CN114209813A - 靶向补体抑制剂在制备改善胆汁淤积性肝损伤药物中的应用 - Google Patents

靶向补体抑制剂在制备改善胆汁淤积性肝损伤药物中的应用 Download PDF

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CN114209813A
CN114209813A CN202111443095.0A CN202111443095A CN114209813A CN 114209813 A CN114209813 A CN 114209813A CN 202111443095 A CN202111443095 A CN 202111443095A CN 114209813 A CN114209813 A CN 114209813A
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cholestatic liver
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何松青
郭振亚
袁观斗
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First Affiliated Hospital of Guangxi Medical University
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Abstract

本发明公开了靶向补体抑制剂在制备改善胆汁淤积性肝损伤药物中的应用。靶向补体抑制剂CR2‑Crry在制备改善胆汁淤积性肝损伤药物中的应用，所述的CR2‑Crry的氨基酸序列如SEQ ID NO.1所示。本发明利用补体受体2(Complement receptor 2,CR2)融合C3活化抑制因子Crry，通过CR2靶向性结合到补体活化部位，利用Crry特异性抑制C3活化，进而抑制补体系统活化。通过建立小鼠胆汁淤积性肝损伤模型，比较CR2‑Cryy治疗组与对照组的肝损伤水平变化，结果证明CR2‑Crry可显著改善胆汁淤积性肝损伤，抑制肝内炎性细胞浸润，抑制肝内M1型巨噬细胞极化并降低促炎因子表达。本发明还通过C3基因敲除小鼠进一步验证了抑制补体系统对胆汁淤积性肝损伤的改善作用。

Description

靶向补体抑制剂在制备改善胆汁淤积性肝损伤药物中的应用
技术领域
本发明属于生物医学技术领域，涉及靶向补体抑制剂在制备改善胆汁淤积性肝损伤药物中的应用。
背景技术
胆汁淤积性肝损伤(Cholestatic liver injury,CLI)是指由于多种病因导致的胆汁生成、分泌或排泄异常，胆汁不能正常经由胆管排入肠道，在肝脏内淤积、进而反流入血而引起的一系列器质性损害和功能紊乱的病理状态，临床主要表现为黄疸、肝功能损害，如病情进一步发展可引起肝功能衰竭、甚至死亡。在外科系统疾病中，肝癌、胆管肿瘤、胰头占位性病变等疾病引起的胆道梗阻是导致CLI的常见原因。CLI的机制目前并不十分明确，以往的研究表明，其损伤机制依赖于无菌性炎症反应和氧化应激。因此，多种炎症相关细胞，如巨噬细胞和中性粒细胞，在CLI病程中发挥着重要作用。CLI可显著增加手术及预后风险，但其临床防治手段却非常有限。因此，在围手术期如何防治CLI是临床面临的一个重要课题。
发明内容
本发明的目的是针对现有技术的不足，提供靶向补体抑制剂在制备改善胆汁淤积性肝损伤药物中的应用。
本发明利用补体受体2(Complement receptor 2,CR2)融合C3活化抑制因子Crry，通过CR2靶向性结合到补体活化部位，利用Crry特异性抑制C3活化，进而抑制补体系统活化。通过建立小鼠胆汁淤积性肝损伤模型，比较CR2-Cryy治疗组与对照组的肝损伤水平变化，结果证明CR2-Crry可显著改善胆汁淤积性肝损伤，抑制肝内巨噬细胞及中性粒细胞浸润，抑制肝内M1型巨噬细胞极化并降低炎症因子表达。本发明还通过C3基因敲除小鼠进一步验证了抑制补体系统对胆汁淤积性肝损伤的改善作用。
因此，本发明的第一个目的是提供靶向补体抑制剂CR2-Crry在制备改善胆汁淤积性肝损伤药物中的应用。CR2-Crry的氨基酸序列如SEQ ID NO.1所示。
优选，所述的改善胆汁淤积性肝损伤药物为在胆汁淤积时减轻肝细胞损伤坏死的药物。
优选，所述的改善胆汁淤积性肝损伤药物为在胆汁淤积时减轻肝内巨噬细胞及中性粒细胞浸润的药物。
优选，所述的改善胆汁淤积性肝损伤药物为在胆汁淤积时抑制肝内M1型巨噬细胞极化并降低炎症因子表达的药物。
本发明的第二个目的是提供一种改善胆汁淤积性肝损伤的药物，其含有有效量的靶向补体抑制剂CR2-Crry作为活性成分，所述的靶向补体抑制剂CR2-Crry的氨基酸序列如SEQ ID NO.1所示。所述的药物还可以含有药学上可以接受的辅料，可以制成不同的剂型。
本发明具有以下有益效果：
1.靶向补体抑制剂CR2-Crry具有靶向性强、高效、安全、不影响宿主全身免疫功能的优点。
2.靶向补体抑制剂CR2-Crry可改善胆汁淤积性肝损伤小鼠模型的肝功能。小鼠胆道结扎术后立即给药，每只小鼠腹腔注射CR2-crry蛋白0.25mg，每24小时给药一次。术后72h取肝脏组织及血清，通过病理学及血清学可检测到肝功能的改变。
3.靶向补体抑制剂CR2-Crry可在胆汁淤积时减轻肝内巨噬细胞及中性粒细胞的浸润。
4.靶向补体抑制剂CR2-Crry可在胆汁淤积时抑制肝内M1型巨噬细胞极化并降低炎症因子表达。
附图说明
图1是小鼠胆道结扎手术(Bile duct ligation，BDL)术后补体系统活化检测。A、B:小鼠肝组织内C3d、MAC免疫组化检测及免疫组化评分；C：Elisa检测小鼠血清C3a水平；**表示P＜0.01。
图2是BDL术后小鼠肝损伤检测；A、B：生化检测小鼠血清谷丙转氨酶(ALT)、谷草转氨酶(AST)水平；C：肝组织HE染色及肝组织坏死面积百分率；*表示P＜0.05，**表示P＜0.01。
图3是BDL术后小鼠肝内中性粒细胞及巨噬细胞浸润水平检测；A:特异性酯酶染色标记中性粒细胞及肝组织内每高倍镜视野中中性粒细胞计数；B：MPO免疫组化染色及免疫组化评分；C：F4/80免疫组化染色及及免疫组化评分；*表示P＜0.05，**表示P＜0.01。
图4是BDL术后小鼠肝内M1/M2巨噬细胞及促炎因子表达水平检测；A:M1/M2巨噬细胞流式细胞检测及M1巨噬细胞百分比。B-D依次为肝组织内促炎因子TNF-α、IL-6、IL-1β表达水平；*表示P＜0.05，**表示P＜0.01。
具体实施方式：
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
以下实例中未具体注明的实验方法，均可按照常规方法进行，或按照所用产品生产厂商的使用说明；所使用的材料、试剂等，如无特殊说明，均可通过商业途径得到。
以下实施例中所用的野生型小鼠均为C57BL/6野生型小鼠。
靶向补体抑制剂CR2-Crry的制备：是将补体受体2(Complement receptor 2,CR2)连接膜结合性调节因子(Crry)而制备得到的，具体制备参见：Atkinson C,Song H,Lu B,etal.Targeted complement inhibition by C3d recognition ameliorates tissueinjury without apparent increase in susceptibility to infection.J ClinInvest.2005；115(9):2444-2453文中Methods中CR2-Crry fusion protein的制备。制备的用于实施例中的靶向补体抑制剂CR2-Crry的氨基酸序列如SEQ ID NO.1所示，含585个氨基酸。
补体C3基因敲除小鼠(C3-/-小鼠、C3敲除小鼠)为B6；129S4-C3tm1Crr/J品系，购自The Jackson Laboratories(Bar Harbor,Maine,USA)。
实施例1
1，实验相关整体模型的建立
对小鼠进行胆道结扎手术(Bile duct ligation，BDL)以建立胆汁淤积性肝损伤模型。步骤如下：使用异氟烷将小鼠麻醉后固定其四肢，对小鼠腹部消毒。用剪刀沿小鼠腹壁中线纵行依次剪开腹壁，切口长约2cm。扩张腹部切口，暴露肝门，用棉签轻压胃窦及十二指肠部，向下轻微用力牵拉，可见一条透明管道行走于肝门静脉的前方，即为胆总管。使用镊子尖部从胆总管与门静脉之间进行钝性剥离，游离出2-3mm的胆总管。穿入两根9-0尼龙线进行双重结扎，剪去线尾。缝合腹壁后将小鼠转移至饲养笼，苏醒后给予普通饲料、灭菌饮用水。
使用C57BL/6野生型小鼠根据上述模型制备的为野生鼠胆道结扎组(WT-BDL)，野生鼠假手术组(WT-Sham)为麻醉后行开关腹操作，无其他处理。
使用补体C3基因敲除小鼠根据上述模型制备的为转基因鼠胆道结扎组(C3-/--BDL)，转基因鼠假手术组(C3-/--Sham)为麻醉后行开关腹操作，无其他处理。
使用C57BL/6野生型小鼠胆道结扎模型，在术后腹腔注射CR2-crry蛋白0.25mg，每24小时给药一次，为体抑制剂CR2-Crry处理组(WT-BDL+CR2-Crry)。
每组6只小鼠模型。
所有小鼠模型均在术后72h通过下腔静脉取静脉血及移除肝脏组织。部分肝脏组织经10％福尔马林固定24h后石蜡包埋用于组织学检测，其余放置-80℃冰箱保存用于RNA提取。静脉血4℃下静置6h后离心取血清以备检测肝功能等相关指标。模型出现以下情况则提示造模失败：1，开腹取样时见小鼠胆囊未见明显肿大或腹腔有胆汁积液。2，术后72h取样检测肝功提示血清总胆红素未见显著升高。
2，抑制补体活化对胆汁淤积性肝损伤的作用
通过对C57BL/6野生型及C3基因敲除小鼠进行BDL手术以建立胆汁淤积性肝损伤模型，并对野生型实验组进行CR2-Crry干预，在术后72小时取样，研究抑制补体活化对胆汁淤积性肝损伤的影响。
2.1在胆汁淤积性肝损伤中补体系统过度活化
通过免疫组化检测发现WT-BDL组小鼠肝组织内有大量C3d与MAC沉积(图1A&B)，提示补体系统的过度活化，同时Elisa检测提示其血清C3a水平显著升高(图1C)。而C3基因敲除与CR2-Crry均可显著抑制BDL术后肝组织内C3d与MAC的沉积及血清C3a水平(图1A-C)。这说明在胆汁淤积性肝损伤中补体过度活化，而CR2-Crry可显著抑制补体系统在肝组织内的活化。
2.2抑制补体系统活化可显著改善胆汁淤积性肝损伤
通过生化检测发现WT-BDL组小鼠血清ALT及AST显著升高(图2A&B)，同时HE染色可见其肝组织表现为大面积融合性坏死，肝小叶汇管区域有大量炎性细胞浸润(图2C)。而C3敲除与CR2-Crry均可显著著降低ALT和AST及肝组织坏死程度(图2A-C)，通过计算肝组织坏死面积百分率，其差异具有显著性。
2.3抑制补体系统活化可在胆汁淤积时降低巨噬细胞及中性粒细胞在肝内的浸润
中性粒细胞是氧化应激的重要效应细胞，通过特异性酯酶染色与MPO免疫组化染色对中性粒细胞进行标记，可见WT-BDL组小鼠肝组织内可见中性粒细胞大量浸润，而C3敲除与CR2-Crry可显著减少肝实质内中性粒细胞浸润数量(图3A&B)。巨噬细胞是重要的炎症调节细胞，通过F4/80免疫组化染色对肝内巨噬细胞进行标记可见BDL术后肝内巨噬细胞显著增多，而C3敲除与CR2-Crry均可显著减少肝内巨噬细胞的数量(图3C)。
2.4抑制补体系统活化可在胆汁淤积时抑制肝内M1型巨噬细胞极化并降低炎症因子表达
巨噬细胞在不同微环境中功能特性不同,按照其表型和分泌的细胞因子可分为两大类,即经典活化型巨噬细胞(M1型)和替代活化型巨噬细胞(M2型)，其中M1型巨噬细胞的特征是分泌大量炎症因子，诱导炎症反应。通过流式细胞检测发现，WT-BDL组小鼠肝组织内M1型巨噬细胞比例显著增多，而C3敲除与CR2-Crry可显著减少肝实质内M1巨噬细胞百分比(图4A)。通过RT-PCR检测小鼠肝组织内相关促炎因子表达，可见WT-BDL组TNF-α、IL-6、IL-1β显著升高，而C3敲除和CR2-Crry均可显著降低BDL术后小鼠肝内TNF-α、IL-6、IL-1β表达水平(图4B-D)。
RT-PCR检测引物序列：GAPDH:forward,5’-ACTCCACTCACGGCAAATTC-3’；reverse,5’-TCTCCATGGTGGTGAAGACA-3’.TNF-α:forward,5’-GAGGACAGCAAGGGACTAGC-3’；reverse,5’-AGGGAGGCCATTTGGGAACT-3’.IL-6:forward,5’-CTCTGCAAGAGACTTCCATCCAGT-3’；reverse,5’-ACTCCAGGTAGCTATGGTACTCCA-3’.IL-1β:forward,5’-ACTACAGGCTCCGAGATGAACA-3’；reverse,5’-TTGCTTGGGATCCACACTCTCC-3’。
序列表
<110> 广西医科大学第一附属医院
<120> 靶向补体抑制剂在制备改善胆汁淤积性肝损伤药物中的应用
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 585
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Ile Ser Cys Asp Pro Pro Pro Glu Val Lys Asn Ala Arg Lys Pro Tyr
1 5 10 15
Tyr Ser Leu Pro Ile Val Pro Gly Thr Val Leu Arg Tyr Thr Cys Ser
20 25 30
Pro Ser Tyr Arg Leu Ile Gly Glu Lys Ala Ile Phe Cys Ile Ser Glu
35 40 45
Asn Gln Val His Ala Thr Trp Asp Lys Ala Pro Pro Ile Cys Glu Ser
50 55 60
Val Asn Lys Thr Ile Ser Cys Ser Asp Pro Ile Val Pro Gly Gly Phe
65 70 75 80
Met Asn Lys Gly Ser Lys Ala Pro Phe Arg His Gly Asp Ser Val Thr
85 90 95
Phe Thr Cys Lys Ala Asn Phe Thr Met Lys Gly Ser Lys Thr Val Trp
100 105 110
Cys Gln Ala Asn Glu Met Trp Gly Pro Thr Ala Leu Pro Val Cys Glu
115 120 125
Ser Asp Phe Pro Leu Glu Cys Pro Ser Leu Pro Thr Ile His Asn Gly
130 135 140
His His Thr Gly Gln His Val Asp Gln Phe Val Ala Gly Leu Ser Val
145 150 155 160
Thr Tyr Ser Cys Glu Pro Gly Tyr Leu Leu Thr Gly Lys Lys Thr Ile
165 170 175
Lys Cys Leu Ser Ser Gly Asp Trp Asp Gly Val Ile Pro Thr Cys Lys
180 185 190
Glu Ala Gln Cys Glu His Pro Gly Lys Phe Pro Asn Gly Gln Val Lys
195 200 205
Glu Pro Leu Ser Leu Gln Val Gly Thr Thr Val Tyr Phe Ser Cys Asn
210 215 220
Glu Gly Tyr Gln Leu Gln Gly Gln Pro Ser Ser Gln Cys Val Ile Val
225 230 235 240
Glu Gln Lys Ala Ile Trp Thr Lys Lys Pro Val Cys Lys Glu Ile Leu
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Cys Pro Ala Pro Ser Gln
260 265 270
Leu Pro Ser Ala Lys Pro Ile Asn Leu Thr Asp Glu Ser Met Phe Pro
275 280 285
Ile Gly Thr Tyr Leu Leu Tyr Glu Cys Leu Pro Gly Tyr Ile Lys Arg
290 295 300
Gln Phe Ser Ile Thr Cys Lys Gln Asp Ser Thr Trp Thr Ser Ala Glu
305 310 315 320
Asp Lys Cys Ile Arg Lys Gln Cys Lys Thr Pro Ser Asp Pro Glu Asn
325 330 335
Gly Leu Val His Val His Thr Gly Ile Gln Phe Gly Ser Arg Ile Asn
340 345 350
Tyr Thr Cys Asn Gln Gly Tyr Arg Leu Ile Gly Ser Ser Ser Ala Val
355 360 365
Cys Val Ile Thr Asp Gln Ser Val Asp Trp Asp Thr Glu Ala Pro Ile
370 375 380
Cys Glu Trp Ile Pro Cys Glu Ile Pro Pro Gly Ile Pro Asn Gly Asp
385 390 395 400
Phe Phe Ser Ser Thr Arg Glu Asp Phe His Tyr Gly Met Val Val Thr
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Tyr Arg Cys Asn Thr Asp Ala Arg Gly Lys Ala Leu Phe Asn Leu Val
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Gly Glu Pro Ser Leu Tyr Cys Thr Ser Asn Asp Gly Glu Ile Gly Val
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Trp Ser Gly Pro Pro Pro Gln Cys Ile Glu Leu Asn Lys Cys Thr Pro
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Pro Pro Tyr Val Glu Asn Ala Val Met Leu Ser Glu Asn Arg Ser Leu
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Phe Ser Leu Arg Asp Ile Val Glu Phe Arg Cys His Pro Gly Phe Ile
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Met Lys Gly Ala Ser Ser Val His Cys Gln Ser Leu Asn Lys Trp Glu
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Pro Glu Leu Pro Ser Cys Phe Lys Gly Val Ile Cys Arg Leu Pro Gln
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Glu Met Ser Gly Phe Gln Lys Gly Leu Gly Met Lys Lys Glu Tyr Tyr
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Tyr Gly Glu Asn Val Thr Leu Glu Cys Glu Asp Gly Tyr Thr Leu Glu
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Gly Ser Ser Gln Ser Gln Cys Gln Ser Asp Gly Ser Trp Asn Pro Leu
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Leu Ala Lys Cys Val Ser Arg Ser Ile
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Claims (6)

1.靶向补体抑制剂CR2-Crry在制备改善胆汁淤积性肝损伤药物中的应用，所述的CR2-Crry的氨基酸序列如SEQ ID NO.1所示。
2.根据权利要求1所述的应用，其特征在于，所述的改善胆汁淤积性肝损伤药物为在胆汁淤积时减轻肝细胞损伤坏死的药物。
3.根据权利要求1所述的应用，其特征在于，所述的改善胆汁淤积性肝损伤药物为在胆汁淤积时减轻肝内巨噬细胞及中性粒细胞浸润的药物。
4.根据权利要求1所述的应用，其特征在于，所述的改善胆汁淤积性肝损伤药物为在胆汁淤积时抑制肝内M1型巨噬细胞极化并降低炎症因子表达的药物。
5.一种改善胆汁淤积性肝损伤的药物，其特征在于，含有有效量的靶向补体抑制剂CR2-Crry作为活性成分，所述的靶向补体抑制剂CR2-Crry的氨基酸序列如SEQ ID NO.1所示。
6.根据权利要求5所述的药物，其特征在于，还含有药学上可以接受的辅料。
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