修回日期: 2014-04-02
接受日期: 2014-04-09
在线出版日期: 2014-06-08
急性胰腺炎(acute pancreatitis, AP)是胰腺外分泌急性炎症的疾病, 其发病机制至今尚未阐明. 胰腺腺泡细胞内酶原激活是公认的AP发病的始动环节, 越来越多的证据表明, 异常自噬酶原激活将导致腺泡细胞损伤和AP. 腺泡细胞在病理因素的刺激下发生线粒体通透性转换, 线粒体去极化和ATP下降, 可导致细胞内胰酶活性升高和细胞坏死. 我们认为, 阐明线粒体通透性转换与自噬二者之间的关系及腺泡细胞自噬在AP中的作用, 将有望推进对AP发病机制的认识, 为AP的有效防治提供新思路和药物作用新靶点.
核心提示: 胰腺腺泡细胞异常自噬激活酶原是公认的急性胰腺炎发病的始动环节, 但诱导自噬的上游机制尚未阐明. 我们根据相关文献报道和前期研究结果, 提出"线粒体通透性转换诱导自噬是促进急性胰腺炎发生发展的重要环节"这一观点.
引文著录: 邓力珲, 夏庆. 腺泡细胞自噬与急性胰腺炎. 世界华人消化杂志 2014; 22(16): 2252-2257
Revised: April 2, 2014
Accepted: April 9, 2014
Published online: June 8, 2014
Acute pancreatitis is an inflammatory disorder of the pancreas, and its pathogenesis remains poorly understood. Autodigestion of the pancreas by its own prematurely activated digestive proteases is a critical event in the onset of acute pancreatitis. Mitochondrial permeability transition results in mitochondrial depolarization and loss of ATP production, which has been found to induce autophagy in several cell types, e.g. cardiomyocytes and hepatocytes and is of vital importance for the fate of cells. Elucidating the relationship between mitochondrial permeability transition and autophagy within pancreatic acinar cells may enlighten the pathogenesis of acute pancreatitis and help provide potential therapeutic targets for this disease.
- Citation: Deng LH, Xia Q. Autophagy in pancreatic acinar cells and pathogenesis of acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2014; 22(16): 2252-2257
- URL: https://www.wjgnet.com/1009-3079/full/v22/i16/2252.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v22.i16.2252
急性胰腺炎(acute pancreatitis, AP)是多种病因引起腺泡细胞内胰酶异常激活, 继以胰腺炎症反应为主要特征的疾病[1,2]. 其发病率逐年来呈上升趋势, 已成为最常见的急腹症之一, 造成巨大的社会和经济负担[3]. 其中重型AP一直是临床上治疗的难点和挑战, 死亡率高达30%-50%[4]. 迄今为止, AP确切的发病机制尚未阐明. 一百多年前提出的"胰酶消化学说"和腺泡细胞内胰蛋白酶原异常激活是国内外公认的AP发病的始动环节[2,5]. 追溯酶原激活的具体机制, 人们在30多年前发现了腺泡细胞内自噬空泡现象, 并提出自噬是酶原激活关键过程[6-8], 然而直到近十年来在酵母菌及哺乳动物细胞中发现了参与自噬的分子机制, 自噬才迅速成为一个全新的研究领域, 已经成为生物医学的热点.
自噬(autophagy)是细胞将胞质及细胞器运送至溶酶体进行自我降解的途径[9,10]. 根据细胞内底物运送到溶酶体腔的方式不同, 哺乳动物细胞自噬可分为大自噬(macroautophagy)、小自噬(microautophagy)和分子伴侣介导的自噬(chaperone-mediated autophagy), 通常所说的自噬是指大自噬[11,12]. 自噬对细胞的作用非常复杂, 一方面自噬通过降解自身的物质, 清除对细胞生长有害的物质, 促进细胞生存; 另一方面, 当细胞受到过多的损伤打击, 产生异常的自噬也会引起细胞死亡, 与许多疾病的发病机制密切相关[13,14].
自噬在AP中的作用尚未明确, 其争议在于激活自噬的意义是加速细胞能量营养补充从而有益于细胞存活或及时提供ATP使细胞应激时启动凋亡以减轻损伤, 还是使胰蛋白酶原激活而直接损伤腺泡[15]. 但是, 越来越多的证据表明, 异常自噬酶原激活将导致腺泡细胞损伤和AP[16-18]. 有研究发现胰腺腺泡在诱发实验性AP时腺泡细胞中出现的空泡是双层膜的, 且膜上有自噬标志物轻链蛋白3Ⅱ(light chain 3Ⅱ, LC3Ⅱ)存在, 因此考虑这些空泡是自噬来源的, 并且在这些空泡中发现未完全消化的细胞内容物及胰蛋白酶更进一步证实胰蛋白酶原的激活可能与自噬有关[19]. 有研究认为自噬既可使胰蛋白酶原与组织蛋白水解酶"共位置", 又可提供胰蛋白酶原"自我激活"所需要的适当pH值, 因此在胰蛋白酶原提前过度激活中起关键作用[16].
自噬被诱导后, 细胞内形成一种称为隔离膜(isolation membrane)或吞噬泡(phagopore)的小囊泡样结构, 并与需降解的胞浆成分、线粒体及酶原颗粒集结在一起, 吞噬泡膜延伸并包裹封闭胞浆成分形成一个双层膜的自噬(autophosome), 自噬体与溶酶体(lysosome)直接融合形成自噬溶酶体(autopholysome), 或先与内涵体(endosome)融合形成自噬内涵体(amphisome)后再与溶酶体融合, 包裹的胞浆成分最终在溶酶体酶[组织蛋白水解酶B(cathepsin B, CatB)和组织蛋白水解酶L(cathepsin L, CatL)]的作用下被降解, 此过程中酶原可被溶酶体酶(主要是Cat B)激活成为有活性的酶, 腺泡细胞自身消化, 触发AP[16,20].
自噬形成的过程有多种分子参与, 哺乳动物参与自噬形成过程的相关基因现统一命名为自噬相关基因Atg(autophagy-related gene)[21,22], 监测标志性自噬分子的荧光及蛋白能够反映自噬活性. (1)微管相关蛋白1轻链3(microtubule-associated protein 1 light chain 3, MAP1-LC3)是哺乳动物中自噬体形成及胞浆到空泡靶向囊泡必需的蛋白, 胞浆型LC3B-Ⅰ散在分布于细胞浆内, 当自噬体形成后, LC3B-Ⅰ形成LC3B-Ⅱ并始终稳定地保留在自噬体膜上直到与溶酶体融合, 因此LC3B -Ⅱ被用来作为自噬体的标记性蛋白, 其表达水平在某种程度上反映了自噬体的数量, Western blot和荧光显微镜检测胞浆型LC3B-Ⅰ转位为自噬体膜 LC3-Ⅱ已成为监测"自噬潮"(自噬体形成/降解)的推荐方法[23-25]; (2)Beclin1是酵母ATG6的同系物, 与Ⅲ型磷脂酰肌醇三磷酸激酶(classⅢ PI3K)形成复合物参与到自噬形成, 在自噬体的形成及膜来源中发挥作用[26]; (3)空泡膜蛋白1(vacuole membrane protein 1, VMP1)的表达被认为是AP早期的分子事件, 雨蛙肽刺激大鼠6 h后, 可以在胰腺自噬空泡膜上检测到高表达, 因此VMP1被认为是AP早期的分子事件[27]; (4)p62蛋(SQSTM1/sequestome-1)对降解底物的识别和包裹起着关键作用, 其表达量的变化与自噬活性成负相关.
异常自噬造成酶原激活主要有3方面的原因[28]: (1)自噬体形成增多: 诱导AP小鼠腺泡细胞内自噬体形成增多, 过多自噬体堆积, 胰蛋白酶原大量激活导致胰腺细胞死亡, 阻断或抑制自噬体大量形成可减轻AP的程度[29-31]; (2)自噬体与溶酶体融合障碍: Fortunato等[32,33]发现在AP小鼠胰腺腺泡细胞中出现大量自噬体, 但是自噬溶酶体并没有明显上升, 伴随溶酶体相关膜蛋白LAMP-2的缺失, 推测LAMP-2缺失导致自噬体和溶酶体融合障碍, 自噬途径被阻断, 使受损细胞器降解减少, 即细胞可循环利用的小分子物质减少, 从而使细胞向坏死方向发展; (3)自噬降解障碍: 溶酶体中成熟的CatB和CatL减少及分解功能下降, 大量的酶原堆积在自噬溶酶体内引起酶原激活和细胞损伤; CatB与CatL比例失衡, CatB激活胰蛋白酶, 从而引起AP[19].
自噬调节机制相当复杂, 目前比较明确的是Ⅲ型PI3K/Akt(PKB)途径、Bcl-2/Beclin-1途径、p53途径、雷帕霉素调控的雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)/MAPK途径[31]. 细胞能量下降诱导自噬与AMPK信号途径密切相关[34,35]. 腺苷酸活化蛋白激酶(adenosine 5-monophosphate-activated protein kinase, AMPK)被称为"细胞能量感受器", 正常情况下AMPK抑制酶原活化对腺泡细胞起保护作用, CCK-8类似物雨蛙肽(caerulin)刺激腺泡细胞后, AMPK活性增加[36]. mTOR是AP中重要的信号传导激酶之一[37,38], 其与Raptor及LST8共同形成复合物mTORC1. 在能量充足的情况下, mTORC1抑制其下游效应因子ULK1-ATG13-FIP200自噬复合物从而抑制自噬的发生, 是自噬的负调控因子, 雷帕霉素(rapamycin)能够与Raptor亚基相互作用而增强自噬. 在能量不足的情况下, AMPK磷酸化使其成为有活性的AMPK-P, AMPK-P磷酸化激活mTORC1的Raptor亚基, 然后mTORC1整合上游信号解除对下游分子ULK1的抑制作用, ULK1磷酸化活化整个ULK1-ATG13-FIP200复合物, 从而开启自噬的"第一步"[39]. 最新的研究显示AMPK-P也能直接磷酸化激活ULK1诱导自噬[40,41].
线粒体是细胞内氧化磷酸化和形成 ATP 的主要场所, 还参与细胞内信号传导和炎症反应, 决定着细胞存活和死亡[42-45]. 外界损伤因素使线粒体通透性转换孔(mitochondrial permeability transition pore, MPTP)放引起线粒体通透性转换(mitochondrial permeability transition, MPT), 导致了线粒体能量、代谢与功能下降. 定位于线粒体基质的亲环蛋白D(cyclophilin D, CypD)是调节MPTP开放与关闭从而调节MPT的关键蛋白[28], 环孢素A(cyclosporine A, CsA)与CypD结合特异性抑制MPT造成的线粒体损伤. 有证据显示, CypD主要调节了线粒体相关的细胞坏死, 对细胞凋亡过程没有调节作用[46-48]. (精氨酸诱导)ATP合成减少、(雨蛙肽和胆酸诱导)Ca2+超载[49]、(酒精诱导)NAD减少[50]、精氨酸等损伤因素可导致MPTP开放[51], 线粒体膜电位下降, 在AP发病机制中起到重要作用[52,53]. Shalbueva等[54]报道结果显示: CCK-8刺激腺泡细胞内Ca2+浓度上升, 线粒体膜电位降低, 线粒体能量产生链的控制标志物NAD(P)H减少反映细胞ATP生成下降, 同时细胞坏死释放乳酸脱氢酶(LDH)增多; 使用公认的MPT特异性抑制剂CsA能维持线粒体膜电位和NAD(P)H, 降低胰淀粉酶和胰蛋白酶活性, 减轻细胞坏死.
MPT和自噬在AP损伤中均可能扮演了关键角色, 但是在AP中有关二者之间究竟是否存在一定联系以及存在何种联系尚未见报道. 不过有少量研究已证实MPT诱导自噬与心血管疾病、癌症、神经退行性疾病等疾病的发生有密切关系[55-57].
腺泡细胞自噬过程中伴有线粒体功能受损, 在AP发病机制中起了重要作用[28,32,53,58]. 细胞主要通过自噬机制清除受损伤或不需要的线粒体, 以往研究在电镜下观察到AP动物胰腺腺泡细胞自噬溶酶体中存在着异常的线粒体[32,51,59], 并且MPT诱导自噬已在多种细胞中得到证实[35,60]. 已有研究证实CCK-8能诱导腺泡细胞自噬和AP[32], 自噬是酶原激活的关键过程, 因此我们推测CCK-8刺激腺泡细胞引起MPT, 很可能通过诱导自噬和酶原激活而造成细胞损伤坏死, MPT可能是调节自噬和腺泡细胞坏死的关键靶点. 已有研究证实饥饿诱导的心肌细胞和肝细胞自噬是依赖CypD调节MPT的过程, CsA能够降低自噬程度[61,62], 因此我们推测CsA可能抑制胰腺腺泡细胞自噬.
腺泡细胞自噬与在AP中发挥了重要作用. 我们进一步推测, 腺泡细胞在病理因素刺激下发生MPT诱导自噬现象, 进而AP, 抑制线粒体通透性转换诱导自噬也有可能为AP治疗的新靶点.
急性胰腺炎(acute pancreatitis, AP)发病机制尚不清楚, 腺泡细胞异常自噬导致胰蛋白酶原激活可能是急性胰腺炎发病的关键环节. 损伤因素导致线粒体发生通透性转换(mitochondrial permeability transition, MPT)可能诱导腺泡细胞自噬. 明确线粒体通透性转换诱导腺泡细胞自噬的机制有助于加深对急性胰腺炎发病机制的认识.
毛恩强, 教授, 主任医师, 上海交通大学医学院附属瑞金医院EICU
自噬是目前生物医学的研究热点, 胰腺腺泡细胞内异常自噬酶原活化是急性胰腺炎发病的始动环节已得到公认, 但诱导自噬的上游机制仍是本学科领域待解决的关键问题.
自噬异常与许多疾病的发病机制密切相关. 越来越多的证据表明, 异常自噬酶原激活将导致腺泡细胞损伤和急性胰腺炎. 研究发现腺泡细胞自噬过程中伴有线粒体功能受损, 在急性胰腺炎发病机制中起了重要作用.
有文献报道心肌细胞、肝细胞等细胞发生MPT能够诱导自噬、决定细胞的存活与死亡, 但是胰腺腺泡细胞MPT能否诱导自噬尚缺少足够的证据. 我们首次提出MPT诱导自噬是酶原活化、促进AP发生发展的重要环节这一观点.
急性胰腺炎至今尚无特异性治疗. 阐明线粒体通透性转换与自噬二者之间的关系, 将揭示诱导腺泡细胞自噬的新机制, 从新的角度深入探讨急性胰腺炎的发生机制, 为其防治提供新思路和药物作用新靶点, 具有理论和实际意义.
本文科学性较好, 对深入研究急性胰腺炎的发病机制具有一定指导意义.
编辑:田滢 电编:鲁亚静
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