肝硬化门脉高压症的防治: 新的细胞与分子靶点

摘要

肝窦内皮细胞一氧化氮合酶、赖氨酸氧化酶-2表达减少、新生血管形成及病理性肝窦重建是肝硬化门脉高压的病理生理新机制, 黑巧克力、咖啡及绿茶可改善肝窦内皮细胞功能障碍及抑制新生血管形成, 可能是延缓、逆转肝硬化门脉高压及其并发症的新方法.

关键词: 肝硬化; 门脉高压症; 肝窦内皮细胞; 新生血管; 防治

核心提示: 围绕肝硬化门脉高压病理生理的细胞与分子新机制, 基本阐明黑巧克力、咖啡及绿茶可改善肝窦内皮细胞功能障碍及抑制新生血管形成及其临床转化应用.

Prevention and treatment of cirrhotic portal hypertension: New cellular and molecular targets

Yan Zhang, Hui-Guo Ding

Yan Zhang, Hui-Guo Ding, Department of Gastroenterology and Hepatology, Beijing Youan Hospital Affiliated to Capital Medical University, Beijing 100069, China

Supported by: Clinical Medicine Development Special Fund of Beijing Municipal Administration of Hospitals, No. ZYLX201610; High-level Technical Personnel Training Plan of Beijing Municipal Administration, No. 2011-2-19.

Correspondence to: Hui-Guo Ding, Professor, Chief Physician, Department of Gastroenterology and Hepatology, Beijing Youan Hospital Affiliated to Capital Medical University, 8 Youan Outside the West Toutiao, Fengtai District, Beijing 100069, China. dinghuiguo@ccmu.edu.cn

Received: March 14, 2016
Revised: March 31, 2016
Accepted: April 11, 2016
Published online: July 8, 2016

Abstract

Cirrhotic portal hypertension results from a variety of pathological conditions including decreased expression of endothelial NO synthase and lysyl oxidase-like 2, newly formed vessels and pathological hepatic sinusoid reconstruction. Dark chocolate, coffee and green tea polyphenol can improve endothelial dysfunction and inhibit angiogenesis and thus may be new options for treating and preventing the progression of cirrhotic portal hypertension.

Key Words: Liver cirrhosis; Portal hypertension; Liver sinusoidal endothelial cells; Newly formed vessels; Prevention

0 引言

近10年来, 随着新的强效抗病毒药在临床上广泛应用, 丙型肝炎病毒(hepatitis C virus, HCV)/乙型肝炎病毒(hepatitis B virus, HBV)感染导致肝硬化逐年减少[1,2], 但全球范围肝硬化的发病率和死亡率仍在逐年上升, 门脉高压并发症是肝硬化患者死亡的主要原因[3-6]. 从80年代以来, 以门脉高压病理生理新概念为基础的合理治疗, 特别是非选择性β受体拮抗剂、血管加压素及生长抑素及其类似物的临床应用, 使得肝硬化门脉高压症并发食管胃静脉曲张(esophagogastric varices, EGV)首次出血(esophagogastric variceal bleeding, EVB)6 wk内的病死率从60%降为20%左右[7-9]. 本文从肝硬化门脉高压病理生理的细胞与分子新机制, 概述可能早期有效逆转肝硬化门脉高压及其并发症的新靶点.

1 肝硬化门脉高压症的自然史

在肝硬化门脉高压的自然病程中, 将肝硬化临床分为5期[10-13]. 代偿期肝硬化分为1期(无EGV)和2期(无EVB). 失代偿期肝硬化分为3期(腹水, 无EVB)、4期(EVB, 有或无腹水或肝性脑病)及5期(感染及肾脏等多器官功能衰竭). 研究[14-16]证明, 肝硬化患者门脉压力的持续升高提示疾病进展以及不良的预后. 目前肝静脉压力梯度(hepatic venous pressure gradient, HVPG)仍作为反映门脉压力的金标准[8,15]. HVPG>5 mmHg定义为门脉高压. HVPG: 5-10 mmHg, 定义为亚临床门脉高压(subclinical portal hypertension, SCPH). HVPG>10 mmHg, 定义为显著临床门脉高压, 表现EGVB及腹水等并发症. 在一项平均随访4年的研究中, HVPG<10 mmHg的患者有90%不进展至失代偿期, 且发生肝细胞癌及EGVB风险显著降低[14]. 很遗憾的是SCPH患者常常被临床漏诊或延误诊断. Walker等[17]报道1201例肝细胞癌伴肝硬化患者, 在诊断肝癌前24.6%患者肝硬化被漏诊, 特别是老年人(>65岁, OR: 2.32), 伴有酒精或非酒精性肝病患者(OR: 1.69/4.77). 我们报道了连续12年共12948例首次住院肝硬化患者的临床特征, Ⅰ、Ⅱ期肝硬化患者仅占28.8%. 因此, 如何提高SCPH的早期诊断仍是临床亟待解决的难题之一.

2 肝硬化门脉高压病理生理的细胞与分子新机制

高动力循环、血管增生及侧枝循环形成是肝硬化门脉高压症特征性的病理生理变化, 而肝内血管阻力增加(包括肝纤维化、再生结节及新生血管)、门脉血流量增加、血管活性物质与具有收缩功能的细胞(如肝星状细胞、肝窦内皮细胞及Kuffer细胞)的"交叉对话"(cross-talk)导致肝脏微循环及内皮细胞功能异常, 决定门脉压力的水平[18-21]. 启动以上血液动力学异常的"扳机"是多方面, 包括持续肝脏损伤、内毒素血症、氧化应激、内源性大麻素样物质(endocannabinoids)、肝脏低血流灌注等[22].

2.1 肝窦内皮细胞功能障碍与一氧化氮

多研究[23-25]表明, 肝硬化时肝窦内皮细胞(liver sinusoidal endothelial cell, LSEC)一氧化氮合酶(nitric oxide synthase, NOS)表达显著减少, 导致血管扩张剂因子: NO合成减少. 同时, LSEC合成血管收缩因子-血栓素A2(thromboxane A2, TXA2)增加, 引起肝星状细胞(hepatic stellate cell, HSC)收缩增强, 导致肝内以及肝窦微循环阻力升高[18,26]. 肝脏特异NO供体(NCX1000)可显著降低肝硬化大鼠对缩血管活性物质的作用, 并降低肝内阻力, 但是临床试验没有观察到降门脉压的作用[27]. 另一方面, NO在肝硬化门脉高压形成中也有重要的负面作用. 在肝硬化门脉高压大鼠肠微循环中发现, 肠系膜血管内皮细胞eNOS表达增加导致血管扩张, 可能是肝硬化高动力循环的始动因素. 研究[18,26]也发现, 尽管血管收缩活性因子, 如血管内皮生长因子(vascular endothelial growth factor, VEGF)及VEGF受体-2(VEGFR-2)、血小板衍生生长因子(platelet-derived growth factor, PDGF)及胎盘生长因子(placental growth factor, PLGF)表达增加, 但是由于内脏血管的扩张导致血管收缩反应性下降及新血管形成, 进一步加重肝硬化高动力循环及侧枝循环形成(图1). 目前, 针对肝硬化内脏血管扩张的药物, 如非选择性β受体阻滞剂、血管加压素及其类似物、生长抑素及其类似物, 均广泛应用于临床[8,9]. 因此, 血管生成抑制剂(antiangiogenics)从基础到临床转化应用, 可能是肝硬化门脉高压未来药物治疗的重要策略.

2.2 肾素-血管紧张素-醛固酮系统活化

内脏血管扩张, 导致有效循环血容量相对不足, 必然激活肾素-血管紧张素-醛固酮(renin-angiotensin-aldosteronesystem, RAAS)系统, 引起醛固酮分泌增加, 导致水钠储溜, 形成高动力循环, 进一步加重肝硬化门脉高压[18,28]. 拮抗醛固酮药物可以显著改善肝硬化水钠潴留, 但对门脉压力的影响不明显. 针对拮抗血管紧张素-2及其受体的新药防治肝硬化门脉高压值得关注[28,29].

2.3 赖氨酸氧化酶-2与血管增生

赖氨酸氧化酶-2(lysine oxidase 2, LOX2)及LOX2同工酶(lysine oxidase-like 2, LOXL2)属于赖氨酸氧化酶家族, LOXL2与LOX在细胞外作用方式相似, 与血管增生及纤维组织形成密切相关[30-34]. 最近在肿瘤微环境的研究中发现, 抑制LOXL2表达可以显著减少活化的肌纤维母细胞(myofibroblast, MFB)以及纤维结缔组织生成, 并抑制转化生长因子β(transforming growth factor-β, TGF-β)信号通路, 从而抑制肿瘤细胞的转移与上皮细胞间质转化(epithelial-mesenchymal transition, EMT)[33,35]. 特异性LOXL2抑制剂(单克隆抗体AB0023), 通过抑制肿瘤新生血管形成, 从而抑制EMT[36]. 特异性LOXL2抑制剂, 也可能成为肝硬化门脉高压新的治疗药物.

2.4 病理性肝窦重建

新生血管形成(angiogenesis)的分子机制阐明了肝硬化门脉高压形成过程中病理性肝窦血管重建(sinusoidal remodeling)[18,37-41]. 近年来发现, Notch家族拥有5个配体(Jagged1、Jagged2、Dll1、Dll3和Dll4)和4个受体(Notch1、Notch2、Notch3和Notch4), 他们通过相邻细胞之间的互相接触使配体和受体结合, 参与血管增生、肝脏再生[42]. Dll4是VEGF信号途径最主要下游调控蛋白, 其转化应用值得关注[43].

3 防治肝硬化门脉高压的新靶点

研究发现, 通过有效的病因、抗纤维化及抗血管形成治疗, 可以显著改善持续的肝脏损伤及其组织学异常, 也是临床早期防治肝硬化门脉高压的重要策略[44]. 而以上基础研究结果的合理转化应用, 也可能为早期有效逆转肝硬化门脉高压及其并发症提供新方法.

3.1 他汀类药物

通过改善LSEC功能, 降低门脉压力. 有趣的是, 他汀类药物(Statins)可以降低慢性肝炎发展为肝细胞癌风险[14]. 大麻素样物质、抗氧化剂(Antioxidants)、环氧化酶抑制剂(COX-1 inhibitors), 通过影响肝脏微环境中肝细胞、HSC、LSEC及Kuffer细胞的交叉对话功能, 以减轻肝脏损伤及阻断门脉高压形成中的"扳机"[14,45], 对于早期防治非酒精脂肪性肝硬化导致的门脉高压可能有效.

3.2 吡格列酮

为噻唑烷二酮类抗糖尿病药物, 可降低外周组织和肝脏的胰岛素抵抗, 增加依赖胰岛素的葡萄糖的利用. 有研究[46,47]报道, 吡格列酮可显著减少肝硬化大鼠内脏血管eNOS、PDGF、PLGF、TGF-β、VEGFR1及血管紧张素-2多种基因的表达. 我们推测, 吡格列酮对于早期防治非酒精脂肪性肝硬化导致的门脉高压可能有较好的应用前景.

3.3 黑巧克力或咖啡

研究[48]发现, 黑巧克力或者咖啡显著下调肝硬化门脉高压大鼠肠系膜血管eNOS、VEGF、VEGF-磷酸化受体2及磷酸化Akt蛋白表达, 并且改善LSEC的功能, 抑制血管生成. 但是, 黑巧克力或者咖啡不影响缩血管活性物质对肠系膜及侧枝血管床的收缩作用.

3.4 绿茶酚

绿茶可以通过抑制HIF-1α、Akt活化及VEGF, 从而抑制肝硬化大鼠门体侧枝循环的形成及肠系膜血管增生, 降低门脉高压[49].

3.5 微生态制剂

一项随机双盲安慰剂对照试验将94例食管静脉曲张无出血史的肝硬化患者随机分为3组: 普萘洛尔加安慰剂、普萘洛尔加用抗生素(诺氟沙星400 mg/d)或普萘洛尔加益生菌. 以HVPG下降≥20%或≤12 mmHg作为治疗应答反应的指标. 与单独应用普萘洛尔比较, 益生菌提高了应答率(58% vs 31%, P = 0.046), 效果与抗生素相似(54%). 因此认为, 辅助应用益生菌, 减少肠源性内毒素的水平, 抑制了门脉高压形成的"扳机"之一, 也可以显著提高普萘洛尔的治疗效果[50].

4 结论

总之, 药物是肝硬化门脉高压症长期治疗的重要策略, 黑巧克力、咖啡及绿茶等食品类血管生成抑制剂的基础研究结果, 可直接转化应用于临床, 作为药物联合治疗策略值得探讨. 从基础到临床转化研究, 可能是寻找防治肝硬化门脉高压症及其并发症新靶点的重要策略.

评论

背景资料

以门脉高压病理生理新概念为基础的合理治疗, 使肝硬化门脉高压症并发食管胃静脉曲张(esophagogastric varices, EGV)首次出血(esophagogastric variceal bleeding, EVB)病死率显著降低. 从基础到临床转化研究, 可能是早期有效逆转肝硬化门脉高压及其并发症的新策略.

同行评议者

荚卫东, 教授, 安徽省立院普外科

创新盘点

本文全面综合了肝窦内皮细胞一氧化氮合酶、赖氨酸氧化酶-2表达减少、新生血管形成及病理性肝窦重建在肝硬化门脉高压发生发展中的病理生理机制, 在此基础上, 探讨了改善肝窦内皮细胞功能障碍及抑制新生血管形成在延缓、逆转肝硬化门脉高压及其并发症中可能的治疗作用.

应用要点

黑巧克力、咖啡及绿茶可改善肝窦内皮细胞功能障碍及抑制新生血管形成. 该结果可直接转化应用于临床, 作为药物联合治疗策略值得探讨.

同行评价

本文资料详实、有一定的新颖性, 文章可读性较好.

备注

编辑:于明茜 电编:都珍珍

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