陈瑞玲等胆汁淤积导致肝纤维化的机制及其阻断策略２４７ '()* 胆汁淤积导致肝纤维化的机制及其阻断策略陈瑞玲马雄上海交通大学医学院附属仁济医院消化内科上海市消化病研究所上海２００００１摘要胆汁淤积是指胆汁流形成分泌和排泄障碍的一种病理状态而肝纤维化是肝损伤引起的组织修复过程

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1 陈瑞玲等机制及其阻断策略２４７ '()* 机制及其阻断策略陈瑞玲马雄海交通学医学院附属仁济医院消科海市消研究所海２００００１摘指流形排泄障碍种理态组织修复程由渐破坏持存在所种慢逐步结合目前研究对机制阻断策略综述关键词硬类盐类图类号Ｒ５７５２２文献标志码Ａ文章编号１００１５２５６２０１９０２０２４７０５ＰａｔｈｏｇｅｎｅｓｉｓｏｆｃｈｏｌｅｓｔａｓｉｓｉｎｄｕｃｅｄｌｉｖｅｒｆｉｂｒｏｓｉｓａｎｄｔｈｏｕｇｈｔｓｆｏｒｂｌｏｃｋａｄｅＤｅｐａｒｔｍｅｎｔｏｆＧａｓｔｒｏｅｎｔｅｒｏｌｏｇｙＲｅｎｊｉＨｏｓｐｉｔａｌＳｈａｎｇｈａｉＪｉａｏＴｏｎｇＵｎｉｖｅｒｓｉｔｙＳｃｈｏｏｌｏｆＭｅｄｉｃｉｎｅＳｈａｎｇｈａｉＩｎｓｔｉｔｕｔｅｏｆＤｉｇｅｓｔｉｖｅＤｉｓｅａｓｅｓＳｈａｎｇｈａｉ２００００１ＣｈｉｎａＡｂｓｔｒａｃｔＣｈｏｌｅｓｔａｓｉｓｒｅｆｅｒｓｔｏａｐａｔｈｏｌｏｇｉｃａｌｓｔａｔｅｏｆｄｉｓｏｒｄｅｒｓｉｎｔｈｅｆｏｒｍａｔｉｏｎｓｅｃｒｅｔｉｏｎａｎｄｅｘｃｒｅｔｉｏｎｏｆｂｉｌｅｆｌｏｗａｎｄｌｉｖｅｒｆｉｂｒｏｓｉｓｉｓａｐｒｏｃｅｓｓｏｆｔｉｓｓｕｅｒｅｐａｉｒｉｎｄｕｃｅｄｂｙｌｉｖｅｒｉｎｊｕｒｙＣｈｏｌｅｓｔａｔｉｃｌｉｖｅｒｄｉｓｅａｓｅｉｓａｃｈｒｏｎｉｃｌｉｖｅｒｄｉｓｅａｓｅｃａｕｓｅｄｂｙｃｈｏｌｅｓｔａｓｉｓｐｒｏｇｒｅｓｓｉｖｅｂｉｌｅｄｕｃｔｉｎｊｕｒｙａｎｄｐｅｒｓｉｓｔｅｎｔｉｎｔｒａｈｅｐａｔｉｃｉｎｆｌａｍｍａｔｉｏｎａｎｄｉｔｍａｙｃａｕｓｅｃｈｏｌａｎｇｉｏｃｙｔｅａｎｄｈｅｐａｔｏｃｙｔｅｉｎｊｕｒｙｗｈｉｃｈｗｉｌｌｇｒａｄｕａｌｌｙｐｒｏｇｒｅｓｓｔｏｌｉｖｅｒｆｉｂｒｏｓｉｓＷｉｔｈｒｅｆｅｒｅｎｃｅｔｏｔｈｅｃｕｒｒｅｎｔｒｅｓｅａｒｃｈａｄｖａｎｃｅｓｔｈｉｓａｒｔｉｃｌｅｒｅｖｉｅｗｓｔｈｅｐａｔｈｏｇｅｎｅｓｉｓｏｆｃｈｏｌｅｓｔａｓｉｓｉｎｄｕｃｅｄｌｉｖｅｒｆｉｂｒｏｓｉｓａｎｄｔｈｅＣＨＥＮＲｕｉｌｉｎｇＭＡＸｉｏｎｇｓｔｒａｔｅｇｉｅｓｆｏｒｂｌｏｃｋａｄｅ疾程两种常且程由ＭＦＢ度逆理态几乎所慢都会逐渐疤痕形结节再最终硬如酒等在各种很如菌寄虫药物素基ＥＣＭ合降失衡造或物酒身肿瘤机械梗阻素等弥漫度最终逆硬临床黄疸疲劳瘙痒主现由渐破坏ＡＬＰ水平升高主指标异常身介持存在所种慢ＰＢＣ硬逐步硬ＰＳＣ最常两种类持终末与非硬同硬慢特点汇较快伴异常逐步扩到实这些组织汇指流形排障碍由或ＴＢ淋巴浸润同程度形障碍或流阻断持慢研究认机制通种调节激肌汇慢ｍｙｏｆｉｂｒｏｂｌａｓｔｍｆｂＥＣＭ度从浸润释放学本文就机制等ＭＦＢＥＣＭ阻断策略综述在汇随着疾范扩至１与非及汇窦系统明被认慢组织创愈合显造行步加重浸润扩范汇由来行或稿日修回日板结构形即在态简介陈瑞玲女博士主从事身研究通信马雄电信箱ＭＦＢ共同推动疾朝Ｋｅｙｗｏｒｄｓｃｈｏｌｅｓｔａｓｉｓｌｉｖｅｒｃｉｒｒｈｏｓｉｓｂｉｌｅａｃｉｄｓａｎｄｓａｌｔｓ１ｄｏｉ１０３９６９ｊｉｓｓｎ１００１５２５６２０１９０２００２２０１８１１０７２０１８１１０７１９９３ｍａｘｉｏｎｇｍｄ１６３ｃｏｍ

2 临床杂志第３５卷第２２０１９年２月ＪＣｌｉｎＨｅｐａｔｏｌＶｏｌ３５Ｎｏ２Ｆｅｂ２０１９２４８调节在局部形个环境此向２ＭＦＢ通旁式在局部建立个强机制２１ＭＦＢＭＦＢ再核交流网络持度群来异具２２ＭＦＢ从心环节这但否能直激ＭＦＢ目前仍存在很强能力其达释放种调节旁争议在态疏水造同达调节相ＭＦＢ通或式如ＴＧＦβ 传递局部固信号合 Ⅰ Ⅲ 主 α 平滑肌肌动适被募集激释放调节连等挥ＭＦＢ高达ＭＦＢ从使基金属酶对金属酶１组织抑制剂态膜运达水平降与清除减度在小板改变减重吸排泄这种改变ＰＤＧＦＴＧＦ等机对种代偿保护机制但该代偿ＭＦＢ持断能够足抵抗造破坏从疾ＭＦＢ包括星ＨＳＣ汇５０２００１５２５ μｍ低浓度盐信号ｐｏｒｔａｌｆｉｂｒｏｂｌａｓｔｐｆ骨髓来或 μｍ盐会凋亡超２００ μｍ则会激超２０００ μｍ充干及２００２０００ μｍ会坏死ＨＳＣ数最ＭＦＢ位窦慢挥垢疏水强亲水ＨＳＣ由息态能力ＭＦＢ凋亡或坏死疾重事件疏水合主ＥＣＭ释放素１这种缩能够直线粒产ＲＯＳ步氧素１缩在种慢小鼠模ＨＳＣ来激氧磷减加线粒通透线ＭＦＢ占８２９６研究现ＰＦ在粒肿胀裂释放酶凋亡重ＰＦ存在汇结缔直激膜面死亡通垢组织其达标记ＰＦ破坏膜膜溶从死都与ＨＳＣ完全相同目前ＰＦ在亡破坏存在着争议但否认在紧密连屏障结构疏水盐易漏入基ＰＦ该最先被激步入之理扩至小叶被ＨＳＣ开始主此骨髓来充干或近年来Ｂｅｕｅｒｓ提碳根伞理论到广在骨髓迁移到但占ＭＦＢ总数泛认与关注碳根伞保护人足５还极部ＭＦＢ来汇疏水单破坏这面层单层目前认它在充达ＡＥ２ａｎｉｏｎｅｘｃｈａｎｇｅｒ２向运碳所极小学提根膜顶端完整糖衣结构捕获碳根从在面形道碳根伞保护屏障通ｅｐｉｔｈｅｌｉａｌｍｅｓｅｎｃｈｙｍａｌｔｒａｎｓｉｔｉｏｎｅｍｔ形ＭＦＢＥＭＴ指熟ＰＢＣ膜ＡＥ２达水平降失触特达特征碳盐减能持面碳获特征然目前没研究证盐保护屏障易到疏水据支持这说法ＥＭＴ正常理破坏答但这些只非２３与密切相关ＭＦＢ个重机制即这个参与动态ＭＦＢ迁移与赖种调节募集程汇现排列形道支伸这些来来或Ｋｕｐｆｆｅｒ具神经架祖ｈｅｐａｔｉｃｐｒｏｇｅｎｉｔｏｒｃｅｌｌｈｐｃ招ｄｕｃｔｕｌａｒｒｅａｃｔｉｖｅｃｅｌｌｄｒｃ及被激ＭＦＢ等这些共同释放学氧ＲＯＳ等募种至汇释放调节ＭＦＢ２３４１３５６７８１４１５１６９１０１７１８２１１１２１９２０

3 陈瑞玲等机制及其阻断策略２４９缓疾ＥＣＭ居Ｈｅｒｉｎｇ小改ＨＰＣ值注意３２１熊氧ｕｒｓｏｄｅｏｘｙｃｈｏｌｉｃａｃｉｄｕｄｃａＵＤ此具神经ＤＲＣ这ＣＡ熊之具利调节ＭＦＢ类似ＤＲＣ能够学与ＨＳＣ排泄它改ＰＢＣＰＳＣ指标改无移植存情达丰富此还能缓组织学临床治ＰＢＣ线药常剂其他基建立强旁信号交流网络如况ＵＤＣＡＰＦＨＳＣ等ＤＲＣ达标志１３１５ｍｇｋｇｄ但仍约４０ＰＢＣ对答物但ＤＲＣ身能ＥＣＭ需通刺激强ＵＤＣＡ无其他挥如ＤＲＣ释放３２２奥贝ｏｂｅｔｉｃｈｏｌｉｃａｃｉｄｏｃａＯＣＡ人ＰＤＧＦ级鹅氧类新衍物种较强ＭＦＢ基达ＨＰＣ趋初入汇ＨＳＣ法尼酯ＸｆａｒｎｅｓｏｉｄＸｒｅｃｅｐｔｏｒｆｘｒ激动剂４种类 Ⅰ 即典ＦＸＲ达肠道核被仅汇数此汇合减清除加肠重吸减该类在人类疾急阻塞项临床试验ＰＯＩＳＥ显示ＯＣＡ治ＰＢＣ改道闭锁慢早 Ⅱ 基该结果２０１６年５月ＯＣＡ被批准治即非典汇规则且范扩到ＰＢＣ对ＵＤＣＡ答佳联ＯＣＡ行治耐单ＯＣＡ目前暂无确切证据明门脉实这些新无排泄功能此对ＵＤＣＡＨＰＣ此类在人类疾ＯＣＡ治改预ＰＢＣＰＳＣ梗阻 Ⅲ称３２３布地奈德布地奈德第二代肾腺糖激理卵圆或ＨＰＣ素口服首效高达９０减激素伴坏死慢晚 Ⅳ即良它种孕烷Ｘ激动剂调节卵圆结构规则腔清晰小叶结脱代谢减合项研究明构紊乱癌物动物模早阶段ＵＤＣＡ联合布地奈德６９ｍｇｄ治ＰＢＣ在抗抗最常类面均取很好效 Ⅱ ２０１７年Ｊａｎｓｅｎ等指３３抗治ＭＦＢ在种此抑制ＨＳＣ遵循个相同模式由此提行减机制游游相对流向言通ＥＣＭ产ＥＣＭ降治略高达整合素ανβ６结合常情况初始灶现在或小游处随策着情逐渐游小网实参与连及辅助激ＭＦＢ所需ＴＧＦβ１信来啮齿动物结扎现道压力号从实验 ανβ６小抑制剂或ＥＣＭ在汇特异抗阻断该整合缓非ＭＦＢＰＦＨＳＣ亦但未临床试验ＨＳＣ达种核小扩张腔容小叶则录如氧物酶物激ＰＰＡＲ明显结构重塑先在腔侧形皱褶腔总面ＦＸＲＸ素Ｄ等能够抑制ＨＳＣ扩约５倍继伸支支身连些针对核药物已临床试行环最门脉小叶网密集程度验ＰＰＡＲ家族包括如ＰＰＡＲ激动剂ＦＸＲ激动剂但这些径没明显扩ＰＰＡＲα ＰＰＡＲγ ＰＰＡＲδ 研究构建非酒加约５倍３阻肪动物模现ＰＰＡＲα ＰＰＡＲδ 双激动剂断策略除逆ＧＦＴ５０５３１除改肪变步临试验现ＧＦＴ５０５１２０ｍｇｄ治缓非酒重措施比如行抗治戒床酒缓酒程然数肪加重ＦＸＲ难除这使治限激动剂ＯＣＡ改具抗３２改项心临床试验现ＯＣＡ治明显改非 Ⅱ 通酒肪组织程度ＨＳＣＭＦＢ此催弹交联酶ＬＯＸＬ２最初２１２６２２１１２３２４２７２８２９３１１３３２３３２５３４３５３６３７

4 250 临床杂志第 35 卷第年 2 月 J Clin Hepatol,Vol.35 No.2,Feb.2019 项临床试验研究 [38] 现, 抗 LOXL2 单抗 Simtuzumab(G6-6624) 治丙具安全之项 Ⅱ 临床试验研究其在非酒肪相关硬治, 但药物没效止 4 小结与望如何阻断疾临床治个重点难点问题此, 探明在机制具重意义 MFB 根本, 这赖旁 / 式行调控此, 靶向及其信号通路抗治提供新思路种抗药物仍需更更靠临床研究来证实其效安全 : [1] POLLHEIMER MJ, FICKERT P, STIEGER B. Chronic choles tatic liver diseases: Clues from histopathology for pathogene sis[j]. Mol Aspects Med, 2014, 37: [2] WELLS RG, SCHWABE RF. Origin and function of myofibro blasts in the liver[j]. Semin Liver Dis, 2015, 35(2): e1. [3] TSUCHIDA T, FRIEDMAN SL. Mechanisms of hepatic stellate cell activation[ J]. Nat Rev Gastroenterol Hepatol, 2017, 14 (7): [4] FRIEDMAN SL. Hepatic stellate cells: Protean, multifunction al, and enigmatic cells of the liver[j]. Physiol Rev, 2008, 88 (1): [5 ] HIGASHI T, FRIEDMAN SL, HOSHIDA Y. Hepatic stellate cells as key target in liver fibrosis[ J]. Adv Drug Deliv Rev, 2017, 121: [6] MEDERACKE I, HSU CC, TROEGER JS, et al. 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Lineage tracing demon strates no evidence of cholangiocyte epithelial - to - mesen chymal transition in murine models of hepatic fibrosis [ J ]. Hepatology, 2011, 53(5): [13] JANSEN PL, GHALLAB A, VARTAK N, et al. The ascending pathophysiology of cholestatic liver disease[ J]. Hepatology, 2017, 65(2): [14] YIN XM, DING WX. Death receptor activation -induced hepa tocyte apoptosis and liver injury[ J]. Curr Mol Med, 2003, 3 (6): [15] BORGOGNONE M, P?REZ LM, BASIGLIO CL, et al. Signa ling modulation of bile salt - induced necrosis in isolated rat hepatocytes[ J]. Toxicol Sci, 2005, 83(1): [16] SAKISAKA S, KAWAGUCHI T, TANIGUCHI E, et al. Altera tions in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis[ J]. Hepatology, 2001, 33 (6): [17] HOHENESTER S, WENNIGER LM, PAULUSMA CC, et al. A biliary HCO3 - umbrella constitutes a protective mechanism a gainst bile acid - induced injury in human cholangiocytes[ J]. 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