瘦素在实验性大鼠肝纤维化发生中的作用机制研究

目的:探讨瘦素(L eptin)在大鼠肝纤维化发生中的作用机制。方法:对32只雄性SD大鼠皮下注射40%四氯化碳(CC l4)油剂制备大鼠肝纤维化模型,分别于注射后1、4、8周处理动物,留取肝组织,应用免疫组织化学方法检测大鼠肝组织中瘦素的表达。结果:免疫组化结果显示,瘦素主要表达于肝星状细胞胞质中。注射CC l4诱导后,大鼠肝组织中瘦素表达较正常对照明显增强(P<0.01,<0.05),且1,4,8周肝组织中瘦素的表达强度呈明显递增趋势(P<0.01,<0.05)。结论:在肝纤维化的形成过程中,瘦素主要表达于肝星状细胞,并可能通过窦内皮细胞发挥着重要的促纤维化作用。     

环氧合酶-2与瘦素对肝纤维化的影响

目前公认肝星状细胞是肝纤维化发生发展的关键细胞,只有活化的肝星状细胞才能出现增殖和凋亡,肝星状细胞只有活化后才能参与胶原的合成、降解和细胞外基质（ECM）的沉积。有研究表明肝纤维过程中,肝形状细胞活化增加,且环氧合酶-2与瘦素的分泌也明显增加,并对肝纤维化的发展起着重要影响。     

酒精性肝纤维化中肝星状细胞活化的机制研究进展

肝星状细胞（HSC）活化是各种病因所致肝纤维化过程中的关键环节。在酒精性肝病的发展过程中,乙醇和代谢产物乙醛可改变机体氧化还原状态,活化枯否细胞,释放大量细胞因子,诱导HSC活化、增殖和胶原合成,形成肝纤维化。本文将对酒精性肝纤维化中HSC活化的机制和相关靶点加以综述,为开发抗肝纤维化药物和临床治疗提供新的思路。     

瘦素诱导人肝星状细胞活化及其作用机制

目的探讨瘦素通过何种机制诱导人肝星状细胞(HSCs)活化及其机制。方法采用瘦素处理体外培养HSCs细胞的方法,模拟高瘦素血症对肝纤维化影响的研究模型,经过不同时间和不同浓度的瘦素处理后,Western-blot方法检测TGF-β1、SREBP-1c、α-SMA和Ⅰ型胶原的蛋白表达量。结果瘦素可以促进HSCs表达α-SMA、Ⅰ型胶原和TGF-β1的表达,而抑制SREBP-1c的蛋白表达。结论瘦素活化人肝星状细胞参与肝纤维化过程,其中机制可能与激活TGF-β1通路和抑制SREBP-1c表达有关。     

肝窦内皮细胞参与肝纤维化的机制

肝窦内皮细胞在肝纤维发生发展过程中具有重要作用.它主要通过表达相关细胞因子、介导肝脏炎症反应、活化星状细胞、参与细胞外基质的生成与降解、参与肝窦毛细血管化、调节肝脏血管等参与肝纤维化.本文就肝窦内皮细胞与肝纤维化的机制进行综述.     

肝星状细胞与肝纤维化的关系

肝纤维化是各种慢性肝病向肝硬变发展的必经阶段,临床上能否将病变终止于肝纤维化阶段或者逆转正常是治疗慢性肝病的关键。肝纤维化机理涉及细胞、生物因子及相互作用等因素。肝星状细胞及其激活在肝纤维化中起重要作用,本文仅就肝星状细胞与肝纤维化的关系予以阐述。1　肝星状细胞的形态及显示方法1876年ＶｏｎＫｕｆｆｅｎ在文献中首次描述肝内有贮脂细胞存在,将肝内贮脂细胞与枯否氏细胞归做同一细胞群,至本世纪40年代,人们仍旧认为贮脂细胞是肝脏网状内皮系统中枯否氏细胞的指肪变性形式,直到1951年伊东等才首次提出肝脏贮脂细胞是一有…     

肝窦周细胞与肝纤维化的研究进展

肝窦周细胞与肝纤维化的研究进展白娟①段永强②李文凡③王慎①关键词肝纤维化枯否细胞贮脂细胞窦内皮细胞中图分类号Ｒ３６３“肝纤维化”属于病理学术语，是慢性肝病发展的重要病理阶段，其病理学特征为汇管区和肝小叶内有大量纤维组织增生和沉积。肝纤维化的形成涉及到...     

肝纤维化的药物治疗进展

肝纤维化是各种致病因子引起的慢性肝病的共同病理过程。致病因子造成肝细胞损伤并激活枯否细胞(KC)，分泌多种细胞因子，随同血小板、肝窦内皮细胞(SEC)和肝细胞等分泌的多种细胞因子及一些化学介质共同作用于肝星状细胞(HSC)，使其激活，转化为肌成纤维细胞。细胞因子还通过旁分泌、自分泌作用，使HSC增殖，合成大量的细胞外间质(ECM)。ECM合成、分泌增加，降解减少，导致肝纤维化形成。     

肝细胞微环境:抗肝纤维化药物的新靶点

本文以肝星状细胞为切入点,分析了肝细胞微环境与肝纤维化的关系。肝细胞微环境由肝星状细胞、细胞外基质、基质金属蛋白酶、枯否细胞、自然杀伤细胞等共同构成,而肝纤维化是由其相互作用的失衡所致。因此提出,应将肝细胞微环境作为治疗肝纤维化的复合靶点并应用于传统民族药物筛选,以充分发挥民族药物多机制、多靶点的优势,研制抗肝纤维化的创新药物。     

肝纤维化相关因子与治疗展望

中国是乙肝大国，肝纤维化是多种慢性肝病发展至肝硬化的必经阶段，肝细胞、内皮细胞、枯否细胞等能够通过产生转化生长因子．血小板衍生生长因子、肝细胞生长因子、肿瘤坏死因子等细胞因子直接或间接地促进肝星状细胞（HSC）活化，继而原癌基因和核因子等转录因子被激活，导致HSC增殖，细胞外基质（ECM）降解减少并沉积。因此，针对特定的细胞因子，在体细胞基因水平进行调控，可以阻止肝纤维化病理进程。研究肝纤维化及细胞因子的关系，可以为通过相关因子治疗肝纤维化提供理论基础。     

Differentially expressed genes identified by microarray analysis following leptin treatment of hepatic stellate cells

Background Liver fibrosis is the process through which numerous chronic liver diseases develop into liver cirrhosis. Leptin can activate hepatic stellate cells （HSCs） and play an important role in the formation of liver fibrosis. However, the process by which leptin activates HSCs is complicated, and research on this process is limited. The aim of this study was to explore the related changes in gene expression and the control mechanisms involved in leptin activated HSCs to understand the overall mechanism of liver fibrosis development. Methods We cultivate rat HSCs, with and without stimulation by leptin, and extracted mRNA. Differentially expressed genes were detected by microarray analysis. Results The differentially expressed genes identified included six upregulated genes and six downregulated genes. The representative upregulated genes included short chain dehydrogenase （CY5/CY3=2.265） and pulmonary surfactant protein A1 （CY5/CY3=2.036）. The significant downregulated gene encoded hepatic stearoyl coenzyme A desaturase 1 （SCD-1） （CY5/CY3=0.351）.Conclusion Leptin might mediate the molecular biological mechanisms of liver fibrosis.     

An adipocentric view of liver fibrosis and cirrhosis

Liver fibrosis is the consequence of chronic or repeated liver injury caused by hepatotoxic agents like alcohol and viruses, as well as immune and congenital metabolic disorders. Nonalcoholic fatty liver disease (NAFLD), caused by obesity and abnormal lipid metabolism, may be the latest known cause of liver fibrosis and cirrhosis. Furthermore, NAFLD with obesity can provide a terrain in which alcoholic and viral liver diseases, such as chronic hepatitis C, are prone to cause liver cirrhosis. Insulin, insulin-like growth factor (IGF)-1, peroxisome proliferator-activated receptors (PPARs), leptin, adiponectin, and preadipocyte factor-1/delta-like1 (Pref-1/dlk1) are hormones, growth factors, nuclear receptors, and cytokines that are actively involved in lipid metabolism. They share common target cells important in liver fibrosis, i.e., hepatic stellate cells (HSCs). Activation of HSCs is known to initiate and perpetuate liver fibrosis. Insulin and IGF-1 stimulate HSC activation and collagen production in vitro. However, IGF-1 alleviates liver fibrosis in vivo. Ligands of PPARy inhibit HSC activation and collagen synthesis in vivo and in vitro, and are helpful in decreasing liver fibrosis. But ligands of PPARbeta enhance proliferation of HSCs. Leptin is profibrogenic, and liver fibrosis is decreased in leptin- or leptin receptor-deficient mice. Adiponectin is, on the contrary, anti-fibrogenic. Extensive liver fibrosis may develop in adiponectin-knockout mice and is alleviated by administration of recombinant adiponectin. Pref-1/dlkl is implicated in fibrogenesis of the liver through its modulation of HSCs. The use of such biologically active molecules in lipid metabolism as ligands of PPARgamma and adiponectin might not help slim down a patient on the whole, but can potentially be used to halt the progression of liver fibrosis. Weight reduction, a strategy for controlling obesity and metabolic syndromes, may also be a tool for decreasing NAFLD and alleviating liver cirrhosis.     

瘦素对大鼠肝纤维化星状细胞的作用及相关ERK信号转导机制

目的：探讨瘦素（leptin）对大鼠肝纤维化星状细胞（HSC）的作用及相关信号转导机制。方法采用改良原位灌注、Optiprep密度梯度离心法分离纯化大鼠HSC。通过台盼蓝拒染试验评估细胞存活率,α-平滑肌肌动蛋白（α- SMA）免疫组化鉴定,光镜观察形态学变化。将40只SD大鼠分为4个处理组：对照组、血管紧张素Ⅱ（AngⅡ）组（加入10-7mol/L AngⅡ）、Leptin组（加入100ng/ml Leptin）、Leptin＋AngⅡ组（加入100ng/ml Leptin＋10-7mol/L AngⅡ）。分别采用3H- TdR和3H- Pro掺入法进行HSC增殖和胶原合成的测定。Western blot检测各处理组p- ERK1/ERK1、p- ERK2/ERK2、AngⅡ蛋白表达情况。结果大鼠HSC存活率＞90%,传代1次后HSC纯度＞95%。与对照组相比,AngⅡ组、Leptin组、Leptin＋AngⅡ组的HSC增殖和胶原合成均明显增加（均P＜0.05）;与AngⅡ组、Leptin组相比,Leptin＋AngⅡ组HSC增殖和胶原合成明显增加（均P＜0.05）。Western blot显示,AngⅡ组、Leptin组、Leptin＋AngⅡ组的p- ERK1/ERK1、p- ERK2/ERK2、AngⅡ蛋白水平均较对照组明显升高（均P＜0.05）;与AngⅡ组、Lep-tin组相比,Leptin＋AngⅡ组p- ERK1/ERK1、p- ERK2/ERK2、AngⅡ蛋白水平明显升高（均P＜0.05）。结论瘦素可通过上调AngⅡ水平,激活ERK信号转导通路,刺激HSC增殖和胶原合成,导致肝纤维化。     

肝星形细胞中细胞凋亡和存活的信号调控

肝星状细胞(hepatic stellate cells,HSCs)在肝脏纤维化发生过程中起着关键作用.当正常肝脏受到损伤时,HSCs由静息状态转分化为类肌成纤维细胞,并保持这种处于激活状态的表型,它们接收到的凋亡和存活的生物信号将决定激活态HSCs的最终细胞寿命.HSCs凋亡的发生与一系列复杂而又相互关联的生物信号传导和调控有关,HSCs凋亡信号来自于细胞膜受体,如死亡受体、神经生长因子受体和外周型苯甲二氮卓受体(peripheral-type benzodiazepine receptor);以及胞浆蛋白,如Bcl-2家族蛋白和细胞周期蛋白等.HSCs存活信号受到多种激酶和细胞因子的诱导,如金属蛋白酶组织抑制剂-1(tissue jnhibitors of metalloproteinase-1)、Rho/Rho激酶、血小板源生长因子(platelet-derived growth factor)、转化生长因子-β1(transforming growth factor-β1)和胰岛素样生长因子(insulin-like growth factor-1)等.特异性地诱导HSCs发生凋亡是治疗肝脏纤维化的直接和有效手段,虽然目前对HSCs由激活态到静息状态的转归尚需进一步研究,但诱导HSCs凋亡将是治疗肝脏纤维化和肝硬化的研究热点和主要发展方向.     

活化型肝星状细胞清除机制及其相关抗肝纤维化策略

已知肝星状细胞(hepatic stellate cells, HSCs)活化是肝纤维化的核心环节。越来越多的基础和临床研究证实,肝纤维化可以逆转。而肝纤维化消退的主要表现之一是活化型HSCs数量不断减少。因此,如何清除活化型HSCs并使之成为抗肝纤维化治疗新策略正逐渐受到关注。现有两种可能机制用于解释活化型HSCs的清除现象,即活化型HSCs的表型逆转和凋亡。本文旨在对基于活化型HSCs清除机制的抗肝纤维化策略进展做一综述。     

肝星状细胞的免疫学特性

 活化的肝星状细胞（hepatic stellate cells,HSCs）可合成大量细胞外基质（extracellular matrix,ECM）,并可分泌转化生长因子β（transforming growth factor-β,TGF-β）、血小板源性生长因子（platelet derived growth factor,PDGF）等促纤维化因子,在肝纤维化的发生发展中起着关键作用。近来研究发现活化的肝星状细胞具有多种免疫细胞的特性,可直接参与肝脏局部免疫调控,而免疫因素在肝纤维化发病机制中占据着重要地位,因此深刻认识肝星状细胞的免疫学特征有助于进一步阐明肝纤维化的发病机制。     

N-乙酰半胱氨酸保护大鼠肝纤维化的机制初步研究

目的研究N-乙酰半胱氨酸保护大鼠肝纤维化的机制。方法用四氯化碳（CC!。）制造大鼠肝纤维化模型,同时予100mg·kg^-1·d^-1N-乙酰半胱氨酸腹腔注射。在造模的第3个月末处死大鼠,用α-SMA单抗标记活化的肝脏星状细胞,并计算其数量,同时进行肝脏纤维化评分。结果N-乙酰半胱氨酸可以显著减少活化的HSC数量,降低CCl4诱导大鼠肝脏纤维化评分。结论N-乙酰半胱氨酸是通过抑制HSC的活化达到保护CCl4诱导的大鼠肝纤维化作用。     

Roles of the Lipid Metabolism in Hepatic Stellate Cells Activation

Abstract The lipids present in hepatic stellate cells （HSCs） lipid droplets include retinyl ester, triglyceride, cholesteryl ester, cholesterol, phospholipids and free fatty acids. Activation of HSCs is crucial to the development of fibrosis in liver disease. During activation, HSCs transform into myofibroblasts with concomitant loss of their lipid droplets and production of excessive extracellular matrix. Release of lipid droplets containing retinyl esters and triglyceride is a defining feature of activated HSCs. Accumulating evidence supports the proposal that recovering the accumulation of lipids would inhibit the activation of HSCs. In healthy liver, quiescent HSCs store 80% of total liver retinols and release them depending on the extracellular retinol status. However, in injured liver activated HSCs lose their retinols and produce a considerable amount of extracelhilar matrix, subsequently leading to liver fibrosis. Further findings prove that lipid metabolism of HSCs is closely associated with its activation, yet relationship between activated HSCs and the lipid metabolism has remained mysterious.     

褪黑素保护大鼠肝纤维化的机制初步研究

目的研究褪黑素保护大鼠肝纤维化的机制。方法用四氯化碳(CCl4)制造大鼠肝纤维化模型,同时予10mg/(kg.d)褪黑素腹腔注射;在造模的第3月末处死大鼠,用α-SMA单抗标记活化的肝脏星状细胞(HSC),并计算其数量,同时进行肝脏纤维化评分。结果褪黑素可以显著降低CCl4诱导大鼠肝脏纤维化评分,减少活化的HSC数量。结论褪黑素是通过抑制HSC的活化达到保护CCl4诱导的大鼠肝纤维化作用。