修回日期: 2010-09-12
接受日期: 2010-09-13
在线出版日期: 2010-10-28
肝脏具有惊人的再生能力. 然而, 部分肝门胆管癌患者术前所出现的梗阻性黄疸将会影响到术后的肝再生, 甚至引起肝衰竭. 从某种意义而言, 梗阻性黄疸患者肝再生的受损程度将决定着是否可以进行外科手术治疗. 目前, 研究者对梗阻性黄疸肝再生受损机制已经进行了大量的研究. 研究结果表明, 肝再生受损机制主要包括: (1)门静脉血流量减少; (2)肝细胞凋亡率增加; (3)肝再生相关因子表达的变化. 因此, 调节上述因素将有可能改善梗阻性黄疸患者术后的肝再生.
引文著录: 曹阳, 戴朝六, 徐锋. 梗阻性黄疸肝再生受损机制的研究进展. 世界华人消化杂志 2010; 18(30): 3210-3214
Revised: September 12, 2010
Accepted: September 13, 2010
Published online: October 28, 2010
The regenerative capacity of the liver is extraordinary. However, it has been observed preoperatively in some patients, such as those with hilar cholangiocarcinoma, that obstructive jaundice may affect hepatocyte proliferation and even cause hepatic failure after hepatectomy. The extent of impaired hepatic regeneration caused by biliary obstruction may determine whether surgical treatment should be conducted. Nowadays, the mechanisms of impaired hepatic regeneration in patients with obstructive jaundice have been studied extensively. The possible mechanisms include restricted portal venous flow, increased hepatocyte apoptosis, and altered expression of liver regeneration-associated factors. Thus, regulation of these factors might have beneficial effects on liver regeneration after hepatectomy in patients with obstructive jaundice.
- Citation: Cao Y, Dai CL, Xu F. Advances in understanding the mechanisms of impaired hepatic regeneration in patients with obstructive jaundice. Shijie Huaren Xiaohua Zazhi 2010; 18(30): 3210-3214
- URL: https://www.wjgnet.com/1009-3079/full/v18/i30/3210.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v18.i30.3210
近些年来, 肝大部分切除术已经广泛应用于进展期肝细胞癌和胆管细胞癌的治疗过程中. 然而, 梗阻性黄疸患者肝大部分切除术后往往出现肝衰竭等并发症, 这表明梗阻性黄疸有可能影响肝再生并导致肝大部分切除术后的肝衰竭[1,2]. Yokoyama等[3]的研究表明肝外胆汁淤积抑制肝部分切除后的肝再生. 目前, 国内外研究者已经对梗阻性黄疸术后肝再生相关因子表达、门静脉血流量及肝细胞凋亡等方面展开了一系列研究, 但梗阻性黄疸肝再生受损的具体作用机制尚不清楚. 因此, 本文对最近几年梗阻性黄疸肝再生受损机制的研究进展综述如下.
梗阻性黄疸时肝脏有效供血不足与肝脏血流动力学改变有关. 胆管发生梗阻时肝内胆管扩张压迫门静脉分支, 使门静脉血流减少, 同时门静脉下腔静脉侧支分流, 使门静脉血流进一步减少, 肝组织受压小叶内血流淤滞, 导致全肝血流减少, 肝组织血流障碍[4]. Kanda等[5]用实时超声流计仪检测胆总管结扎犬发现, 胆道梗阻后肝动脉血流迅速增加, 门静脉血流明显减少, 而肝总血流量只在胆道梗阻后的最初2 h内增加, 此后逐渐减少. 在门静脉血流减少的同时, 肝脏的微循环亦发生障碍. 在内毒素产生的早期, 肝脏的循环灌注量显著减少, 这可能与血管收缩物质释放致使肝脏血流阻力增加有关. 后期, 胆道梗阻加重了肝脏微血管对内毒素的炎症反应[6].
梗阻性黄疸时肝内胆汁酸盐蓄积, 诱发肝细胞和胆管细胞凋亡, 过多的细胞凋亡又造成抗凋亡异常, 这种凋亡与抗凋亡的失衡是梗阻性黄疸肝再生受抑制的又一因素. 肝内毒性胆盐通过Fas依赖机制诱导肝细胞的凋亡. 另外, 肝内自然杀伤细胞中的Toll样受体2(Toll-like receptor 2, TLR2)和Fas配体表达增加也与肝细胞凋亡相关[7]. 有研究表明, 胆盐中的甘氨鹅脱氧胆酸钠(glycochenodeoxycholic acid, GCDC)通过蛋白激酶C介导肝细胞凋亡, 随着GCDC浓度增高, 细胞凋亡率明显增加[8,9]. 上述结果表明, 梗阻性黄疸可以启动肝细胞的凋亡程序. 正常肝细胞增殖过程中肝细胞通过核因子κB(nuclear factor kappa-B, NF-κB)、Bcl-2家族、肿瘤坏死因子-α(tumor necrosis factor-alpha, TNF-α)、白介素-6(interleukin-6, IL-6)的抗凋亡效应能有效减少细胞凋亡. 胆管梗阻大鼠行肝部分切除术后胆管内和正常肝细胞周围均可观察到凋亡细胞, 而这在正常大鼠肝脏很少发生. 此外, 肝部分切除后出现的DNA片段寡核苷酸酶和caspase3活性的增加在胆管梗阻大鼠也较正常大鼠明显[10]. Kurosawa等[11]用胆总管结扎大鼠作为梗阻性黄疸模型, 研究了Bcl-2在胆汁酸盐诱导的肝细胞凋亡中的作用, 结果在此模型的肝细胞上观察到了正常情况下的肝细胞不表达的Bcl-2受体. 提示这可能是抵抗毒性胆汁酸盐诱导的凋亡机制. 王剑明等[12]研究表明, Bcl-2和Bax蛋白均参与了梗阻性黄疸肝细胞凋亡的调节.
肝再生过程中一些生长因子可以促进或抑制肝细胞增殖, 在肝再生调节机制中起着重要的作用. 表皮生长因子(epidermal growth factor, EGF), 转化生长因子α(transforming growth factor-alpha, TGF-α), 肝细胞生长因子(hepatocyte growth factor, HGF)等生长因子在体内、体外实验中均可以促进肝细胞合成DNA, 而其中HGF被公认为最强烈的促肝细胞增殖因子. HGF主要由肝内非实质细胞中的肝星形细胞(hepatic stellate cell, HSC)产生, 并通过其受体c-met以旁分泌的方式作用于肝细胞[13-15]. TGF-β1是一种强烈的肝细胞增殖抑制因子, 正常肝脏中其mRNA表达量很低甚至不能被测出, 但在肝部分切除术后其表达量明显增加[16]. 从正常肝再生的肝脏中进行细胞分离培养发现: TGF-β1 mRNA主要由肝窦内皮细胞、库普弗细胞(kupffer cell, KC)、HSC表达[17,18]. HSC是分布在肝窦Disse间隙内的非实质细胞, 正常条件下处于静止状态, 表达为结蛋白(desmin), 一旦被活化后转化为肌成纤维样细胞, 则表达为α-平滑肌肌动蛋白(alpha-smooth muscle actin, α-SMA). 而且, 活化的HSC会合成大量的TGF-β1, 而新合成的TGF-β1会进一步促进活化的HSC产生更多的TGF-β1, 形成逐级放大效应, 从而导致TGF-β1大量生成和激活[19]. 虽然HGF主要由处于静止状态下的HSC合成, 但HSC一旦被活化后将失去合成HGF的能力[20]. 梗阻性黄疸影响了一些肝再生相关因子的表达, 从而抑制肝再生, 这在许多研究中已被证实. 梗阻性黄疸早期, 肝部分切除后IL-6表达水平与正常对照组相比明显减弱[21]. Bissig等[22]发现, 梗阻性黄疸也抑制了肝内血管内皮生长因子(vascular endothelial growth factor, VEGF)的表达, 肝部分切除后其表达水平也未见明显增高. Zhao等[23]认为, 梗阻性黄疸抑制CCAAT增强子结合蛋白α和β的表达和激活, 进而抑制细胞周期蛋白E的表达. Makino等认为, 梗阻性黄疸引起HSC的增殖活化, 使其通过自分泌及旁分泌作用方式使肝再生抑制因子如TGF-β1大量表达, 而同时也引起促肝再生因子如HGF及VEGF表达量明显降低, 从而抑制了肝部分切除术后或肝门静脉分支结扎术后的肝再生[24,25]. 促肝再生因子表达的减弱和肝再生抑制因子表达的增强是梗阻性黄疸肝再生受抑制的直接表现. Deneme等[26]实验表明: 梗阻性黄疸大鼠行肝部分切除术同时给予抗TGF-β1单克隆抗体可降低血清中TGF-β1的含量, 并从形态上和功能上促进了肝部分切除术后的肝再生. Makino等[24]研究表明, 随着黄疸时间延长TGF-β1 mRNA的表达量逐渐增加, 而且TGF-β1 mRNA主要由HSC表达. 同时, desmin染色阳性的HSC和α-SMA染色阳性的HSC在门静脉区域表达也随着黄疸时间的延续而逐渐增加. Makino等认为, 梗阻性黄疸大鼠肝部分切除术后或门静脉分支结扎术后HSC大量增殖活化, 而且活化的HSC在梗阻性黄疸肝再生中TGF-β1 mRNA的表达量升高和HGF mRNA表达量降低调节机制中起着重要的作用[24,25]. 因此, 通过调节HSC的增殖活化或改变肝再生调节因子的表达将会改善梗阻性黄疸肝部分切除术后或门静脉分支结扎术后的肝再生.
梗阻性黄疸时胆汁的肝肠循环量减少, 胆汁对肠内细菌的抑制作用减弱, 同时分泌型IgA减少, 使得肠内细菌过度繁殖, 内毒素释放增多. 在肠道内毒素产生增加的同时, 肠道黏膜上皮细胞间的紧密连接构成的机械屏障亦受到损害. 这些病变进一步造成肠道生物屏障、机械屏障受损, 肠道化学、免疫屏障功能下降, 导致内毒素吸收增加[27,28]. 此外, 肝脏网状内皮系统和全身免疫功能亦受损, 不能有效清除血中的细菌和内毒素, 从而使内毒素血症(endotoxemia, ETM)持续存在[29,30]. 因此, 梗阻性黄疸发生的同时往往并发ETM. ETM发生后脂多糖(lipopolysaccharide, LPS)通过TLR4/LPS信号途径激活HSC. LPS在TLR4和髓样分化因子88(myeloid differentiation factor 88, Myd88)调节下进行信号传导, 使活化的HSC内的NF-κB激活进而增加趋化因子和黏附分子的表达量[31,32]. HSC激活过程中NF-κB表达水平上调, 介导大量细胞因子的转录如TGF-β1、TNF-α和IL-6等. 用阻断剂阻断NF-κB信号途径可以阻断上述细胞因子的表达, 从而减轻肝脏的损伤. 上述结果提示NF-κB激活后各种细胞因子表达分泌的增加是诱导肝脏损伤的关键因子[33]. HSC活化后细胞表面将会表达CD40受体, 一些表达CD40配体的免疫细胞可以激活HSC的CD40信号途径进而激活NF-κB[34]. KC条件培养基内的KC可以释放一些细胞因子, 刺激HSC活化. 而LPS可以进一步刺激KC合成该类细胞因子, 进而增强KC条件培养基对HSC活化的作用. 同时, 也发现抗TGF-β1单克隆抗体可以减弱但并不能完全消除LPS上述的促进作用. 这表明LPS可以促进KC合成TGF-β1和一些其他的细胞因子进而促进HSC活化[35]. 而IL-10可以抑制KC诱导的HSC增殖活化, 并呈剂量依赖性抑制[36]. 在IL-10对肝纤维化大鼠TGF-β1及相应受体表达影响的实验中发现: 外源性IL-10可以抑制肝组织中TGF-β1及相应受体的表达[37]. 此外, 外源性IL-10还可以抑制体外培养活化的HSC表达TGF-β1和碱性成纤维生长因子的mRNA及促进HSC的凋亡[38-41]. 上述研究结果表明: IL-10可以通过抑制NF-κB表达进而减少TGF-β1等细胞因子的表达. 目前研究表明: IL-10至少通过两条途径抑制NF-κB的活性: (1)通过抑制IκB激酶的活性, 阻断NF-κB与其抑制蛋白IκB的解离; (2)抑制NF-κB与DNA转录调控区的结合, 从而抑制相应炎症因子的转录[42].
Louis等[43]利用基因敲除技术证明内源性IL-10的抗炎作用, 并发现内源性IL-10的抗炎机制可能在于降低炎症介质TNF-α的表达, 但同时, 也发现IL-10具有抑制肝细胞增殖的作用. 林羡屏等[44]在IL-10对大鼠原代肝细胞增殖影响的研究中发现: 大鼠原代肝细胞表达IL-10/IL-10R mRNA, IL-10抑制大鼠原代肝细胞增殖. 然而, Dinant等[45]从组织学水平上对IL-10进行研究, 却发现IL-10可以促进缺血再灌注损伤后大鼠的肝再生. 从上述研究结果, 我们可以看出: IL-10抑制HSC活化、肝再生抑制因子TGF-β1的表达的同时也抑制了肝再生重要的启动因子TNF-α和IL-6的表达. 因此, 将有待于进一步综合评价IL-10对梗阻性黄疸肝再生的作用.
梗阻性黄疸肝再生受抑制影响因素繁多, 涉及许多细胞因子, 相互作用非常复杂, 其精确机制尚未完全认识. 梗阻性黄疸肝再生的受损使部分患者失去手术治疗机会. 明确梗阻性黄疸肝再生受损机制, 有助于寻找纠正这种损伤的对策, 对提高手术的安全性及降低术后严重并发症的发生有着重要意义, 这将成为今后研究的重点.
近些年来, 肝大部分切除术已经广泛应用于进展期肝细胞癌和胆管细胞癌的治疗过程中. 然而, 梗阻性黄疸患者肝大部分切除术后往往出现肝衰竭等并发症, 这表明梗阻性黄疸可以影响肝再生并导致肝大部分切除术后的肝衰竭. 明确梗阻性黄疸肝再生受损机制有助于改善梗阻性黄疸患者术后肝再生, 对提高手术的安全性及降低术后严重并发症的发生有着重要的意义.
于聪慧, 教授, 中国人民解放军北京军区总医院肝胆外科
改善梗阻性黄疸肝再生已日益成为肝胆外科研究领域中亟待解决的问题之一. 目前, 国内外研究者对梗阻性黄疸术后肝再生相关因子表达、门静脉血流量及肝细胞凋亡等方面展开了大量的研究.
Deneme等实验表明: 梗阻性黄疸引起的TGF-β1高表达抑制了肝部分切除术后的肝再生, 行肝部分切除术的同时给予抗TGF-β1单克隆抗体可以降低血清中TGF-β1的含量, 并从形态上和功能上促进了肝部分切除术后的肝再生.
本文从梗阻性黄疸术后肝再生相关因子表达、门静脉血流量及肝细胞凋亡等方面, 多角度地向读者介绍了梗阻性黄疸肝再生受损机制的研究进展, 为改善梗阻性黄疸患者术后肝再生提供了一定的理论基础和临床参考价值.
本文观点新颖, 数据可靠, 结论明确, 有较好的临床和科研的实用价值.
编辑:李薇 电编:何基才
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