修回日期: 2011-04-20
接受日期: 2011-04-26
在线出版日期: 2011-05-08
环氧合酶-2是人体合成前列腺素的关键酶, 参与炎症反应、细胞增殖与凋亡, 在多种疾病中发挥作用. 近年来研究发现, 环氧合酶-2与肝脏疾病发生发展密切相关, 选择性环氧合酶-2抑制剂有望成为临床治疗肝病的有效药物. 本文就环氧合酶-2与肝脏疾病的研究进展作一综述.
引文著录: 陈晶, 杜雅菊. 环氧合酶-2与肝脏疾病的研究进展. 世界华人消化杂志 2011; 19(13): 1321-1325
Revised: April 20, 2011
Accepted: April 26, 2011
Published online: May 8, 2011
Cyclooxygenase (COX) enzymes catalyze the rate limiting steps in prostaglandin synthesis and play an important role in inflammation, cell proliferation and apoptosis that are involved in the pathogenesis of many diseases. In recent years, great advances have been made in understanding the role of cyclooxygenase-2 in the pathogenesis of liver diseases. The use of selective cyclooxygenase-2 inhibitors provides a new avenue for clinical therapy of liver diseases. In this article, we will review recent advances in understanding the role of cyclooxygenase-2 in the pathogenesis of liver diseases.
- Citation: Chen J, Du YJ. Advances in understanding the role of cyclooxygenase-2 in the pathogenesis of liver diseases. Shijie Huaren Xiaohua Zazhi 2011; 19(13): 1321-1325
- URL: https://www.wjgnet.com/1009-3079/full/v19/i13/1321.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v19.i13.1321
环氧合酶(cyclooxygenase, COX)是体内催化花生四烯酸合成前列腺素(prostaglandin, PG)的关键酶, 哺乳动物细胞表达2个亚型的COX, 即COX-1和COX-2. 其中COX-1为结构型酶, 参与维持机体的正常功能; COX-2属诱导型酶, 参与炎症反应、细胞增殖、细胞凋亡等多种病理过程. 研究发现, COX-2在正常肝组织中仅有极少量表达, 在肝脏疾病中表达则明显增强, 因此, COX-2在各种肝脏疾病中的作用越来越受重视[1,2]. 为此, 本文将对COX-2在各种肝脏疾病发病机制中的作用进行综述.
酒精性肝病(alcoholic liver disease, ALD)是由于长期大量饮酒所致的肝脏疾病, 初期通常表现为脂肪肝, 进而可发展成酒精性肝炎、酒精性肝纤维化和酒精性肝硬化. 虽然此病多见于西方国家, 但近年来在我国发病呈上升趋势, 严重危害人民健康. ALD的发病机制仍未完全明确, 研究热点集中在酒精和其代谢产物的毒性作用, 氧应激和脂质过氧化, 以及炎症介质和细胞因子的作用. COX-2就是其中一个重要的炎症因子. 酒精性肝损伤时, 肝组织中多种细胞, 如库普弗细胞、肝细胞和肝星状细胞等, COX-2表达明显增高, 且库普弗细胞是COX-2的主要来源[3]. 氯化轧(Gdcl3)灭活库普弗细胞后, COX-2表达明显下降, 酒精诱导的肝脂肪变性减轻[4]. 实验性大鼠酒精性肝损伤时, 除COX-2基因表达增强外, 血浆内毒素、肝内TNF-α mRNA和脂质过氧化均增高, 故推测乙醇所致的脂质过氧化和内毒素在酒精性肝损伤时可能起协同作用, 即共同作用于库普弗细胞致TNF-α、COX-2合成增加, COX-2和TNF-α共同介导LPS的肝细胞毒性而损伤肝脏. COX-2被认为是这一系列复杂环节中的关键最后通路[3].
有研究表明, 在酒精性肝损伤时, 内毒素血症和氧化应激激活NF-κB, 且NF-κB的活化与大鼠肝脏坏死性炎症的进展有关. NF-κB活化后, COX-2随后表达增强, 起到促炎症作用[5,6]. 乙醇在肝脏代谢过程中产生大量的活性氧与肝细胞膜性结构中的非饱和脂肪酸反应, 生成以丙二醛(malondialdehyde, MDA)为主的脂质过氧化物, MDA通过G蛋白及丝裂原激活的蛋白激酶(mitogen activated protein kinase, MAPK)介导的信号通路激活NF-κB抑制物α(inhibitor κBα, IκBα)激酶, 使NF-κB活化发生核移位. 因COX-2 启动子上含有2个NF-κB的结合位点, NF-κB与该位点结合后诱导COX-2的转录[7].
COX-2表达增强后发挥促炎症作用, 可能与诱导PG系统表达改变有关. 氧应激激活PLA2, 使细胞内游离的氨基酸增多, 大量的氨基酸在高表达的COX-2作用下, 产生PG, 导致肝损伤进一步加重. Enomoto等[8]对酒精喂养的动物模型进行研究时证实被激活的库普弗细胞表达COX-2增高, PGE2水平升高, PGE2与肝细胞膜上EP2/ EP4受体结合后活化腺苷酸环化酶, 使肝细胞内cAMP增多, 引起三酰甘油在肝细胞中堆积, 参与肝细胞中的脂肪蓄积过程. Ganey等[9]报道, 使用酒精处理大鼠, 在ALT和AST升高的同时, 肝脏COX-2表达也明显增高, 血浆PGD2升高, 而使用COX-2抑制剂NS2398可以降低血浆PGD2浓度, 同时使ALT和AST水平下降. 但此观点尚存在学术争议, 相反的观点认为, PGE2水平升高起到抑制脂肪肝的作用. 长期小剂量的选择性COX-2抑制剂, 可促进酒精诱导的脂肪性肝炎的进展及肝脏炎症, 可能与其减少COX-2产物PGE2从而消除其他前列腺素的内源性保护作用有关[10].
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是一种与胰岛素抵抗(insulin resistance, IR)和遗传易感密切相关的代谢应激性肝脏损伤, 其病理学改变与ALD相似, 但患者无过量饮酒史, 疾病谱包括非酒精性单纯性脂肪肝(nonalcoholic simple fatty liver, NAFL)、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis, NASH)及其相关肝硬化和肝细胞癌[11]. NAFLD是21世纪全球重要的公共健康问题之一, 亦是我国愈来愈重视的慢性肝病问题.
目前认为, NASH与酒精性肝炎有着相似的肝组织病理改变, Day等[12-14]提出的"二次打击"学说可能为他们共同的发病机制. 该学说认为各种原因引起的肝细胞脂肪积聚和脂肪变性作为"初次打击", 使肝细胞对各种损伤的易感性增高, 氧应激、脂质过氧化、炎性细胞因子释放、线粒体功能异常等形成"二次打击", 诱导肝脏的炎症反应, 肝细胞发生变性坏死、肝纤维化, 最终导致肝硬化. 有关COX-2在NASH中的作用机制报道较少. 研究表明[15], 胆碱缺乏饮食诱导的大鼠NASH模型中, 肝脏表达COX-2明显增高, 且其高表达与NF-κB激活有关. 高表达的COX-2诱导TNF-α、IL-6、细胞间黏附分子1(intercellular adhesion molecule 1, ICAM-1), 同时这些因子反过来又可诱导COX-2进一步持续高表达. 使用选择性COX-2抑制剂NS2398和塞来昔布可减轻NASH大鼠肝脏的脂肪变及炎症反应, 证实COX-2在NASH发病中起重要作用.
慢性HBV、HCV感染常常发展为肝硬化及肝癌, 威胁着我国人民的生命和健康. 近年研究表明, COX-2在慢性乙型肝炎和慢性丙型肝炎的进展中发挥着重要的作用. Cheng等[16]研究了COX-2在病毒性肝炎所致肝纤维化患者肝脏中的表达情况, 发现随着肝纤维化程度的加重, COX-2的表达逐渐增强. 我国学者邵建国等[17]研究发现, COX-2在慢性乙型肝炎患者肝组织中表达增强, 且其表达随肝脏炎症程度的加重而增强, 但COX-2增高水平与HBV DNA水平无关, 提示可作为反映肝脏炎症程度的一项指标. 但也有不同的观点认为[18], 虽然慢性乙型肝炎患者肝脏COX-2表达较正常肝组织明显升高, 但在炎症坏死程度不同的HBeAg阳性和阴性组, COX-2表达并无显著差异, 说明COX-2的高低不能作为反映肝脏炎症程度的指标. 在有效抗病毒治疗后, COX-2仍持续处于高水平状态而无明显下降. COX-2在慢乙型肝炎患者肝脏中升高的机制, 可能由于COX-2与HBx之间存在交互协同作用, HBx诱导COX-2表达有助于病毒逃避免疫系统, 且与HBV慢性感染进展到肝硬化及肝细胞癌有关[19].
HCV感染可以上调COX-2 mRNA和蛋白, 阿司匹林可以通过激活MEK1/2/p38 MAPK通路, 抑制COX-2表达, 从而发挥抑制HCV-RNA复制的作用[20]. 学者们对HCV致COX-2表达增强的机制进行了相关的研究. 在慢性丙型肝炎患者肝脏中, COX-2和MMP-9表达增强, 且其表达增强与HCV核心蛋白和NS5A蛋白的作用有关[21]. 这可能与HCV核心蛋白和NS5A蛋白能够激活NF-κB基因的转录有关[22]. 研究发现[23], HCV可以诱导活性氧族的升高, 进而激活NF-κB, 促进COX-2和PGE2的表达, COX-2和PGE2在HCV复制中发挥着重要的调控作用. 此外, 人体对HCV感染的易感性及感染HCV后患者肝脏的炎症程度, 均与COX-2启动子的基因多态性有关[24].
肿瘤的发生、发展是一个多因素多步骤的相互协同过程, 由多种因素参与. 目前研究证实COX-2的过度表达可能参与人类多种肿瘤的发生、发展过程, 其在肝癌中的作用正成为研究热点[25,26]. COX-2在肝细胞癌中的阳性表达不仅仅是一个早期事件, 而且参与了肝细胞癌的发生、发展、侵袭转移的全过程[27]. 目前认为其可能的机制为影响肿瘤细胞的增殖及凋亡、促进肿瘤血管的形成, 并参与肿瘤的转移和复发[28,29].
调节肿瘤细胞的增殖和凋亡 正常的p53基因产物可抑制COX-2表达, p53或ras基因突变可使COX-2表达增强. COX-2可催化一系列异位氧化反应, 包括致癌物产生的氧化胺与DNA作用从而影响抑癌基因导致肿瘤产生, 在抑癌基因突变为癌基因的过程中起重要的作用.
HBx能够激活被P53抑制的抗凋亡蛋白Mcl-1, 从而阻断P53诱导的肿瘤细胞凋亡. 这一过程可以被COX-2抑制剂所阻断, 说明上述过程是通过活化COX-2/PGE2而实现的[30]. Leng等[31]研究发现, 将COX-2基因的质粒转染至多种肝细胞癌细胞株, 能明显促进肿瘤细胞的增殖; 将反义COX-2质粒转染上述肿瘤细胞则可抑制细胞增殖. 使用塞来昔布处理肝癌细胞株后细胞出现明显的凋亡征象, 且这一过程可能通过线粒体-细胞色素c/caspase-9/caspase-3通路完成. 选择性COX-2抑制剂能够促进肝癌细胞凋亡、抑制肝癌细胞增殖而发挥抗癌作用[31,32]. 研究发现, 肝癌细胞株HepG2和Hep3B对TRAIL耐药, 塞来昔布的促凋亡作用, 可能与其作用于肝癌细胞后, 肝癌细胞对TRAIL的敏感性增强有关[33].
COX-2在肿瘤血管形成中的作用包括: 增加促血管生成因子的表达; COX-2的催化产物, 如血栓烷A2、PGE2、PGI2等产生能直接刺激内皮的迁移和生长因子诱导的血管生成; COX-2通过刺激Bcl-2和Akt的活化, 抑制血管内皮细胞凋亡的能力[34,35].
Rahman等[36]测定100例肝癌患者肝组织COX-2和诱导性一氧化氮合酶(inducible nitric oxide synthase, iNOS)表达及癌组织中血管密度发现, COX-2和iNOS的表达和肿瘤血管密度呈显著相关, COX-2参与肿瘤血管形成. COX-2、iNOS、IL-8是一组可诱导蛋白, 其启动子均含有NF-κB应答元件, 炎症反应时IL-1和TNF-α等细胞因子水平提高, 激活NF-κB, 从而使COX-2表达上调. 表达COX-2的细胞也表达iNOS, 两者具有协同作用. HCV阳性的HCC患者中, iNOS及COX-2表达阴性者的存活时间比阳性者明显延长[37].
COX-2作为PG合成过程中的关键酶, 在肝脏炎症和肝癌的发生发展中起重要促进作用. 选择性COX-2抑制剂, 如塞来昔布、NS2398等, 高选择性的抑制COX-2而对COX-1抑制较弱, 避免了抑制COX-1后所致的胃肠黏膜损害等不良反应, 已广泛应用于心血管病的预防及治疗中. 在临床应用中发现, COX-2抑制剂具有安全性高的优点, 但也有一些个案报道其导致黄疸、转氨酶升高等肝脏毒性作用. 因此, 虽然大量基础实验证实, COX-2在肝脏疾病中高表达及COX-2抑制剂对肝脏疾病的有效治疗作用, 但COX-2抑制剂应用于肝脏疾病患者群中, 仍需谨慎对待和进一步研究.
前列腺素广泛存在于人体许多组织中, 其生理作用极其广泛, 在内分泌、生殖、消化、血液、呼吸、心血管、泌尿、神经等多种系统中发挥病理生理作用. 研究发现, 前列腺素参与多种肝脏疾病的发生发展, 而环氧合酶-2作为前列腺素合成中的限速酶, 在肝脏疾病中具有重要的作用.
朴云峰, 教授, 吉林大学第一临床医院消化科
目前研究证实COX-2的过度表达可能参与人类多种肿瘤的发生、发展过程, 其在肝癌中的作用正成为研究热点.
Iwamoto等研究发现, 肿瘤组织中COX-2升高抑制局部免疫应答, 从而参与肿瘤切除后剩余肝组织的肿瘤复发.
肝脏疾病发病机制复杂多样, 环氧合酶-2在不同的肝脏疾病中的作用及机制均不尽相同. 本文把环氧合酶-2在多种肝脏疾病中的作用和机制作了详细的综述, 为环氧合酶-2抑制剂应用于肝脏疾病的临床治疗提供了一定的方向.
本文新颖性较好, 具有较好的学术价值和可读性.
编辑: 李军亮 电编:何基才
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