肝星状细胞与肝纤维化的现代治疗进展

随着对肝纤维化机制认识的不断深入，近年来抗肝纤维化的策略发生了深刻的变化，逐渐由过去的抗炎治疗为主转变为针对肝星状细胞激活为基础的各种手段的综合运用。业已知道，肝纤维化过程实质上是机体应答各种慢性刺激，形成损伤与抗损伤反复演变的过程。期间涉及肝细胞的变性、坏死，炎症细胞浸润，细胞因子作用以及肝组织中细胞外基质过度产生和沉积等复杂变化。然而，长期以来由于缺乏有效且特异性的治疗手段，不少患者肝脏机能储备严重下降，出现转氨酶升高、黄疸、门静脉高压等临床症状，生命安全直接受到危害。因此，以肝星状细胞作治疗标靶的理念转变将为摆脱多年来肝纤维化临床处理的困境带来希望。本文以下就肝星状细胞在肝纤维化发生中的作用及某些抗肝纤维化治疗进展作一综述。     

血小板衍生生长因子在肝纤维化发生中的作用

肝纤维化常常伴随于肝脏的各种慢性炎症病变过程中,是发生肝硬化的必经阶段。肝星状细胞(HSC)是细胞外基质的主要合成细胞,在肝纤维化的发生发展中起重要作用。多种细胞因子介质参与了肝星状细胞功能的活化和调节,其中血小板衍生生长因子是目前已知的多肽生长因子中对HSC作用最强的有丝分裂原,多种因素通过这一途径发挥作用。但其具体作用方式目前还不太清楚,本文就血小板衍生生长因子的作用机制、来源、结构、分类、在肝纤维化的临床诊断和治疗中的应用作一综述。     

激活蛋白-1与肝纤维化关系研究现状

肝纤维化是肝脏对多种慢性损伤刺激的修复反应,与多种肝脏细胞如肝星状细胞、肝细胞和枯否细胞等有关。激活蛋白-1是近年来发现的重要核转录因子,在肝纤维化过程中有高度表达。本文主要对目前激活蛋白-1与肝纤维化相关细胞的关系研究作一综述。     

肝星状细胞激活与信号转导

肝纤维化是多种慢性肝病向肝硬化发展的必经阶段,是所有慢性肝病的共同病理基础.目前认为肝星状细胞的激活是肝纤维化形成的关键,各种致病因素作用下引起肝损伤,释放多种细胞因子,如转化生长因子β、血管紧张素、瘦素,通过各种信号转导使肝星状细胞激活.本文就肝星状细胞激活过程中一些重要的膜受体、核受体信号转导途径及其研究进展作一综述.     

骨髓干细胞在肝纤维化治疗中的作用机制

近年来,骨髓干细胞(bone marrow stem cell,BMSC)在肝纤维化中的应用研究日益增多,显示出一定的抗肝纤维化作用,但具体机制尚不明确.众多研究结果显示,BMSC可能主要从两方面发挥抗肝纤维化作用,一是通过分化为功能性肝细胞、分泌生长因子和增强内源性肝细胞增殖来促进肝再生,二是通过分泌抗纤维化细胞因子、影响肝星状细胞和表达基质金属蛋白酶-9来抑制肝组织纤维化的形成.本文对骨髓干细胞在肝纤维化治疗中可能的作用机制作一系统阐述,为从事骨髓干细胞移植治疗肝纤维化的研究者提供借鉴和指导.     

肝纤维化治疗的现状和展望

肝纤维化是肝脏在损害因子作用下渐进性的病理过程。以细胞外基质(ECM)增加为特征,最终可导致肝硬化和肝功能衰竭。因此,抗肝纤维化治疗素为肝病学者所关注。既往多注重病因的去除,炎症反应的抑制及阻止纤维形成。如驱除血吸虫(吡喹酮)、戒酒、限制过量进食、抑制或清除肝炎病毒(α-干扰素)、抑制炎症反应(皮质类固醇)、阻止纤维形成(青霉胺、秋水仙碱)等。近年来,对于肝纤维化机理的认识更为深入。现已证明肝星状细胞(stellate cell)是肝ECM胶原成分的主要来源。星状细胞被持续激活可产生大量胶原沉积在汇管区、中央静脉周围、肝窦和肝细胞间形成肝纤维化的基本病理图像。细胞因子网络在激活星状细胞中的重要作用正在不断阐明,指导人们探索更多更有效的抗纤维化途径。 当肝受到损伤时,炎症细胞和肝窦Kupffer细胞释出活化因子激活星状细胞,使星状细胞变为表达α-平滑肌肌动蛋白(α-SMA)的肌成纤维细胞,并且产生大量Ⅰ型胶原。活化的星状细胞上血小板衍生生长因子(PDGF)、转化生长因子(TGF-β_1)等增殖性细胞因子的受体数增加,PDGF和TGF-β_1等以旁分泌和自分泌方式作用于星状细胞,使其增殖并产生ECM。此外,还有乙醛、过氧化脂质、铁等可促进星状细胞产生ECM。肝损伤持续呈慢性化时,纤维化亦继     

细胞凋亡在肝纤维化发生、发展中的作用研究进展

细胞凋亡是一种自主、有序的细胞死亡方式。迄今为止的研究发现,在肝损伤中有两种主要的细胞凋亡途径：外源性途径和内源性途径。细胞凋亡涉及一组半胱天冬酶的激活,以及将起始刺激与细胞最终死亡联系起来的复杂级联事件。细胞凋亡在肝纤维化的发生和发展过程中起到十分重要的作用,因此诱导肝细胞、肝星状细胞凋亡是近年来治疗肝纤维化的重要靶点。本文主要对细胞凋亡的分子机制,以及肝细胞、肝星状细胞与肝纤维化的关系进行综述。     

肝纤维化形成机制研究进展

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性反应 ,以细胞外基质 (ＥＣＭ )在肝内过量沉积为病理特征。肝纤维化已成为世界范围内的一个主要健康问题。现已证实肝纤维化发生的中心事件是 :由损伤所引起的肝星状细胞(ＨＳＣ)的激活及其转化为肌成纤维细胞 ,从而大量合成各种细胞外基质蛋白 ,沉积于肝脏最终导致肝纤维化。本文就肝星状细胞的激活及调控对近年来肝纤维化形成机制的有关进展作一简介。一、肝星状细胞的活化与ＥＣＭ的产生ＨＳＣ是肝脏间质细胞之一 ,位于肝细胞与窦内皮细胞间的Ｄｉｓｓｅ腔内。正常时呈静止状态 ,…     

肝细胞凋亡在肝纤维化中的作用

肝纤维化系肝组织内细胞外基质(ECM)过度增生与异常沉积,导致肝脏结构和/或功能异常改变的病理变化。过去20年,对肝纤维化的病理机制研究取得了长足进步,如明确了肝纤维化的细胞学基础在于肝星状细胞(HSC)活化,生化学基础在于ECM代谢紊乱,尤其是近年来基本明确了转化生长因子β(TGF-β)等促纤维化细胞因子刺激HSC活化。但是治疗学进展缓慢,治疗策略主要针对HSC活化与ECM代谢降解等,而这些方法尚未取得理想的临床疗效。肝细胞约占肝脏细胞总量的80%,数量最多,功能重要。肝细胞损伤尤其是肝细胞凋亡、细胞支架结构完整性在肝纤维化中…     

中药抗肝纤维化作用与诱导肝星状细胞凋亡机制研究概述

肝纤维化是指肝脏中细胞外基质尤其是胶原的过量沉积，是许多慢性肝病发展为肝硬化的共同病理过程。肝纤维化的发生，首先是有肝细胞的损伤，然后是肝损伤所致的肝星状细胞（hepatic stellate cell，HSC）的激活，两者关系密切，均为肝纤维化发生发展中的重要环节。目前，越来越多的学者认为肝星状细胞凋亡在肝纤维化的消退中扮演了重要角色。     

肝损伤修复过程中p75神经营养因子受体的作用

p75神经营养因子受体(p75NTR)是肝星状细胞(HSC)表面表达的与神经生长因子(NGF)特异结合的受体,在肝脏损伤修复过程中发挥重要作用。在肝脏损伤修复过程中,p75NTR能提高肝组织肝细胞生长因子的表达,促进受损肝细胞的再生和肝组织结构的恢复;对于静息状态的HSC,p75NTR能促进HSC活化;在肝损伤晚期,随着再生肝细胞和活化HSC的增多,NGF分泌明显增加,NGF与p75NTR结合能促进活化的HSC凋亡和肝纤维化逆转。     

肝纤维化治疗新策略

肝纤维化是各种慢性肝病共有的病理改变,逆转肝纤维化可阻止大多数慢性肝病进展。肝星状细胞（HSC）活化是肝纤维化发生的中心环节,故传统治疗策略大多以HSC为治疗靶点,并在动物实验取得良好疗效。但最近研究发现活化HSC也可促进肝细胞再生和肝脏损伤修复。肝细胞核因子是一组对肝细胞分化和功能维持起关键作用的转录因子,既可减少细胞外基质（ECM）分泌,又可促进肝细胞再生,保护肝细胞功能。促进肝细胞核因子表达是治疗肝纤维化更为理想的策略。     

促纤维化因子在肝纤维化发生中的作用研究进展

肝纤维化是多种病因所致的慢性肝损伤的一种创伤愈合反应,持续的炎症与纤维形成最终导致肝硬化。肝星状细胞（HSC）是肝纤维化的主要生成细胞,肝脏内细胞外基质（ECM）的过度沉积是其主要功能。各种促纤维化因子如血管紧张素-II（AngII）、血小板衍生生长因子（PDGF）、血管内皮生长因子（VEGF）、转化生长因子-β（TGF-β）、瘦素、结缔组织因子等可与HSC表面上相应的受体结合,并激活相应的信号通路,进而导致HSC的激活、增殖,ECM过度沉积,引起肝纤维化形成。因此,了解各种促纤维化因子与肝纤维化的关系,可为抗纤维化的科学研究及临床治疗提供理论依据。     

Hepatic fibrogenesis requires sympathetic neurotransmitters

BACKGROUND AND AIMS: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. METHODS: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. RESULTS: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by alpha- and beta-adrenoceptor antagonists. HSC from dopamine beta-hydroxylase deficient (Dbh(-/-)) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh(-/-) mice, as evidenced by reduced hepatic accumulation of alpha-smooth muscle actin(+ve) HSC and decreased induction of transforming growth factor beta1 (TGF-beta1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-beta1 and collagen, and increased liver fibrosis. CONCLUSIONS: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis.     

体外四氯化碳损伤肝细胞对肝星状细胞活化的影响及其丹酚酸A的干预效果

目的 体外观察肝细胞四氯化碳过氧化损伤后肝星状细胞（ＨＳＣ）活化的影响,并观察丹参水溶性成分丹酚酸Ａ的干预效果,以研究脂质过氧化损伤与肝纤维化的关系和丹酚酸Ａ的作用机理。方法 肝细胞分离后分组,分别添加不同浓度的丹酚酸Ａ以及对照药维生素Ｅ,同时以四氯化碳熏蒸２４ｈ并测定各组细胞上清液ＡＬＴ、ＡＳＴ活性后,换液培养２４ｈ并测定ＭＤＡ含量,再以此上清液作为“肝细胞条件培养液”作用于ＨＳＣ４８ｈ,观察Ｈ     

Relationship between hepatic progenitor cell‐mediated liver regeneration and non‐parenchymal cells

Hepatic progenitor cells (HPCs) are thought to reside in the canals of Hering and can be activated and contribute to liver regeneration in response to liver injury by proliferating and differentiating towards both hepatocytes and biliary epithelial cells. In this setting, several cytokines, chemokines, and growth factors related to liver inflammation and other liver cells comprising the HPC niche, namely hepatic stellate cells (HSCs), play crucial roles in HPC activation and differentiation. In response to several types of liver injury, tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) is secreted by several inflammatory cells, including monocytes, T lymphocytes, and macrophages, and acts as an initiator of the HPC niche and HSC activation. Following TWEAK‐induced activation of the HPC niche, fibroblast growth factor 7 and hepatocyte growth factor released from activated HSC play central roles in maintaining HPC proliferation. In contrast, HGF‐MET and Wnt3a‐β‐catenin signals are the predominant mediators of the hepatocyte differentiation of HPC, whereas epidermal growth factor receptor–NOTCH signaling controls HPC differentiation towards biliary epithelial cells. These signals are maintained exclusively by activated HSC and inflammatory cells surrounding HPC. Together, HSC and inflammatory cells surrounding HPC are responsible for the precise control of HPC proliferation and differentiation fate. In this review, we discuss recent progress in understanding of interactions between HPC and other liver cells in HPC‐mediated liver regeneration in the setting of liver inflammation.     

Hepatic stellate cells: a target for the treatment of liver fibrosis

Hepatic fibrosis is a wound-healing process that occurs when the liver is injured chronically. Hepatic stellate cells (HSC) are responsible for the excess production of extracellular matrix (ECM) components. The activation of HSC, a key issue in the pathogenesis of hepatic fibrosis, is mediated by various cytokines and reactive oxygen species released from the damaged hepatocytes and activated Kupffer cells. Therefore, inhibition of HSC activation and its related subsequent events, such as increased production of ECM components and enhanced proliferation, are crucial goals for intervention in the hepatic fibrogenesis cascade. This is especially true when the etiology is unknown or there is no established therapy for the cause of the chronic injury. This review explores the rationale for choosing HSC as a target for the pharmacological, molecular, and other novel therapeutics for hepatic fibrosis. One focus of this review is the inhibition of two cytokines, transforming growth factor-β and platelet-derived growth factor, which are important in hepatic fibrogenesis. A number of new agents, such as Chinese herbal recipes and herbal extracts, silymarin, S-adenosyl-l-methionine, polyenylphosphatidylcholine, and pentoxifylline are also discussed. Received: April 3, 2000 / Accepted: April 28, 2000     

Role of angiotensin‐1 receptor blockade in cirrhotic liver resection

Background: The regeneration capacity of cirrhotic livers might be affected by angiotensin‐1 (AT1) receptors located on hepatic stellate cells (HSC). The effect of AT1 receptor blockade on microcirculation, fibrosis and liver regeneration was investigated. Materials and methods: In 112 Lewis rats, cirrhosis was induced by repetitive intraperitoneal injections of CCl₄. Six hours, 3, 7 and 14 days after partial hepatectomy or sham operation, rats were sacrificed for analysis. Animals were treated with either vehicle or 5 mg/kg body weight losartan pre‐operatively and once daily after surgery by gavage. Microcirculation and portal vein flow were investigated at 6 h. The degree of cirrhosis was assessed by Azan Heidenhein staining, activation of HSC by desmin staining, apoptosis by ssDNA detection and liver regeneration by Ki‐67 staining. Changes in expression of various genes important for liver regeneration and fibrosis were analysed at 6 h and 3 days. Haemodynamic parameters and liver enzymes were monitored. Results: Losartan treatment increased sinusoidal diameter, sinusoidal blood flow and portal vein flow after partial hepatectomy (P<0.05), but not after sham operation. AT1 receptor blockade resulted in increased apoptosis early after resection. HSC activation was reduced and after 7 days, a significantly lower degree of cirrhosis in resected animals was observed. Losartan increased the proliferation of hepatocytes at late time‐points and of non‐parenchymal cells early after partial hepatectomy (P<0.05). Tumour necrosis factor (TNF)‐α was significantly upregulated at 6 h and stem cell growth factor (SCF) was downregulated at 3 days (P<0.05). Conclusion: Losartan increased hepatic blood flow, reduced HSC activation and liver fibrosis, but interfered with hepatocyte proliferation after partial hepatectomy in cirrhotic livers.