修回日期: 2016-05-29
接受日期: 2016-06-06
在线出版日期: 2016-07-08
急性胰腺炎(acute pancreatitis, AP)作为临床上常见的急性病症之一, 对人们健康的危害性极大. 调查显示约1/5的病例会发展至急性呼吸窘迫综合征和多器官功能障碍阶段, 伴随高死亡率. 早期学者们对该病发病机制的认识仅限于胰酶在胰腺内被异常激活后引起胰腺组织自身消化、水肿、出血甚至坏死的炎症反应. 近年来, 随着医学界对该病重视程度的增高, 研究逐渐深入, 方向集中于其发病过程中的免疫炎症反应, 以下对其中研究比较热门的磷脂酰肌醇-3激酶信号通路与AP免疫炎症之间的关系作一阐述.
核心提示: 磷脂酰肌醇-3激酶(phospho inositide-3 kinase, PI3K)参与炎症反应, 在急性胰腺炎相关免疫炎症的发病机制方面, 磷酸化的PI3K产物的积累可能导致胰蛋白酶原的激活, 也有可能通过调节胞内cAMP浓度来影响该病的发生发展.
引文著录: 刁花玉, 邵建国, 卞兆连, 陈琳, 居林玲, 张玉. PI3K信号通路在急性胰腺炎发病机制中的研究进展. 世界华人消化杂志 2016; 24(19): 3002-3008
Revised: May 29, 2016
Accepted: June 6, 2016
Published online: July 8, 2016
Acute pancreatitis (AP) as a common acute disease poses a great threat to people's health. According to statistics, about one-fifth of cases develop acute respiratory distress syndrome and multiple organ dysfunction, which result in high mortality. The early understanding of the pathogenesis of this disease is limited to an inflammatory response resulting in autodigestion, edema, hemorrhage and necrosis of pancreatic tissue after the abnormal activation of trypsin. In recent years, researchers have focused their research on the role of immune inflammatory response in the pathogenesis of AP. Here we discuss the relationship between the immune inflammation and PI3K signaling pathways in AP.
- Citation: Diao HY, Shao JG, Bian ZL, Chen L, Ju LL, Zhang Y. Role of phosphoinositide-3 kinase signaling pathways in pathogenesis of acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2016; 24(19): 3002-3008
- URL: https://www.wjgnet.com/1009-3079/full/v24/i19/3002.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i19.3002
长期以来, 胰腺腺泡细胞中消化酶原的过早激活导致胰腺组织的自身病理性消化被认为是急性胰腺炎(acute pancreatitis, AP)发生发展的关键初始事件[1,2], 近年来研究者们纷纷致力于探讨胞内酶原激活的生化机制, 包括病理钙信号的传导、早期核因子-κB(nuclear factor-κB, NF-κB)的激活、自我吞噬、氧化应激等[3-7]. 胞内消化酶原激活会导致细胞坏死及局部炎症反应, 这一过程随着时间的推移会呈现出自我修复的现象[8]. 但是, 持续的炎症刺激将会促使胰腺自身甚至其他靶器官并发症的发生, 最终导致器官功能障碍, 使得该病死亡率居高不下. 近来实验及临床数据表明, AP的炎症反应在局部及系统性损伤的发病机制中起至关重要的作用, 并且是该疾病严重程度的决定性因素[9,10]. 由此, 一系列实验性抗炎症方法应运而生, 从敲除细胞因子受体相关基因[11], 到中和细胞因子、趋化因子、黏附分子或其他介质[12-14]; 从阻止中性粒细胞的招募[15], 到补体抑制[16]等, 都能明显降低AP的死亡率. 尽管大量的实验研究更新丰富了我们对AP免疫炎症方面发病机制的认知, 但是其结果并没有给临床治疗方法带来很大的帮助. 所以, 近来人们又将目光锁定于与该病免疫炎症机制方面有联系的一些信号通路, 其中, 我们选择当前比较热门的一条信号通路磷脂酰肌醇-3激酶(phospho inositide-3 kinase, PI3K)来对其结构和功能以及在炎症发展过程中的机制作进一步阐述.
PI3K/Akt通路广泛存在细胞中, 是参与细胞生长、增殖、分化调节的信号传导通路[17]. PI3K是一类参与细胞内信号转导的酶类, 他们本身具有丝氨酸/苏氨酸(Ser/Thr)激酶的活性, 也具有磷脂酰肌醇激酶的活性, 而后者被研究得更多. PI3K可分为3类, 其结构与功能各异. 其中研究最广泛的为Ⅰ类PI3K, 此类PI3K为异源二聚体, 由一个调节亚基和一个催化亚基组成. 调节亚基含有SH2和SH3结构域, 与含有相应结合位点的靶蛋白相作用. Ⅰ类PI3K又可进一步分为两个亚组: ⅠA和ⅠB. ⅠA亚组包含PI3Kα、PI3Kβ及PI3Kδ, 分别由共同的调节亚基p85和p110α、p110β、p110δ 3种特定的催化亚基组成[18]. 其中, PI3Kα是激活胰岛素受体酪氨酸激酶的特定上游序列[19], PI3Kδ常作为酪氨酸激酶受体的下游序列, T细胞、B细胞受体, 自然杀伤性受体, Fc受体及Toll样受体被激活时, PI3Kδ会被特定招募到免疫细胞中发挥作用[20,21], 而PI3Kβ却更多的被G蛋白偶联受体激活[22]. IB组仅含有PI3Kγ, 他是由调节亚基p84/p87或p101和催化亚基p110γ组成. PI3Kγ通过直接绑定G蛋白βγ亚基激活信号, 也可被Ras蛋白激活[23]. 此外, 他们的组织分布也有很大不同, PI3Kα和PI3Kβ广泛分布于各组织中, PI3Kγ和PI3Kδ仅限于白细胞表达[24-27]. 当然, 也有报道称在心脏、内皮组织、乳腺及胰腺中发现PI3Kγ的表达[28,29]. 而PI3Kδ也被发现在神3/4元、黑色素瘤和乳腺癌细胞中表达[30]. 近几年, 对探讨Ⅱ类和Ⅲ类PI3K与癌症的关系进而研制抗癌药物的研究较为热门[31,32], 但其具体机制研究还不够成熟, 在这里就不展开叙述.
随着基因学手段的发展和PI3Ks各种亚型抑制药物的出现, PI3Ks参与炎症反应的过程被越来越多的研究者们研究. 敲除PI3Kα和PI3Kβ基因会使小鼠胚胎致死[33], 而PI3Kδ和PI3Kγ基因敲除小鼠是有生命活力的, 并且仅在先天和获得性免疫反应方面与野生小鼠有差异[34,35]. 研究[36]表明, PI3Kδ和PI3Kγ很多方面发挥协同作用, 例如: 内皮细胞中的PI3Kγ和PI3Kδ信号会共同参与调节中性粒细胞黏附到发炎血管壁的过程. 在炎症聚集部位, PI3Kγ和PI3Kδ共同调节活性氧产物, 这一过程初始是由PI3Kγ诱导激活, 随后由PI3Kδ介导放大. PI3Kγ基因敲除小鼠体内中性粒细胞和巨噬细胞迁移速度减慢, 这种反应通过fMLPs、C5a, 或白介素-8等G蛋白偶联受体起作用[37]. 而PI3Kδ在中性粒细胞定向运动方面表现出特定的调节作用[29]. 除了对中性粒细胞和巨噬细胞起作用外, PI3Ks还参与调节肥大细胞和嗜酸性粒细胞胞内的基本功能. PI3Kδ抑制剂能减弱被(Ig)E刺激的肥大细胞的脱颗粒作用及细胞因子的释放, 并且可以减轻被IgE和抗原注射诱导的模型鼠的被动皮肤过敏反应[38]. 同样的, PI3Kγ抑制剂可减轻腺苷诱导的肥大细胞脱颗粒并降低对被动系统性速发型过敏反应的抵抗性[39]. 此外, PI3Kγ也会参与嗜酸性粒细胞聚集过程及过敏原诱导的嗜酸粒细胞性气道炎症和气道重塑[40]. 而又有研究者提出, PI3Kγ和PI3Kδ对T细胞发育至关重要, 这一论点通过观察基因敲除小鼠的外周血T淋巴细胞数量减少及胸腺中CD4+CD8+双阳性细胞比率下降得以证实. 而进一步研究证实, PI3Kδ对CD4+ T细胞的成熟和分化以及B细胞的成熟和激活起作用[22,27,24]. 与这些结果相一致, PI3Kγ和PI3Kδ抑制剂在对抗临床各种恶性血液病尤其是淋巴瘤的细胞增殖方面显现出一定的研究价值[41].
除了对细胞的作用, PI3K信号通路在许多自身免疫性和过敏性疾病中也会涉及, 他在炎症的发生和发展起着至关重要的作用. 例如: 敲除PI3Kγ基因或者使用其抑制剂会明显降低系统性红斑狼疮[42]的发生率及严重性; 类风湿性关节炎模型动物在使用同样的方法后发现体内肿瘤坏死因子α减少[43]; 与对细胞的作用一致, 抑制PI3Kγ基因可减轻由白蛋白诱导的哮喘模型动物肺内白细胞浸润, 气道高反应性及气道重塑[44]. 抑制骨关节炎模型动物体内PI3Kδ表达可减弱炎症的发展及骨和软骨的侵蚀程度[45]. 此外, 有研究[46]证实, 一种PI3Kγ和PI3Kδ的双重抑制剂-TG100-115, 运用到心肌梗死动物模型上可以缩小心肌梗死的范围以及维护心肌的功能.
有关PI3Ks在胰腺腺泡细胞中的生理作用知之甚少. PI3Ks在AP的发病机制中发挥的作用首次在Singh等[47]的一项研究中被提及, 研究者在两种AP模型动物(一种通过雨蛙肽诱导, 一种通过胆胰管逆行注射)上分别使用PI3K两种亚型的抑制剂-渥曼青霉素和LY294002. 结果发现, 对雨蛙肽诱导的模型而言, 渥曼青霉素抑制早期胰蛋白酶原的激活, 这与细胞内组织蛋白酶的再分布及溶酶体水解酶与消化酶原的共区域化作用减弱有关. 此外, 胰腺水肿的程度, 胰腺内中性粒细胞的浸润, 腺泡细胞的坏死和高淀粉酶血症在这种模型上也明显减轻. 同样, 在胆胰管逆行注射钠牛磺胆酸盐的大鼠AP模型上, 渥曼青霉素同样可以降低胰蛋白酶和髓过氧化物酶活性, 腺泡坏死也得以减轻. 研究证实, 渥曼青霉素和LY294002对胰腺的保护作用并不会影响腺泡细胞的骨架构成. 此外, 研究者还进一步设计实验证实在胰蛋白酶原激活的过程中发挥主要作用的是Ⅲ类PI3K, Ⅰ类 PI3K并未涉及, 因为在使用以上两种抑制剂后, Ⅲ类PI3K表达产物水平明显下降. 因此, 研究者提出AP发生时胰蛋白酶原的激活很可能是磷酸化的Ⅲ类PI3K产物的不断积累所引起.
随后的研究则更深一步的分析了PI3Kγ在急性胰腺炎的发病机制所扮演的角色. Gukovsky等[48]用PI3Kγ基因敲除小鼠和PI3K抑制剂研究PI3K对CCK处理过的胰腺腺泡细胞的作用, 结果表明不管是基因敲除还是使用PI3K抑制剂均能通过抑制胞内钙释放和胞外钙流入大幅度减弱胰腺腺泡钙离子反应. 随后, 该研究小组又证实PI3Kγ通过抑制肌浆网的钙-ATP酶来调节腺泡细胞内的钙信号. 除此之外, PI3Kγ也会调节胰蛋白酶原激活, 这或许也是其调节钙信号作用的体现. 研究还发现, PI3Kγ可以促进NF-κB的激活, 这一结果与之前Singh等的研究结果并不相符. Lupia等[49]通过雨蛙肽和CDE饮食的方法制造小鼠AP模型, 结果发现, PI3Kγ基因敲除小鼠腺泡细胞坏死程度明显较未敲除小鼠减轻, 而对于雨蛙肽诱导的AP小鼠而言, 这一结果在诱导剂处理6 h后就会显现, 而此时中性粒细胞浸润并不明显. 在雨蛙肽处理13 h后, PI3Kγ敲除小鼠的腺泡细胞内中性粒细胞浸润也明显下降. 该研究团队还发现PI3Kγ基因敲除小鼠凋亡腺泡细胞数量增多, 这也进一步证明细胞凋亡在急性胰腺炎中是起保护作用的. 而对于CDE饮食诱导的AP小鼠而言, 敲除PI3Kγ基因除了会减轻腺泡细胞的坏死、中性粒细胞的浸润, 作为AP发展的靶器官, 肺损伤的程度也被发现较未基因敲除小鼠减轻, 死亡率也随之下降. 最近, Yang等[50]的研究也证实, PI3K-Akt信号通路可以通过雌激素介导来减轻雨蛙肽诱导的小鼠的肺损伤程度, 间接验证Lupia等的研究成果.
当然, PI3Kγ还被证实可通过制约PKA和各种磷酸二酯酶活力, 控制PKA介导的负反馈, 从而促进cAMP的降解, 调节胞内cAMP浓度[51,52]. 因此可以推测PI3Kγ极有可能通过对胞内cAMP浓度的调节来影响AP的发生发展.
目前AP的发病机制还没有完全阐述清楚, 各种致病因素导致胰酶原过度激活、胰酶入血是其启动因素; 坏死物质激活免疫系统, 释放大量CK及炎性介质, 是AP病情失控的关键环节; 全身血循环障碍, 组织的缺血坏死, 诱发SIRS及MOF是AP导致死亡的主要原因. 另外, 细胞凋亡学说、胰腺腺泡内钙超载学说也在AP发病过程中受到重视. 然而其机制复杂多样, 使得临床治疗成为一个困扰临床医师的难题. 目前PI3K/Akt信号途径在AP中的研究, 可能由于模型动物和用药剂量的不同使实验结果出现差异. 但是研究PI3K/Akt信号途径在AP及其并发症中的作用, 有助于进一步了解炎性反应及细胞凋亡等生理、病理现象在其发病中的作用, 进而为临床治疗提供新的靶点.
目前人们对急性胰腺炎发病机制的认识仍不够深入, 临床治疗方法因此得不到丰富, 本文介绍当前研究较热门的磷脂酰肌醇-3激酶(phospho inositide-3 kinase, PI3K)在该病发病机制中所扮演的角色.
孙昀, 副主任医师, 安徽医科大学第二附属医院重症医学科
目前急性胰腺炎免疫炎症方面的发病机制尚待进一步研究, PI3Ks作为其中之一, 其具体作用途径仍需深入了解.
Xu等及Abliz等均详细的阐述了PI3K/Akt信号通路对胰腺炎的调节过程.
不同于早期胰酶异常激活学说, 本文从免疫炎症的角度阐述PI3Ks在急性胰腺炎中所发挥的作用.
研究PI3Ks在急性胰腺炎及其并发症中的作用, 有助于进一步了解该病的炎症反应及细胞凋亡机制, 进而为临床治疗提供新的靶点.
G蛋白偶联受体: 是一肽类膜蛋白受体的统称. 这类受体的共同点是其立体结构中都有七个跨膜α螺旋, 且其肽链的C端和连接第5和第6个跨膜螺旋的胞内环上都有G蛋白(鸟苷酸结合蛋白)的结合位点.
本文综述了PI3K的分类及结构、其信号通路在胞内炎症反应中的作用以及在急性胰腺炎发生机制中的作用, 综述条理清晰, 有一定的参考价值.
编辑:郭鹏 电编:都珍珍
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