修回日期: 2013-07-26
接受日期: 2013-07-31
在线出版日期: 2013-09-18
肾素-血管紧张素系统(renin angiotensin system, RAS)是一种在调节血压、维持水电解质平衡的循环或内分泌系统. 近年来研究发现, 除循环系统的RAS, 很多组织器官也存在局部RAS. 胰腺组织RAS不仅参与胰腺内外分泌功能的调节, 而且通过旁分泌和/或自分泌方式参与胰腺相关疾病如急性胰腺炎(acute pancreatitis, AP)、糖尿病、胰腺癌、胰岛移植的病理和病理生理过程. AP为消化系统常见的急腹症. 由于其病情重, 并发症多, 导致死亡率高, 其病因和发病机制尚未完全阐明且一直为研究的焦点. 因此, 胰腺局部RAS的提出, 为缺乏特异性治疗方法的AP提供了新的思路. 本文对RAS的不同分轴在AP中的调控作用做一综述, 为胰腺炎的治疗提供了一条新思路.
核心提示: 急性胰腺炎(acute pancreatitis, AP)时肾素-血管紧张素系统的两大轴血管紧张素转换酶-血管紧张素Ⅱ-血管紧张素Ⅱ 1型受体轴与血管紧张素转换酶2-血管紧张素(1-7)-Mas轴激活, 前者主要起病理生理作用, 而后者可拮抗前者起到一定保护作用, 通过对两大轴的调控可以减轻AP所致的损伤.
引文著录: 黄元龙, 邓明明. 肾素-血管紧张素系统在急性胰腺炎中的调控作用. 世界华人消化杂志 2013; 21(26): 2661-2667
Revised: July 26, 2013
Accepted: July 31, 2013
Published online: September 18, 2013
The renin-angiotensin system (RAS) is known as a circulating or hormonal system regulating blood pressure, electrolyte and fluid homeostasis. Recent studies have found that, in addition to the circulating RAS, local renin-angiotensin systems also exist in several tissues and organs. Pancreatic renin-angiotensin system can not only regulate exocrine and endocrine function but also, via paracrine and (or) autocrine mechanisms, participate in the pathology and pathophysiology of pancreas-related diseases such as acute pancreatitis, diabetes, and pancreatic cancer. Acute pancreatitis (AP) is a common acute abdominal disease of the digestive system, which is often complicated with many other serious diseases and is therefore associated with a high overall mortality. At present, the etiology and pathogenesis of AP have not been fully elucidated yet. Thus, the proposed concept of a local RAS in the pancreas may provide a new avenue for the development of new treatments for AP.
- Citation: Huang YL, Deng MM. Regulatory role of the rennin-angiotensin system in acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2013; 21(26): 2661-2667
- URL: https://www.wjgnet.com/1009-3079/full/v21/i26/2661.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i26.2661
急性胰腺炎(acute pancreatitis, AP)是临床常见的急腹症之一, 尤其是重症急性胰腺炎(severe acute pancreatitis, SAP), 病程进展快, 并发症多, 临床常并发全身炎症反应综合征(systemic inflammatory response syndrome, SIRS)和多器官功能衰竭(multiple organ failure, MOF), 导致病情严重, 死亡率增高. AP的发病机制目前尚不完全清楚, 有多种学说和观点. 近年来, 研究发现肾素-血管紧张素系统(renin-angiotensin system, RAS)还广泛存在于大脑、心脏、肾脏、性腺、肾上腺、消化系统等多种组织和器官, 局部的RAS通过自分泌和旁分泌及胞内分泌途径在各自组织器官的生理和病理生理的调节中起着重要作用[1-3]. 因此RAS与AP关系亦得到重视. 越来越多研究发现, 较循环系统中的RAS, 胰腺组织局部RAS通过旁分泌和/或自分泌方式在AP的病理和病理生理过程中有着更为重要的作用. 随着对RAS的深入研究和RAS组分的新发现, 近年来将RAS系统分为两大轴, 即血管紧张素转换酶(angiotensin-coverting enzyme, ACE)-血管紧张素Ⅱ(angiotensinⅡ, AngⅡ)-血管紧张素Ⅱ 1型受体(angiotensin Ⅱ receptor type 1, AT1R)轴与血管紧张素转换酶2(angiotensin-coverting enzyme 2, ACE2)-血管紧张素(1-7)[angiotensin(1-7), Ang(1-7)]-Mas受体轴, 两轴系统的平衡主要集中两种效应分子AngⅡ与Ang(1-7)的平衡上, 前者主要起病理生理作用, 而后者可拮抗前者起到一定保护作用, 本文就这两大轴与AP的关系作一综述.
ACE-AngⅡ-AT1R轴为经典的RAS组成链, 即肾素酶切血管紧张素原(angiotensinogen, AGT)生成十肽的血管紧张素Ⅰ(angiotensin Ⅰ, AngⅠ), AngⅠ随后被血管紧张素转换酶(angiotensin-coverting enzyme, ACE)酶切去除两个氨基酸后产生8肽有活性的AngⅡ. AngⅡ为一线状小肽, 是ACE-AngⅡ-AT1R轴主要的效应成分[4]. AngⅡ除由ACE作用产生外, 还可通过其他途径产生, 如糜蛋白酶催化AngⅠ转化为AngⅡ[5], 组织蛋白酶G、组织型纤溶酶原激活剂(tissue type plasminogen activator, tPA)直接催化AGT形成AngⅡ; 前肾素/肾素受体广泛分布于局部器官组织[6], 通过与前肾素结合并内化后不但刺激细胞内AngⅡ的大量合成, 同时可以不依赖于AngⅡ直接激活细胞内丝裂原激活蛋白激酶(mitogen-activated protein kinase, MAPK)磷酸化[7]. 来源于多条途径的AngⅡ作用于其不同受体发挥不同的特定作用.
在过去十几年, 局部RAS在胰腺内外分泌腺的存在逐渐得以证实[8-10]. Chappell等[11,12]首先在狗的胰腺组织中证实AGT、AngⅡ的表达, 随后亦首次报道大鼠胰腺泡细胞AR42J细胞系表达ACE-AngⅡ-AT1R轴的全部组分, 包括: AGT、肾素、ACE和AT1a、AT1b、AT2受体. 1999年Leung等[13]在大鼠胰腺组织中也发现肾素、血管紧张素原等RAS组分的表达及AT1a、AT1b、AT2受体亚型的表达, 且主要位于胰腺导管上皮细胞、血管内皮细胞、胰岛细胞, 而胰腺腺泡细胞相对较少. Lam等[14]发现人类胰腺的胰岛细胞表达AGT、导管细胞表达AT1和AT2受体, 在胰腺肿瘤时上述组分表达上调; 随后Ramrancheya等[15]发现胰岛素的分泌直接由AngⅡ调控. 进一步研究显示AngⅡ及其受体AT1、AT2在啮齿类动物及人的胰腺中主要位于胰腺导管上皮细胞、血管内皮细胞等导管系统中[16]. AngⅡ受体亚型有4种: AT1、AT2、AT3、AT4受体. AT1受体是其中的最为重要的受体. 在啮齿类动物中, AT1受体亚型又分为两种异构型: AT1a和AT1b, 特别是AT1a在胰腺炎时表达增加, 而AT1b表达无明显变化. AT1受体主要介导AngⅡ的经典生物学活性, 包括血管收缩、钠的重吸收、细胞增殖、胞外间质形成、炎症反应及氧化应激等[17]. AT2受体主要存在于人胚胎组织、脑组织等, 其也定位于啮齿类动物的胰腺导管上皮细胞和血管内皮细胞等[13]. AT2受体激活一方面拮抗ATI受体来阻断血管收缩, 促进细胞凋亡等效应; 另一方面, 过度激活时则导致心肌肥大、纤维化、动脉粥样硬化、炎性因子活化等病理状态. AT3、AT4受体的分布和所介导的功能目前尚不十分清楚.
AP是以胰腺组织水肿、腺泡细胞坏死以及受损腺体的出血和炎症为特点的一种炎症性疾病. AP时ACE-AngⅡ-AT1轴激活上调, 胰腺组织中肾素、血管紧张素原、AngⅡ及其受体等RAS组分明显增加[13,18]. AP损伤结局与胰腺RAS活化密切相关. RAS可能在以下几个方面参与AP的发病机制: (1)微循环障碍. 胰腺小叶微动脉为终末动脉, 其间无吻合支, AP时RAS激活产生的AngⅡ与其受体结合后产生强烈的缩血管作用, 引起胰腺组织缺血, 毛细血管淤血, 氧分压下降, 这些因素相互作用使胰腺微血管持续痉挛导致微循环处于恶性循环状态. 微循环障碍既是AP发生的使动因子, 同时AP又能损伤胰腺自身和全身微循环[19]. AngⅡ亦可通过激活酪氨酸激酶Jak2/Rho转化因子Arhgef1/RhoA途径来介导血管收缩, 调节血管紧张度[20]. 因此抑制AngⅡ的作用可以减弱胰腺局部RAS的激活, 减轻微循环障碍所致的损伤. Carlsson等[21]用微球技术发现AngⅡ呈剂量依赖性的减少胰岛血液灌注和胰岛素的分泌, 给以ACE抑制剂enalaprilate能够改善上述情况. Tsang等[22]在雨蛙素诱导的AP模型中应用AT1受体亚型拮抗剂Losartan与血管平滑肌AT1受体结合而拮抗AngⅡ的血管收缩作用, 降低末梢血管阻力, 改善胰腺微循环障碍, 减轻胰腺损伤. Ip等[23]研究发现ACE抑制剂Captopril能够减低胰腺炎时ACE的蛋白表达量, 对胰腺炎病变起到保护作用, 其机制可能与降低应激反应程度, 改善微血管内皮功能, 保护胰腺微循环有关; (2)促进炎症介质产生. RAS参与了像黏附分子、趋化因子、细胞因子、转化因子等前炎症因子的产生[24]. 肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)是发生AP时体内重要的前炎症因子之一, 其水平变化与AP的严重程度密切相关[25]. AngⅡ促进黏附分子(胞间黏附分子-1、E-选择素等)和细胞因子[TNF-α、白介素-6(interleukin-6, IL-6)、IL-1等]的合成和释放, 其机制可能是激活炎症信号转导通路核因子-κB(nuclear factor-κB, NF-κB), 继而调节细胞因子、黏附分子、趋化因子的等基因表达, 同时上述前炎症因子刺激各种炎症细胞, 形成炎症瀑布, 使炎症反应不断放大失控, 从而参与SIRS发病机制. 由于NF-κB在AngⅡ介导的炎症损伤中起着关键作用, 故抑制AngⅡ可降低NF-κB活性, 减少其调控的炎症因子的表达, 减轻炎症反应[26]. Oruc等[27]证实在大鼠AP模型中应用TNF-α拮抗剂英夫利昔能够明显降低血清淀粉酶、胰腺组织病理评分以及抑制炎细胞的浸润和改善AP时所致相关脏器的功能障碍. Pupilli等和Williams等[28,29]研究表明AngⅡ可以有效促进血管渗透因子/血管内皮生长因子(vascularpermeability factor/vascular endothelial growth factor, VPF/VEGF)合成分泌, 并呈剂量、时间依赖性, 从而导致血管通透性的增加, 导致胰腺组织局部炎细胞浸润和血管内大分子物质的渗出, 促进组织炎性水肿, 这种作用是通过AT1受体介导的. AT1拮抗剂络沙坦可以可以阻断其作用改善AP的病理变化及减轻肺部炎症等全身炎症反应[30]; (3)大量氧自由基的产生. 自由基的释放和清除机制的紊乱与AP的发病以及发展进程有关. AP时的"缺血-再灌注"损伤产生大量氧自由基. Schieffer等[31]证实血管紧张素Ⅱ可增加氧自由基, 活化炎症信号传导通路JAK激酶/信号传导和转录激活因子[(janus kinase, JAK)/(signal transducer and activator of transcription, STAT)]. Leung等[32]通过研究发现, AngⅡ可通过增加还原型烟酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate, NADPH)氧化酶或黄嘌呤氧化酶(xanthine oxidase, XOD)的活性刺激血管内皮细胞和平滑肌细胞大量合成活性氧(reactive oxygen species, ROS). 大量氧自由基的产生引起细胞膜脂质过氧化而导致细胞毒效应, 他是机体内细胞损伤的分子机制中重要一环[33]. Mervaala等[34]在双转基因大鼠试验研究中, 用ATI受体拮抗剂缬沙坦可恢复AngⅡ引起的黄嘌呤氧化酶活性增加和氧化应激所致的血管内皮细胞功能失调. 因此急性胰腺时ACE-AngⅡ-AT1R轴的组分表达增加, 阻断该轴显示对胰腺损伤起到保护性作用.
ACE2是ACE家族中第一个被发现的ACE同系物, 其为一单羧肽多底物金属蛋白酶, 也是SARS冠状病毒感染易感细胞必需的功能性受体[35]. ACE2存在于胃肠、心脏、肾脏、睾丸、胰腺和子宫内膜等处[36]. Ang-(1-7)是RAS中重要的活性七肽, 其产生有3条途径: (1)由脯氨酸内肽酶(prolyl endopeptidase, PE)、脯氨酸羧基肽酶、ACE2水解AngⅡ产生, 这条途径也是Ang-(1-7)产生的主要途径[37]; (2)PE、中性肽链内切酶(neprilysin, NEP)水解AngⅠ直接产生; (3)AngⅠ经ACE2代谢生成血管紧张素(1-9)[angiotensin(1-9), Ang(1-9)], 再经ACE作用产生. Mas受体是一种原癌基因编码的7次跨模G蛋白偶联受体[38]. Ang(1-7)是该受体的内源性结合物, Mas转染可增加Ang(1-7)的活性. Mas受体在体内可以对抗AT1R的作用[39].
Chappell等[11]在发现犬胰腺局部AngⅡ、血管紧张素原时, 亦检测到发现胰腺组织局部AngⅡ、AngⅢ及Ang-(1-7)的表达高于血浆浓度数倍. Bindom等[40,41]研究也证实ACE2和Mas受体亦存在小鼠胰腺中, 且胰腺局部ACE、ACE2表达失衡与胰岛β细胞功能障碍和糖代谢紊乱相关. 郭丽敏等[42]用免疫电镜方法检测到ACE2在大鼠胰腺内、外分泌腺均有表达, ACE2在胰腺内分泌腺表达非常弱, 在胰腺外分泌腺呈较强表达. 周琳等[43]在研究ACE2和ACE在人胰腺癌组织中的表达情况及相互关系时, 发现ACE2和ACE蛋白均主要表达于胰腺导管细胞或胰腺导管癌细胞胞浆, ACE2在胰腺癌中的转录和蛋白水平均明显下调, 且与ACE呈负相关. Wang等[44]近期在小鼠重症AP模型观察到胰腺局部ACE2-Ang(1-7)-Mas轴的各组分ACE2、Ang(1-7)、Mas受体的表达明显升高, 血浆Ang(1-7)的水平在造模后也明显升高.
越来越多的证据表明ACE2-Ang(1-7)-Mas轴的众多保护性生物学作用是通过对ACE-AngⅡ-AT1R轴的负性调节表现出来的[45]. ACE2水解AngⅡ的产物Ang(1-7)能拮抗AngⅡ的作用, 因此ACE2是RAS中起负调节作用的金属鳌合蛋白酶. 研究证明ACE2的高表达可负向调节AngⅡ导致的NADPH氧化酶的活性、炎症和单核细胞的黏附表达[46-48]. Sampaio等[49]的研究也证实Ang-(1-7)通过其特异性Mas受体介导了依赖蛋白激酶B(protein kinase B, PKB)途径磷酸化, 刺激一氧化氮的产生, 拮抗AngⅡ引起的外周缩血管效应. Ang-(1-7)与Mas结合后亦可抑制AngⅡ引起的MAPK磷酸化来发挥保护作用[50]. da Silveira等[51]研究发现Mas受体激动剂AVE0991可以减轻关节炎大鼠的炎性细胞的聚集, TNF-α、IL-1β等细胞因子的产生. 张雪莲等[52]发现肥胖自发性糖尿病大鼠(otsuka long-evans tokushima fatty, OLETF)大鼠胰岛细胞Mas在mRNA及蛋白水平均显著低于同种系同龄糖耐量正常(long-evans tokushima otsuka, LETO)大鼠, ACE2 mRNA及蛋白水平仅呈现下降趋势, 说明Mas缺失导致大鼠出现葡萄糖耐量异常和胰岛素敏感性下降, 提示Mas受体在胰岛素抵抗发生和发展中的作用. 近年有报道应用Mas受体阻断剂可观察到第一时相胰岛素分泌缺失, Mas缺失小鼠呈现内皮细胞功能受损NO产生减少[53]. Wang等[44]在小鼠重症AP中发现ACE2、Mas受体基因及蛋白表达上调, 故推测ACE2-Ang(l-7)-Mas轴在AP的发生发展过程中也起到一定的保护作用, 能对抗RAS经典轴ACE-AngⅡ-AT1R的损伤作用. 因此Ang(l-7)是AngⅡ天然的拮抗剂, 在机体内大多数通过作用于特异性受体Mas从而引起其下游一些细胞因子如缓激肽、前列腺素、转化生长因子-β、巨噬细胞迁移抑制因子(macrophage migration inhibitory, MIF)、葡萄糖转运子-4等表达量和活性变化来发挥舒张血管、抗纤维化、抗炎、利钠利尿、降血压、改善心脏功能、保护血管内皮、增加胰岛素敏感性等生物学效应[54]. 但目前ACE2-Ang(1-7)-Mas轴在AP的研究报道相对较少, 需要进一步深入通过基因敲除、转导等生物技术或运用该轴激动剂及拮抗剂等方法来深入研究ACE2-Ang(1-7)-Mas轴对胰腺炎损伤保护作用潜能.
近年来通过新的生物技术方法发现胰腺RAS组分在不同物种和离体细胞表达情况不甚相同. 随着对胰腺等局部组织器官RAS的深入研究, 其新成员的不断增加, 形成了一多元系统, 其不同分支点在RAS的不同位点发挥着不同作用, 从而在AP等胰腺相关疾病的发生发展过程中发挥着相应的保护或加重损伤作用. 那么, 可从蛋白基因水平对RAS的缺陷或过度作用进行调控, 同时亦可应用RAS抑制剂或激动剂作用于其不同位点发挥抑制或促进作用, 如: (1)血管紧张素转换酶抑制减少血管紧张素Ⅰ向血管紧张素Ⅱ转化; (2)血管紧张素Ⅱ受体拮抗剂阻断血管紧张素Ⅱ的作用; (3)肾素抑制剂则从源头上阻断RAS, 有效减少AngⅠ、AngⅡ的生成, 亦抑制肾素或前肾素与前肾素/肾素受体结合后的催化活性[55]; (4)Ang(1-7)非肽类似物如AVE0991作用于MAS受体, 起到与Ang(1-7)同样的保护作用; (5)糜蛋白酶抑制剂减少依赖糜蛋白酶的AngⅡ生成途径. 因此, 针对胰腺RAS不同分轴的调控, 将为胰腺炎的治疗提供一条新的思路.
急性胰腺炎(acute pancreatitis, AP)是临床常见的急腹症, 其病因和发病机制尚不明确, 缺乏特异性的治疗.肾素血管紧张素系统这一多元系统的不同分轴的不同组分在AP时表达程度不同, 因此以该系统作为靶点治疗AP可能具有重要的临床意义.
陈其奎, 教授, 广东省广州市, 中山大学附属第二医院消化内科
胰腺组织内肾素-血管紧张素系统(renin angiotensin system, RAS)的激活在AP的发病机制中为一研究焦点. 但胰腺炎局部RAS激活后不同分支RAS组分的改变及其调控的上下游炎症途径尚需进一步研究阐明, 从而为AP的治疗奠定新的理论和方法.
Wang等的研究显示在雨蛙素诱导的小鼠重症AP模型中胰腺局部ACE2- Ang(1-7)-Mas轴的各组分的表达显著上调. 这是该轴在AP表达的较新报道.
本文从肾素血管紧张素系统两大轴与AP的关系入手. 综述了其对AP调控作用, 探讨抑制亦或上调该系统两大轴对AP的所产生的保护作用.
肾素-血管紧张素系统为一多元系统, 在AP的发生发展过程中, 其不同分支点的组分与不同受体结合对胰腺起着保护或加重损伤的作用. 因此, 应用该系统不同分支位点的抑制剂或激动剂作用于其受体, 为AP的治疗提供了一条新思路.
本文总结了肾素-血管紧张素系统两大分支轴与AP的关系. 对AP的发生发展提出了新的发病机制, 同时为胰腺炎的治疗提供了新靶点, 有理论意义与临床价值.
编辑: 黄新珍 电编: 闫晋利
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