CN111214467A - 吲哚布洛芬在抵抗hmgb1促炎活性中的应用 - Google Patents
吲哚布洛芬在抵抗hmgb1促炎活性中的应用 Download PDFInfo
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Abstract
本发明公开了吲哚布洛芬在抵抗HMGB1引起的炎症瀑布的应用。本发明通过系列实验,证明了吲哚布洛芬通过促进PP2A活性与MKP‑1的蛋白水平,下调HMGB1诱导的MAPKs和NF‑κB信号通路的激活,以及减弱促炎细胞因子TNF‑α、IL‑1β、IL‑6的释放水平,达到阻滞HMGB1介导的炎性瀑布的效果。另外,本发明研究证明了吲哚布洛芬对以HMGB1为重要促炎因子的脓毒症具有较好的治疗效果,且联合广谱抗生素(环丙沙星)可以更显著地提高脓毒症动物的存活率,此项发明为以HMGB1为治疗靶点的脓毒症或其他危重性炎症性疾病的临床治疗提供新的治疗策略和良好的理论依据。
Description
技术领域
本发明属于医药生物技术领域,具体涉及吲哚布洛芬在抵抗HMGB1促炎活性中的应用,尤其是涉及吲哚布洛芬对以HMGB1为重要调节因子的脓毒症的治疗效果。
背景技术
脓毒症是创伤、烧伤、休克、感染、外科大手术等临床危重患者常见的并发症和主要死亡原因之一。根据流行病学研究报告显示,每年全球有超过3000万脓毒症病例,且以每年1.5%~8.0% 的速度增长,其致死率超过了艾滋病、乳腺癌和***癌的总和。近年来,研究人员一直致力于找到有效的脓毒症治疗策略。目前,对脓毒症的急诊治疗措施主要有:确诊1小时内抗生素治疗,确诊6小时内液体复苏、血管活性药物治疗、活化蛋白C抗凝治疗等,但由于诊断标准的不完善,一些脓毒症患者没有早期及时治疗,患者出现器官脏器功能衰竭时,再去治疗,治疗难度会增加,使病死率仍然居高不下。
随着对脓毒症从细胞及分子水平认识的逐渐加深,研究人员发现高迁移率族蛋白B1 (HMGB1)作为晚期炎症因子与脓毒症引起的死亡密切相关,在外源性细菌内毒素等刺激后8小时HMGB1被明显检测到,并且在18-24小时左右达到峰值,为脓毒症治疗提供了宽阔的窗口,有可能是治疗脓毒症的新的靶点。HMGB1作为机体炎症介质,与许多疾病特别是脓毒症的发生、发展密切相关。大量临床研究中发现,脓毒症死亡患者血清中的HMGB1水平显著高于存活者,表明HMGB1水平与脓毒症严重程度呈正相关。且重组HMGB1经腹腔注射到小鼠体内后,短时间内就会出现毒血症的症状,小鼠均死亡。而HMGB1 cDNA缺陷转化大肠杆菌中提纯的蛋白质片段注射小鼠,并未出现内毒素血症的临床症状,以上实验结果进一步表明脓毒症所出现的毒血症是HMGB1所为。无论小鼠对LPS是否敏感,腹腔注射重组HMGB1后16小时内,小鼠均死亡,因此脓毒症动物的死亡原因系HMGB1所介导,而非LPS。研究发现HMGB1抗体处理或运用HMGB1 A box等手段,在降低脓毒症实验动物的死亡率中取得显著的疗效。
HMGB1在真核细胞中广泛存在,是细胞内高丰度的染色体结合蛋白。细胞在静息状态下, HMGB1持续表达并储存于细胞核内,A box 和B box 上的核定位序列NLS使其定位于细胞核内,HMGB1只有释放到细胞外之后才会发挥促炎作用。HMGB1作为新的潜在的免疫调节因子,在损伤或应激条件下释放到细胞外,可作为重要的致炎因子诱导免疫细胞激活,使其产生分泌多种细胞因子和趋化因子,而这些炎症因子的表达上调又可进一步刺激免疫细胞分泌HMGB1,这种正反馈在炎症类疾病的发生、发展中起着至关重要的作用,是所谓的炎症瀑布。例如,在人血管内皮细胞中,HMGB1能够诱导ERK、JNK、p38MAPK以及转录因子NF-κB、AP-1的活化。在大鼠平滑肌细胞中,HMGB1通过RAGE和MAPK信号途径诱导细胞迁移。在人中性粒细胞中,HMGB1通过TLR2受体活化Akt、MAPK、NF-κB信号通路。研究证实,在中性粒细胞及巨噬细胞中,HMGB1与其受体RAGE、TLRs结合后,可以激活MAPK(ERK、JNK、p38MAPK)的磷酸化,进而引发转录因子NF-κB和活化蛋白AP-1的转位入核,诱发TNF-α、IL-1、IL-6、IL-8等细胞因子的表达与释放从而导致炎症反应级联放大。基于上述原因,HMGB1被认定为是脓毒症治病的关键性细胞因子,对已经释放到细胞外HMGB1的促炎活性的控制很可能是一种有效的脓毒症治疗方法,但目前国内外尚无有效手段控制HMGB1引起的炎症瀑布,这也是脓毒症发生后引起高死亡率的原因所在。
大量研究表明,MAPK的磷酸化是由特异性MAPK激酶和磷酸酶来平衡[13]。MAPK级联的平行信号途径取决于蛋白磷酸酶的表达和活性,如丝氨酸/苏氨酸蛋白磷酸酶2A(PP2A),和 MAPK磷酸酶1(MKP-1),已被鉴定为可直接使细胞中的JNK,p38和ERK途径去磷酸化和失活[14, 15]。研究数据表明PP2A/MKP-1在包括炎症性疾病等许多疾病中起着重要作用。例如,PP2A敲除的巨噬细胞在LPS刺激后会释放更多的TNF-α。MKP-1缺陷型小鼠对LPS所致的致命性休克高度敏感。LPS刺激后的MKP-1缺陷小鼠的肺泡巨噬细胞可明显延长p38MAPK的活化并增强IL-6和TNF-α的产生。
吲哚布洛芬(indoprofen)是一种非甾体抗炎药,可用于治疗风湿性关节炎、骨关节炎和癌症疼等。到目前为止对吲哚布洛芬发挥抗炎镇痛作用的具体机制仍然所知甚少。本发明通过细胞及动物试验,得出吲哚布洛芬可以通过逆转HMGB1引起的PP2A活性下调与MKP-1降解来抑制HMGB1的促炎活性,以削弱HMGB1介导的炎性瀑布,且对以HMGB1为治疗靶点的脓毒症动物模型具有良好的治疗效果。
发明内容
本发明的目的之一在于提供吲哚布洛芬在抵抗HMGB1促炎活性中的新用途。
本发明的目的之二在于提供吲哚布洛芬对以HMGB1为重要调节因子的脓毒症具有较好的治疗效果。
本发明的目的之三在于提供吲哚布洛芬联合广谱抗生素(环丙沙星)可以更显著的提高脓毒症动物的存活率。
为了实现上述目的,本发明采用了如下技术方案:
本发明的第一个方面,提供了吲哚布洛芬可以抑制HMGB1诱导的TNF-α、IL-1β、IL-6的上调;吲哚布洛芬可以剂量依赖性的抑制HMGB1激活的MAPKs和NF-κB信号通路;吲哚布洛芬并不影响PP2A的蛋白水平,但通过使PTPA从非活性PP2A-PME-1复合物上竞争结合PP2A,来抑制HMGB1诱导的PP2A失活;而对MKP-1的影响是通过减缓MKP-1蛋白的泛素化降解来维持MKP-1在细胞内的高水平。
本发明的第二个方面,提供了吲哚布洛芬可以有效提高CLP诱导的脓毒症模型动物的存活率,且可有效减轻脓毒症引起的器官组织病理性损伤。
本发明的第三个方面,提供了吲哚布洛芬与环丙沙星联用可以得到更加显著的脓毒症治疗效果。
吲哚布洛芬在抵抗HMGB1促炎活性中的应用,所述吲哚布洛芬能够抑制HMGB1诱导的TNF-α、IL-1β、IL-6的上调,所述吲哚布洛芬能够逆转HMGB1引起的PP2A活性下调与MKP-1泛素化降解,从而抑制MAPKs和NF-κB信号通路的激活。
进一步地,所述药物的细胞用药有效浓度为7.5μM及以上。
进一步地,脓毒症造模8小时后吲哚布洛芬治疗对以HMGB1为重要调节因子的脓毒症小鼠具有较好的治疗效果。
进一步地,所述吲哚布洛芬为注射剂型。
一种用于治疗脓毒症的药物组合物,所述药物组合物包括吲哚布洛芬与环丙沙星。
进一步地,所述药物中吲哚布洛芬的小鼠用药有效浓度为20mg/kg及以上,环丙沙星的小鼠用药有效浓度为5mg/kg及以上。
本发明的显著优点:本发明所述的吲哚布洛芬能够通过挽救PP2A活性与MKP-1的蛋白水平,从而减弱HMGB1的促炎活性;在CLP造模后8小时腹腔注射吲哚布洛芬可有效的延长模型动物的存活时间,使小鼠的存活率达到40%,这显著高于CLP模型组(0%),且脓毒症所致的器官病理损伤也得到了改善;在CLP造模后术后1小时尾静脉注射环丙沙星(5mg/kg)与术后8小时腹腔注射吲哚布洛芬联用,可使小鼠的存活率提高到70%,为以HMGB1为治疗靶标的脓毒症或其他危重性炎症性疾病的临床治疗提供了新的治疗方式。
本发明中的吲哚布洛芬为Sigma-Aldrich生产,环丙沙星为上海同仁药业生产。
附图说明
图1a ELISA方法检测吲哚布洛芬对HMGB1诱导的TNF-α、IL-1β和IL-6的释放的影响;
图1b Western Blot 方法检测吲哚布洛芬对HMGB1激活的MAPKs(p-JNK、p-ERK、p-P38)信号通路的影响;
图1c Western Blot 方法检测吲哚布洛芬对HMGB1激活的NF-κB(p-IKK和p-IκB)信号通路的影响;
图1d Western Blot 方法检测吲哚布洛芬对蛋白磷酸酶PP2A和MKP-1的影响;
图1e Co-immunoprecipitation 方法检测吲哚布洛芬对PTPA、PME-1与PP2A蛋白结合的影响;
图1f RT-qPCR检测吲哚布洛芬对MKP-1的mRNA水平的影响。
图1g Western Blot 方法检测吲哚布洛芬对MKP-1泛素化水平的影响。
图2a Kaplan-Meier曲线统计分析吲哚布洛芬对CLP脓毒症小鼠生存率的影响;
图2b Hematoxylin-Eosin染色方法检测各组CLP脓毒症小鼠肺组织病理学变化图;其中I为假手术对照组(Sham组)、II为生理盐水治疗组(CLP组)、III 为吲哚布洛芬治疗组(CLP+Indo组);
图2c Hematoxylin-Eosin染色方法检测各组CLP脓毒症小鼠结肠组织病理学变化图;其中I为假手术对照组(Sham组)、II为生理盐水治疗组(CLP组)、III 为吲哚布洛芬治疗组(CLP+Indo组);
图2d Hematoxylin-Eosin染色方法检测各组CLP脓毒症小鼠肾组织病理学变化图;其中I为假手术对照组(Sham组)、II为生理盐水治疗组(CLP组)、III 为吲哚布洛芬治疗组(CLP+Indo组);
图2e Hematoxylin-Eosin染色方法检测各组CLP脓毒症小鼠肝组织病理学变化图;其中I为假手术对照组(Sham组)、II为生理盐水治疗组(CLP组)、III 为吲哚布洛芬治疗组(CLP+Indo组);
图3a Kaplan-Meier曲线统计分析吲哚布洛芬联用抗生素(环丙沙星)对CLP脓毒症小鼠生存率的影响;
图3b Hematoxylin-Eosin染色方法检测各组CLP脓毒症小鼠肺组织病理学变化图;其中I为假手术对照组(Sham组)、II为生理盐水治疗组(CLP组)、III 为环丙沙星治疗组(CLP+CIP组)、IV为吲哚布洛芬联用环丙沙星治疗组(CLP+CIP+Indo组);
图3c Hematoxylin-Eosin染色方法检测各组CLP脓毒症小鼠结肠组织病理学变化图;其中I为假手术对照组(Sham组)、II为生理盐水治疗组(CLP组)、III 为环丙沙星治疗组(CLP+CIP组)、IV为吲哚布洛芬联用环丙沙星治疗组(CLP+CIP+Indo组);
图3d Hematoxylin-Eosin染色方法检测各组CLP脓毒症小鼠肾组织病理学变化图;其中I为假手术对照组(Sham组)、II为生理盐水治疗组(CLP组)、 III 为环丙沙星治疗组(CLP+CIP组)、IV为吲哚布洛芬联用环丙沙星治疗组(CLP+CIP+Indo组);
图3e Hematoxylin-Eosin染色方法检测各组CLP脓毒症小鼠肝组织病理学变化图;其中I为假手术对照组(Sham组)、II为生理盐水治疗组(CLP组)、III 为环丙沙星治疗组(CLP+CIP组)、IV为吲哚布洛芬联用环丙沙星治疗组(CLP+CIP+Indo组)。
具体实施方式:
为了加深对本发明的理解,下面结合附图对本发明的实施例做详细的说明。
实施例1 吲哚布洛芬通过调控PP2A活性与MKP-1降解而对HMGB1促炎活性的影响
细胞培养:人单核细胞型淋巴瘤细胞株THP1(购买自中国科学院上海分院生物化学与细胞生物学研究所细胞库) 在37℃,5% CO2 条件下,用含15%胎牛血清(Wisent公司) 和抗生素(100U/ml 青霉素和100μg/ml 链霉素,Wisent公司) 的RPMI 1640 完全培养液(Wisent公司) 培养。
实验步骤:将THP1细胞以5×105 /孔接种于12孔板中,当细胞密度达到70%-80%时,吲哚布洛芬与THP1细胞预孵育2小时,然后与重组人源HMGB1蛋白rhHMGB1(500ng/ml)共孵育12小时,ELISA检测细胞上清中TNF-α、IL-1β和IL-6水平。
将THP1细胞以5×105 /孔接种于12孔板中,当细胞密度达到70%-80%时,吲哚布洛芬与THP1细胞预孵育2小时,然后与rhHMGB1(100ng/ml)共孵育30分钟,免疫印迹方法检测JNK、ERK、p38、IKKα/β和IκB的磷酸化水平。
将THP1细胞以5×105 /孔接种于12孔板中,当细胞密度达到70%-80%时,吲哚布洛芬与THP1细胞预孵育2小时,然后与rhHMGB1(100ng/ml)共孵育30分钟,免疫印迹方法检测PP2A、MKP-1的磷酸化水平以及PP2A的甲基化;用PP2A-cα/β抗体免疫沉淀细胞裂解液,然后用PME-1和PTPA抗体进行免疫印迹分析;RT-qPCR检测MKP-1的mRNA水平;抗MKP-1抗体进行免疫共沉淀,然后用泛素抗体(UB)进行免疫印迹分析。
结果显示:rhHMGB1(500ng/ml)刺激THP1细胞12小时后,细胞上清中释放的TNF-α、IL-1β和IL-6水平明显增多;而不同浓度吲哚布洛芬(7.5、20μM)处理细胞,能剂量依赖性的抑制rhHMGB1引起的TNF-α、IL-1β和IL-6释放(图1a)。
吲哚布洛芬处理THP1细胞后再与rhHMGB1共孵育1小时,MAPKs(JNK、ERK、P38)的磷酸化被显著削弱,并呈现出明显的吲哚布洛芬剂量依赖效应;且吲哚布洛芬预处理后,rhHMGB1引起的IKKα/β和IκB的磷酸化程度以及IKBα蛋白的降解均发生明显的阻滞,且呈现剂量依赖性(图1b和1c)。
rhHMGB1刺激THP-1细胞1小时后,并未影响PP2A的表达,但可检测到PP2A的甲基化程度明显减少,且PP2A的Tyr307位磷酸化增加,而这二种变化都会导致PP2A活性的减弱。而吲哚布洛芬逆转了rhHMGB1诱导的PP2A甲基化与磷酸化的改变,并进一步增强了rhHMGB1所引起的MKP-1蛋白水平上升(图1d)。
在rhHMGB1刺激的THP-1细胞中,吲哚布洛芬处理后,可使PP2A从PME-1上脱离,然后与激活因子PTPA结合,从而使PP2A重新获得磷酸酶活性(图1e)。
rhHMGB1刺激细胞1小时,能显著增加MKP-1的mRNA水平,而吲哚布洛芬对rhHMGB1引起的MKP-1转录水平升高并无显著的影响(图1f)。已有研究表明,MKP-1蛋白的稳定性与其磷酸化修饰有关,MKP-1的磷酸化作用可减少其泛素化依赖性的降解。吲哚布洛芬明显增强了rhHMGB1引起的p-MKP-1的激活(图1d),随后导致MKP-1泛素化的明显减少(图1g)。
实施例2 吲哚布洛芬对CLP脓毒症小鼠的治疗效果
脓毒症动物模型的制备:实验分为三组:假手术对照组(Sham组)、生理盐水治疗组(CLP组)、吲哚布洛芬治疗组(CLP+Indo组),16只/组。BALB/c小鼠(购自江苏青龙山动物繁殖场,许可证号:SCXK(苏)2017-0001a)造模前12小时禁食。称重后,按体重腹腔注射3%戊巴比妥钠(45mg/kg)进行麻醉。小鼠固定,剪去腹部被毛进行碘伏消毒后,在腹中线做1厘米左右的切口。找到盲肠后,在盲肠(距游离端)的2/3处结扎后用12号针头对穿远端盲肠体一次,形成盲肠漏后将肠内容物挤压出(假手术组不做结扎和穿刺)。最后,将盲肠归位后逐层缝合切口,进行碘伏消毒,立即背部皮下注射1ml 37℃的生理盐水以补充手术所致的体液流失。
实验步骤:CLP脓毒症造模术后8小时分别腹腔注射0.9%生理盐水或吲哚布洛芬(20mg/kg),每组20只小鼠,其中10只在术后每隔1小时观察一次,记录死亡时间,连续记录72小时。余下6只小鼠在造模后18小时处死,取小鼠肺、结肠、肾、肝脏,置于4%多聚甲醛中固定后,进行石蜡切片及H&E染色。
结果显示:CLP造模后,生理盐水治疗组在18小时便有小鼠出现死亡,观察到72小时仅剩1只小鼠存活。而术后8小时腹腔注射吲哚布洛芬(20mg/kg)有效延长了模型动物的存活时间,存活率为50%,显著高于CLP模型组(10%)(图2a)。并且在实验观察中发现,吲哚布洛芬治疗组可明显改善脓毒症小鼠的临床表现,如腹泻、眼睛脓肿等。
CLP造模后18小时肺组织病理检测结果:生理盐水治疗组(CLP组)肺泡腔中可见明显出血、渗出,多数肺泡萎陷不张。肺间质增宽,细支气管周围及肺泡间隔内大量炎症细胞浸润;吲哚布洛芬治疗组(CLP+Indo组)可以显著地改善脓毒症小鼠的肺组织损伤,肺组织充气情况出现明显好转,间隔增宽情况减轻,减轻炎症细胞浸润程度(图2b)。
CLP造模后18小时结肠组织病理检测结果:生理盐水治疗组(CLP组)肠黏膜固有膜崩裂,出现出血和溃疡的症状,且淋巴小结肿胀,绒毛脱落,坏死血管扩张,肠壁各层均有大量炎性细胞浸润,肠腺破坏;吲哚布洛芬治疗组(CLP+Indo组)可以减轻淋巴小结肿胀、肠腺破坏,绒毛脱落情况也有一定程度上好转(图2c)。
CLP造模后18小时肾组织病理检测结果:生理盐水治疗组(CLP组)肾脏可见部分肾小球皱缩,肾小管上皮细胞肿胀变性,部分肾小管上皮细胞出现坏死脱落,空泡变性,刷状缘广泛脱落,毛细血管淤血,蛋白管型形成,肾间质有大量炎性细胞聚集;吲哚布洛芬治疗组(CLP+Indo组)可以使肾小球皱缩程度减轻,空泡变性、刷状缘脱落情况有明显好转,肾间质的炎性细胞减少(图2d)。
CLP造模后18小时肝脏组织病理检测结果:生理盐水治疗组(CLP组)可见中央静脉充血,肝窦扩张,多数肝细胞有大量炎性细胞浸润且点状坏死 ;吲哚布洛芬治疗组(CLP+Indo组),中央静脉充血减缓,炎性细胞浸润程度也有一定的症状减轻趋势(图2e)。
实施例3 吲哚布洛芬联用环丙沙星对CLP脓毒症小鼠的治疗效果
实验步骤:CLP脓毒症造模术后1小时尾静脉注射环丙沙星(5mg/kg)与术后8小时腹腔注射吲哚布洛芬(20mg/kg),每组20只小鼠,其中10只在术后每隔1小时观察一次,记录死亡时间,连续记录72小时。余下6只小鼠在造模后18小时处死,取小鼠肺、结肠、肾、肝脏,置于4%多聚甲醛中固定后,进行石蜡切片及H&E染色。
结果显示:CLP造模后,生理盐水治疗组在19小时便有小鼠出现死亡,观察到72小时无小鼠存活。术后1小时尾静脉注射环丙沙星(5mg/kg),可以可见的延长小鼠的存活时间,但对存活率的提高没有显著效果。而术后1小时尾静脉注射环丙沙星(5mg/kg)与术后8小时腹腔注射吲哚布洛芬联用,有效的延长了模型动物的存活时间,存活率为70%,显著高于单用药组(CLP+CIP组为20%;CLP+Indo组为40%)(图3a)。
CLP造模后18小时肺组织病理检测结果:吲哚布洛芬联用环丙沙星治疗组(CLP+CIP+Indo组)可以显著地改善脓毒症小鼠的肺组织损伤,肺泡间质增宽现象基本消除,充血水肿现象减轻,肺泡腔形态完整,炎症细胞浸润区域减少(图3b)。
CLP造模后18小时结肠组织病理检测结果:吲哚布洛芬联用环丙沙星治疗组(CLP+CIP+Indo组)可以显著地改善脓毒症小鼠的结肠组织损伤,肠粘膜固有层无崩裂及出血溃疡,肠腺破坏程度显著减弱,肠壁各层炎症细胞浸润程度明显好转(图3c)。
CLP造模后18小时肾组织病理检测结果:吲哚布洛芬联用环丙沙星治疗组(CLP+CIP+Indo组)可以显著地改善脓毒症小鼠的肾组织损伤,明显减轻肾小球皱缩,上皮细胞坏死肿胀程度减弱,刷状缘脱落情况消除,肾间质炎性细胞浸润情况减轻(图3d)。
CLP造模后18小时肝脏组织病理检测结果:吲哚布洛芬联用环丙沙星治疗组(CLP+CIP+Indo组)可以显著地改善脓毒症小鼠的肝脏组织损伤,肝窦扩张水肿、中央静脉与肝窦充血、炎性细胞浸润等病理指标都有明显好转(图3e)。 本发明方案所公开的技术手段不仅限于上述技术手段所公开的技术手段,还包括由以上技术特征等同替换所组成的技术方案。本发明的未尽事宜,属于本领域技术人员的公知常识。
Claims (6)
1.吲哚布洛芬在抵抗HMGB1促炎活性中的应用,其特征在于,所述吲哚布洛芬能够抑制HMGB1诱导的TNF-α、IL-1β、IL-6的上调,所述吲哚布洛芬能够逆转HMGB1引起的PP2A活性下调与MKP-1泛素化降解,从而抑制MAPKs和NF-κB信号通路的激活。
2.权利要求1所述的应用,其特征在于,所述药物的细胞用药有效浓度为7.5μM及以上。
3.权利要求1所述的应用,其特征在于,脓毒症造模8小时后吲哚布洛芬治疗对以HMGB1为重要调节因子的脓毒症小鼠具有较好的治疗效果。
4.权利要求1~3所述的应用,其特征在于,所述吲哚布洛芬为注射剂型。
5.一种用于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吲哚布洛芬与环丙沙星。
6.权利要求5所述的药物组合物,其特征在于,所述药物中吲哚布洛芬的小鼠用药有效浓度为20mg/kg及以上,环丙沙星的小鼠用药有效浓度为5mg/kg及以上。
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