甘草次酸靶向肝星状细胞治疗肝纤维化的体内研究

目的观察以6-磷酸甘露糖修饰的白蛋白(M6P26-HSA)作为特异性载体,将甘草次酸(GA) 靶向释放到肝星状细胞治疗肝纤维化的效果。方法用125I记由M6P26-HSA和GA在体外合成新的偶合物GA-HSA-M6P26,观察其在体内的器官分布情况,用双重免疫组织化学的方法观察星状细胞对GA- HSA-M6P26的选择性摄取;选用Sirius红染色观察GA-HSA-M6P26对肝纤维化时胶原沉积的影响,用定量聚合酶链反应检测GA-HSA-M6P26对Ⅰ型前胶原mRNA表达的影响。结果静脉注射后10min,GA-HSA- M6P26选择性地分布于肝脏,摄取高峰可达(5 5.093±5.404)%。双重免疫组织化学染色证实GA-HSA- M6P26主要被星状细胞选择性摄取,GA-HSA-M6P26治疗后肝脏胶原沉积明显减少,Ⅰ型前胶原和α-平滑肌肌动蛋白mRNA表达明显降低。结论GA-HSA-M6P26可以选择性地分布于肝脏星状细胞,有显著的抗肝纤维化作用。     

特异性靶向肝星状细胞治疗肝纤维化研究进展

肝纤维化是慢性肝病进展过程必经的一种病理组织学改变,而肝星状细胞的激活和增生是肝纤维化发生进展的中心环节.目前研究通过基因调控治疗及受体介导药物靶向肝星状细胞,可提高肝纤维化治疗的特异性,为临床应用开辟了新方向.     

肝纤维化的靶向治疗

肝纤维化是各种致病因子造成肝细胞损伤,激活库普弗细胞并使之分泌多种细胞因子,随同血小板、炎性细胞等分泌的多种细胞因子共同作用于HSC,使之转化为肌成纤维细胞；细胞因子同时激活纤维母细胞,合成并分泌大量的ECM沉积在肝Disse间隙内,抑制肝细胞生长因子及胶原酶的合成和分泌,导致肝纤维化形成,Ⅰ、Ⅲ型胶原是ECM的主要成分。[第一段]     

肝星状细胞与抗肝纤维化治疗的研究进展

肝纤维化是肝脏对各种慢性损伤性刺激的修复反应。肝星状细胞的活化是整个事件的核心环节。以肝星状细胞为靶点,抑制其活化或者诱导其凋亡,进行抗肝纤维化研究有良好应用前景。     

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。     

肝星状细胞与肝纤维化

肝纤维化是各种慢性肝病损伤修复过程的共同结果,由于肝内纤维生成和降解失衡,导致过多的胶原在肝内沉积,常伴有炎症、缺血缺氧,最终可发展为肝硬化。目前认为,细胞外基质（ECM）过多产生和沉积是肝纤维化的核心表现,活化的肝星状细胞（HSC）仍是细胞外基质的主要细胞来源。因此,肝星状细胞的活化是肝纤维化发生的中心环节。     

肝星状细胞与肝纤维化

1　肝纤维化的基本概念(1)肝纤维化是指各种原因所致的肝脏内纤维结缔组织增生,其特征为大量细胞外基质在Ｄｉｓｓｅ间隙沉积。(2)肝纤维化时不仅细胞外基质含量增加,而且细胞外基质的组成成分也发生了改变,正常肝脏Ｄｉｓｓｅ间隙细胞外基质是构成基底膜的成分,而肝纤维化时细胞外基质为形成纤维的胶原和纤维连接蛋白〔1〕。(3)在各种原因引起的肝纤维化中,肝脏细胞外基质含量均增加,但原因不同的肝纤维化早期,其肝脏增加的细胞外基质分布是不同的,如病毒性肝炎引起的肝纤维化主要分布在门脉区,而酒精引起的肝纤维化主要分布在中央静脉周围…     

肝星状细胞的活化与肝纤维化

肝纤维化是机体对损伤的一种修复作用，即使可以应用基因或其他疗法彻底消除纤维化，但机体对抑制或消除纤维化后将产生何种反应及后果尚难预测。肝星状细胞（hepatic stellate cells，HSC）是引起肝纤维化的主要细胞，对HSC与其活化型一肌成纤维细胞（myofibroblast，MF）在肝损伤中作用的研究已颇为深入，而HSC激活在肝纤维化发生、发展中的作用甚为重要。     

肝星状细胞凋亡与肝纤维化

近十年来对肝纤维化形成的机理研究取得了令人鼓舞的进展。越来越多的临床及实验证据表明,肝纤维化是可以逆转的［１］,这一观点逐渐被广泛接受。肝星状细胞（ｈｏｐａｔｉｃｓｔｅｌｌａｔｅｃｅｌｌ,ＨＳＣ）的激活是肝纤维化形成的中心环节［２］,ＨＳＣ在肝纤维化逆转过程中的作用也成为研究热点之一。Ｂｕｒｔ［３］认为,肝纤维化逆转时ＨＳＣ的减少是由于激活状态的ＨＳＣ转化为静止状态。但最新的研究表明,肝纤维化恢复期,激活状态的ＨＳＣ减少主要通过凋亡机制,而不是表型的转化［４］。几位学者分别对ＨＳＣ凋亡的机制进行…     

Effects of glycyrrhetinic acid on collagen metabolism of hepatic stellate cells at different stages of liver fibrosis in rats

Liver fibrosis is a dynamic course leading tocirrhosis from a various chronic liver diseases. Thepathological basis of fibrosis is the disturbance ofproduction and degradation of the extracellularmatrix(ECM), which causes accumulation of ECMin the liver. The deposition of collagen isderived primarily from collagen types Ⅰ and Ⅲ inliver fibrosis. The main sources of ECM are thehepatic stellate cells(HSCs), especially whenHSCs are activated by hepatic injury. One ofthe important methods for preventing liver fibrosis     

Effects of glycyrrhetinic acid on collagen metabolism of hepatic stellate cells at different stages of liver fibrosis in rats

INTRODUCTIONLiver fibrosis is a dynamic course leading tocirrhosis from a various chronic liver diseases. Thepathological basis of fibrosis is the disturbance ofproduction and degradation of the extracellularmatrix (ECM), which causes accumulation of ECMin the liver[1,2].     

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     

肝星状细胞的可塑性及其对肝纤维化的意义

在肝纤维化形成过程中,肝星状细胞(hepatic stellate cells,HSC)发挥着重要的作用.基础和临床研究结果显示,在特殊的内环境因素的影响下HSC具有朝多方向分化的潜能.对HSC命运的干预能够在一定程度上预防肝纤维化的发生,甚至逆转肝纤维化,因此HSC的可塑性研究可能为慢性肝病治疗开辟一条新途径.本文就HSC的起源、结构、可塑性及其对肝纤维化的潜在治疗意义作一综述.     

肝星状细胞在逆转肝纤维化中的作用

肝纤维化是一种能够导致门静脉高压、肝硬化、肝衰竭的严重疾病。已经发现肝星状细胞的活化是引起肝纤维化的中心环节,因此抑制肝星状细胞的活化、加速肝星状细胞的清除有望逆转肝纤维化。本文将对活化的肝星状细胞的凋亡、衰老以及清除的研究进展作综述,阐明肝星状细胞在肝纤维化过程中所起的作用及相关机制。     

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

Following chronic liver injury of any etiology, there is progressive fibrosis. To date, removing the causative agent is the only effective therapy to stop or even reverse liver fibrosis. Therefore, the development of effective antifibrotic therapies represents a challenge for modern hepatology. In the past decade, dramatic advances have been made in the understanding of the cellular and molecular mechanisms underlying liver fibrogenesis. The identification of activated hepatic stellate cells (HSCs) as the major fibrogenic cell type in the injured liver, as well as the recognition of key cytokines involved in this process, have facilitated the design of promising new antifibrotic therapies. These therapies are aimed at inhibiting the accumulation of activated HSCs at the sites of liver injury and preventing the deposition of extracellular matrix. Although many of these approaches are effective in experimental models of liver fibrosis, their efficacy and safety in humans are still unknown. This review describes the current therapeutic approaches for liver fibrosis and discusses different features of activated HSCs as a target to design new treatments to inhibit scar formation in chronic liver diseases.     

PARs对肝纤维化大鼠HSC活化和增殖的调控作用

目的探讨蛋白酶活化受体（proteinase—activated receptors，PARs）对大鼠肝组织中肝星状细胞（hepatic stellate cell，HSC）活化和增殖的调控及其在肝纤维化中的作用。方法应用改良的Friedman方法和Nycodenz一步密度梯度离心法分离和培养结扎胆管诱导的肝纤维化sD大鼠HSC。观察HSC形态学变化，MTT法观察细胞的增殖能力，Western blotting检测a—SMA、PAR1和PAR2在HSC的表达，同时设立正常对照组和假手术组。结果随着培养HSCs时间的延长，HSC的VitA和脂滴逐渐减少，甚至消失，HSC形态发生改变呈星状，细胞增殖活跃，而a—SMA、PAR1和PAR2随着培养时间延长其表达逐渐增强，原代培养14天达到高峰。a-SMA与PAR1和PAR2的表达呈一致关系。结论PARs可促进a-SMA的表达，PARs表达与HSC的活化和增殖相关，参与了肝纤维化的形成。