修回日期: 2007-01-04
接受日期: 2007-01-31
在线出版日期: 2007-03-28
蛋白酶激活受体-2(protease activated receptor-2, PAR-2)属于G蛋白耦联受体, 具有蛋白酶受体家族较特异的分子结构与激活方式, 广泛分布于胃肠道, 可被多种蛋白酶激活, 产生多种生物学效应, 包括影响多种消化腺的分泌, 具有胃黏膜保护作用, 影响胃肠道运动, 参与胰腺炎的发生、发展, 与消化道恶性肿瘤密切相关. PAR-2与消化系统疾病的关系正成为当前研究的一个热点.
引文著录: 刘建, 李非. 蛋白酶激活受体-2与消化系统疾病的研究进展. 世界华人消化杂志 2007; 15(9): 986-990
Revised: January 4, 2007
Accepted: January 31, 2007
Published online: March 28, 2007
Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptor, and its special molecule structure and activation way are similar to other protease-activated receptors. PAR-2 is widely distributed in alimentary system and series of effects are produced when it is activated by certain proteases. For example, PAR-2 exerts gastric mucosal cytoprotective effect, influences the secretion of digestive glands and movement of gastrointestinal tract, participates in the development of pancreatitis, and associates closely with malignant tumors in alimentary system. More and more researches are now focusing on the relationship between PAR-2 and alimentary system diseases.
- Citation: Liu J, Li F. New developments in the relationship between protease activated recerptor-2 and alimentary system diseases. Shijie Huaren Xiaohua Zazhi 2007; 15(9): 986-990
- URL: https://www.wjgnet.com/1009-3079/full/v15/i9/986.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v15.i9.986
Nystedt[1]于1994年首先在鼠DNA序列中发现了一种G蛋白耦联受体的基因序列, 表达出的目的蛋白因具有类似于凝血酶受体的结构和活化机制, 故被命名为蛋白酶激活受体-2(protease activated receptor-2, PAR-2). PAR-2属于蛋白酶激活受体家族(PARs), 该家族目前已发现的受体有4种亚型, 分别被命名为PAR-1, PAR-2, PAR-3, PAR-4. PAR-2在体内分布较广泛, 尤其是胃肠道; 胃肠道内同时富含能将其激活的多种蛋白酶, 被激活后可产生多种生物学效应, 影响消化系统功能, 与消化系统疾病关系密切, 本文将近年研究进展综述如下.
人PAR-2基因位于5q13, 由两个外显子组成. 在蛋白质水平推测由397个氨基酸残基构成, 与大鼠PAR-2的氨基酸序列有83%的同源性. 分子结构方面, PAR-2由细胞外区(N-末端和细胞外袢)、跨膜区(7个跨膜螺旋)及细胞内区(细胞内袢和C-末端)组成[2]. 其中N-末端含丝氨酸蛋白酶裂解位点, 细胞外袢在PAR-2激活过程中起关键作用, 而C-端可能在受体活化后起介导信号转导的作用. PAR-2可被体内多种分子激活, 目前已发现的有: 胰蛋白酶、类胰蛋白酶、膜型丝氨酸蛋白酶-1、人气道胰蛋白酶样蛋白酶、精子顶体酶、组织因子Xa、活化的凝血因子VIIa和Xa、具有丝氨酸蛋白酶活性的尘螨抗原等. 人工合成的PAR-2活化肽如丝-亮-异亮-甘-精-亮(SLIGRL)也具有激活作用.
PAR-2的生理激活有赖于上述分子对受体N-末端的裂解. 激活剂识别裂解位点, 裂解N-末端的特殊部位, 完整受体的N-末端被裂解后形成新的N-末端(即系锁配体), 系锁配体与细胞外袢相互作用进而激活PAR-2. 激活PAR-2后的大部分信号传导途径是由活化磷脂酶C通过Gq/11蛋白介导的[3]. PAR-2的激活是不可逆的, 即N-末端一旦被裂解, 蛋白酶的裂解部位丢失, 故不能够被再次裂解. 激活剂持续或反复刺激可导致受体对激活剂的反应性下降(即受体脱敏), 脱敏后的PAR-2还可复敏, PAR-2的脱敏及复敏与PAR-2内陷有关. 一些人工合成的短肽包括PAR-2活化肽及反义活化肽本身无蛋白酶活性, 不能裂解受体N-末端, 但可直接结合到细胞外袢上起激活PAR-2的作用. 这些短肽仅含几个氨基酸序列, 实验研究中被用来激活或封闭PAR-2.
腮腺、舌下腺及颌下腺均已发现有PAR-2的表达. 腮腺腺泡细胞PAR-2被激活后可刺激唾液及淀粉酶的分泌[4], 并可引起三叉神经伤害性神经元的活化. 激活鼠舌下腺PAR-2可刺激淀粉酶及黏液的分泌[5], 酪氨酸激酶抑制剂可以减少黏液的分泌量[6].
食管上皮细胞已发现PAR-2的表达. 食管炎症时白介素-8水平升高, 而胰蛋白酶或PAR-2活化肽可促进食管上皮细胞分泌IL-8, 与食管炎的发生有关[7]; Naito et al[8]也得出了类似结论.
PAR-2在胃主细胞胞膜及胞质均有表达, 被激活后可通过Ca2+-ERK依赖的途径刺激胃蛋白酶原的分泌[9]. PAR-2活化肽可抑制卡巴胆碱、胃泌素、2-甲基-D-葡萄糖引起的胃酸分泌[10], 同时刺激黏液的分泌, 呈现剂量依赖性. 静脉给活化肽可引起胃血流量的短暂增加, 通过刺激感觉神经元分泌CGRP及缓激肽可以明显减轻盐酸/乙醇、吲哚美辛导致的胃黏膜损害, 且随PAR-2浓度的增加损害程度减轻[11]. 蛋白酶激活受体-1(PAR-1)也具有胃黏膜保护作用, 但两者作用机制不同. PAR-2还可影响胃的运动, 引起胃纵形肌的收缩, 这种作用可被环氧化酶抑制剂及酪氨酸激酶抑制剂所阻断[12]. 在胃底则具有引起舒张及随后收缩的双重效应.
在肠道PAR-2分布于肠道上皮细胞顶端及基膜侧、平滑肌细胞、成纤维细胞、肌间及黏膜下神经丛神经元、内皮细胞及一些免疫细胞. 生理情况下上皮细胞就直接暴露于胰蛋白酶、类胰蛋白酶、细菌分泌的一些蛋白酶等. (1)对分泌功能的影响: 激活PAR-2可促进小肠、结肠、直肠氯离子的分泌, 进而可能引起腹泻, 这一过程在小肠与肠神经系统无关, 在结肠则依赖神经元的参与. 还发现激活PAR-2能刺激前列腺素E2和F1的分泌, 可能具有调节肠道分泌及肠道保护的作用[13]; (2)对肠道运动的影响: 激活PAR-2后通过神经机制促进小肠平滑肌的运动, 这一过程依赖感觉神经通路及NK1及NK2受体的参与[14]. 在体外, PAR-2激活剂可抑制结肠环形肌的自主性收缩, 纵形肌则呈现收缩或先松弛随后收缩的双期效应; (3)其他: PAR-2可介导肠道的痛觉过敏, 如结肠内灌注PAR-2活化肽可加重腹痛. PAR-2还参与肠道炎症的发生[15], 在结肠炎症中的作用是复杂的, 既有前炎性效应又有抗炎效应. Jacob et al[16]认为, 应激状态及炎症时, 肥大细胞释放类胰蛋白酶激活结肠上皮细胞的PAR-2, 增加上皮的通透性, 促进炎症反应. 结肠内给予PAR-2激动剂可引起结肠炎症的迅速发展, 辣椒素敏感性神经元、NO和细胞渗透性改变参与了此机制[17]. 而Fiorucci et al[18]皮下给PAR-2活化肽可以阻止Th1细胞介导的实验性结肠炎的发展, 减轻炎症程度, 呈现剂量依赖性. 肠易激综合征时肠道生理的变化包括肠道运动模式的改变、炎症介质的释放、肠道通透性的改变、离子转运障碍及改变伤害性疼痛的产生等, 而这些改变均有PAR-2的参与, 推测PAR-2与肠易激综合征的发生有关.
激活离体胆囊内PAR-2后可引起剂量依赖性的胆囊收缩效应, 这一过程与神经机制无关, 可能是由前列腺素的释放引起[19]. 在肝脏则可刺激星状细胞的增生和胶原的形成, 可能与肝脏纤维化的维持有关[20]. 肝硬变时肝内肥大细胞的数量增加, 而PAR-2 mRNA及蛋白的表达与肥大细胞的量呈正比[21].
PAR-2在胰腺腺泡及导管细胞高表达[22], 导管或细胞间隙的胰蛋白酶原活化后即可激活细胞膜上的PAR-2, 而胰蛋白酶是目前发现的最有效的PAR-2生理激活剂, 因而PAR-2与胰腺疾病的关系引起了人们的关注. (1)对胰腺外分泌的影响: 激活PAR-2后胰液的分泌量先增加, 之后经历了先短暂下降后轻度升高的过程[4]; 十二指肠内淀粉酶的量增加, NO可能参与PAR-2介导的胰腺淀粉酶的分泌[23]. 向离体胰腺腺泡细胞培养液中加入胰蛋白酶或PAR-2活化肽后发现淀粉酶水平升高. 另有体外实验发现激活PAR-2后HCO3-的分泌减少, 提示可能是胰腺炎时胰液分泌受到抑制的原因[24]; (2)胰腺细胞损害时的表达及作用: 腺泡/导管细胞在胰腺损伤时高表达PAR-2[25]. PAR-2可参与胰腺炎的发生及发展, 在胰腺炎时可能发挥胰腺局部保护作用. 当使用PAR-2活化肽预处理腺泡细胞并暴露于低浓度胆汁时细胞死亡率下降, 提示PAR-2可能拮抗腺泡和导管细胞的细胞损害[22]. PAR-2基因缺失的胰腺炎模型大鼠其胰腺炎症程度要明显重于野生型组, 使用PAR-2活化肽预处理后胰腺炎症程度明显减轻[22,26]. 但也有研究表明, PAR-2基因缺失大鼠的胰腺炎症程度与野生型组相比无明显差异[27]. PAR-2具有这种保护作用的机制尚不明确, Singh et al[28]认为与其促进胰腺外分泌有关. PAR-2可能还参与急性胰腺炎时的一些全身反应. 激活PAR-2后血中NF-κB, IL-8的水平升高[29]; PAR-2抗体可以抑制胰腺炎时血中IL-6, IFN-γ的升高[29]. Hirota et al[30]认为PAR-2活化后通过产生细胞因子提示机体胰腺腺泡细胞内已有大量胰蛋白酶产生, 即将发生腺泡细胞损害. 合并内毒素血症时胰蛋白酶对肺PAR-2的激活可以调节MIF的转录水平, 增加MIF引起的肺TLR-4的表达, 从而导致急性肺损伤的形成[31]. 激活PAR-2可使胰腺炎时动脉血压下降, 舒张压的下降更明显[22]; (3)其他: Hoogerwerf et al[32]认为, 胰蛋白酶通过激活PAR-2来介导急性胰腺炎时的疼痛反应; Kawabata et al[27]则认为, 激活PAR-2后可减轻胰腺炎相关的腹部疼痛/痛觉过敏, 但两人均认为上述过程与胰腺炎症程度本身无关. 在慢性胰腺炎合并重度纤维化时PAR-2表现为高水平, 并可通过刺激胰腺星状细胞的增生及胶原的产生来维持胰腺纤维化[33].
肿瘤细胞本身既可表达PAR-2, 又可分泌类胰蛋白酶等分子; 同时肿瘤微环境内充满了多种可以激活PAR-2的蛋白酶, 作用于PAR-2后可影响肿瘤细胞的增生、分化、侵袭性等; (1)胃癌: PAR-2在胃癌细胞中过表达, 体外研究发现, 他可以反式激活EGFR, 从而刺激癌细胞的增生[34]. 免疫组化检查提示, 42.1%的人胃癌组织内发现PAR-2的表达, 原发部位癌细胞的胞膜呈高表达, 表达程度还与肿瘤的浸润深度、淋巴结及静脉侵犯与否、是否有肝转移有关, 阳性表达PAR-2的肿瘤患者预后较差, 提示PAR-2与胃癌的进展有关[35]; (2)胰腺癌: 多组体内体外实验均发现PAR-2被胰蛋白酶、人工合成的活化肽激活后可刺激胰腺癌细胞系的增生. 此时COX-2的表达升高, PAR-2抗体可抑制细胞的增生; 临床上85.0%的导管内乳头状癌患者及65.8%的浸润性导管癌患者的癌组织表达PAR-2[36]; 并与癌细胞的侵袭性、纤维化的诱导有关. 肿瘤呈浸润性生长时比膨胀性生长时更多的表达PAR-2, 纤维化程度越重, PAR-2的表达越高[37]; (3)结肠癌: 激活PAR-2可刺激结肠癌细胞的增生, 甚至有些结肠癌细胞系可自主分泌胰蛋白酶, 其浓度足以激活PAR-2, 发挥自分泌或旁分泌的作用[38-39]; (4)胆囊癌: 一组临床病理分析数据表明64%的胆囊癌患者癌组织表达PAR-2, 且以乳头状腺癌多见(94%的此类患者表达PAR-2), 表达程度与肿瘤是否有淋巴结转移及静脉侵犯无关[40].
总之, PAR-2作为一种未被完全了解的丝氨酸蛋白酶受体, 广泛分布于消化道及消化腺, 其生理作用可能与促进营养物质的转运有关[41]. 目前人们对PAR-2在消化系统的活化、生物学效应等有了一定的了解, 还有必要对其与消化系统相关疾病的关系以及致病机制进行更深入的研究. 相信随着对PAR-2研究的深入及其病理生理作用的进一步阐明, PAR-2可能为某些消化系统疾病的研究提供一个新的方向, 如胃黏膜保护, 内脏疼痛及肠道炎症性疾病的治疗, 肠易激综合征的治疗, 急性胰腺炎的发病机制及治疗, 消化道恶性肿瘤的研究等.
蛋白酶激活受-2(PAR-2)是10余年前发现的一种细胞膜表面受, 属于G蛋白耦联受体家族. PAR-2广泛分布于全身多种器官组织, 可被多种分子激活, 其中最有效的生理激活剂是胰蛋白酶. 目前关于PAR-2病理生理作用的研究主要集中在消化系统、肿瘤、心血管系统、变态反应、疼痛等.
目前研究热点主要集中在PAR-2对恶性肿瘤生物学行为、对胃黏膜保护作用、对消化系统炎症的影响等. 但仍有许多问题有待解决, 研究的当务之急是尽快发现能特异性阻断PAR-2活性的多肽或抗体.
本文综述了PAR-2与消化系统疾病的研究进展, 内容较新, 有参考价值和一定的指导意义.
编辑:王晓瑜 电编:张敏
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