abstract
本发明公开了一种香豆素化合物Isomeranzin作为活性成分应用于治疗炎症性疾病的用途。化合物Isomeranzin作为抗炎活性成分,具有毒性小、疗效好的特点,对炎症因子尤其是巨噬细胞因子有显著抑制作用,因此可作为抗炎制剂用于其它多种巨噬细胞参与的炎症性疾病,如脓毒症、胃炎、关节炎、免疫型肠炎、糖尿病等,特别对难以治愈的脓毒症具有良好的治疗作用。
Description
技术领域
本发明属于生物制药技术领域,具体涉及一种天然香豆素化合物Isomeranzin作为活性成分治疗炎症性疾病中的应用,主要应用于多种巨噬细胞参与的炎症性疾病,如脓毒症、关节炎、胃炎、免疫型肠炎、糖尿病等,特别对难以治愈的脓毒症具有良好的治疗作用。
背景技术
炎症是常见疾病, 在各方面影响着人们的健康。在一系列的医学突破中, 科学家们发现炎症与骨关节炎、脓毒症、动脉硬化、心脏病、中风、癌症、糖尿病、哮喘、偏头疼、老年性痴呆、牙周炎、肠易激综合征、慢性疲劳综合征等都密切相关。可见, 炎症影响着整个身体。很多慢性的炎症性疾病危害很大:一可引起高胆固醇、高血压、心脏病,研究发现, 炎症和心脏病是相关性最强的疾病之一, 特别是动脉硬化。过去, 我们总认为动脉硬化的致病原因是过多的胆固醇, 所以科学家们关注于如何控制较低的胆固醇含量。现在已经知道,胆固醇仅起到间接作用, 炎症才是致病的因素。炎症通过化学吸引导致白细胞、低密度脂蛋白胆固醇和血小板凝积在血管壁上, 导致动脉硬化症, 我们称这些生成的物质为斑块。随着斑块的积累, 增加了血管的损伤, 从而产生更多的损害, 导致更多的炎症斑块发生,危害心血管系统;二可引发糖尿病,科学家们很早就知道1型糖尿病是由自身免疫性反应而导致的疾病,这种反应可进攻并破坏胰腺中产生胰岛素的细胞,近来的研究显示, 2型糖尿病也与炎症有关。苏格兰一项调查发现, 一种名为C-反应性蛋白的炎症制造物数量较多,将可能在5年内发展成为2型糖尿病。通过控制炎症来控制2型糖尿病的发生已是完全必要了;三可引发自身免疫性疾病如类风湿性关节炎、红斑狼疮或多重硬化病综合征, 均发于不可控的炎症反应;四可导致牙龈炎或牙周病,很多炎症的生理信号都是隐而不显的, 但是牙龈炎却可引起体内其他部位病变, 如动脉硬化、冠心病等, 应引起高度重视;五可引起癌症病变,任何长期炎症的袭击都能够引发癌症。参与炎症过程的细胞和化学物质可引起细胞的变异: 使细胞更易发生癌变, 使得癌前期细胞变为活化的癌细胞, 导致癌细胞的生长。有些炎症性疾病比如脓毒症在世界范围仍然是一个巨大的医疗难题,伴随有严重的全身性炎症综合征,导致多器官衰竭,并造成极高的死亡率。在北美国家,推测脓毒症发病率每年超过600000例,死亡率高达30%-50%。目前临床上对脓毒症的治疗尚缺乏有效的治愈手段。因此亟待开发更多的抗炎新药以满足人们的需要。
炎症,是机体对各种致炎刺激物引起损害所产生的一种以防御为主的反应,是极为常见和重要的病理过程。巨噬细胞是天然免疫的必要组成成分,在抵抗炎症和宿主防御反应过程中发挥重要作用,并且巨噬细胞也具有维护机体稳态的功能,包括在个体发育过程中的器官重塑、代谢功能的调节。巨噬细胞具有高度的多样性和特异性,广泛分布于各个组织器官,感知不同的微环境刺激并作出反应,从而分化出不同的表型。M1 型巨噬细胞,即经典活化的巨噬细胞,表达高水平的促炎因子、活性氮、活性氧,具有较高的微生物以及肿瘤杀伤作用,促进TH1 反应。M2 型巨噬细胞,即替代活化的巨噬细胞,抗原虫能力增强,促进组织再生和肿瘤进展。巨噬细胞向M1、M2 分化的过程称为极化。M1、M2 是巨噬细胞极化的两个极端,实际情况下,巨噬细胞可能处于极化的任一阶段。M1-M2型巨噬细胞在一定程度上可以相互转化。疾病的病理状态也与巨噬细胞活化状态的动态变化密切相关。经典活化的M1 型巨噬细胞参与炎症的起始和持续,M2 或者类-M2 型巨噬细胞参与慢性炎症的解决。M1、M2 的不同功能单核细胞和巨噬细胞是机体防御反应的第一道防线。因此靶向巨噬细胞介导的炎症可以作为抗炎药物的筛选指标。
机体的炎症反应主要由内毒素进入作用于巨噬细胞产生。 内毒素是存在于革兰氏阴性细菌胞壁外膜,主要成分脂多糖 (LPS),是广泛存在于自然界的致病源。LPS 作用于细胞,特别是单核细胞、巨噬细胞和中性粒细胞等通过信号转导通路诱发巨噬细胞和中性粒细胞产生生物活性分子,在革兰氏阴性菌致病机制中扮演着重要角色。当内毒素进入人体后,引起发热、腹泻、痢疾、弥散性血管内溶血和脓毒性休克,甚至死亡。造成内毒素休克的主要原因是,大量内毒素作用于机体的巨噬细胞等系统产生IL -1 beta、IL -6、TNF -alpha 等生物活性质。这些物质作用于小血管造成功能紊乱从而导致微循环障碍,临床表现微循环衰竭、低血压缺氧酸中毒等,最终导致病人休克甚至死亡。由此可知,巨噬细胞作为内毒素休克的重要细胞,参与疾病发生和进展。因此全面深入了解内毒素作用机制,研究快速有效的内毒素拮抗剂,对预防和治疗炎症性疾病有重要意义。
香豆素化合物做为多种中药制剂的有效成分已经被广泛的研究,Isomeranzin,溶于甲醇、乙醇、丙酮和氯仿等有机溶剂,但未见有此化合物通过调控巨噬细胞功能来改善炎症性疾病的研究,此化合物也未应用于治疗任何炎症性疾病。
Isomeranzin, 分子式C15H16O4,分子量260.3,CAS号: 1088-17-1,化学名称:7-Methoxy-8-(3-methyl-2-oxobutyl)coumarin,分子结构:
发明内容
本发明的目的是探索Isomeranzin作为抗炎药物治疗多种巨噬细胞参与的炎症性疾病的应用,特别对难以治愈的脓毒症具有良好的治疗作用。
本发明通过研究证明,Isomeranzin主要抗炎机制为调整巨噬细胞极化,可用于治疗多种巨噬细胞参与的炎症性疾病,特别对难以治愈的脓毒症具有良好的治疗作用。
Isomeranzin是从天然植物中分离纯化得到或合成可得。化合物Isomeranzin能够特异性作用于巨噬细胞,抑制M1型巨噬细胞的极化如降低M1型炎症因子(IL-1β、IL-6、TNF-α等)和表面marker(CD11c、iNOS)的表达,抑制M1型巨噬细胞的吞噬作用但不影响细胞增殖,同时对T细胞和B细胞无明显作用。进一步体内试验显示,Isomeranzin对LPS介导的sepsis模型具有改善作用,能够提高小鼠存活率,降低炎症因子的表达,改善组织病变。表明化合物Isomeranzin具有较好的抗炎作用。Isomeranzin良好的体内抗炎活性揭示了其可能通过抑制M1型巨噬细胞的功能发挥抗炎机制以及可能具有的潜在应用价值。
与现有技术比较本发明的有益效果:化合物Isomeranzin来源于天然植物的提取物中,作为抗炎活性成分,具有毒性小、疗效好的特点,对炎症因子尤其是巨噬细胞因子有显著抑制作用,因此可作为抗炎制剂用于其它多种巨噬细胞参与的炎症性疾病,如脓毒症、关节炎、免疫型肠炎、胃炎、糖尿病等。
具体实施方式
以下通过具体实施方式对本发明效果做进一步说明:
实施例1. Isomeranzin 对T细胞和B细胞的毒性检测
从C57小鼠分离出淋巴细胞和脾脏细胞,分别培养在加或不加ConA或LPS的Isomeranzin浓度为3ul、10ul、30ul的培养基中,37℃培养箱孵育24h。MTT法检测化合物对T细胞和B细胞存活的影响 (图1 Fig.1A);加ConA或LPS活化的T细胞和B细胞培养24h后收集细胞,流式细胞仪分别检测T细胞表面marker CD25 & CD69以及B细胞表面marker CD23 &CD69 (图1 Fig.1B~D)。
结果表明,Isomeranzin对正常T细胞和B细胞及ConA或LPS活化的T细胞和B细胞均无明显抑制作用。
实施例2. Isomeranzin 抑制巨噬细胞的M1极化
从C57小鼠分离出的BMDMs和单细胞株Raw264.7分别培养在Isomeranzin浓度为3ul、10ul、30ul的培养基中,分别加M1刺激因子 (10ng/ml IFN-γ & 10 ng/ml LPS)或M2刺激因子 (10ng/ml IL-4)。37℃培养箱孵育6h后收细胞提取RNA, Q-PCR法检测细胞因子mRNA 水平的变化;Elisa检测上清中细胞因子表达的变化 (图2 Fig.2A~B)。
取BMDMs培养在上述条件培养基中,加M1刺激因子(10ng/ml IFN-γ & 10 ng/mlLPS),24h后收集细胞,流式细胞仪分别检测M1表面marker CD11c 与iNOS和M2 表面markerCD206 (图2 Fig.2C~E、G)。
单细胞株Raw264.7培养在上述条件培养基中,分别加M1刺激因子(10ng/ml IFN-γ & 10 ng/ml LPS) 或M2刺激因子 (10ng/ml IL-4),37℃培养箱孵育18h后检测其对微珠的吞噬功能 (图2 Fig.2F~G)。
结果显示,Isomeranzin能够抑制巨噬细胞分泌M1型促炎因子如IL-1β、IL-6和TNF-α,降低M1表面marker CD11c和iNOS的表达、抑制M1巨噬细胞的吞噬功能。
实施例3. Isomeranzin 改善小鼠sepsis模型
C57小鼠腹腔注射10 mg/kg LPS,同时腹腔注射10mg/kg、20mg/kg、30mg/kgIsomeranzin,观察小鼠存活率 (图3 Fig.3A)。
C57小鼠腹腔注射LPS和10mg/kg、30mg/kg Isomeranzin 4小时后,取肺灌洗液、取血,ELISA检测肺灌洗液及血清中炎症因子的含量 (图3 Fig.3B~C);同时取肺和肝脏组织提取RNA ,Q-PCR法检测细胞因子mRNA 水平的变化 (图3 Fig.3D);肺组织切片进行HE染色检测组织病变情况 (图3 Fig.3E)。
结果显示,Isomeranzin可以提高LPS诱导的内毒素休克小鼠的生存率,降低肺灌洗液和血清中炎症因子水平,抑制肺和肝脏组织中促炎因子的基因表达,缓解肺组织病变。
综合以上结果,表明化合物Isomeranzin能够特异性作用于巨噬细胞,抑制M1型巨噬细胞的极化如降低M1型炎症因子(IL-1β、IL-6、TNF-α等)和表面marker(CD11c、iNOS)的表达,抑制M1型巨噬细胞的吞噬作用但不影响细胞增殖,同时对T细胞和B细胞无明显作用。进一步体内试验显示,Isomeranzin对LPS介导的sepsis模型具有改善作用,能够提高小鼠存活率,降低炎症因子的表达,改善组织病变。表明化合物Isomeranzin具有较好的抗炎作用。因此可作为抗炎制剂用于其它多种巨噬细胞参与的炎症性疾病,如脓毒症、关节炎、免疫型肠炎、糖尿病、胃炎等。
附图说明
图1是Isomeranzin 对T细胞和B细胞的毒性检测结果
(A)从C57小鼠分离出淋巴细胞和脾脏细胞,分别培养在加或不加ConA或LPS的Isomeranzin浓度为3ul、10ul、30ul的培养基中,37℃培养箱孵育24h。MTT法检测化合物对T细胞和B细胞存活的影响;
(B-D)加ConA或LPS活化的T细胞和B细胞培养24h后收集细胞,流式细胞仪分别检测T细胞表面marker CD25 & CD69以及B细胞表面marker CD23 & CD69。
图2是Isomeranzin 抑制巨噬细胞的M1极化的结果
(A-B)从C57小鼠分离出的BMDMs和单细胞株Raw264.7分别培养在Isomeranzin浓度为3ul、10ul、30ul的培养基中,分别加M1刺激因子 (10ng/ml IFN-γ & 10 ng/ml LPS)或M2刺激因子 (10ng/ml IL-4)。37℃培养箱孵育6h后收细胞提取RNA, Q-PCR法检测细胞因子mRNA 水平的变化;Elisa检测上清中细胞因子表达的变化。
(C~E、G)取BMDMs培养在上述条件培养基中,加M1刺激因子(10ng/ml IFN-γ & 10ng/ml LPS),24h后收集细胞,流式细胞仪分别检测M1表面marker CD11c 与iNOS和M2 表面marker CD206 (图2 Fig.2C~E、G)。
(F~G)单细胞株Raw264.7培养在上述条件培养基中,分别加M1刺激因子(10ng/mlIFN-γ & 10 ng/ml LPS) 或M2刺激因子 (10ng/ml IL-4),37℃培养箱孵育18h后检测其对微珠的吞噬功能。
图3是Isomeranzin 改善小鼠sepsis模型结果
(A)C57小鼠腹腔注射10 mg/kg LPS,同时腹腔注射10mg/kg、20mg/kg、30mg/kgIsomeranzin,小鼠存活率结果。
(B-E)C57小鼠腹腔注射LPS和10mg/kg、30mg/kg Isomeranzin 4小时后,取灌洗液、取血,ELISA检测肺灌洗液及血清中炎症因子的含量 (图3 B~C);同时取肺和肝脏组织提取RNA ,Q-PCR法检测细胞因子mRNA 水平的变化 (图3 D);肺组织切片进行HE染色检测组织病变情况 (图3 E)。
Claims (1)
1.化合物Isomeranzin作为唯一活性成分用于制备治疗炎症性疾病脓毒症药物中的用途。
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