修回日期: 2006-05-02
接受日期: 2006-05-11
在线出版日期: 2006-07-08
急性胰腺炎(acute pancreatitis, AP)是临床常见的急腹症之一, 并发症多, 死亡率较高. 除了导致胰腺病变外, 肺是最早受累器官之一, 从低氧血症到急性呼吸窘迫综合征(acute respiratory depress syndrome, ARDS)均可出现. 目前, 国内外学者对于AP合并急性肺损伤(acute lung injury, ALI)的发病机制进行了许多实验及临床研究, 现就AP合并肺损伤时炎性介质的作用作一综述.
引文著录: 张喜平, 李志军. 急性胰腺炎合并肺损伤时炎性介质的作用. 世界华人消化杂志 2006; 14(19): 1900-1905
Revised: May 2, 2006
Accepted: May 11, 2006
Published online: July 8, 2006
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2006; 14(19): 1900-1905
- URL: https://www.wjgnet.com/1009-3079/full/v14/i19/1900.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v14.i19.1900
急性胰腺炎(acute pancreatitis, AP)不仅引起胰腺本身病变, 并且常累及肝、肺、肾、肠、胃等器官[1-5], 导致多器官损害[6], 而肺脏是最常受累的胰外器官之一[7]. 据各种资料统计表明, 在发病2 w内死亡的患者, 有80%的患者同ARDS直接相关[8], 目前对于AP合并肺损伤(acute lung injury, ALI)的机制目前仍不确切, 但许多研究表明同多种促炎细胞因子介导的全身反应综合征有关[9], 如中性粒细胞的"滚动效应"、 肿瘤坏死因子(tumor necrosis factor-α, TNF-α)、血小板活化因子(platelet activating factor, PAF)、核因子-kB (nuclear factor-kappa B, NF-κB)、白细胞介素等炎性介质在肺组织的积聚、活化, 是AP并发ALI的一个重要病理机制[10-11], 现从炎性介质方面探讨AP合并ALI的发病机制.
具有多种生物学功能, 能影响组织微循环的血流灌注量. 近年来许多学者研究发现NO在AP的发病机制中有重要的作用. 绝大多数研究提示NO能明显减轻胰、肺的病变, 对AP并发ALI具有一定的治疗作用[12-17]. 可能与以下机制有关: 一方面NO能扩张血管、凋节局部血流、抑制血小板聚集及白细胞黏附、降低血液黏稠度、改善微循环障碍、从而凋节胰肺血流[18-20]; 另一方面NO具有清除氧自由基(oxygen free radical, OFR)的能力, 抑制炎性细胞因子生成, 减少胰酶释放, 减少TNF-α的生成[21], 减轻肺脏的损伤. 但同时也有学者提出相反的结论, 认为在AP合并ALI过程中, 由于NO大量产生会加重肺损伤[22], 已有实验证明给予NO抑制剂能减轻肺损伤的发生及发展[23], 其具体机制如下: (1)NO释放过多, 可引起毛细血管麻痹性扩张, 血液淤滞, 造成局部充血, 使肺组织缺血[24]; (2)高水平的NO可致大量的自由基和过氧化亚硝酸盐激活, 进而损伤线粒体电子传递系, 引发蛋白质降解, 脂质过氧化, 导致ALI[14]; (3)NO的大量产生还可增强核因子-kB(nuclear factor-kappa B, NF-κB)活性, 从而增加前炎症细胞因子的产生, 促进内皮细胞和平滑肌细胞黏附因子的表达, 扩大炎症反应[25-26]; (4)在病理状态下, 高浓度NO可抑制三羧酸循环和DNA复制中的关键酶, 造成能量代谢障碍和DNA损伤, 从而加重肺损伤的进展. 从目前的研究结果来看, NO尤如一把双刃剑, 少量时可以减轻AP时各脏器的损伤程度, 大量又可以加重胰腺及肺损伤[27-28], NO在AP合并肺损伤中的作用机制仍有待于进一步研究.
主要分为由活化T细胞产生的TNF-b和活化单核细胞产生的TNF-α, 后者是参与炎症反应的重要因子. TNF-α是一类重要的炎症、免疫凋节因子, 具有双重作用, 适量释放可提高白细胞对病原体清除能力, 促进组织的修复, 但过量释放对机体具有强烈的毒性作用. AP时TNF-α升高与AP的发展及ALI密切相关[29]. 研究表明AP早期肺组织有TNF-α mRNA的高度表达[30-31], 导致TNF-α的过量产生, 引起和加重ALI, 是ALI的发病机制之一[32-34]. 主要有以下几方面: (1)损伤肺内皮细胞屏障功能, 使细胞间隙增大, 从而引起毛细血管通透性显著增加, 导致肺微循环障碍; (2)诱导中性粒细胞在肺毛细血管中黏附、积聚、滞留; (3)可促进中性粒细胞和溶酶体酶释放, 产生氧自由基, 导致肺组织和血管内皮损伤; (4)促进细胞间黏连分子(intercellular adhesion molecule-1, ICAM-1)表达[35]; (5)TNF-α及微血栓可刺激内皮细胞产生内皮素(ET), 引起肺动脉高压[36]; (6)血循环中增多的内毒素、TNF-α以及肺脏局部合成的TNF-α,能够延缓肺内浸润的中性粒细胞凋亡[37].(7)在TNF-α合成释放后能引起其他细胞因子和炎性介质的瀑布式释放, 从而导致胰腺及胰外多脏器的损伤[38]. 早期检测TNF-α不仅可以反映AP的严重程度, 同时有助于预测肺损伤发生及其严重程度, 作出及时准确的治疗[39].
是迄今发现的最强的血小板聚集剂及最强的血管活性脂类递质, PAF主要由病灶局部或全身内皮细胞、巨噬细胞等分泌, 肿瘤坏死因子、血栓素、白三烯、氧自由基和缓激肽等也可刺激PAF产生. PAF具有重要的生物学效应, 在AP时全身炎症反应中被作为关键性炎症递质[40-41]. 近年来, PAF在AP合并ALI的发病中的作用已受到极大的关注[42]. 实验证明, PAF参与AP时ALI的发展[43]. 在AP合并ALI的发病过程中, 肺血管内皮细胞是合成和释放PAF的主要细胞, 胰源性炎性介质释放入血直接损伤肺血管内皮细胞,可能是导致PAF在胰腺炎性肺损伤中大量释放的启动因子. 其机制有以下几点: (1)PAF通过活化血小板, 促进血小板聚集, 使血液黏稠度增加, 血流速度减慢, 血栓形成, 引起毛细血管通透性增加, 而造成肺微循环障碍[44-46]; (2)对血管的直接损伤作用、致休克作用, 已证实外源性PAF可直接损害心肌收缩力, 使心输出量降低, 造成肺组织低灌注, 引起肺缺血; (3)激活中性粒细胞, 促进OFR释放; (4)抑制肺组织气管黏膜抗氧化还原系统, 加重肺损伤; (5)PAF引起PMN、弹性蛋白酶(neutrophil elastase, NE)和磷脂酶A2(phospholipase A2, PLA2)在肺脏积聚, 损伤肺组织[47].
是一种由内皮细胞表达的蛋白质, 正常情况下在大多数组织不表达或低表达, 当其表达升高时, 可与粒细胞表面的整合素相互作用, 是白细胞黏附于内皮细胞的关键所在, 由此促使白细胞通过血管内皮屏障迁移至炎性区域, 引起组织的炎症反应[48]. 有实验证明AP时大鼠肺组织ICAM-1基因过度表达, 且与ALI严重程度相关[49]. AP时生成大量的炎性因子和炎症递质刺激肺血管内皮表达ICAM-1等黏附分子, 促进中性粒细胞浸润, 造成肺组织损伤[50-51]. 一方面ICAM-1的高表达可以通过引起内皮细胞-白细胞相互间反应造成白细胞的浸润, 并不断加重肺损伤; 另一方面ICAM-1高表达可诱导PMN在肺脏聚集,导致肺损伤[52]; ICAM-1可显著减少胰腺和肺毛细血管血流量, 导致白细胞黏附, 增加毛细血管通透性, 降低毛细血管血流速度, 引起胰腺和肺脏微循环障碍[53], 造成肺组织缺血缺氧.
是一个多功能核转录因子, 主要参与机体免疫和炎症分子表达的凋控[54]. NF-κB 最先发现在B淋巴细胞中, NF-κB具有广泛的生物学活性, 正常生理情况下, NF-κB以无活性的形式存在于其他细胞的胞质中, 激活后促进多种细胞因子的基因转录, 在细胞因子介导的感染、炎症反应、氧化应激、细胞增生、细胞凋亡等过程中起重要作用, 在炎症反应复杂的细胞因子网络中, NF-κB的活化可能是一个中心环节[55-58]. 研究表明NF-κB通过凋控炎症因子表达参与了AP合并ALI的进展[59]. NF-κB引起ALI主要通过以下机制: (1)肺组织NF-κB活化并通过促进TNF-α、IL-6、IL-8、ICAM-1 mRNA的表达而参与ALI的发生[60]; (2)NF-κB通过凋节iNOS的表达进而显著影响NO生成的量, NO产生过多可导致肺损伤[61]. 临床上应用NF-κB活化抑制剂PDTC抑制NF-κB活化及iNOS mRNA过度表达, 从而改善肺脏损害[62-64]. 但是, 对于抑制NF-κB活化, 不同学者有不同的看法, 有的认为完全抑制NF-κB时, 会加重组织损伤; 当部分抑制时, 对组织有保护作用[65].
激活并聚集于肺组织, 是导致急性坏死型胰腺炎(ANP)早期合并肺损伤的重要因素[66-69]. ANP并发ALI时, 肺脏总有大量的PMN聚集[70], 组织中的髓过氧化酶活性(MPO)可以反映PMN在肺组织中滞留的数量[71]. 研究表明AP合并肺损伤时肺组织中MPO活性显著升高[72]. PMN引起肺损伤的机制有以下几个方面: (1)直接释放大量细胞毒性物质如弹性蛋白酶、胶原酶、蛋白水解酶、活性氧代谢产物、PAF及促炎细胞因子, 发挥细胞毒性作用, 使肺内皮细胞损伤、变性、血管通透性增加, 肺间质水肿, 氧交换障碍, 从而导致肺损伤[73-74]; (2)聚集的中性粒细胞机械堵塞毛细血管致肺组织微循环障碍; (3)中性粒细胞和内皮细胞还可以产生PAF、TXA2, 两者均是强有力的缩血管物质, 使肺血管收缩, 导致通气/血流比例失凋, 低氧血症, 加重肺损伤[75]. 目前, 也有研究者发现用干扰中性粒细胞迁移的方法, 能减轻AP大鼠的胰腺及肺损害的严重程度, 证明了PMN参与了肺损害, 或许可以为临床治疗提供思路[76].
内源性ET是由血管内皮细胞分泌释放的一种血管生物活性肽, 体外实验证明ET几乎能够引起所有动脉和静脉收缩[77]. 实验证明, ET参与了AP合并ALI的发生[78], 其作用机制为: (1)ET通过内皮素受体, 增加毛细血管通透性, 增加血浆渗出, 血流速度缓慢, 导致肺微循环障碍[79]; (2)ET可引起肺血管及支气管强烈收缩, 并具有类内毒素作用, 损伤肺脏; (3)ET可以引起冠脉收缩, 影响心肌血供, 减少心输出量, 引起肺脏缺血; (4)ET血症能通过诱导机体内TNF-α等炎症因子的过度生成,导致肺脏损害[80].
大量实验研究表明, 在AP早期胰腺细胞受损后, 会释放大量的OFR[82]. OFR与AP的严重程度相关[81], 也是胰腺与其他器官损害的重要凋节因子[83-84]. OFR可以促进内源性ICAM-1的表达, 损伤血管内皮细胞, 使毛细血管通透性增加, 导致肺脏微循环障碍; 同时OFR也可以破坏多不饱和脂肪酸、蛋白质、黏多糖等重要的生物分子, 并且过多的OFR还可引发再灌注损伤.
IL-6主要由单核细胞在IL-1, TNF等诱导下产生, 也可由激活的巨噬细胞、内皮细胞、成纤维细胞等产生. IL-6的水平可以反映AP的严重度[85], 他有强烈致炎活性, 可直接作用于血管内皮细胞, 使其通透性增加, 导致大量炎性渗出. 亦可与TNF-α等协同, 构成炎性介质网络, 促使炎症的扩展, 并使中性粒细胞的弹力酶及产生的氧自由基损伤内皮细胞, 引起血管内皮肿胀、血流淤滞, 致肺脏血液循环障碍. AP时大量的IL-8产生, 通过趋化、激活中性粒细胞, 表达ICAM-1等黏附分子, 释放蛋白水解酶及产生活性氧代谢产物而导致胰腺及肺脏的损害[86]. IL-10主要来源于单核细胞[87], 能通过增加胰腺及肺脏毛细血管血流量, 改善肺脏微循环损伤[88-89], 抑制内毒素介导的促凝反应, 阻断活化的巨噬细胞释放OFR及NO[90], 因此IL-10具有保护肺脏的作用. 此外, 林栋栋 et al[91]研究发现, IL-8和IL-10为一对促炎和抗炎因子, 在AP的发展过程中, 两者之间的平衡失凋可以引起及加重肺损伤.
也有学者提出肺血管内皮细胞凋亡所引起的微循环障碍是引起肺损伤的重要原因之一[48]. 潘玉明 et al[95]发现P选择素通过介导PMN在肺脏积聚、沉积, 参与肺损伤的发生.
总之, AP病情凶险, 容易损伤胰腺及合并胰外器官损害, 导致多脏器功能衰竭, 肺脏是首先受累脏器之一. AP合并ALI发病机制比较复杂, 虽然许多临床及实验研究都从炎性介质出发寻找ALI的病因, 取得了不小的成就. 但目前仍存在一些问题, 而且对于肺损伤机制的探索能否为临床所用, 从而减轻肺损害, 降低死亡率, 还要进一步探讨.
急性胰腺炎(acute pan-creatitis, AP)是外科常见的急腹症之一, 发病迅速, 病情凶险. 他不仅能引起胰腺本身病变, 还引起胰外器官受累, 导致多器官损害, 肺脏是最常受累的胰外器官之一. 炎性介质在急性胰腺炎合并肺损伤时起着非常重要的作用.
本文系统介绍了急性胰腺炎合并肺损伤时多种重要的炎性介质, 覆盖面广, 可以为临床和实验研究提供思路.
本文探讨了急性胰腺炎时炎性介质在肺损伤中的作用, 具有较好的临床和实验意义.
电编:李琪 编辑:潘伯荣
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