修回日期: 2013-06-27
接受日期: 2013-07-03
在线出版日期: 2013-08-08
尾加压素(urotensin Ⅱ, UⅡ)是一种有效的血管活性物质. UⅡ通过与其特异性孤儿G-蛋白耦联受体GPR-14结合发挥血管活性作用. UⅡ的血管活性作用具有种族特异性和疾病特异性. 随着对UⅡ进一步深入的研究, 发现其除具有血管活性作用以外, 还具有促有丝分裂和促纤维化作用. 有研究发现UⅡ在肝硬化患者血浆中表达升高, 但其在慢性肝病以及门脉高压发生发展中的作用机制尚不明确. 这篇综述主要介绍了UⅡ作为血管活性物质在慢性肝病发生发展中的潜在作用以及探讨肝脏中表达UⅡ的位点.
核心提示: 尾加压素在肝硬化患者中表达升高, 提示其在慢性肝病发生发展中的潜在作用, 其受体拮抗剂的研究可能为肝硬化门脉高压症的治疗提供新的思路.
引文著录: 梁冬雨, 侯彦强, 娄晓丽, 叶长根. 尾加压素在肝硬化中的研究进展. 世界华人消化杂志 2013; 21(22): 2164-2168
Revised: June 27, 2013
Accepted: July 3, 2013
Published online: August 8, 2013
Urotensin Ⅱ (UⅡ) is a potent vasoactive substance that can result in vasoactive response through interaction with its specific orphan G-protein-coupled receptor GPR-14. In addition to the role of vasoactivity, UⅡ can promote mitosis and fibrosis. The vascular role of UⅡ is to some degree both species- and disease-specific. Studies have found that plasma levels of UⅡ are elevated in patients with cirrhosis, but the relationship between plasma levels of UⅡ and the development of chronic liver disease and portal hypertension has yet to be fully elucidated. This review focuses on the potential relevance of UⅡ as vasoactive substance in chronic liver disease and the site where UⅡ is overproduced.
- Citation: Liang DY, Hou YQ, Lou XL, Ye CG. Progress in understanding role of urotensin Ⅱ in hepatic cirrhosis. Shijie Huaren Xiaohua Zazhi 2013; 21(22): 2164-2168
- URL: https://www.wjgnet.com/1009-3079/full/v21/i22/2164.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i22.2164
肝硬化是一种常见的慢性肝病, 发病率和病死率很高, 目前认为其形成的机制主要是肝内阻力增加和门脉血流量增多, 但多种因素均可能参与其发病过程[1,2]. 近年来, 不断发现新的因素参与了肝硬化的发生、发展. 尾加压素(urotensin Ⅱ, UⅡ)是一种有效的血管活性肽, UⅡ通过与其特异性孤儿G-蛋白耦联受体GPR-14结合发挥血管活性作用[3,4]. 最近研究发现UⅡ在肝硬化患者血浆和组织中表达升高, 提示UⅡ可能与肝硬化的发生、发展及预后密切相关[5]. UⅡ拮抗剂的研究也许可揭示肝硬化的发病机制, 为肝硬化的治疗提供新的方向.
上消化道出血是肝硬化门脉高压症最严重的并发症之一, 严重威胁着肝硬化患者的生命. 生长抑素(somatostatin, SST)及其类似物奥曲肽(octreotide, OCT)是目前治疗门脉高压引起上消化道出血的有效药物, 然而SST和OCT降低门静脉压力控制静脉曲张出血的机制尚未明确, 众多研究认为, SST和OCT通过抑制内脏血管收缩来降低门静脉压力[6,7]. 人尾加压素Ⅱ(human urotensinⅡ, hUⅡ)是一种由11个氨基酸组成的多肽, 一级结构为Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val, 是迄今所知体内最强的缩血管肽, 其C末端高度保守的六肽结构Cys-Phe-Trp-Lys-Tyr-Cys与SST和OCT非常相似[8]. UⅡ通过与其特异性受体GPR14结合发挥血管活性作用, 研究发现SST和OCT在高浓度条件下也能竞争结合GPR14受体, 抑制UⅡ的缩血管活性[9]. Pomier-Layrargues等[10]通过尾静脉注射OCT, 发现其能对抗UⅡ引起的大鼠主动脉环的收缩, 而且这种现象在肝硬化老鼠模型中更为明显, 这一发现说明OCT可以通过与UⅡ受体结合抑制UⅡ引起的缩血管作用. 另外, UⅡ除具有缩血管活性外, 对大鼠肠系膜血管、人腹部阻力血管具有舒张作用[11,12]. 肝硬化门脉高压发生上消化道出血的原因之一是由于肠系膜血管舒张, 导致内脏血流增加[13]. 因此, 我们推测奥曲肽治疗上消化道出血的机制可能是通过竞争结合UⅡ受体, 从而拮抗UⅡ的血管活性作用. UⅡ的发现及研究为肝硬化门脉高压的发生发展机制提供新的视野. UⅡ拮抗剂在治疗肝硬化方面的研究目前已成为国内外的热点, 希望在不久的将来, UⅡ受体拮抗剂将为这种疾病的治疗提供新的选择.
在以往的研究中, 由于所选患者不同, 方法和敏感度不同, UⅡ及其受体在肝脏中的表达量有所差异, 但总的来说, 在正常情况下, UⅡ及其受体在肝脏中呈低水平表达[14-18]. Charles等[19]通过同时收集已麻醉羊的动脉和静脉样本来检测UⅡ在肝脏中的分布, 结果发现肝静脉中UⅡ表达量明显高于同时间收集的颈动脉标本, 这说明UⅡ可能来源于肝脏, 当然也不排除UⅡ可能来自内脏循环或门静脉系统. 为了进一步证明UⅡ的来源, Heller等[20]检测了30例经颈静脉肝内门体支架分流术肝硬化患者肝静脉和门静脉中UⅡ的表达水平, 结果发现UⅡ在肝静脉中表达显著高于门静脉, 由此推断UⅡ是通过肝脏释放出来的. 有学者研究发现在胆管结扎的肝硬化大鼠肝脏中UⅡ/UT的表达显著高于正常大鼠, 免疫组织化学染色显示UⅡ、UT在肝脏表达定位于动静脉及胆管的内皮细胞、库普弗细胞, 而这些细胞在肝硬化门脉高压中发挥重要作用, UⅡ/UT可能通过调节这些细胞而在肝硬化门脉高压中发挥重要作用[21,22].
血浆UⅡ水平在多种疾病中表达升高, 如高血压、糖尿病、肾衰竭等[23-29], 但目前对于UⅡ是否通过改变体内平衡参与这些疾病的发生发展及临床意义目前尚不完全清楚. 肝硬化患者的主要特征之一是存在着明显的高动力循环状态, 表现为"血管阻力下降, 血压降低, 心输出量增加, 局部脏器血流增加及明显的门体分流". Heller等[20]发现肝硬化门脉高压患者肝脏UⅡ/UT基因水平较正常人群明显升高, 血UⅡ/UT水平也显著升高, 然而由于患者群体多样化及其他潜在的影响因素如肝肾综合征, 血流动力不稳定等, 这一发现无法说明UⅡ在肝硬化发病中的作用. 为了进一步揭示UⅡ/UT系统在肝硬化门脉高压发生发展中的作用, Kemp等[30]收集了80例经过血流动力学评估的肝硬化患者及年龄相匹配的健康人的血清, ELISA法检测了UⅡ的表达水平, 结果显示肝硬化患者血清中UⅡ表达水平较健康人显著升高, 且按Child-Pugh分级评分系统评估后, 发现UⅡ水平与疾病的严重程度呈正相关[31]. 但Kemp等[32]的研究发现UⅡ在股静脉中的表达显著高于肝静脉, 这与Heller的研究结果不一致, 这种差异的可能原因是两组患者的疾病程度不同, Kemp等[30]组收集的60%是Child-Pugh分级A级的患者, 而Heller组收集的60%是Child-Pugh分级C级的患者, 这也间接说明了只有在疾病严重的情况下, 肝脏才过表达UⅡ.
UⅡ及其受体在人体多种器官组织中均有表达[33-37], 但通常认为循环中的UⅡ多来自于心脏组织和肾组织[38]. 肝硬化门脉高压的高动力循环对全身器官的功能改变有显著影响, 其中对心脏有很大的影响, 而血浆UⅡ水平在缺血及非缺血性心衰中均表达升高[39,40]. 另外, 肝硬化尤其是晚期肝硬化患者常由于肾素血管紧张素醛固酮的激活, 引起钠水储留, 发生功能性肾衰竭. 在动物体内的研究表明, UⅡ可以作为一种渗透调节剂引起钠水储留, 应用UⅡ受体拮抗剂urantide可引起大鼠肾小球滤过率增加, 尿量增加以及尿钠排出增多, 这些结果与Heller和Kemp的研究结果一致, 肝硬化伴腹水患者血浆UⅡ水平明显高于无腹水的肝硬化患者[41]. 当然, 肝硬化患者UⅡ升高的机制也可能是由于肝清除减少所致, 但Kemp通过在一个比较恒定的浓度范围内比较外周血和肝内血UⅡ的表达发现肝硬化时UⅡ的升高与肝清除无关. 总之, 目前研究提示肝硬化门脉高压时UⅡ/UT表达升高, 但升高的具体机制尚不明确.
UⅡ受体拮抗剂的研究对理解UⅡ/UT在各种疾病中的生理作用及揭示其治疗潜力方面非常重要, 如血管紧张素Ⅱ受体拮抗剂和内皮素受体拮抗剂能用于治疗门脉高压. UⅡ受体拮抗剂的研究可能为治疗该病提供新的选择.
Behm等[42]在2002年首次发现生长激素释放抑制因子(somatostatin, SST)拮抗剂SB-710411, 10 µmol/L的SB-710411能显著地抑制hUⅡ引起的离体大鼠主动脉的收缩反应. 随后Patacchini等[43]又发现一种新的hUⅡ受体拮抗剂-Urantide, 在离体的大鼠主动脉研究中发现, 该拮抗剂可以与hUⅡ受体高选择性结合, 极低水平即可产生激动效能, 其拮抗hUⅡ的作用是其他任何化学物的50-100倍. Palosuran(ACT-058362)是新合成的一种非肽类UⅡ受体拮抗剂, 具有高度特异性, Clozel等[44]发现其能以剂量依赖的方式拮抗UⅡ引起的兔主动脉环收缩, 且与hUⅡ受体的结合能力明显高于兔UⅡ受体.
UⅡ受体拮抗剂在疾病中的治疗作用已成为国内外研究的热点, 叶向或等[45]在糖尿病大鼠动物模型中, 通过比较对照组和Paosuran治疗组视网膜周细胞和基底膜的改变发现, Palosuran能有效抑制糖尿病的早期微血管病变. Clozel等[46]发现UⅡ受体拮抗剂的应用可以提高糖尿病小鼠生存率, 增加胰岛素分泌, 延缓血糖、糖化血红蛋白和血脂的升高, 增加肾血流, 延缓蛋白尿和肾损伤的发展. 在对肾脏的研究中发现, Palosuran可以选择性舒张肾脏血管, 在增加缺血后肾血流量的同时不合并任何全身血管舒张效应, 静脉注射Palosuran治疗缺血性急性肾衰竭大鼠, 可明显减轻肾小球和肾小管的结构损伤及功能障碍[47,48]. 在对肺损伤的研究中, 赖荣德等[49]发现UⅡ受体拮抗剂能减轻肺泡细胞损害, 增多肺泡合成表面活性物质, 减轻肺泡萎陷, 改善透影血流值, 提高氧合功能, 表现出对的肺保护作用.
关于UT拮抗剂在肝硬化门脉高压症中的作用目前也有一些研究, Trebicka等[50]在肝硬化大鼠模型中研究发现, UT拮抗剂SB-710411预防给药可以改善肝硬化大鼠的高动力循环状态, 降低肝硬化大鼠的肝纤维化评分、肝组织中羟脯氨酸含量、血肝纤维化指标, 下调大鼠肝脏I型胶原、Ⅲ型胶原以及TIMP-1 mRNA的表达, 改善肝脏纤维化. Trebicka等[50]发现Palosuran可以增加胆管结扎肝硬化大鼠的内脏血管阻力, 降低门脉血流, 而降低门脉压力. 此外Palosuran可以增加胆管结扎肝硬化大鼠的肾小球率过滤, 促进水钠排泄. 上述研究提示UT拮抗剂可以降低肝硬化门脉高压患者的门脉压力, 预防肝纤维化, 促进水钠排泄, 在肝硬化门脉高压症方面具有潜在的治疗作用.
UⅡ及其受体UT在肝硬化门脉中的表达升高, 且与疾病的严重程度和并发症如腹水密切相关, 但UⅡ/UT系统在肝硬化门脉症发生发展中的具体作用机制尚不清楚. UⅡ受体拮抗剂的应用可以改善门脉高压的血流动力学紊乱, 预防肝纤维化, 提示UⅡ受体拮抗剂可能成为防治肝硬化门脉高压的重要工具, 进一步研究UⅡ在肝硬化门脉高压中的作用, 可为肝硬化门脉高压症的治疗提供新的思路.
肝硬化是一种常见的慢性肝病, 发病率和病死率很高. 尾加压素(urotensin Ⅱ, UⅡ)是新发现的一种血管活性肽, 研究发现UⅡ在肝硬化患者血浆和组织中表达升高, 提示UⅡ可能与肝硬化的发病有关.
王小众, 教授, 福建医科大学附属协和医院消化内科; 庄林, 主任医师, 昆明市第三人民医院肝病科
肝硬化及其并发症严重危害着人类健康, 目前对其发病机制尚不完全明确, 多种因素可能参与其发病过程, 近年来, 不断发现新的因素参与肝硬化的发病, 因此揭示肝硬化的发病机制及寻找新的治疗肝硬化的药物是目前亟待解决的问题.
目前认为肝硬化的发生机制是肝内阻力增加和门脉血流量增多. UⅡ具有强血管活性. Leifeld等在2010年发现UⅡ在肝硬化患者血浆和组织中表达升高.
本文分别通过UⅡ与生长抑素、UⅡ及其受体在肝脏中的表达、UⅡ/UT在慢性肝病患者中的表达和UⅡ受体拮抗剂的全面阐述, 完整、系统、较全面的介绍了UⅡ在肝硬化中的研究.
UⅡ是一种有效的血管活性肽, 该文章阐述了UⅡ可能与肝硬化的发生、发展及预后密切相关. UⅡ拮抗剂的研究也许可揭示肝硬化的发病机制, 为肝硬化的治疗提供新的方向.
尾加压素: 一种血管活性肽, 具有强缩血管活性, 但在特定组织, 特定情况下如大鼠肠系膜血管、人腹部阻力血管中具有舒张作用.
本文对UⅡ与生长抑素的可能作用, UⅡ及其受体在实验动物及肝硬化患者中的表达水平变化, 以及受体拮抗剂的作用进行综述, 对肝硬化发病机制的认识及可能的治疗作用提供了新的思路.
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