修回日期: 2002-10-30
接受日期: 2002-11-16
在线出版日期: 2003-05-15
肝纤维化是继发于肝脏炎症或损伤后组织修复过程中的代偿反应, 细胞外基质(ECM)合成增加、降解减少, 最终导致ECM在肝内的过度沉积, 引起肝纤维化以致肝硬化; 以往对肝纤维化过程中ECM的合成研究较多, 随着肝纤维化发生发展研究的深入, 近年来逐渐认识到ECM的降解在肝纤维化发生发展中的重要地位, 目前认为, 基质金属蛋白酶(MMPs)及其抑制物(TIMPs)是调节ECM降解的主要酶, MMPs是一组能降解ECM的重要蛋白分解酶, 通过降低胶原螺旋结构的稳定性, 改变底物的二级结构, 为其他蛋白酶作进一步降解创造条件, 因此, 在ECM降解过程中起决定作用; 而TIMPs是一组具有抑制MMPs功能的活性多肽, TIMPs能与MMPs非共价结合抑制MMP的活性, 也可与酶原结合阻止其活化, 抑制ECM的降解; 在肝纤维化形成过程中, MMPs及其抑制因子的平衡在肝纤维化形成过程中起着至关重要的作用.
引文著录: 谢玉梅, 聂青和. 肝纤维化治疗的新热点-TIMPs. 世界华人消化杂志 2003; 11(5): 601-605
Revised: October 30, 2002
Accepted: November 16, 2002
Published online: May 15, 2003
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2003; 11(5): 601-605
- URL: https://www.wjgnet.com/1009-3079/full/v11/i5/601.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v11.i5.601
目前, 世界范围内对慢性肝病治疗的两大策略是抗病毒[1]治疗和阻止肝纤维化的发生[2-5], 在抗肝炎病毒治疗方面, 虽经多年努力, 但因肝炎病毒经常发生变异, 其治疗效果总是不尽人意, 可以说, 目前尚无特效疗法治疗慢性病毒性肝炎. 因此, 许多科学家把肝病的治疗重点转到如何控制肝病的进展, 防止肝纤维化以致肝硬化的发生方面[6], 随之而来的是对肝纤维化发生机制的研究.
近年来, 细胞外基质(extracellular matrix ECM )的研究飞速发展, 在正常肝脏的纤维组织中存在着ECM生成与降解的动态平衡, 肝纤维化是ECM生成与降解过程失衡的结果[7,8], 既往对ECM的生成与沉积研究较多, 近年开始对ECM降解的研究也日益深入, 在ECM降解过程中, 基质金属蛋白酶及其抑制物的平衡起着至关重要的作用[9], 基质金属蛋白酶(matrix metalloproteinases, MMPs)是一组能降解细胞外基质成分的重要蛋白分解酶, MMPs是一组锌酶, 几乎能降解除多糖以外的所有ECM成分, 并能使别的MMPs激活, 形成瀑布效应[10-13] .人体已发现的MMP有20种, 按照作用底物不同, MMP可分为4类: (1)间质胶原酶(主要包括MMP-1, MMP-8, MMP-13)主要作用Ⅰ, Ⅱ, Ⅲ型胶原; (2)基质溶解素, 主要包括MMP-3, MMP-10, MMP-11及MMP-7, 主要作用于蛋白多糖等; (3)明胶酶, 主要包括MMP-2及MMP-9, 其中明胶酶A(MMP-2), 即Ⅳ型胶原酶, 主要参与基底膜Ⅳ型胶原的代谢, 与肝纤维化的发生发展紧密相关. (4)膜型金属蛋白酶(含MT-MMP1及MT-MMP2), 位于细胞的表面, 主要与MMP-2的激活有关.肝纤维化早期, MMPs轻度增高, 而肝纤维化中晚期, MMPs活性则明显降低, 以致于ECM合成超过降解, 引起ECM大量沉积[14]. 通过调节MMPs活性, 有助于增加基质的降解, 促进肝纤维化的逆转, MMPs在肝内主要由肝星状细胞(HSC)和Kupffer细胞分泌表达[15,16], 激活的MMP可被普通的蛋白酶清除剂抑制, 如α2-巨球蛋白, 但主要被特异的TIMPs所抑制.
组织金属蛋白酶抑制物(tissue inhibitor of metallop-roteinasas TIMP)是一组具有抑制MMPs功能的活性多肽, 他们在ECM代谢的调节中起着非常重要的作用[17,18]. TIMPs在肝脏中来源主要为HSC、Kupffer细胞少量来源于肝细胞[19]. TIMPs是组织中MMPs主要的内源性抑制因子, 受许多参与MMP基因调控的细胞因子和生长因子的同步调控[20-22], 现已发现四种TIMP即TIMP-1、TIMP-2、TIMP-3、TIMP-4, 其种类及特点(见表1), 肝脏中仅有TIMP-1和TIMP-2存在. TIMPs对目前已知的MMPs均具有抑制作用.
| 种类 | 分子量(ku) | 转录产物大小(kb) | 抑制MMPs | 特点 | 在肝病中的意义 |
| TIMP-1 | 29 | 0.9 | + | 与MMP-9前体结合 | 由激活的HSCs释放, 在纤维化肝脏中明显表达或是肝细胞释放的一种急性期反应物 |
| TIMP-2 | 21 | 1.0, 3.5 | + | 与前体MMP-2结合与基质结合 | 由激活的HSCs释放, 在纤维化肝脏中明显表达不清楚 |
| TIMP-3 | 24 | 4.5-5.0 | + | ||
| TIMP-4 | 22.6 | 1.2-1.4 | ? | 于心肌组织发现 | 不清楚 |
TIMP-1是分子质量为29 ku的糖蛋白, 分子中有184个氨基酸, 其中含有12个半胱氨酸残基, 构成6个双硫键; TIMP-1对MMP活性的抑制是通过N末端3个绊而实现的, TIMP-1由多种结缔组织细胞产生, 在肝脏由Kupffer细胞、HSC及肌纤维母细胞产生, 以活化的HSC表达TIMP-1最强[23,24]; TGF-β、干扰素能够诱导TIMP-1的基因表达, TIMP-1能结合除14、19以外的所有MMP而使其活性减弱, TIMP-1与MMP-1、MMP-3结合形成1:1化合物. 肝组织内TIMP-1表达增强可促进纤维化肝间质胶原的沉积; 在病损肝中TIMP-1明显增高, 出现时间较早, 因此, 越来越多的研究人员将其看作是肝纤维化发生过程中一个非常重要的促发因素.
TIMP-2是分子质量为21 ku的蛋白质, 人的TIMP-2cDNA序列有38%与TIMP-1序列相同, 12个半胱氨酸残基与TIMP-1在同样的位置, 具有同样的立体结构, 但是不伴有糖基化, TIMP-2可与MMP-1、MMP-2和MMP-3呈1:1结合; TIMP-1及TIMP-2通过N末端结合MMP而形成复合体, 不可逆地抑制MMP的活性, TIMP-1和TIMP-2除能与活性MMP结合抑制其活性外, 还能以非共价形式与明胶酶原结合, 与明胶酶原结合的TIMP-1或TIMP-2仍能抑制MMP的活性, 提示TIMP可与明胶酶原、MMP形成三联复合体, TIMP-1及和TIMP- 2的基因表达同样可被调节MMP基因表达的生长因子所调节, TNF-α、EGF、b-FGF增加TIMP-1和间质胶原酶的表达, TGF-β1可抑制间质胶原酶、基质溶解素、PA及TIMP-2, 促进TIMP-1, PAI合成, 使前MMP-1, TIMP-1, MMP-2表达增加[25]. IL-1及IL-6可增加TIMP-1的表达, 间质胶原酶表达减少; PDGF可以增加间质胶原酶的含量. TIMP-1及和TIMP-2的基因表达可被调节MMP基因表达的生长因子所调节. TNF-α、EGF、b-FGF增加TIMP-1和间质胶原酶的表达, TGF-β1可抑制间质胶原酶、基质溶解素、PA及TIMP-2, 促进TIMP-1, PAI合成, 使前MMP-1, TIMP-1, MMP-2表达增加.
TIMP-3是分子量为24 kDa的蛋白质由188个氨基酸残基组成, 与TIMP-1、TIMP-2分别有28%和48%的同源性, 相互之间无免疫交叉反应, 他与TIMP-2均为非糖基化的蛋白质, TIMP-3以不溶性形式与ECM结合, 也能抑制各种MMP活性, 与TIMP-1、TIMP-2不同的是, 他是以与ECM结合状态存在, 能抑制各种MMP活性[26-33].
TIMP-4是分子量为22.6kDa的蛋白质, 于心肌组织中发现, 其作用机制不详[34-36]. TIMP-2、3、4主要结合前MMP2、9, 因而在肝纤维化时, TIMP-1、TIMP-2的过多表达而抑制MMP活性是纤维生成和沉积的一个重要机制.
当前肝组织活检仍是诊断肝纤维化的最可靠方法, 但由于肝脏病变的不均一性以及损伤性检查等问题不易被患者接受, 难以反复取材, 以致不能动态观察肝纤维化的形成过程及其程度, 而目前尚无简便、可靠的方法确定肝组织的胶原含量. 因此, 仅根据肝内纤维增生的情况进行估计, 具有一定的局限性; 而血清学诊断是近年来研究最广泛的肝纤维化诊断方法. 由于取材方便, 费用低, 便于开展, 较为实用. 通过对有关的血清学指标进行研究, 至今仍未能取得具有确诊意义的指标. 测定Ⅲ型前胶原N-末端前肽(PⅢ NP)主要反映纤维化形成和炎症的活动性, 并不能反映肝纤维化的程度. 近年来, 有人检测肝纤维化患者血清中的TIMP-1和胶原酶的活性, 发现TIMP-1的水平增高, 而胶原酶的活性降低, 且二者呈负相关. Li et al用EIA法检测酒精性肝病患者血清TIMP-1水平, 并与组织学指标和血清PⅢP作对比, 结果发现: 血清TIMP-1在酒精性脂肪肝患者不增高而早期酒精性肝纤维化即有升高, 升高程度与肝组织学纤维化呈显著正相关, 因而可以鉴别酒精性脂肪肝与早期酒精性肝纤维化. 血清TIMPs水平升高, 能使MMPs活性下降, 引起肝脏细胞外间质积聚, 促使肝纤维化, 因此认为检测血清TIMP-1的水平可作为肝纤维化的诊断指标. 血清TIMPs与肝纤维化分级呈显著正相关, 且在各组慢性肝病之间重叠较少, 是一种反映肝脏细胞外基质降解活性低下的指标. Walsh et al[37-47]亦对慢性肝病患者亦进行了研究, 发现血清TIMP-1水平较正常人明显升高, 且与血清PⅢP和Ⅳ型胶原密切相关. 我们采用单克隆抗体固相致敏红细胞黏附技术快速检测TIMP-1和TIMP-2[48-53], 以病理学诊断为肝硬化患者血清标本为阳性对照, 正常人血清为阴性对照, 检测408例肝病患者血清中TIMP-1和TIMP-2, 其中急性肝炎128例, 慢性肝炎174例, 肝硬化106例, 表明肝硬化阳性率明显高于慢性肝炎和急性肝炎, 并随着病损程度加重而升高(慢性肝炎明显高于急性肝炎), 并同时以TIMP-1 mAb及TIMP-2 mAb进行免疫组化检测其相关蛋白, 并以原位杂交法检测TIMP-1 mRNA和TIMP-2 mRNA, 对40例肝硬化患者肝组织中TIMP-1和TIMP-2的基因和蛋白表达进行了研究, 结果支持我们上述检测结果. 免疫组化及原位杂交技术检测结果显示: 肝纤维化时肝脏组织TIMP-1表达增多且主要位于新生血管、新生胆管及汇管区和纤维隔中的成纤维细胞[54-56]. TIMP-1的异常升高可反映体内ECM降解减少, TIMP-1的血浆水平能反映纤维降解的减少, 故TIMP-1作为反映此类患者肝纤维化的血清学指标[57]有良好的应用前景.
随着对肝纤维化发生机制研究的日益深入, 国内虽涌现出了大量自拟中药制剂, 但其治疗机制和作用的靶基因尚不清楚, 故而难以得到专家认可, 使其应用得到限制.药物的靶向治疗和基因治疗是目前肝纤维化治疗研究中的两种非常有前途的治疗策略. 所谓基因治疗就是指通过基因水平操作将外源基因导入目的细胞并有效表达, 从而达到治疗或预防疾病的目的. 核酸是生物体的核心物质, 与基因组DNA/RNA互补的核酸称反义核酸, 包括反义DNA、反义RNA、核酶三大反义技术. 根据杂交互补原理, 寡核苷酸可特异性结合基因组DNA/RNA, 从而定向抑制和阻断特定基因的复制、转录和翻译, 这一寡核苷酸被称为反义寡核苷酸(asON). asON具有特异、高效、易人工合成等优势, 一般认为asON作用表现在当其进入细胞后, 能与互补mRNA分子特异结合, 发挥"杂交扣留"或"基因封条"作用而阻止蛋白质翻译过程. 我们选用TIMP-1为靶基因, 应用硫代修饰反义寡核苷酸特异性阻断TIMP-1的基因和蛋白表达, 实验结果发现, 模型组TIMP-1的表达值较正常对照组增高400%以上. 通过尾静脉给予asON后, 经免疫组化和PCR技术检测肝组织TIMP-1, 发现其TIMP-1的蛋白和基因表达量均显著低于其他实验组, 说明经硫代修饰后的asON在活体内能确切表达, 并在mRNA水平上封闭了实验性肝纤维化大鼠肝脏中的TIMP-1的基因和蛋白表达, 使肝纤维化逆转成为可能.
迄今为止, 对MMP、TIMP与肝纤维化的关系仍有不少问题尚在探索之中. 对TIMP在肝纤维化发病中作用的研究尚属起步阶段, 肝纤维化时, MMP、TIMP调控机制、细胞来源、ECM各种成分之间及其与细胞之间的相互关系等问题有待进一步研究. 近年随着分子生物学进展, 对MMP、TIMP的分子结构和基因调控有了一定的了解, 这对肝纤维化的发病机制研究提供了途径, 并将为临床上各种肝病特别是慢性肝炎和肝癌的诊断提供更加合理的方法, 加强这些方面的研究将对各种肝病的诊治及其发病机制的研究都有深远的意义.
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