修回日期: 2016-05-11
接受日期: 2016-05-16
在线出版日期: 2016-08-28
肝纤维化是肝组织内细胞外基质蛋白的异常积聚, 是各种慢性肝损伤的特征性改变, 有发展成肝硬化、肝衰竭以及肝癌的潜在可能性, 因此被广泛认为是破坏性的病理学过程. 然而, 相关的研究提示肝纤维化不仅是可逆转的, 而且肝纤维化存在对肝脏损伤的保护作用. 目前肝纤维化发挥保护作用的机制也逐渐成为研究热点, 其核心在于促进剩余的正常肝细胞的再生及凋亡抵抗. 我们就目前肝纤维化损伤耐受现象及其分子机制研究做一述评, 为临床上阐明慢加急性肝衰竭的发病机制及寻找新的治疗靶点提供理论依据.
核心提要: 肝纤维化是肝组织内细胞外基质蛋白的异常积聚, 相关的研究提示肝纤维化不仅是可逆转的, 而且存在对肝脏损伤的保护作用. 目前肝纤维化发挥保护作用的机制在于促进剩余的正常肝细胞的再生及凋亡抵抗.
引文著录: 郑庆芬, 李建生, 白丽, 郑素军. 肝纤维化诱导急性肝损伤耐受的研究进展. 世界华人消化杂志 2016; 24(24): 3537-3542
Revised: May 11, 2016
Accepted: May 16, 2016
Published online: August 28, 2016
Liver fibrosis is the excessive accumulation of extracellular matrix proteins in liver tissue. Liver fibrosis as the characteristic change of chronic liver injury has the potential to develop into liver cirrhosis, liver failure and hepatic carcinoma, and is considered a devastating pathologic process. However, recent studies demonstrate that liver fibrosis is not only reversible, but also can protect the liver from acute injury. Currently, the mechanisms of hepatoprotective effect of liver fibrosis have become a hot research area, which include promoted regeneration of the remaining normal liver cells and apoptotic resistance. In the present article, we will review the hepatoprotective effect of liver fibrosis and the underlying molecular mechanisms, aiming to provide a theoretical basis for understanding the pathogenesis of acute-on-chronic liver failure and provide new therapeutic targets for this disease.
- Citation: Zheng QF, Li JS, Bai L, Zheng SJ. Protective effect of liver fibrosis against acute liver injury. Shijie Huaren Xiaohua Zazhi 2016; 24(24): 3537-3542
- URL: https://www.wjgnet.com/1009-3079/full/v24/i24/3537.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i24.3537
肝纤维化是慢性肝损伤的特征性改变, 在慢性损伤的长期刺激下, 细胞外基质蛋白过度积聚, 最终导致肝硬化、肝衰竭及肝癌的发生. 肝纤维化目前在临床上被视为有害的病理反应. 然而, 近年来的研究显示, 肝纤维化是对损伤刺激的修复反应, 肝纤维化通过促进剩余的正常肝细胞再生及凋亡抵抗发挥肝脏保护效应. 随着研究者对肝纤维化诱导急性肝损伤耐受研究的深入, 将为临床上阐明慢加急性肝衰竭(acute-on-chronic liver failure, ACLF)的发病机制及寻找新的治疗方法提供理论依据.
肝纤维化指肝组织内细胞外基质蛋白(extracellular matrix, ECM)的过多积聚[1,2]. 其主要的病因包括病毒性肝炎、过量饮酒、非酒精性脂肪肝以及自身免疫性肝病等[3]. ECM成分包括胶原蛋白(Ⅰ, Ⅲ, Ⅳ)、纤连蛋白、粗纤维调节素、弹性蛋白、层黏连蛋白、透明质酸以及蛋白聚糖, 在纤维化肝脏中, 胶原蛋白的类型以Ⅰ型胶原居多[4]. 有研究[5]认为, 肝脏纤维化进程中ECM的过度积聚包括合成增加以及降解减少. 在慢性肝损伤因素的长期刺激下, 肝星状细胞(hepatic stellate cell, HSC)被激活, 激活的HSC迁移并积聚在肝损伤部位, 分泌大量的ECM[6-8], 除此之外, HSC还能分泌基质金属蛋白酶(matrix metalloproteinase, MMPs), 而MMPs能够降解ECM, 另一方面, 基质金属蛋白酶抑制剂(tissue inhibitor metalloproteinase, TIMPs)通过和活化的MMPs形成稳定的复合物来抑制MMPs的活性[9,10], MMPs的减少主要是由于TIMPs的过表达造成的, 而TIMPs主要由枯否细胞释放[3].
病理情况下, 慢性肝损伤的刺激引起ECM的产生和消融之间的平衡被打破, 过多的ECM蛋白的积聚会重塑肝脏的结构, 形成纤维瘢痕, 纤维瘢痕重新分割再生的肝细胞形成假小叶, 也就是肝硬化的形成. 肝硬化不仅影响肝细胞的功能, 还会导致肝内血流阻力增加, 最终引起肝功能不全和门静脉高压. 肝脏结构上的重塑会导致一系列临床症状的出现, 如黄疸、腹水、食道/胃底静脉曲张以及肝性脑病, 还可能会并发肝细胞癌、肝衰竭[11], 因此临床医生通常把肝纤维化的发生当成一种病理现象. 然而, 对损伤部位的修复是器官组织的一个基本的生物学反应, 新生的组织逐渐取代死亡的以及受损的组织, 这一过程对于机体维持生存非常重要[12], 同样, 肝纤维化也是肝组织对慢性损伤刺激的修复反应, 是肝组织对自身保护的有利因素[13]. 目前, 已经有临床数据证明, 当潜在的病因去除以后, 早中期肝纤维化是可以逆转的[14]. 更重要的是, 研究者发现了肝纤维化损伤耐受现象, 而肝纤维化发挥保护作用的机制也逐渐成为研究热点.
临床和基础实验均证实肝纤维化对肝损伤存在保护作用. 早在2004年, 就有研究发现基线转氨酶水平升高患者对他汀类药物肝毒性的敏感性并不比转氨酶正常者高[15], 慢性肝损伤的患者能够耐受对乙酰氨基酚的肝损伤, 而同等剂量的对乙酰氨基酚却能使正常人转氨酶升高[16], 以上两个临床研究均提示慢性肝损伤患者可能存在损伤耐受现象. 也有研究[17,18]发现, 急性肝衰竭(acute liver failure, ALF)患者中有激活的HSC, 并且其激活程度与肝脏硬度、肝细胞破坏程度呈正相关, 该研究提示肝纤维化是肝脏对损伤的修复反应. 除了临床试验的支持, 体内动物实验及体外细胞实验同样支持存在肝纤维化所致损伤耐受现象. 胆管结扎之后能够引起肝细胞破坏、HSC的激活以及肝纤维化, 是研究慢性肝损伤常见模型[19-22]. 局部胆管结扎小鼠模型显示, 和未结扎叶相比, 结扎的肝叶显示出对肿瘤坏死因子-α(tumour necrosis factor-α, TNF-α)和Fas诱导的肝细胞凋亡有更好的耐受, 并且能够防止小鼠大出血, 预防肝衰竭的发生[23]. 暴露于Ⅰ型胶原的原代鼠肝细胞, 以及硫代乙酰胺或CCl4诱导的纤维化小鼠模型对Fas诱导的细胞死亡耐受性更好[24]. CCl4诱导的纤维化小鼠模型能够抵抗D-GalN/LPS诱导的致死性损伤[25].
临床上, ALF无既往肝病史, 疾病进展迅猛, 病死率极高[26,27]; 相较而言, 发生于肝纤维化/肝硬化基础上的ACLF的肝损伤常常相对较轻, 疾病进展相对较缓慢, 因而用于治疗干预或者等待肝移植的窗口期较长[28-30]. 这一有趣的现象提示我们, 可能存在某种关键机制导致了肝纤维化/肝硬化患者对急性打击的耐受性增强.
2.2.1 肝细胞的再生及凋亡抵抗: 目前, 有关肝纤维化损伤耐受反应的机制研究很多, 而其核心在于促进剩余的正常肝细胞的再生及凋亡抵抗. 其中重要的影响成分包括ECM及活化的枯否细胞.
ECM作为肝纤维化发生过程中最主要的成分, 其对于细胞生长的作用存在争议, 主要集中在促进细胞生长或死亡两个方面. 目前多数倾向于促进细胞存活及再生. 一些研究认为, 肝细胞损伤修复过程中ECM作用复杂, 在多种类型的细胞中作为维持细胞生长的因素存在. 研究证实, 去除了ECM之后, 人内皮细胞很快进入了程序性细胞死亡[31], ECM可以通过维持组织结构及细胞黏附的稳定性阻止细胞死亡[32]. 体外和体内实验也证明, ECM通过整合素介导的机制促进细胞的存活[33,34], 整合素相关激酶降低后, 能引起原代鼠肝细胞凋亡增加[35]. ECM能够影响肝细胞对损伤刺激的敏感性和分化程度[36]. 胶原蛋白对肝细胞促进黏附及贴壁生长的作用已经被大家熟知, 尤其是肝细胞接种于"三明治"夹心的细胞培养板时这种作用更加明显[37,38]. 在缺血再灌注损伤时, 抑制MMPs, 也能间接体现出ECM对肝细胞损伤保护的作用[39]. ECM促进细胞存活的作用在肝癌细胞中同样被证实[40,41]. 而另外一些研究[42]却发现在上皮细胞顶端使用ECM能引起细胞不稳定甚至凋亡, 而抗α2整合素抗体能够清除ECM引起的上皮细胞的形态学变化和凋亡, 提示ECM的这种作用是通过α2整合素实现的.
肝脏中的枯否细胞参与维持肝脏的功能及组织的修复, 是机体防御系统的主要成分[43,44]. 近年来, 研究者更加关注枯否细胞在体内外对肝损伤的保护作用. 部分肝脏切除后诱导激活的枯否细胞能够降低内毒素导致的肝损伤[45], 枯否细胞的保护作用在对乙酰氨基酚诱导的肝损伤过程中也有呈现. 在胆管结扎的肝纤维化小鼠模型中, 耗竭枯否细胞后结扎叶对TNF-α诱导的肝细胞凋亡的敏感性增强, 而再生的肝细胞则明显减少, 从而导致结扎叶的肝脏保护作用消失[46]. 枯否细胞是ECM重塑过程中重要的调节因素[47]. 在肝纤维化进展过程中, 枯否细胞能加快纤维化的发生, 然而在纤维化恢复过程中, 枯否细胞能促进ECM的降解, 这一作用主要是通过MMP-13实现的[48]. 在硫代乙酰胺诱导的肝损伤及随后的肝纤维化模型中, 已经证实存在M1和M2两种极化状态的枯否细胞[49], M1为经典活化的枯否细胞表型, M2为选择活化的枯否细胞表型, 干扰素-γ和白介素-4分别促使枯否细胞向M1和M2两种方向活化[50,51], 但不同极化状态的枯否细胞在肝纤维化损伤耐受现象中所发挥的具体作用并不明确, 这可能是未来的一个研究方向.
2.2.2 分子信号通路: 在胆管结扎的小鼠肝脏中观察到肝细胞再生和存活率增加, 肝细胞凋亡减少, 这一保护性现象是通过蛋白激酶(protein kinase, AKT)的激活及细胞外信号调节激酶介导的信号系统实现的, 而AKT的失活能阻断这种损伤保护作用[23], 其中, 枯否细胞来源的酸性鞘磷脂酶是AKT信号通路激活的关键因素[46]. 也有研究[24]表明, Ⅰ型胶原蛋白对肝细胞凋亡的保护作用可能通过ERK1信号通路实现, 从缺失ERK1小鼠的肝脏中分离出的原代肝细胞, Ⅰ型胶原蛋白对肝细胞的这种保护作用变得不明显, 磷酸化的ERK1能够使从野生型肝纤维化小鼠肝脏中分离出的肝细胞耐受Fas诱导的细胞死亡, 而缺失ERK1的肝纤维化小鼠却没有这种保护作用.
目前, 随着对肝纤维化损伤耐受现象及机制的研究进展, 研究者逐渐认识到肝纤维化对损伤保护作用的重要性及普遍性. 但目前仍存在一些问题: (1)肝纤维化引起的病理后果与肝损伤保护作用的平衡问题: 适当的肝纤维化可诱导机体产生对进一步的肝损伤的抵抗作用, 而过度纤维化则导致门脉高压、肝细胞血供障碍, 加重肝损伤. 如何调节从而使肝纤维化反应适度是目前急需解决的问题; (2)临床上ACLF患者的肝病基础可以是肝纤维化或肝硬化, 这种纤维化程度不同的慢性肝病在急性打击时, 其肝纤维化诱导的损伤耐受之间是否存在差异, 以及与预后的相关性也需要研究; (3)肝纤维化诱导肝损伤耐受的机制尚未完全阐明, 需要进一步从免疫、分子生物学、宿主等方向进一步研究.
随着研究者对肝纤维化诱导的肝脏保护现象及机制的进一步认知, 将为临床上阐明慢性肝损伤、ACLF的发病机制及寻找新的治疗靶点提供思路和依据.
急性肝衰竭(acute liver failure, ALF)无既往肝病史, 疾病进展迅猛, 病死率极高, 而发生于肝纤维化/肝硬化基础上的慢加急性肝衰竭(acute-on-chronic liver failure, ACLF)的肝损伤相对较轻, 疾病进展相对缓慢, 这一有趣的现象提示大家, 可能存在某种关键机制导致了肝纤维化/肝硬化患者对急性打击的耐受性增强, 目前临床和基础实验均证实肝纤维化对肝损伤存在保护作用.
党双锁, 教授, 西安交通大学医学院第二附属医院感染科
(1)适当的肝纤维化可诱导机体产生对进一步的肝损伤的抵抗作用,如何调节从而使肝纤维化反应适度是目前急需解决的问题; (2)临床上ACLF患者的肝病基础可以是肝纤维化或肝硬化, 这种纤维化程度不同的慢性肝病在急性打击时, 其肝纤维化诱导的损伤耐受之间是否存在差异; (3)肝纤维化诱导肝损伤耐受的机制尚未完全阐明, 需要进一步研究.
在胆管结扎的小鼠肝脏中观察到肝细胞再生和存活率增加, 肝细胞凋亡减少, 这一保护性现象是通过蛋白激酶(protein kinase, AKT)的激活及细胞外信号调节激酶介导的信号系统实现的, 而AKT的失活能阻断这种损伤保护作用, 其中, 枯否细胞来源的酸性鞘磷脂酶是AKT信号通路激活的关键因素. 也有研究表明, Ⅰ型胶原蛋白对肝细胞凋亡的保护作用可能通过ERK1信号通路实现.
临床上通常把肝纤维化的发生当成一种病理现象. 然而, 肝纤维化是肝组织对慢性损伤刺激的修复反应, 是肝组织对自身保护的有利因素. 目前, 研究者发现了肝纤维化损伤耐受现象.
随着研究者对肝纤维化诱导的肝脏保护现象及机制的进一步认知, 将为临床上阐明慢性肝损伤、ACLF的发病机制及寻找新的治疗靶点提供思路和依据.
肝纤维化: 指肝组织内细胞外基质蛋白的过多积聚.
本文综述了肝纤维化的产生, 肝纤维化诱导肝损伤耐受及其机制等方面, 条理清楚, 论述简明, 提出新的研究热点和发展方向, 有一定的新意.
手稿来源: 邀请约稿
学科分类: 胃肠病学和肝病学
手稿来源地: 北京市
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