梗阻性黄疸肠黏膜屏障损伤病理生理机制的研究进展

摘要

肠黏膜屏障具有机械屏障、化学屏障、生物屏障、免疫屏障等功能, 是防止肠道内的有害物质和病原体进入机体内环境, 维持内环境稳定的一道重要屏障. 梗阻性黄疸(obstructive jaundice, OJ)患者病死率和并发症发生率居高不下, 主要原因是败血症和肾功能衰竭. 临床与基础研究证实OJ存在肠黏膜屏障损伤, 其主要病理生理机制是肠黏膜通透性增加、肠黏膜上皮氧化应激损伤及肠源性内毒素血症, 具体机制尚未明确. 本文对OJ引起的肠黏膜屏障损伤的病理生理机制作一综述.

关键词: 梗阻性黄疸; 肠黏膜屏障; 内毒素血症; 紧密连接

核心提示: 梗阻性黄疸(obstructive jaundice, OJ)患者病死率和并发症发生率居高不下, 主要原因是肠黏膜屏障功能障碍以及随之而来的内毒素血症和全身炎症反应. 病理生理学研究证实了肠道屏障功能的破坏是多因素的, 包括机械、生物、化学、免疫屏障的破坏, 具体机制尚未明确, 而肠黏膜紧密连接(tight junction)蛋白的表达变化, 氧化应激和细胞增殖与凋亡的失调可能在OJ肠黏膜屏障损伤中起关键作用.

Pathogenesis of intestinal barrier dysfunction in obstructive jaundice

Na Wang, Hui-Qing Jiang

Na Wang, Hui-Qing Jiang, Department of Gastroenterology, the Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang 050000, Hebei Province, China

Correspondence to: Hui-Qing Jiang, Professor, Chief Physician, Department of Gastroenterology, the Second Hospital of Hebei Medical University, 215 Heping West Road, Xinhua District, Shijiazhuang 050000, Hebei Province, China. jianghq@aliyun.com

Received: June 20, 2013
Revised: July 10, 2013
Accepted: July 31, 2013
Published online: September 18, 2013

Abstract

Intestinal mucosal barrier is a key structure that normally prevents the passage of harmful molecules across the mucosa and into the circulation, including mechanical barrier, immunological barrier, biological barrier and chemical barrier. Obstructive jaundice (OJ) is frequently associated with infectious complications, mainly due to sepsis and renal dysfunction. The key events in the pathophysiology of these complications are endotoxemia of gut origin and increased intestinal permeability because of intestinal barrier dysfunction, as demonstrated in experimental and clinical studies. However, the mechanisms involved in this phenomenon remain obscure. Here we review recent progress in understanding the pathogenesis of intestinal barrier dysfunction in OJ.

Key Words: Obstructive jaundice; Intestinal mucosal barrier; Endotoxemia; Tight junction

0 引言

梗阻性黄疸(obstructive Jaundice, OJ)是临床常见病, 近十几年缓解黄疸的外科手术和内镜治疗手段虽然有了很大的提高, 但是患者病死率和并发症发生率仍然居高不下, 严重者出现肾衰竭和败血症[1,2], 其主要病理生理机制是由于OJ时肠黏膜屏障受损所致肠黏膜通透性增加, 而其伴随的肠黏膜上皮氧化应激损伤及肠源性内毒素血症是促成肠道屏障功能障碍发生的关键因素[3-5]. 目前国内外对OJ肠黏膜上皮屏障损伤发病机制的研究很多, 但尚无统一结论, 本文就其病理生理机制作一综述.

1 肠黏膜屏障结构和功能

胃肠黏膜不仅仅具有消化吸收的功能, 还是人体一道重要的自然屏障. 肠黏膜屏障由肠上皮层、黏液层、肠道淋巴系统、肠道菌群和肠-肝轴等组成, 具有机械屏障、化学屏障、生物屏障和免疫屏障等功能, 是防止肠道内的有害物质和病原体进入机体内环境, 维持内环境稳定的一道重要屏障[6].

2 梗阻性黄疸肠黏膜屏障损伤改变

2.1 机械屏障受损

肠黏膜机械屏障是由肠黏膜上皮间的紧密连接(tight junction, TJ)、上皮细胞及其分泌的黏液、表面的菌膜等组成, 共同构成了一道肠道内毒素和细菌不能自由逾越的物理屏障. 环绕黏膜上皮细胞顶侧的TJ是维持肠上皮屏障功能的重要结构基础, 是决定肠上皮细胞间通透性的决定因素. 肠上皮细胞TJ一旦发生变异、减少或缺失, 肠上皮细胞间隙通透性就会增加, 细菌、内毒素及大分子物质就可通过TJ进入体循环. 因此, TJ在肠黏膜屏障功能中的作用至关重要[7-9]. 现已发现有40多种肠黏膜上皮细胞TJ的相关蛋白, 跨膜蛋白Occludin和Claudin相互作用封闭细胞间隙, 在细胞内与胞浆蛋白ZOs(ZO-1/2/3)相连; ZO属于胞浆蛋白, 其对TJ的形成起装配平台样作用, 构成稳定连接. 动物实验已证实与假手术组相比, OJ大鼠小肠黏膜上皮存在功能障碍, 并同时伴随肠上皮TJ蛋白Occludin、ZO-1的表达减低及分布出现区域性缺失[10,11]. 我们首次研究了OJ患者存在小肠黏膜组织学损伤和肠源性内毒素血症; 透射电镜下肠黏膜微绒毛明显稀疏, 连接复合体结构破坏, 细胞TJ增宽, 肠黏膜上皮细胞TJ蛋白Occludin、ZO-1、Claudin-1表达减弱, Claudin-4增加, 这可能是OJ肠黏膜屏障损伤、通透性增加的重要因素[12]. Assimakopoulos等[13]的一项临床研究与我们的研究结果一致, 且证实TJ蛋白表达出现区域分布改变.

2.2 化学屏障受损

肠黏膜化学屏障包括消化系分泌的胃酸、溶菌酶、粘多糖和胰酶、胆盐等组成. 肠道胆盐的存在对正常肠黏膜屏障起重要作用, 他能够促进黏膜生长和修复, 对肠黏膜还有营养作用, 可以增加绒毛密度, 诱导肠壁组织细胞生长. 体外实验证实胆汁酸通过c-myc依赖途径促进肠上皮细胞增殖, 阻止核因子-κB(nuclear factor κB, NF-κB)活化诱导的凋亡[14,15]. OJ时由于胆汁缺乏, 导致肠黏膜组织形态学改变和肠肌电活动减弱, 经胆盐补充后其指标明显改善[16]. Raimondi等[17]用单层小肠上皮细胞培养体外实验研究证实不同浓度胆盐通过激活表皮生长因子受体(epidermal growth factor receptor, EGFR), 从而使肠黏膜上皮TJ蛋白表达增加. 另外胆盐可清除细菌的活性, 使细菌胞壁通透性增高, 最终致细胞损伤和细菌膜碎裂[18], 胆盐还可直接与肠腔内毒素和细菌黏附生成不吸收的去垢剂样复合物, 使内毒素裂解失活, 进而防止肠道内毒素和细菌移位[6].

2.3 生物屏障受损

肠道生物屏障由相当稳定比例的肠道内自身菌群与肠道黏膜结合, 与机体形成一个相互依赖又相互制约的微生态平衡系统[6]. OJ时由于胆汁酸缺乏导致肠道菌群失衡, 以肠杆菌为代表的革兰阴性菌过度生长[3-5]. 动物及临床实验证实致病的大肠杆菌黏附至OJ肠道上皮单层细胞, TJ出现断裂导致肠屏障损伤[19,20]. Geyik等[21]研究发现布拉酵母菌灌胃能明显改善OJ大鼠肠道菌群, 还可明显修复小肠黏膜损伤, 降低致病菌移位. Zhou等[10]报导OJ大鼠应用乳酸菌灌胃可通过蛋白激酶C(protein kinase C, PKC)信号转导途径缓解肠黏膜氧化应激损伤, 抑制细胞凋亡, 改善肠黏膜通透性. 周龙翔等[22]证实OJ患者围手术期服用益生菌后发现患者尿乳果糖/甘露醇(lactulose/mannitol, L/M)比值较对照组明显下降, 表明益生菌可以明显改善OJ肠黏膜通透性和肠道微生态环境.

2.4 免疫屏障受损

肠黏膜免疫屏障由肠黏膜分泌的IgA和肠相关淋巴组织等构成. 大多数肠道中IgA是以sIgA的形式存在的, 可起到抑制肠道细菌黏附、阻止细菌定植、抑制抗原吸收和中和毒素等作用. 肠道内90%的IgA是由胆汁携带而分泌到肠腔的, 缺乏胆汁就意味着肠道内缺少了绝大部分的IgA, 也就失去了IgA对肠黏膜的保护. 另研究表明胆汁中还包含特异或非特异的抗体, 抑制肠道内细菌与肠黏膜的黏附或抑制细菌被上皮细胞摄取而防止细菌转移[19], 所以胆汁对肠道的免疫功能也起着非常重要的作用. OJ时肠道的免疫功能下降, 防御能力减弱. 实验研究表明胆汁影响肠道淋巴组织的分布, 胆汁缺乏时导致CD4⁺和CD8⁺ T淋巴细胞数量的减少和趋化因子TECK/CCL25的表达降低, 胆汁内引流后可以明显改善淋巴细胞的归巢[23]. 另外Ogawa等[24]证实OJ大鼠可能依赖Toll样受体-2(Toll-like receptors, TLR-2)途径促进细胞凋亡, 从而导致Payer淋巴小结内的B淋巴细胞减少.

3 梗阻性黄疸肠黏膜屏障损伤机制

3.1 肠黏膜上皮通透性增加

肠黏膜通透性是指肠黏膜上皮容易被某些分子物质以简单扩散的方式通过的特性. 早在肠黏膜形态学出现明显变化之前, 肠黏膜通透性已经增高. 所以, 肠黏膜通透性的改变可早期反映肠黏膜屏障功能受损程度[25]. 实验和临床研究已经证实OJ时存在肠源性细菌和内毒素血症移位至肠系膜淋巴细胞、体循环和肝脏, 其最主要因素是肠黏膜通透性增加[3-5]. 肠黏膜上皮, 尤其封闭肠上皮细胞顶端间隙的TJ是决定肠黏膜通透性最重要的因素. 正常情况下肠腔内细菌及大分子毒素不能透过肠壁进入全身脏器和组织, 这有赖于肠道的屏障功能的完整. 临床研究中通过测定人尿L/M比值透过实验、门脉内毒素浓度、不同部位细菌培养证实肠道菌群移位, 以反映患者肠黏膜通透性的变化[26]. 我们的研究发现, OJ患者小肠黏膜通透性明显增加[12]. 实验研究发现在普通光镜下观察, OJ大鼠肠黏膜组织学损伤无明显形态学改变, 但电镜下可发现炎症水肿、肠上皮间隙扩大、线粒体损伤及细菌过度生长等, 还有肠黏膜皮下水肿、绒毛稀少和黏膜层与固有层分离等非特异性损伤表现, 而予蜂蜜干预后上述改变明显改善[27].

3.2 肠黏膜上皮氧化应激损伤

肠黏膜氧化应激反应(oxidative stress)可能是导致OJ肠黏膜屏障损伤和通透性增高的一个关键因素. OJ导致内毒素血症、细菌移位及大量炎性介质释放, 诱生型一氧化氮合酶表达增强, 使肠腔组织或细胞内产生大量的活性氧(reactive oxygen species, ROS)蓄积而引起的氧化损伤. 大量的动物和临床试验均已证实OJ可诱发肠黏膜氧化应激损伤, 表现为肠道中脂质过氧化、蛋白氧化增强, 蛋白质、非蛋白巯基化合物或二硫化物比例失调[5,28-32]. OJ大鼠给予抗氧化剂灌胃后, 可以恢复肠黏膜的氧化应激状态, 阻止肠黏膜细胞的凋亡、促进细胞增殖、恢复TJ蛋白表达, 从而增强肠黏膜屏障功能[26]. 肠上皮细胞增值下降、凋亡增加是OJ肠黏膜上皮屏障功能损伤的另一重要因素. 氧化应激可促进肠黏膜细胞凋亡, 抑制细胞增殖, 破坏细胞膜及膜蛋白结构, 导致OJ肠黏膜萎缩. 应用肝外胆汁淤积大鼠模型给予抗氧化剂谷氨酰胺和姜黄素灌胃可以明显缓解大鼠肠黏膜的氧化应激状态, 并改善肠黏膜屏障功能及肠道菌群失衡[33]. Assimakopoulos等[34]研究证实OJ大鼠肠黏膜萎缩, 氧化应激损伤明显, 同时伴随隐窝上皮细胞有丝分裂明显降低, 同时细胞凋亡增加, 应用不同的抗氧化剂(乙酰半胱氨酸, 别嘌呤醇, 维生素E)干预, 可通过影响巯基氧化还原状态提高肠黏膜的抗氧化作用, 改善肠黏膜屏障功能, 防止发生内毒素血症. 最近报道给予OJ大鼠抗氧化剂硫辛酸, 对其肠道起到有效的抗氧化效应, 从而提高肠黏膜屏障功能[35]. 我们研究结果显示, OJ患者肠黏膜组织中丙二醛(malondialdehyde, MDA)水平升高, 超氧化物歧化酶(superoxide dismutase, SOD)水平下降, 肠黏膜上皮细胞凋亡增加, 说明在OJ时肠道存在脂质过氧化损伤及抗氧化能力下降, 随着胆道梗阻的不断进展肠黏膜上皮细胞凋亡逐渐增加, 由此引起的组织结构破坏, 削弱了肠道屏障功能[31]. 最近一项研究也证实了OJ患者小肠黏膜上皮细胞增殖指标Ki67较对照组明显降低, 凋亡指数明显增高[36].

3.3 肠源性内毒素血症及炎症介质反应

淤胆导致肝脏枯否细胞清除能力下降[37-39], 使细菌及其内毒素从门脉"逃逸"至体循环, 进而引起炎性细胞因子 "瀑布样"效应, 即"肠源性内毒素血症"[3-5]. 门脉和体循环过多的细胞因子和其他促炎介质的释放, 如肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)、白介素-1(interleukin, IL-1)、IL-6、干扰素-γ(interferon-γ, IFN-γ), NO和氧自由基对TJ的结构和功能产生破坏, 从而进一步影响OJ肠黏膜屏障功能[3,40-44]. 有研究指出TNF-α和IFN-γ等细胞因子可通过上调人TJ蛋白Claudin-4启动子活性、下调Claudin-1, -5和-7表达, 破坏肠黏膜屏障[45]. 内毒素的主要成分系脂多糖(lipopolysaccharides, LPS), LPS与血清中内毒素结合蛋白结合并与CD14共同形成三者的复合物, 与受体共同参与信号转导, 从而诱导TNF-α、IL-6等细胞因子表达, 并产生各种病理损害. TLR4是LPS跨膜信号转导最重要的受体, 是炎性反应链的启动点, 可以影响整个病理损伤过程[46,47]. Miyaso等[48]研究证实LPS可上调OJ小鼠肠黏膜组织及门脉血的TLR-4 mRNA和CD14 mRNA水平, 进一步加重肠黏膜屏障的损伤. 而且内毒素血症致内脏血流减少、引起肠道微循环障碍, 进一步导致肠黏膜上皮细胞能量缺失及缺血、缺氧状态, 细胞线粒体和溶酶体损伤, 甚至细胞自溶, 最终引起肠黏膜功能损害[49,50]. Rabaev等[51]报道OJ患者存在内毒素血症和肠道菌群失衡, 胆道减压并联合应用乳果糖干预7 d后患者内毒血症、肠道菌群失衡状态得到明显改善.

4 结论

对OJ肠黏膜屏障功能障碍的病理生理学的深入研究, 进一步证实了肠道屏障功能破坏是多因素的, 包括机械、生物、化学、免疫屏障的破坏. 肠黏膜TJ蛋白的变化、氧化应激和细胞增殖与凋亡失调在OJ肠黏膜屏障损伤中起关键作用. 因此, 在临床工作中患者解除黄疸前后应同时保护肠黏膜屏障功能, 因为肠黏膜屏障功能障碍以及随之而来的内毒素血症和全身炎症反应可能导致严重的甚至危及生命的并发症.

评论

背景资料

梗阻性黄疸(obstructive Jaundice, OJ)是临床常见病, 动物和临床实验均证实存在不同程度的肠黏膜屏障损伤, 其导致肠道细菌及内毒素移位, 继而发生内源性感染及多器官损伤, 亦是OJ的术后并发症发生率和死亡率居高不下的重要原因, 具体机制尚未明确.

同行评议者

庹必光, 教授, 遵义医学院附属医院消化科

研发前沿

OJ肠黏膜屏障损伤主要病理生理机制是肠黏膜通透性增加, 而其伴随的肠黏膜上皮氧化应激损伤及肠源性内毒素血症是促成肠道屏障功能障碍发生的关键因素.

相关报道

OJ肠黏膜屏障功能障碍病理生理学研究证实了肠道屏障功能的破坏是多因素的, 包括机械、生物、化学、免疫屏障的破坏, 其主要病理生理机制是肠黏膜通透性增加、肠黏膜上皮氧化应激损伤及肠源性内毒素血症.

应用要点

本文总结了OJ时肠黏膜屏障损伤的改变以及损伤的发生机制, 为今后肠黏膜屏障功能障碍治疗提供了新的依据. 临床工作中应该重视患者解除黄疸前后应同时保护肠黏膜屏障功能, 因为肠黏膜屏障功能障碍以及随之而来的内毒素血症和全身炎症反应可能导致严重的甚至危及生命的并发症.

同行评价

本文对于提高对OJ肠黏膜屏障损伤的认识、在临床工作中解除黄疸前后肠黏膜屏障功能的保护等有重要指导意义.

备注

编辑: 田滢 电编: 闫晋利

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