修回日期: 2005-01-05
接受日期: 2005-01-10
在线出版日期: 2005-06-15
重症急性胰腺炎(severe acute pancreatitis, SAP)产生的炎性递质对多器官损伤的作用机制的研究是外科领域中的新热点.在临床上, 其并发的脏器功能障碍主要有休克、呼衰、肾衰、脑病, 肝病的并发率紧随其后.重症急性胰腺炎引起的肝损害不但可加重胰腺炎的病情, 也可发展成肝功能衰竭, 导致患者死亡.其发病机制的复杂性给临床治疗造成了一定的困难.在诸多发病因素中, 血浆血管活性物质的变化和炎性递质的参与以及氧自由基、内毒素等因素可能起了重要作用.
引文著录: 张喜平, 王蕾. 重症急性胰腺炎并发肝损害的机制研究进展. 世界华人消化杂志 2005; 13(11): 1335-1339
Revised: January 5, 2005
Accepted: January 10, 2005
Published online: June 15, 2005
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13(11): 1335-1339
- URL: https://www.wjgnet.com/1009-3079/full/v13/i11/1335.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v13.i11.1335
重症急性胰腺炎(severe acute pancreatitis, SAP)的发病机制至今仍未完全清楚[1-5].在临床上发病过程极为凶险, 死亡率很高[6-9], 尽管现代医学飞速发展, 对SAP的发病机制、病理过程和防治对策都进行了广泛的研究, 但迄今SAP的发病率与严重并发症的发生率均仍未见减少[10].早期死亡的主要原因为多器官衰竭, 肝脏是最常受累的器官之一[11].有研究证实, 肝损害的发生率及损害程度与胰腺炎程度呈正相关, 肝损害延长胰腺炎的病程[12].所以研究其致病机理有很高的临床价值.本文在综合国内外资料后对SAP并发肝损害的主要致病机理作一综述.
Trapnell[13]认为, 肝脏的微循环障碍是造成SAP并发肝损害的极其重要原因.SAP时肝脏受损与低血容量和血管活性物质的释放所致的肝内血循环不足有关, 肝血流量下降导致的线粒体ATP合成障碍, 同时细胞色素A和B的磷化率也下降.动态观察血管内皮细胞分泌的内皮素(ET)和一氧化氮(NO)及花生四烯酸的代谢产物血栓素A2(TXA2)和前列环素(PGI2)的变化, 结果提示ET/NO比值及TXA2/PGI2比值与SAP的肝损害之间存在一定联系.
ET和NO是近几年才发现的器官局部血流调节因子.血管内皮细胞通过释放内皮素收缩血管, 同时释放一氧化氮松弛血管内皮细胞.在正常情况下, ET和NO这两种效应相反的血管活性物质处于动态平衡状态, 对血管弹性进行调节, 以维持血管外周阻力和局部血管的舒缩功能.病理情况下, 内皮素升高和一氧化氮下降, ET与NO失衡, 导致血管舒缩功能调节失调, 血管收缩反应增强, 从而致血循环障碍.Rockey et al[14]通过实验发现, AP时内毒素、TNF刺激肝组织.主要是肝细胞、枯否细胞及肝窦内皮细胞上的NO合酶合成NO.IL-1则依赖内源性的INF-γ介导肝细胞合成NO[15].在对SAP患者和正常人的血浆分别进行抽样分析后发现SAP患者内皮素与一氧化氮皆有升高(P<0.05), 且SAP患者血浆中的ET升高显着高于NO的升高, ET/NO比值显着升高, 提示存在E/N失衡[16].并且总胆红素(TB)、谷丙转氨酶(ALT)、乳酸脱氢酶(LDH)的变化规律与ET/NO比值一致, 说明ET/NO比值增大与肝损害相关.
SAP时血浆花生四烯酸的代谢产物也发生了明显的变化, 主要表现为TXA2的升高, TXA2/PGI2比值的升高[17].TXA2在缺血性肝损害中起重要作用, TXA2为强烈的微血管收缩物质和血小板聚集促进剂, 可诱导血小板变形、释放、分泌, 引发局部及(或)全身出、凝血障碍, 细胞保护机制被摧毁[18-19]; 还可促使中性粒细胞活化, 释放氧自由基, 导致血管内皮损伤[20].PGI2具有极强的拮抗TXA2的作用.强烈抑制血小板聚集和激活, 抑制白细胞激活, 保护溶酶体, 防止溶酶体向组织内释放[21-22].PGI2可明显改善SAP时的肝损害.提示花生四烯酸代谢紊乱与SAP时的肝损害有一定的关系.所以, SAP患者血浆中TXA2的显着升高.PGI2虽然也升高但幅度小且升高后很快降至正常, 故使得TXA2/PGI2比值的升高.TXA2/PGI2为一对血管张力调节物质, 其平衡失调势必导致血管运动功能紊乱, 微血栓形成致血管闭塞等病理变化[23-24], 这也可能与肝损害密切相关.ET是迄今所发现的最强的缩血管物质, TXA2的缩血管作用仅次于ET.当二者的升高均显着大于与之相拮抗的主要的舒血管物质时, 必定导致血管收缩、血循环障碍, 进而使器官受损.这可能是SAP引起胰腺和包括肝脏在内的胰外器官受损的共同机制之一.
目前研究发现一些炎性递质在SAP合并多器官功能损伤时起重要作用[25-26].由于多种炎症递质的共同作用, 导致急性胰腺炎从局部病变迅速发展为SAP, 在胰腺组织大量坏死的同时, 并发全身多个脏器功能障碍[27-30].
近年来, 血小板活化因子(PAF)在SAP的外分泌和局部的、全身的炎症反应中被作为关键性的炎性递质[31].PAF的主要作用[32-35]是活化血小板, 促使血小板黏附聚集, 血栓形成; 上调黏附因子β2-整合素, 改变内皮细胞内骨架蛋白, 引起毛细血管通透性增加, 使血浆大量渗出, 血液黏滞度增加, 血流速度减慢; 参与缺血-再灌注损伤; 刺激其他血管活性物质、细胞因子及炎性递质的产生等.
PAF与血管活性物质平衡失调形成恶性循环, 产生一系列连锁反应和放大反应, 即瀑布效应(cascade), 加剧对组织器官的损伤, 导致全身炎症反应综合征(SIRS), 可进一步发展成多器官功能障碍综合征(MODS)和(或)多器官衰竭(MOF), 甚至死亡[36-37].PAF可引起肝细胞内Ca2+的急剧升高, 后者则与肝细胞的损害及肝细胞凋亡有关.所以, PAF的升高对SAP的发生、发展起重要作用[4].
不少研究发现过度激活的中性白细胞对自身组织的损伤是急性胰腺炎导致全身并发症的重要原因[38-51].中性粒细胞在急性胰腺炎炎症刺激下产生释放TNF-α[52-54]等炎性细胞因子.炎性细胞因子特别是TNF-α参与SAP发生、发展的病理机制, 是参与SAP病理机制的重要细胞因子之一.他是具有广泛生物活性的炎性细胞因子.Lipsett et al[55-56]证实AP发生时常伴有炎性细胞因子的升高, 而升高的幅度与病情的严重程度有密切关系.SAP早期的内毒素血症可诱导TNF-α的产生, 当TNF-α的产生超过组织中TNF受体数量时, 过量的TNF-α进入血液循环, 激活中性粒细胞, 使中性粒细胞聚集, 随之刺激IL-1β、IL-8和IL-6等细胞因子的释放[57].另外, TNF-α在严重损伤、休克时可导致广泛的自身免疫病理反应, 也证实了他是诱发SAP伴肝损害的重要启动因子.
IL-1β和TNF-α具有许多相同的生物活性: 如致热作用、促进细胞分解代谢、产生急性反应期的蛋白以及使内皮细胞分泌PGI2和血小板活化因子等, 这将导致炎症面积的扩大以及炎性递质、破坏性酶类、氧自由基分泌的增加.可协同TNF-α加重诱发器官损伤, 他和对粒细胞具有趋化和激活作用, 还可通过自分泌或旁分泌刺激其他炎性递质如IL-8和IL-6等炎性细胞因子的产生.IL-8是一种主要由中性粒细胞产生的强有力的中性粒细胞趋化因子和活化因子, 他由单核/巨噬细胞、内皮细胞产生, 具有激活诱导T、B细胞分化, 增强NK细胞杀伤靶细胞, 促进吞噬等功能.在中性粒细胞介导的组织损伤中起重要作用.IL-8介导粒细胞趋化和参与组织损伤最直接的证据是, 通过腺病毒传染的肝细胞过度表达细胞因子诱导的中性粒细胞趋化物(cytokine-induced neutrophil chemoattractant, CINC)与炎症细胞浸润程度及肝谷丙转氨酶(ALT), 谷草转氨酶(AST)增加密切相关[58].目前认为TNF-α、IL-1、IL-6诱发的炎症反应很大程度上是通过诱导以IL-8为代表的趋化因子的产生而实现的.
IL-6主要由单核巨噬细胞产生, 有广泛的促炎作用, 如促进B细胞活化、增生并最终分化为浆细胞, 增加免疫球蛋白合成, 并能促进T细胞分化增生, 促进急性期反应, 导致组织损伤.IL-6通过血液运送到肝脏, 使肝脏可分泌结合甘露糖的蛋白再同细菌和内毒素结合, 触发一系列补体反应, 造成对肝组织的损害.IL-6激活还使白细胞在肝的脉管系统扣押, 白细胞在肝的脉管系统内皮细胞表面黏附, 黏附在内皮细胞的白细胞释放弹力蛋白酶和氧自由基等毒性物质, 损伤血管的内皮细胞表面[59].
肝组织被大量内源性炎性递质入侵, 肝细胞膜上的钠钾泵被损坏, 导致肝细胞水肿, 而后诱导肝内中性粒细胞浸润, 肝内的炎症反应更进一步加重肝脏的损伤.轻型胰腺炎肝损害经保守治疗后多能自行恢复, 而重型胰腺炎肝损害恢复时间长, 预后差[60].SAP时肝脏对毒性物质、生物活性物质的清除和解毒作用明显下降, 肝细胞的功能受到抑制, 失去了阻止内毒素血症的屏障作用, 导致内毒素血症激发内源性炎性递质的过度释放.如此恶性循环, 大量的内源性炎症递质进入体循环产生持续性全身炎症反应, 引起全身组织的损坏和器官功能丧失, 所产生的一系列连锁反应和放大反应, 即瀑布效应, 导致SIRS和MODS[61-62].MODS是重症胰腺炎死亡的主要原因[63].
内毒素(endotoxin)主要见于革兰阴性细菌, 是细胞壁中脂多糖的组成成分.临床研究表明, 急性胰腺炎, 尤其是SAP状态下存在着内毒素血症, 并认为与SAP的发生、发展及并发多脏器衰竭密切相关.Windsor et al[64]的研究证明他与胰腺炎严重性有关.国内有学者研究急性胰腺炎患者血浆内毒素水平与多器官损害的关系, 表明内毒素在多器官损害发展过程中起着重要的促成作 用.Kazantsev et al[65]证明SAP状态下血液中内毒素主要来源于肠道.胰腺炎后肠道功能受损、肠道屏障功能下降、肠道内微生态环境和正常菌群失调, 引起肠道内细菌和内毒素向邻近组织和肠道外组织易位.内毒素随血液入侵肝脏, 他通过激活血清磷脂酶A2(PLA2)介导膜磷脂降解与诱发产生自由基介导肝细胞脂质过氧化, 除此之外, 还可通过干扰其能量代谢过程, 引起肝脏损伤.肝脏的致伤作用主要表现为ALT、AST、BIL值随着内毒素质量浓度的增高而升高, 增高程度与内毒素浓度相关, 在一定范围内呈正相关[66].
在内毒素引起的肝损中, 除内毒素的直接作用, 更重要的是通过激活枯否细胞释放细胞因子和炎性递质[67-68].肝脏是内毒素主要的清除器官, 而枯否细胞是肝脏主要起清除作用的细胞.枯否细胞一方面具有清除内毒素的功能, 另一方面, 又可被内毒素激活, 产生大量细胞因子[69].Eguchi et al[70]研究结果表明, 由于内毒素所激活的枯否细胞产生一系列化学递质, 如活性OFR、TNF-α、IL-1、IL-6等均可影响白细胞、血小板、窦内皮细胞和实质细胞功能, 进而影响肝脏微循环和肝功能.所以内毒素与肝损害之间存在着密切的关系[71-73].
氧自由基是一类具有高度化学反应活性的含氧基团, 主要包括超氧阴离子自由基(O2-)和羟自由基(OH-)等, 他们在引起脂质氧化的同时, 可增加黏膜的通透性, 使吞噬细胞活动进一步加强, 产生更多的氧自由基, 从而导致组织细胞损伤.Scott et al[74]研究表明, 病理状态下过量的氧自由基可造成组织和细胞的损伤.氧自由基参与AP时胰腺水肿的形成过程, 并可能参与胰腺的坏死过程.在各器官中介导白细胞和血小板被TNF-α激活后, 释放溶酶体、氧自由基(OFR)和脂质炎性递质.氧自由基可与蛋白质及酶发生反应, 使蛋白质变性, 酶失活.氧自由基过氧化反应产物LPO可使膜结合酶失活, 细胞膜损伤及血管通透性增高.氧自由基产生的速率大大超过了体内抗氧化能力或体内抗氧化能力大大耗竭无法及时清除氧自由基, 然后引起一系列氧化暴发反应, 使细胞和细胞器质膜发生脂质过氧化反应, 直接损伤细胞, 破坏肝细胞内溶酶体和线粒体, 甚至肝细胞溶解性坏死、肝细胞间淋巴细胞浸润[75].炎症递质的变化使氧自由基生成以及刺激自身分泌增多, 引起瀑布样连锁放大效应, 导致全身组织炎性反应增强, 继之毛细血管通透性增加, 局部缺血, 更加重了SAP的发展.
核因子κB(NF-κB)是一类主要参与炎性分子表达调控的转录因子[76-77].他是能与某些基因启动因子及增强子区的κB序列结合的蛋白质, 他能启动或增强基因的转录[78-81].在静息的细胞中, NF-κB以无活性的形式存在于细胞质之中, 当受到一定的刺激后, NF-κB活化, 并发生核易位, 同靶基因启动子或增强子上的κB位点结合, 从而启动或增强这些基因的转录[82-85], 进而参与组织的损伤过程[86-88].在急性胰腺炎肝损伤的发生过程中, 肝脏NF-κB的活化同样起着重要作用.Satoh et al发现SAP发生后, NF-κB活化显著增加, NF-κB活化有时间依赖性, 随着时间增加而活化增强.NF-κB的异常活化可促进前炎症因子(TNF-α、IL-1、IL-6)等炎性基因的转录, 而TNF-α、IL-1作为细胞外刺激信号又可激活NF-κB, 进一步放大炎症反应.急性胰腺炎时NF-κB参与调控机体炎症反应, 免疫、应激等有关的细胞因子、炎症递质的基因转录已得到公认[76].
在细胞间黏附分子-1(ICAM-1)启动子上存在着NF-κB结合位点, ICAM-1是细胞黏附分子免疫球蛋白超家族中的一员, 主要介导多形核粒细胞(PMN)同血管内皮细胞之间的黏附, 在PMN向组织聚集的过程中有着重要的作用, 而聚集于组织中的PMN则可导致细胞及组织的损伤.由于在ICAM-1启动子上存在着NF-κB结合位点, 所以SAP时肝脏NF-κB的活化促进了ICAM-1的表达, 进而导致PMN在肝组织中聚集, 从而引起肝损伤.这也再次证明了NF-κB可通过对肝组织ICAM-1的表达的调控作用引起组织损伤效应.
溶酶体广泛存在于体内细胞中, 其中以具有吞噬功能的巨噬细胞、中性粒细胞等含量最高.目前已知溶酶体中的酶多达50多种, 包括β-葡萄糖醛酸酶、组织蛋白酶、酸性磷酸酶、胶原蛋白酶等等, 他们能分解外源性有害物质和细胞内损伤或衰老的细胞器, 参于细胞生理、病理过程以及细胞分化和衰老的演变, 在细胞防御功能上起着重要作用.在各类酶中, 血清磷脂酶A2(PLA2)的水平与SAP严重程度相一致, 并与预后有关.PLA2广泛分布于各种细胞的质膜和细胞器膜.通常血浆中PLA2主要由胰腺分泌, 唾液腺、前列腺等亦可少量分泌.SAP时, 血清PLA2主要来自于胰腺腺泡和胰外的中性粒细胞、巨噬细胞和血小板.SAP发生后当多形核白细胞和单核巨噬细胞受到内毒素等刺激时, 可释放大量PLA2入血, 血液中的PLA2 可攻击并分解膜上的磷脂成分.一方面破坏细胞膜的稳定性, 引起溶酶体酶大量外漏; 另一方面产生具有生物活性的自由脂肪酸和溶解性卵磷脂, 对全身细胞、器官系统的功能和结构起破坏作用.可以认为: PLA2是介导胰腺炎后胰腺组织和胰腺外脏器损伤的重要递质.
肝细胞凋亡也可能是肝功能衰竭的原因之一.Takeyama et al研究SAP大鼠时发现肝细胞有凋亡发生, SAP并发的腹水具有诱导肝细胞凋亡的作用, 肝细胞凋亡和肝细胞损伤可以被IL-1转化酶抑制剂所缓解, 中和转化生长因子β(TGF-β)可以部分的阻止凋亡的发生, 研究人员认为在SAP时肝细胞凋亡的发生与腹水中的TGF-β有关.
总之, SAP并发肝损害是由多因素造成的.在SAP发展中, 这些因素成网络反应, 他们之间相互交叉的协同作用造成了对肝脏的损害.
编辑: 张海宁
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