铁和铁调素在肝纤维化中的作用

多种慢性肝纤维化疾病均伴有肝脏过多的铁沉积,铁在肝纤维化发病中起重要作用。其机制包括:铁通过催化自由基生成和脂质过氧化反应破坏细胞生物大分子,引起细胞凋亡和坏死,激活肝星状细胞转化为肌成纤维细胞等。近来研究证实,由肝脏产生的铁调素(Hepc)表达的降低在慢性肝纤维化疾病肝脏铁沉积中起重要作用,补充外源性Hepc可以降低肝纤维化患者肝脏铁含量。因此,铁调素用于治疗铁过载疾病及肝纤维化具有重要价值。     

中药肝复康干预肝星状细胞及肝组织的蛋白质组学分析

目的：本实验通过中药对肝星状细胞和肝组织蛋白质组的干预实验,从蛋白质组学角度进一步揭示肝纤维化的发病机制和中药的药理作用,为新药研制提供理论依据。方法：制备正常大鼠肝星状细胞、加入血小板衍生生长因子的肝星状细胞及加入肝复康药物血清和血小板衍生生长因子的肝星状细胞,分别设定为正常对照组、模型组及治疗组;同时分别将注射二甲基亚硝胺、肝复康的大鼠设定为模型组及治疗组,并将各组大鼠肝脏取出。分别提取以上各组的总蛋白质并进行等电聚焦电泳,随后进行SDS-PAGE电泳。凝胶染色后比对蛋白质斑点,找出上调和下调的蛋白质。结果：随着治疗时间的不断延长,HSC的蛋白质表达在不同时间有了不同变化。大鼠造模4周后,模型组与治疗组肝组织总蛋白质图谱存在着一定差异,部分蛋白质在两组中表现出不同的丰度。结论：肝纤维化的发生与多种蛋白质的作用有关。中药肝复康治疗肝纤维化是通过调节多个蛋白质表达产生的。     

中医药的抗炎机制在治疗肝纤维化中的作用

肝脏是人体腹腔内最大的实体器官,对维持机体的基本生理功能起着至关重要的作用。肝脏疾病是威胁人类健康的常见病多发病。全球约有10%人口受到不同程度的肝脏疾病的危害,其中,肝纤维化往往成为这些疾病的晚期病理特征。由于肝纤维化的发病机制复杂,尚无有效的合成类药物能够治疗肝纤维化。中药治疗肝纤维化具有多靶点和副作用小的优势。本文综述了肝纤维化的病理特征与诱发炎症的关系,讨论了中药治疗肝纤维化的单味中药、传统配方及其化学活性成分的抗炎症机制。     

肝纤维化肝组织中肾上腺素能受体的表达研究

目的探讨肝纤维化大鼠肝脏组织中交感神经递质受体表达的变化情况。方法应用四氯化碳(CCl4)诱导大鼠慢性肝纤维化模型。23只Wistar大鼠随机分为正常对照组(N组)和肝纤维化模型组(M组)。应用逆转录聚合酶链反应(RT-PCR)和Westernblot方法检测肝脏组织中肾上腺素能受体mRNA及蛋白质的表达情况。结果肝纤维化大鼠肝脏组织中肾上腺素能受体mRNA和蛋白质表达均比正常组明显增加(P<0·01)。结论肝纤维化时,大鼠肝脏组织中肾上腺素能受体α1-AR和β2-AR表达增加,这可能是肝纤维化时交感神经促进肝纤维化发展的作用机制之一。     

食用油与肝纤维化关系的研究进展

慢性肝脏疾病己经成为人类健康的主要威胁,肝纤维化作为其发生发展的必经阶段,对其研究也越来越广泛和深入。随着人们生活水平的提高,饮食方式的不断改变,肝纤维化的发病率有逐年上升的趋势。但目前现有的治疗药物还无法确切有效的控制肝纤维化的发展。近年来,有研究报道,与玉米油相比,橄榄油具有良好的肝保护作用,可以缓解四氯化碳引起的小鼠肝纤维化,这种肝保护作用可能是通过橄榄油中含有较多的油酸及酚类化合物实现的。可见,不同种类的油因其所含成份的不同,对同一种疾病产生截然相反的药理作用。因此,探索和研究膳食脂质与纤维化疾病的关系,或许可以从源头上积极预防和控制肝纤维化的发生发展,不仅可以提高人们的生活质量,而且对于防治恶性肝脏疾病具有积极而深远的意义。本综述将从细胞、细胞因子以及食用油与肝纤维化的关系等方面进行探讨,从而有助于我们更加全面的理解膳食脂质在肝纤维化方面的作用。     

天然产物通过诱导铁死亡改善肝纤维化的研究进展

肝纤维化是多种慢性肝病发展为肝硬化和肝癌所必须经历的共同病理过程,在其发生、发展过程中受到多种细胞因子以及信号通路的调控。铁死亡是由铁过载、氧化还原稳态紊乱和脂质过氧化增加引起的一种新的细胞死亡调控模式,与肝纤维化密切相关。诱导肝星状细胞发生铁死亡可能是肝纤维化治疗的潜在靶标。许多天然产物可以诱导肝星状细胞发生铁死亡进而抑制肝纤维化的进展,因此越来越受到关注。然而,关于天然产物通过铁死亡途径调节肝纤维化的综述文章却相对较少。该文简述了天然产物通过铁死亡调控影响肝纤维化的干预机制及应用,重点探讨铁死亡与肝纤维化的关系,以及天然产物靶向铁死亡对肝纤维化的调控作用,旨在为天然产物治疗代谢性疾病和肝脏疾病的发展提供新的理论依据,也为将来的药物制取提供更多的备选策略。     

肝纤维化动物模型造模方法的研究进展

肝纤维化是肝脏受到损伤后细胞外基质合成、降解与沉积不平衡的一种修复反应。对肝纤维化进行早期诊断、早期治疗,预防肝硬化的发生、发展,对肝病患者的生命质量具有重要的意义。而肝纤维化动物模型的建立,既可深入全面地研究肝纤维化发病机制,又可为临床筛选防治肝纤维化药物提供基础研究。通过对常用的肝纤维化动物模型造模方法的阐述,为肝纤维化的基础实验研究和临床治疗提供参考。     

应用骨髓干细胞治疗肝硬化研究进展

随着干细胞研究的深入和技术的发展,再生医学的干细胞疗法治疗肝脏疾病已成为研究热点。骨髓来源造血干细胞和间充质干细胞等在肝脏疾病治疗方面有巨大潜力。骨髓干细胞参与肝纤维化与肝硬化修复主要包括迁移、归巢与转化等过程,并需要多种细胞因子和趋化因子的协同作用促进肝细胞再生与减轻肝纤维化。本文拟对骨髓干细胞治疗肝硬化的最新研究进展进行综述。     

骨桥蛋白与肝脏发育、肝再生及肝脏疾病

骨桥蛋白(osteopontin,OPN)是一种分泌型磷酸化糖蛋白,结构上与多种胞外基质蛋白相似,功能上具有细胞因子的特点,在多种生理、病理过程中发挥重要作用。在肝中,它可能参与肝脏发育和肝再生,并与急性肝炎、脂肪性肝炎、肝纤维化及肝癌等疾病的发生、发展密切相关。本文综述了OPN在肝脏发育、肝再生和肝脏疾病等中的作用研究进展,为开展OPN在促进肝再生及肝脏疾病诊断、治疗方面的应用提供重要理论基础。     

乙肝纤维化分级相关血浆蛋白标志物的定量蛋白质组筛选

非创伤性肝纤维化检测对于评价肝炎进程、临床治疗以及药效评价等方面,都具有非常重要的作用.通过N末端标签的蛋白质组定量手段,从血浆中筛选肝纤维化分级相关的蛋白候选标志物.首先利用目前纤维化诊断黄金标准——肝穿病理检测,获得纤维化不同分级的合格样本血浆,并对肝纤维化各级间的血浆混合样本进行了蛋白质组定量比较分析,发现了72个与乙肝纤维化分级呈明显相关性的血浆蛋白,构成了一个有重要参考价值的、纤维化分级诊断的候选蛋白标志物库.用WB法进一步验证了定量结果的准确性.利用IPA在线分析后获得了4个生理代谢网络图,提示这些差异蛋白在肝纤维化进程中代表的不同功能影响.总之,利用N末端标签定量蛋白质组技术,全面定量挖掘了血浆中与乙肝纤维化分级相关的差异蛋白及变化规律,对于加深肝纤维化发病机制的认识和理解具有很大帮助,同时也为肝脏纤维化临床诊断和治疗提供有益信息和参照.     

Hepatic fibrosis--role of hepatic stellate cell activation

Hepatic fibrosis is a reversible wound healing response characterized by accumulation of extracellular matrix (ECM), or "scar," that follows chronic but not self-limited liver disease. The ECM components in fibrotic liver are similar regardless of the underlying cause. Activation of hepatic stellate cells is the central event in hepatic fibrosis. These perisinusoidal cells orchestrate an array of changes including degradation of the normal ECM of liver, deposition of scar molecules, vascular and organ contraction, and release of cytokines. Not only is hepatic fibrosis reversible, but it is also increasingly clear that cirrhosis may be reversible as well. The exact stage at which fibrosis/cirrhosis becomes truly irreversible is not known. Antifibrotic therapies will soon be a clinical reality. Emerging therapies will be targeted to those patients with reversible disease. The paradigm of stellate cell activation provides an important framework for defining therapeutic targets.     

Addressing Liver Fibrosis with Liposomes Targeted to Hepatic Stellate Cells

Liver fibrosis is a chronic disease that results from hepatitis B and C infections, alcohol abuse or metabolic and genetic disorders. Ultimately, progression of fibrosis leads to cirrhosis, a stage of the disease characterized by failure of the normal liver functions. Currently, the treatment of liver fibrosis is mainly based on the removal of the underlying cause of the disease and liver transplantation, which is the only treatment for patients with advanced fibrosis. Hepatic stellate cells (HSC) are considered to be key players in the development of liver fibrosis. Chronically activated HSC produces large amounts of extracellular matrix and enhance fibrosis by secreting a broad spectrum of cytokines that exert pro-fibrotic actions in other cells, and in an autocrine manner perpetuate their own activation. Therefore, therapeutic interventions that inhibit activation of HSC and its pro-fibrotic activities are currently under investigation worldwide. In the present study we applied targeted liposomes as drug carriers to HSC in the fibrotic liver and explored the potential of these liposomes in antifibrotic therapies. Moreover, we investigated effects of bioactive compounds delivered by these liposomes on the progression of liver fibrosis. To our knowledge, this is the first study demonstrating that lipid-based drug carriers can be selectively delivered to HSC in the fibrotic liver. By incorporating the bioactive lipid DLPC, these liposomes can modulate different processes such as inflammation and fibrogenesis in the fibrotic liver. This dual functionality of liposomes as a drug carrier system with intrinsic biological effects may be exploited in new approaches to treat liver fibrosis.     

Addressing liver fibrosis with liposomes targeted to hepatic stellate cells

Liver fibrosis is a chronic disease that results from hepatitis B and C infections, alcohol abuse or metabolic and genetic disorders. Ultimately, progression of fibrosis leads to cirrhosis, a stage of the disease characterized by failure of the normal liver functions. Currently, the treatment of liver fibrosis is mainly based on the removal of the underlying cause of the disease and liver transplantation, which is the only treatment for patients with advanced fibrosis. Hepatic stellate cells (HSC) are considered to be key players in the development of liver fibrosis. Chronically activated HSC produces large amounts of extracellular matrix and enhance fibrosis by secreting a broad spectrum of cytokines that exert pro-fibrotic actions in other cells, and in an autocrine manner perpetuate their own activation. Therefore, therapeutic interventions that inhibit activation of HSC and its pro-fibrotic activities are currently under investigation worldwide. In the present study we applied targeted liposomes as drug carriers to HSC in the fibrotic liver and explored the potential of these liposomes in antifibrotic therapies. Moreover, we investigated effects of bioactive compounds delivered by these liposomes on the progression of liver fibrosis. To our knowledge, this is the first study demonstrating that lipid-based drug carriers can be selectively delivered to HSC in the fibrotic liver. By incorporating the bioactive lipid DLPC, these liposomes can modulate different processes such as inflammation and fibrogenesis in the fibrotic liver. This dual functionality of liposomes as a drug carrier system with intrinsic biological effects may be exploited in new approaches to treat liver fibrosis.     

Resolving fibrosis in the diseased liver: translating the scientific promise to the clinic

Liver fibrosis and its end-stage disease cirrhosis are a major cause of mortality and morbidity throughout the world. Fibrosis is a response to chronic liver injury or infection that if unabated leads to the replacement of normal functional liver tissue with scar tissue. Basic research over the past decade has generated a vastly improved knowledge of the cell and molecular biology of liver fibrosis that provides a framework on which to design and develop therapeutics. The field has also witnessed a genuine paradigm shift from the original dogma that liver fibrosis is only ever a progressive process, to the new understanding that liver fibrosis even in an advanced stage can be reversible. There is therefore renewed optimism that liver fibrosis may be cured providing that we develop therapies that halt the fibrogenic process and encourage the natural regenerative properties of the liver. The key to the design of effective therapeutics will be to exploit the ongoing discoveries pertaining to the biology and function of fibrogenic hepatic myofibroblasts and their interplay with other liver cells and with the hepatic extracellular matrix. This review provides a critique of those discoveries in basic research that provide the most promise for translation to the clinic. In addition, we review the latest developments in the search for minimal invasive diagnostic tests for fibrosis that will be essential for determining the efficacy of anti-fibrotic drugs.     

Senescence of activated stellate cells limits liver fibrosis

Cellular senescence acts as a potent mechanism of tumor suppression; however, its functional contribution to noncancer pathologies has not been examined. Here we show that senescent cells accumulate in murine livers treated to produce fibrosis, a precursor pathology to cirrhosis. The senescent cells are derived primarily from activated hepatic stellate cells, which initially proliferate in response to liver damage and produce the extracellular matrix deposited in the fibrotic scar. In mice lacking key senescence regulators, stellate cells continue to proliferate, leading to excessive liver fibrosis. Furthermore, senescent activated stellate cells exhibit gene expression profile consistent with cell-cycle exit, reduced secretion of extracellular matrix components, enhanced secretion of extracellular matrix-degrading enzymes, and enhanced immune surveillance. Accordingly natural killer cells preferentially kill senescent activated stellate cells in vitro and in vivo, thereby facilitating the resolution of fibrosis. Therefore, the senescence program limits the fibrogenic response to acute tissue damage.     

Schistosomes, fibroblasts, and growth factors: how a worm causes liver scarring

The traditional concept of tissue scarring as a static pathological endpoint has been replaced by the modern perspective of a potentially reversible process comprising a sequence of discrete biological events (cell recruitment and hyperplasia, excessive matrix production, and matrix degradation). Cytokines, including several produced by inflammatory cells, have been identified that specifically regulate these events. Research into the cellular and molecular biology of scar formation is motivated by clinical and basic scientific considerations. One model of fibrogenesis that is being studied in detail is the liver fibrosis associated with schistosomiasis. In this helminthic infection, the host's granulomatous inflammatory response to the parasite eggs apparently lead to scar formation. A novel lymphokine that is mitogenic for fibroblasts and is produced by CD4+ lymphocytes in the granuloma has been found in infected livers. Preliminary evidence for the existence of immunoregulatory mechanisms of fibrogenesis in this disease also has been obtained. The potential role of genetic determinants that may influence this process needs to be further studied.     

The antifibrotic effect of TGF-beta1 siRNAs in murine model of liver cirrhosis

Liver fibrosis results from chronic damage to the liver by chronic hepatitis, alcohol, and toxic agents. A characteristic of liver fibrosis is an accumulation of extracellular matrix (ECM) protein, which distorts the hepatic architecture by forming a fibrous scar, and the subsequent development of regenerating nodules defines cirrhosis. Transforming growth factor (TGF)-beta1, one of the most powerful profibrogenic mediators, plays a major role in the development of liver cirrhosis and regulates ECM gene expression and matrix degradation. This study elucidates the changes of TGF-beta1-mediated signals during liver fibrogenesis by using RNA interference. In this experiment, the TGF-beta1 siRNAs reduced the expression of TGF-beta1 in the livers of CCl(4) injection compared with those of control group, and the expression of type I collagen and alpha-smooth muscle actin was decreased. In conclusion, this study demonstrates that TGF-beta1 siRNAs inhibit TGF-beta1 expression in the murine model of liver cirrhosis and might be a good therapeutic strategy to prevent liver cirrhosis in human.     

Induction of cell death in activated hepatic stellate cells by targeted gene expression of the thymidine kinase/ganciclovir system

Liver fibrosis is the result from a relative imbalance between synthesis and degradation of matrix proteins. Following liver injury of any etiology, hepatic stellate cells undergo a response known as activation, which is the transition of quiescent cells into proliferative, fibrogenic, and contractile myofibroblasts. Upon this cellular transdifferentiation the effector cell becomes the major source of fibrillar and non-fibrillar matrix proteins resulting in excessive scar formation and cirrhosis, the end stage of fibrosis. Concomitant with progressive liver fibrosis, the tissue inhibitor of metalloproteinases-1 (TIMP-1) is strongly activated in hepatic stellate cells. We have developed a recombinant replication-defective adenovirus in which the TIMP-1 promoter is coupled to the herpes simplex virus thymidine kinase gene rendering activated hepatic stellate cells susceptible to ganciclovir. This novel targeted suicide gene approach was validated in a culture model considered to reflect an accelerated time course of the cellular and molecular events that occur during liver fibrosis. We demonstrate that transfer of the suicide gene to culture-activated hepatic stellate cells results in a strong expression of the respective transgene as assessed by Northern blot and Western blot analyses. The enzyme catalyzed the proper conversion of its prodrug subsequently initiating programmed cell death as estimated by caspase-3 assay and Annexin V-Fluos staining. Altogether, these results indicate that induction of programmed cell death is a promising approach to eliminate fibrogenic HSC.