修回日期: 2005-09-25
接受日期: 2005-09-30
在线出版日期: 2005-10-15
重症急性胰腺炎(severe acute pancreatitis, SAP)发病凶险, 病情发展迅猛, 由胰腺的局部炎症很快发展成具有潜在危险的全身炎性反应, 死亡率高, 死亡原因多为并发其他重要脏器功能衰竭. 其最大的特点就是疾病一旦开始, 病情常会不断加重, 远离胰腺的脏器损伤程度可以超过原发病灶, 甚至造成多器官功能衰竭而死. 在临床上, 其并发的脏器功能障碍障主要有休克、呼衰、肾衰等. SAP引起的肾损害不但可加重胰腺炎的病情, 也可发展成肾功能衰竭, 导致患者死亡. 研究发现, 大量炎性介质造成的损害、微循环变化及细胞凋亡等因素可能在其发病机制中起着重要作用.
引文著录: 张喜平, 王蕾. 重症急性胰腺炎并发肾损害的发病机制. 世界华人消化杂志 2005; 13(19): 2364-2370
Revised: September 25, 2005
Accepted: September 30, 2005
Published online: October 15, 2005
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13(19): 2364-2370
- URL: https://www.wjgnet.com/1009-3079/full/v13/i19/2364.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v13.i19.2364
急性胰腺炎(acute pancreatitis, AP)为外科常见的急腹症, 多数急性胰腺炎病程呈自限性, 约15-20%的患者可能恶化并出现多器官功能衰竭或局部并发症(包括坏死、假性囊肿和脓肿), 发展为重症急性胰腺炎(severe acute pancreatitis, SAP)[1], 其发病过程凶险, 死亡率较高[2-5], 但发病机制至今仍未完全清楚[6-10]. 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仍未见减少, 其引起早期死亡的主要原因为多器官衰竭. 有资料显示, SAP并发急性肾功能衰竭的患者死亡率高达45-50%[11], 所以研究其致病机制有很高的临床价值. 我们在综合国内外研究资料后, 对SAP并发肾损害的主要致病机制作一综述.
目前研究发现一些炎性介质在SAP合并多器官功能损伤时起重要作用[12,13]. 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[14-17]. 参与SAP时肾功能衰竭的炎症介质主要有细胞因子[18]、磷脂酶A2[19]、花生四烯酸代谢产物[20]、血小板活化因子等.
在AP尤其是SAP期间, 某些炎症细胞及胰腺组织释放炎症介质和细胞因子, 影响胰腺炎全程. 其中影响较大的细胞因子有: 肿瘤坏死因子-a(tumor necrosis factor-a, TNF-α)、白介素(interleukin, IL)、转移生长因子(transforming growth factor, TGF).
1.1.1 肿瘤坏死因子-a(TNF-α): Lipsett和Hirota et al[21,22]均分别证实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. 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AP导致全身并发症的重要原因[23-36], 中性粒细胞在AP炎症刺激下会生成和释放TNF-α[37-39]等炎性细胞因子, 炎性细胞因子特别是TNF-α, 是参与SAP病理机制的重要细胞因子之一. Christoph et al在给SAP大鼠注射TNF-α抗体后, 发现能明显改善大鼠SAP的严重程度并提高生存率, 说明TNF-α在SAP发生、发展中起重要作用[40].
TNF-α诱导胰腺、肾损伤的机制可能为: (1)TNF-α可直接损伤胰管细胞, 产生微血栓, 导致胰泡缺血、出血、坏死、炎症和水肿[41]; 它还可以直接作用于肾小球、肾小管的毛细血管, 使肾小管上皮细胞缺血坏死[42]. (2)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-1b、IL-8和IL-6等细胞因子的释放[43], 产生细胞因子网络效应, 促成全身炎症反应综合征(SIRS), 加重胰腺和肾脏损害. (3)TNF-α的持续存在, 可使内皮黏连分子表达增强, 而内皮黏连分子是聚集炎症细胞所必需的, 大量粒细胞浸入胰腺、肾组织内, 增加粒细胞吞噬、脱颗粒, 产生氧自由基和溶酶体、弹力蛋白酶等, 引起细胞代谢紊乱及肾功能衰竭[44].
1.1.2 白介素(IL): IL-1是一种由胰腺产生的前炎症细胞因子, 在疾病早期起重要作用, 在SAP动物模型中, 使用IL-1受体拮抗剂(IL-1r), 可使病死率下降30%[45], 而且使用IL-1受体拮抗剂亦可明显降低IL-6和TNF-α的浓度[46]. Fink et al[47]也曾在诱导胰腺炎模型前给予IL-1受体拮抗剂, 发现IL-1受体的阻断能显著降低胰淀粉酶的释放和胰组织的坏死, 且呈剂量依赖关系. IL-1b由前IL-1b经IL-1转换酶(ICE)作用产生, 它和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介质、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, 它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介质如IL-8和IL-6等炎性细胞因子的产生.
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. 血清中的IL-6水平可反映SAP的严重程度, 无并发症的AP与有并发症的SAP患者IL-6水平相比有显著性差异, IL-6水平大于140 U/L时, 可视为SAP的提示指标[48]. 有关资料显示: IL-1、IL-6可作用于内皮细胞使其血栓调节蛋白活性降低, 加重肾脏缺血和形成血栓[49], 还激活炎症细胞和一氧化氮与氧自由基释放直接造成肾组织损伤.
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, 它由单核/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. 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. 有研究显示SAP时, IL-6与IL-8往往同时升高, 且与SAP的严重程度呈正相关[50].
1.1.3 转移生长因子(TGF): 关于TGF的作用, Kimura et al[51]通过免疫电镜研究TGF-β1的表达, 发现诱导胰腺炎后12-24 h, 胰腺小叶间及小叶内即出现明显的多形核白细胞渗出及纤维连接蛋白和TGF-β1的沉着, 故认为这种在胰腺炎早期即出现的变化与胰腺组织修复过程中细胞外基质中纤维连接蛋白和Ⅲ型胶原的产生有关. Konturek et al[52]认为TGF-β是通过诱导无炎症的细胞凋亡来修复损伤的胰腺组织.
由于SAP时炎症介质的释放增加, PLA2作为重要的炎症介质会大量产生[53]. 有研究证实, PLA2的水平与SAP严重程度相一致, 并与预后有关[54]. PLA2是人体主要脂肪酶之一, 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. 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[55]. 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介质[56,57], 在SAP引起的肾损害中, PLA2升高, 可水解肾小管上皮细胞膜卵磷脂, 使之生成游离脂肪酸和溶血卵磷脂, 后者使肾小管上皮细胞膜溶解.
PLA2是花生四烯酸的限速酶, 在病理状态下, 此酶的增加会加速花生四烯酸的产生, 在环氧化酶、前列腺素合成酶和血栓素合成酶的作用下, 可生成大量的TXA2和PGI2. 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, 引发局部和/或全身出、凝血障碍, 细胞保护机制被摧毁[58,59]; 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[60]. 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[61,62]. SAP患者血浆中TXA2显著升高, 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比值升高, 二者中单一因素的变化并不重要, 其比例失衡更加重要. TXA2/PGI2为一对血管张力调节物质, 其平衡失调会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[63], 其结果势必引起肾血管异常收缩, 使肾血流量及肾组织灌流量下降, 导致肾脏出现严重损害.
PAF是一种磷脂类炎症介质, 具有广泛的生物活性. 在SAP的外分泌和局部、全身的炎症反应中被作为关键性的炎性介质[64]. PAF的主要作用[65-68]是活化血小板, 促使血小板黏附聚集, 形成血栓; 上调黏附因子b2-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、细胞因子及炎性介质的产生等.
在SAP时, TNF-α升高可激发细胞因子网络效应, 致使PAF升高[69], 一方面促使粒细胞聚集, 加重炎症反应, 另一方面, 可使毛细血管通透性增加, 加重肾小管损伤. 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[70,71]. 临床研究发现, PAF拮抗剂Lexipafant对SAP患者的多器官功能衰竭有显著的治疗效果, 并能降低血清IL-8和IL-6等炎性介质[72].
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[73,74], 它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, 它能启动或增强基因的转录[75-78]. 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kb位点结合, 从而启动或增强这些基因的转录[79-82], 进而参与组织的损伤过程[83-85]. 在AP肾损伤的发生过程中, 肾脏NF-κB的活化同样起着重要作用. Satoh et al[86]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. AP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[73].
在细胞间黏附分子-1(ICAM-1)启动子上存在着NF-κB结合位点[87]. 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时肾脏NF-κB的活化促进了ICAM-1的表达, 使中性粒细胞黏附到内皮细胞上, 从而使中性粒细胞向炎症病灶聚集. 炎症细胞集聚入肾小球, 诱导直接毒性作用致细胞形态改变、细胞增生、毛细血管损伤及新月体形成, 同时TNF-α又激活细胞因子网络效应, 导致大量炎性介质的释放, 进一步损伤肾小球.
内毒素(endotoxin)主要见于革兰氏阴性细菌, 是细胞壁中脂多糖的组成成分. 临床研究表明, AP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[88]的研究证明它与胰腺炎严重程度有关. 国内有学者研究AP患者血浆内毒素水平与多器官损害的关系, 证实内毒素在多器官损害发展过程中起着重要的促成作用. 内毒素又是内皮素最强烈的刺激剂, 从而导致体内内皮素水平升高, 内皮素在血中水平的升高, 将强烈地收缩中、小动脉, 尤其是肾动、静脉, 可能与肾动静脉上存在着高亲和力的受体有关, 这将极大地降低肾血流量, 造成肾脏缺血、坏死、功能障碍, 甚至衰竭. 同时内皮素的升高反过来加重其它组织缺血, 导致细菌易位加强, 血内毒素水平升高, 并升高血中肾素-血管紧张素水平, 形成一种组织缺血-内皮素升高-组织缺血加重的恶性循环链[89].
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, 它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[90]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. 在各器官中白细胞和血小板被TNF-α激活后, 释放溶酶体、OFR和脂质炎性介质. 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.
罗军 et al[91]同步测定AP时肾组织的超氧化物歧化酶(SOD)和脂质过氧化产物丙二醛(MDA)的水平及血浆MDA的水平, 结果发现AP病程越长, 病变程度越重, 肾组织SOD水平越低, 而MDA水平则越高, 肾损害的程度也越重. 这证明氧自由基及其引发的脂质过氧化反应参与了AP时肾损害的全过程.
一氧化氮具有调节微循环、维持毛细血管完整性及抑制白细胞黏附等作用. 肾脏是SAP最早受累的器官, 而病理条件下, NO生成具有截然不同的生物学作用[92]. 近来, Molero et al[93]研究了NO与胰腺炎时胰基础分泌的关系, 结果显示, NO合成酶抑制剂(L-NAME)增加淀粉酶血症、脂酶血症和髓过氧化酶活性, 从而加重胰组织损害, 而此作用能被NO供体(L-精氨酸)逆转. 因此, NO不管从减少胰酶释放还是调节微循环灌注等方面都对AP的发展和病变的严重程度起改善作用.
NO在SAP肾损伤中的作用可能为: (1)NO与内毒素诱发产生的大量的细胞因子, 如TNF-α协同作用对肾脏的损害[94]; (2)随全身NO产生增加, 降低血管对缩血管物质反应, 致肾组织缺血性损害; (3)局部过量NO与氧自由基相互作用后对肾组织细胞的直接毒性作用[95].
微循环障碍是指发生在微循环水平上血管和血液的形态与功能紊乱. 血液及其成分的流变学异常是导致微循环障碍的重要因素. Plusczyk et al[96]研究认为, SAP时, 损伤的内皮细胞释放ET-1是促进胰腺微循环障碍的重要因子, 并最终导致胰腺细胞坏死. 程国祚 et al[97]研究SAP时肾微循环的动态变化及其与肾损害的关系证实: 肾损害在SAP早期即已发生, 肾脏缺血与缺血再灌注损伤引起的肾脏微循环障碍可能为SAP肾损害的重要原因. 在SAP合并SIRS时, 大量炎性介质和活化的白细胞释放的大量氧自由基及溶酶体酶对细胞膜造成损伤, 同时大量白细胞在血管内皮黏附, 肾毛细血管严重受损, PAF、TXA2促凝物质释放, 促使微循环血栓形成, 造成肾缺血-再灌注损伤(IRI).
SAP发生早期炎症介质使腹腔脏器毛细血管剧烈收缩, 神经内分泌系统发生一系列变化而造成内脏血流重新分布, 引起肾血流量急剧下降, 随着病程的进展, 由于循环血量的进一步减少以及炎症介质的过度激活, 肾组织血流量更为降低, 同时肾功能及肾组织学损害进一步恶化. 相关分析表明肾组织血流量与肾功能及肾组织损伤间呈密切负相关, 说明微循环障碍可能直接导致了SAP肾损害. Foitzik et al[16]的研究发现, 通过改善肾、肺微循环可明显减轻其病理损害, 降低动物死亡率, 从另一方面提示微循环障碍在肾损害过程中的重要性.
SAP时血沉方程Ｋ值、红细胞聚集指数、全血黏度明显升高, 提示血液黏滞度增加, 血液流动性降低. 血液流变学异常属于全身性改变, 它不但影响胰腺的微循环, 使胰腺血流灌注量降低, 使组织缺血、缺氧, 胰腺坏死程度加重, 还可引起胰外重要器官微循环障碍, 是引起胰腺及胰外器官损害的病理生理基础. 肾微循环血流量的减少, 肾血管阻力增加, 肾动脉血液流变学异常. 此时全血黏度增高与入球小动脉收缩直接导致肾小球前阻力增高, 从而使肾血流量减少, 且全血黏度增高、红细胞变形性下降等均可影响肾小管毛细血管床的微循环状况, 肾皮质、髓质微循环障碍引起肾衰竭[98].
急性胰腺炎患者所具有的活性胰蛋白酶可显著激活肾素-血管紧张素系统[99], 在临床上出现低血压及低血容量状态时代偿性出现暂时血压升高, 对肾内血管系统强烈作用造成肾血管阻力增高, 肾小球滤过率及有效肾血流量明显降低. 此外, SAP患者常伴有高脂血症, 且尤易沉积于肾小管及血管的周围, 也是促成肾血管阻力增高的一个不容忽视的因素. Nishiwaki et al[100]在实验中观察到AP早期就存在肾微循环血流量的减少, 肾血管阻力增加. 这一肾内血流动力学的失控亦导致肾脏受损.
长期以来, 由AP所致的低血容量低血压状态被视为引发肾脏损害的衡定因素. 近年来研究证实, 系由胰蛋白酶激活激肽释放酶-激肽系统的产物所致强烈的肾毒性作用. AP时大量活化的胰酶释放入血, 其中的PLA2使细胞膜的磷脂和卵磷脂分解, 异常的脂类代谢产物如游离脂肪酸、酰基肉碱、酰基辅酶A和溶血磷脂都是膜活性因子, 可破坏细胞膜. 游离脂肪酸还能使线粒体的氧化磷酸化脱偶联, 阻滞细胞Na+-K+ATP酶的活性, 被激活的补体系统产生C5b、C5b与C6、C7、C8、C9结合产生"膜攻击复合物", 破坏细胞膜, 最终使细胞发生不可逆的损害[101]. 血中胰蛋白酶浓度升高, 激活激肽释放酶-激肽系统, 释放出的血管活性多肽, 具有强烈的肾毒性作用, 同时胰蛋白溶解酶可在降解血浆蛋白的过程中释放多肽, 导致肾小球通透性增加, 并继发出现肾小管及间质损害. 高浓度的胰蛋白酶可导致机体出现高凝状态, 肾脏组织可因一过性凝血, 血管内出现纤维蛋白、血小板及细胞碎片组成的血栓, 造成肾脏功能破坏.
AP时活化的胰酶和大量的毒性物质不仅消化胰腺组织, 而且对胰腺周围和腹腔内脏器造成损伤, 大量炎性渗液和组织液进入第三间隙, 导致血容量不足, 甚至休克. 同时体内释放各种组织因子, 加重休克, 造成肾血管收缩, 肾血流量减少, 滤过率降低, 尿量减少. 一方面肾排水减少, 体内分解代谢增强, 内生水增多导致水中毒, 同时继发形成稀释性低钠血症. AP时体内分解代谢增强, 酸性代谢产物增多, 肾脏不能及时排出, 产生代谢性酸中毒. 酸中毒使钾离子从细胞内外移, 肾小球滤过率下降, 钾离子排出减少, 以及组织破坏, 钾离子生成增多, 造成致命性的高钾血症[102].
当血尿酸增高时, 可因尿中尿酸的排量增多而损害肾脏. 目前认为肾脏排泌尿酸可由三个方面调节, 即小球滤过、小管重吸收以及小管分泌. 肾小球滤过的尿酸几乎全部在近曲小管被吸收; 分泌的尿酸部分也被重吸收, 故尿中排出的尿酸仅为分泌尿酸重吸收后的剩余部分. 众多的有机酸, 诸如乳酸、酒精以及酮体等皆可抑制肾小管排泌尿酸, 但是有报告测得的乳酸含量在正常范围, 故认为与胰腺损伤后, 释放毒性物质, 加速组织分解, 导致尿酸前体增加有关. 此类高尿酸血症对肾功能恢复无明显不利[103].
胆源性急性胰腺炎患者相当多部分合并严重的阻塞性黄疸, 直接胆红素能阻塞肾小球囊腔及肾小管, 影响尿素氮的排泄, 而且黄疸增加肾脏对低血压、缺氧的敏感性, 使肾脏易于受损[104].
细胞凋亡是细胞遵循其自身的程序, 由基因调控的主动死亡过程. 最突出的特征是染色质的有控降解, 另一特征是有新的蛋白质合成[105]. Kaiser et al[106]用不同方法诱导急性胰腺炎模型进行观察发现胰腺炎症状的严重程度与胰腺细胞的凋亡发生率呈负相关.
目前有研究证实, 在SAP进展过程中, 胰腺炎相关蛋白(PAP)[107]基因、谷氨酸合成(GS)基因、胰腺内IL-1b基因[108]和TNF基因[109]的表达均有升高, 呈上调趋势, 且表现出组织特异性, 并与胰腺的损伤和炎症的严重程度有关.
急性胰腺炎并发肾小球肾炎患者肾活检证实在肾小球膜内细胞下有补体C及IgM的沉淀, 这种免疫复合物的存在可能是造成肾脏损害的原因.
解剖部位上胰腺与肾脏关系密. 因此, 胰腺及其周围炎症性病变时常可波及肾脏.
总之, SAP并发肾损害是由多因素造成的. 在SAP发展中, 这些因素相互交叉作用, 通过不同途径介导了SAP的发生发展, 造成对肾脏的损害.
电编:张敏 编辑:潘伯荣 审读:张海宁
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