修回日期: 2019-01-08
接受日期: 2019-01-29
在线出版日期: 2019-03-28
非甾体类抗炎药(non-steroidal anti-inflammatory drugs, NSAIDs)广泛应用于临床, 胃黏膜损伤是其主要的不良反应. 随着诊疗技术的进步, 近年发现NSAIDs对小肠黏膜的损伤远比以往估计的严重. 阐明NSAIDs对小肠黏膜的损伤机制对临床防治具有重要的意义, 本文结合国内外文献综述此方面的研究进展.
核心提要: 非甾体类抗炎药(non-steroidal anti-inflam-matory drugs, NSAIDs)致胃黏膜的损伤常见, 而随着诊疗技术的进步, 近年发现NSAIDs对小肠黏膜的损伤远比以往估计的严重, 阐明对小肠黏膜的损伤机制对临床防治其不良反应具有重要的意义, 本文对该方面的研究进展进行综述.
引文著录: 杨成, 崔梅花. NSAIDs相关性小肠黏膜损伤机制及防治研究进展. 世界华人消化杂志 2019; 27(6): 347-351
Revised: January 8, 2019
Accepted: January 29, 2019
Published online: March 28, 2019
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in clinical practice. It was well known in the past that the main side effect of NSAIDs was gastric mucosal injury. However, with the advancement of the diagnostic and therapeutic technology, NSAIDs have been found to cause much more severe damage to the small intestinal mucosa than we expected in recent years. Therefore, it is of great significance to elucidate the mechanism for NSAIDs to cause small intestinal mucosal injury to aid the clinical prevention and treatment of this condition. This paper aims to review the progress in the research of the mechanism, prevention, and treatment of NSAID-induced small intestinal mucosal injury.
- Citation: Yang C, Cui MH. NSAID-induced small intestinal mucosal injury: Mechanism, prevention and treatment. Shijie Huaren Xiaohua Zazhi 2019; 27(6): 347-351
- URL: https://www.wjgnet.com/1009-3079/full/v27/i6/347.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v27.i6.347
非甾体类抗炎药(non-steroidal anti-inflammatory drugs, NSAIDs)因有解热、镇痛、抗炎、抗风湿等作用广泛应用于临床, 其代表药之一的阿司匹林更因具有抗血小板作用广泛应用于心脑血管疾病的防治. 由此带来的副作用影响到患者健康, 其中最明显的不良反应发生在胃肠道, 如胃黏膜的糜烂、溃疡、出血甚至穿孔[1], 严重者可致死亡[2], 故全面系统的认识NSAIDs对胃肠系统的致病机制有非常重要的意义. 最初多数研究者将NSAIDs的副作用归因于其对环氧化酶(cyclooxygenase, COX)的抑制作用, 导致前列腺素的缺乏, 大量的研究揭示了前列腺素在胃黏膜防御系统中的重大意义[3]. 由于胶囊内镜和小肠镜的发展和临床应用, 发现NSAIDs对小肠黏膜的损伤作用远比以往估计的严重[4-6], 研究者们开始将目光转向NSAIDs对小肠黏膜的损伤作用. 本文将对NSAIDs相关性小肠黏膜损伤的作用机制及其临床防治的研究进展作一综述.
NSAIDs致胃黏膜损伤机制主要是由于胃酸和NSAIDs等致病因素和胃黏膜保护机制失衡而致, 其中前列腺素在胃黏膜保护机制中发挥重要的作用[7]. 目前对于NSAIDs致小肠黏膜损伤作用机制的认识不如对胃黏膜损伤机制详尽, 普遍认为是一个多因素、多步骤的过程, 提出了"三级打击"学说[8]. 首先, NSAIDs被肠上皮黏膜细胞吸收, 抑制了线粒体氧化磷酸化; 其次, 氧化磷酸化的抑制作用导致上皮间的紧密连接功能障碍致肠黏膜上皮通透性增加; 最后, 由于肠上皮黏膜屏障受损, 肠上皮细胞暴露于肠腔内容物, 肠道细菌也可通过肠上皮, 导致中性粒细胞的趋化及中性粒细胞的激活, 使黏膜产生非特异性的炎症和溃疡发生.
在小肠黏膜损伤的致病过程中, NSAIDs导致细胞内线粒体氧化磷酸化的抑制作用可能是重要的机制之一[9]. 有研究对大鼠小肠黏膜的微观结构进行观察, 在应用吲哚美辛1 h后, 大鼠的小肠黏膜细胞肿胀, 空泡形成, 肠上皮细胞线粒体膨胀和破坏, 证实了这是由于线粒体氧化磷酸化解偶联的存在而导致[10]. 然而, NSAIDs如何抑制或者解偶联线粒体氧化磷酸化的确切生物化学机制并不明确. 体外研究表明, NSAIDs解偶联作用在一定程度上是由于凋亡蛋白的上调和抗凋亡蛋白Bcl-2家族的下调导致的, 由此诱导凋亡蛋白Bax易位至线粒体, 进一步诱导和打开线粒体渗透性转变孔道(mitochondrial permeability transition pore, MPTP). MPTP是一种蛋白孔道, 是由线粒体膜在某些病理条件或者药理条件下诱导产生的, 该孔道的改变导致线粒体的跨膜电位降低, 从而导致线粒体氧化磷酸化的抑制. MPTP的开放也会导致细胞色素C释放进入胞浆, 启动细胞凋亡[11]. 线粒体氧化磷酸化解偶联的直接结果将使ATP产生减少, 线粒体中的钙离子漏入胞浆中, ATP的缺乏、ADP和AMP的积聚促进了肠上皮细胞的糖酵解反应, 使乳酸产生增多. 胞浆钙离子的增加活化了对钙离子敏感的蛋白酶、核酸内切酶、磷脂酶等, 从而增强了细胞脂质过氧化[12,13].
线粒体氧化磷酸化解偶联增加肠道上皮黏膜通透性的具体作用机制尚未完全阐明, 目前认为线粒体氧化磷酸化解偶联导致细胞内ATP缺乏, 线粒体中的钙离子外漏, 造成胞浆中的钙离子增加, 从而增加活性氧的生成. 而活性氧会干扰钠离子和钾离子的比例, 导致细胞电位失平衡, 最终使细胞紧密连接蛋白减少, 致肠道上皮黏膜的通透性增加. 闭锁小带蛋白1(zonula occludens protein 1, ZO-1)和Occludin是最重要的紧密连接蛋白, 它们的完整性是构成紧密连接的前提, 对肠黏膜屏障的完整性起关键作用. 当NSAIDs持续与肠黏膜接触, 使紧密连接蛋白表达减少, 可导致黏膜通透性增加及黏膜屏障的障碍, 从而导致小肠黏膜上皮的损伤[14,15]. 另外, 研究显示NSAIDs导致小肠黏膜损伤中, 细胞凋亡也参与了肠道黏膜通透性的改变[16].
一旦肠黏膜屏障受损, 肠腔内的侵袭因素将进一步导致炎症的发生. 肠腔内的环境与胃腔内的环境差异很大, 胃黏膜的侵袭因素主要是胃酸和胃蛋白酶, 而小肠黏膜的侵袭因素主要为胆汁酸、蛋白水解酶、胰液的分泌和肠道内的细菌等. 因此, 肠腔内有别于胃腔内的侵袭性因素在一定程度上可以解释肠黏膜损伤与胃黏膜损伤机制上的不同. 在一项动物实验中, 结扎胆道使NSAIDs导致小肠黏膜损伤的程度明显降低, 证实了NSAIDs导致小肠黏膜损伤中胆汁酸的重要作用, 虽然具体的生物学机制尚不清楚, 但研究者认为胆汁酸可能使小肠内的肠球菌数量增加[17]. NSAIDs与胆汁酸可形成共轭连接, 在细菌的作用下转变为游离的活性形式. 肠道中的细菌也是NSAIDs致小肠黏膜损伤中的重要因素[18], 研究表明对无菌小鼠给予NSAIDs或对服用NSAIDs的小鼠给予抗生素都明显减轻肠黏膜的损伤. 在黏膜损伤过程中, 中性粒细胞的集聚发挥了重要作用, 而微生物的侵袭和黏膜的受损是最重要的趋化因子, 中性粒细胞的激活会产生大量活性氧自由基, 对小肠黏膜有明显破坏作用.
前列腺素缺乏在NSAIDs诱导小肠黏膜损伤中的作用并不明确, 也存在一定争议. 部分研究认为前列腺素在动物模型上能为NSAIDs诱导小肠黏膜损伤提供保护作用, 前列腺素缺乏为NSAIDs诱导小肠黏膜损伤的主要因素[19]. 然而, 也有研究认为前列腺素在小肠黏膜损伤中是非重要因素. Somasundaram等[20]应用动物模型研究, 证实了经胃肠外应用阿司匹林能减少前列腺素的产生, 但并未影响肠上皮线粒体和细胞通透性, 也未产生炎症作用. 应用解偶联剂二硝基苯酚, 会增加肠黏膜通透性, 造成炎症反应, 但并不影响前列腺素的水平. 因此, 研究者认为内源性前列腺素的减少在短期内并不足以影响小肠黏膜通透性.
目前可用于防治小肠损伤的药物有限, 其中很大部分原因是由于对阿司匹林导致小肠黏膜损伤的作用机制认识不足. 目前临床上用于防治NSAIDs致小肠黏膜损伤的药物主要有新型NSAIDs类药、黏膜保护剂、抗生素和益生菌类药物[21]、可溶性食物纤维素[22,23]等.
以往认为传统的NSAIDs对胃肠道的副作用主要是对COX-1的抑制作用, 使得研究人员致力于研究安全性能更高的选择性COX-2抑制剂, 期望由此减轻对胃肠道的损伤作用. 但在之后的临床研究中, 发现它出现了严重的心血管毒性作用, 且发现长期应用选择性COX-2抑制剂与应用传统NSAIDs患者的胃肠道损伤并无太大差别, 无论应用传统NSAIDs类药还是应用选择性COX-2抑制剂, 其药物安全性都有不理想的方面. 因此, 迫切需要研发新型且安全性更高的NSAIDs类药. 目前基于NSAIDs最新研究主要包括NO-NSAIDs和H2S-NSAIDs、抗胆碱能NSAIDs、COX与LOX双重抑制剂、倾向型 COX-2 抑制剂、氨基酸NSAIDs和糖类NSAIDs、磷脂酰胆碱NSAIDs、抗氧化型NSAIDs[21]. 这些新型药物的研制基于对小肠黏膜损伤机制的研究, 其安全性能和疗效均会得到很大提升, 具有较好的应用前景.
近年研究发现多种胃黏膜保护剂对小肠黏膜损伤也有保护作用. 瑞巴派特为新型抗溃疡药, 主要是通过增加胃黏膜血流量、前列腺素E2合成和胃黏液分泌、清除氧自由基等环节, 促进消化性溃疡的愈合及炎症的改善. 近年的研究发现瑞巴派特对小肠黏膜损伤也有很好的保护作用. 一项多中心随机双盲的临床研究[24]表明, 大剂量瑞巴派特治疗阿司匹林所致中重度小肠黏膜损伤取得很好的疗效, 且病人有很好的耐受性. 在动物实验研究[25,26]中发现, 瑞巴派特能上调肠道中α-defensin的表达, 增加乳酸菌的比例, 减少拟杆菌属和梭杆菌属的比例, 从而减轻吲哚美辛所致的小肠黏膜损伤. 瑞巴派特还能通过增加β-Catenin的表达, 促进肠黏膜再生, 加速阿司匹林所致小肠黏膜损伤的修复[27]. 该药还具有保护肠上皮细胞线粒体的作用, 从而减轻由双氯芬酸引起的小肠黏膜通透性的增加[28]. 国内学者陈琳等[29]制备吲哚美辛所致大鼠小肠黏膜损伤疾病模型, 应用云母颗粒等药物对大鼠进行保护, 研究结果提示云母可以治疗NSAIDs相关小肠黏膜损伤, 其机制与抑制小肠黏膜通透性的增加从而增强肠黏膜屏障作用、拮抗小肠黏膜细菌移位有关. 同时, 黏膜保护剂米索前列醇和蒙脱石也可以通过上述机制在一定程度上起到保护作用. 谷氨酰胺不仅是快速生长和分化肠黏膜上皮细胞的重要氧化燃料和能量合成底物, 也是维护肠黏膜结构完整性、黏膜屏障功能、肠道免疫功能和微生态环境的重要调节因子. 大量研究表明, 谷氨酰胺营养支持在肠道黏膜屏障功能、改善肠道内微环境和预防肠源性细菌和内毒素移位中起着非常重要的作用[30].
肠道菌群在NSAIDs肠病的发生发展中起重要作用, 大量的研究证明应用NSAIDs后肠道菌群发生了改变, 而应用抗生素治疗能取得一定疗效. Scarpignato等[31]给予志愿者口服NSAIDs, 发现同时口服作用于肠道的广谱抗生素利福昔明组小肠黏膜损伤少仅为20%, 且没有出现严重损伤, 而没有口服利福昔明的空白对照组中43%的人发生了黏膜损伤. Fornai等[21]同样证明应用利福昔明可以平衡由吲哚美辛导致的变形杆菌和厚壁菌数量的改变, 从而稳定肠道内环境, 减轻肠道损伤. 其他抗生素如青霉素G、红霉素和甲硝唑等也能减轻炎症的程度[32,33]. 应用益生菌尤其是双歧杆菌、乳酸杆菌也有一定的治疗前景[34].
临床常规应用质子泵抑制剂(proton pump inhibitors, PPI)治疗NSAIDs相关胃黏膜损伤取得较理想的疗效, 但对于抑酸药物能否减少NSAIDs相关肠病的发生还存在争议. (1)有研究显示应用PPI对NSAIDs相关小肠黏膜损伤有一定的治疗效果. 日本学者Yoda等[35]应用兰索拉唑治疗吲哚美辛所致大鼠小肠黏膜溃疡, 发现通过减少诱导型一氧化氮合酶(inducible nitric oxide synthase, iNOS)mRNA的表达及炎性指标髓过氧化物酶(myeloperoxidase, MPO)的生成, 而减轻黏膜损伤程度, 然而奥美拉唑没有相同的治疗效果. 国内学者陈汉卿等[36]也进行了相似的研究, 应用四种PPI(奥美拉唑、雷贝拉唑、埃索美拉唑、兰索拉唑)治疗NSAIDs肠黏膜损伤, 结果显示除奥美拉唑外, 其余三种PPI能使NSAIDs肠黏膜损伤缓解, 其机制可能与上调血红素氧合酶1的表达有关. (2)有研究显示奥美拉唑、兰索拉唑和泮托拉唑与NSAIDs联合应用并没有起到保护作用, 反而导致肠道菌群发生改变使肠道黏膜溃疡和出血加重[37], 此观点近年随着PPI在临床过度使用而得到更多重视, 多项研究结果均支持长期应用PPI是导致NSAIDs肠病加重的因素. 对于PPI对NSAIDs小肠黏膜损伤方面相对立的研究结果, 还需要进一步的临床研究去明确.
鉴于目前PPI在胃黏膜损伤的防治地位, 以及其对小肠黏膜损伤防治作用的不确定性, 临床上对于应用NSAIDs类药的患者可以考虑以下两种治疗策略: (1)对于有上消化道疾病的高危患者, 如伴有反流性食管炎、消化性溃疡、胃出血等病史, 可同时应用PPI加黏膜保护剂, 可同时保护胃黏膜和肠黏膜. (2)非上消化道高风险患者可只应用黏膜保护剂来对整个消化道进行保护. 具体治疗方案还需结合不同病人的差异性, 根据患者对NSAIDs药和保护性药的反应适时调整, 做到个体化治疗. 为了更好防治NSAIDs相关小肠黏膜损伤, 相关的基础机制研究和大样本临床研究还需要进一步完善.
学科分类: 胃肠病学和肝病学
手稿来源地: 北京市
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