转录因子FoxO1与肝纤维化

肝纤维化是各种肝细胞毒性物质对肝脏慢性或重复性损伤所引起的肝脏病理改变,肝星形细胞(HSC)激活是肝纤维化的关键因素.研究发现,转录因子FoxO1是调节HSC激活、增殖和迁移的重要因子之一.     

TGF-β1/Smads信号通路与肝纤维化

肝纤维化是肝脏对各种刺激的创伤性愈合,主要表现为细胞外基质的过量沉积.肝星形细胞(HSC)被认为是引起肝纤维化的主要细胞,它的活化受到多种细胞因子的调节.TGF-β1在启动和促进HSC向肌成纤维细胞转化的过程中有着重要作用,是目前已知最重要的敛肝纤维化细胞因子之一.此文就TGF-β1/Smads信号通路在肝纤维化发病机制及其治疗方面的作用进行综述.     

上皮细胞间充质化在肝脏发育和肝纤维化中的作用

上皮细胞间充质化(EMT)是一个复杂的病理生理过程,受多种信号途径的调节,主要包括Wnt/β-catenin和TGF-β/Smads信号通路.EMT能促进肝细胞以及胆管上皮细胞转化为肝星形细胞,从而导致肝纤维化的进展,此文就其在肝脏发育和肝纤维形成中的作用进行综述.     

中西药物治疗肝纤维化的进展

<正>肝纤维化是各种损害因素导致的肝细胞发生炎症坏死,肝内纤维结缔组织异常增生。目前认为其机制主要是肝星状细胞(HSC)的活化、细胞外基质(ECM)的合成与降解失衡导致ECM在细胞间质过度沉积所致。肝纤维化是慢性肝损伤向肝硬化发展的动态过程。目前认为,进展性肝纤维化具有可逆性。药物     

非编码RNA在肝纤维化发展中的作用

肝纤维化是各种慢性肝脏疾病发展为肝硬化、肝癌的共同初始阶段, 是一种可逆的创伤愈合反应。其中肝星状细胞的活化是肝纤维化的一个关键环节。近年来, 越来越多的研究表明非编码RNA通过调节基因表达、信号传导通路和细胞功能等多种方式参与调节肝纤维化的发生和发展, 具有重要作用。本文综述了非编码RNA(微小RNA、长链非编码RNA和环状RNA)在肝纤维化中的作用机制及相关研究进展, 旨在为肝纤维化的临床诊疗及预后等各方面提供新思路。     

认识肝纤维化

肝纤维化的发生机制肝纤维化是继发于各种原因引起的肝脏炎症或损伤后组织修复过程中肝内纤维性结缔组织异常增生的代偿反应,是慢性肝病最重要的病理改变,也是慢性肝炎、肝硬化等进一步发展、恶化的重要原因。肝纤维化的病理特征是肝细胞外基质在肝内的过量沉积。其中肝星状细胞的激活是肝纤维化发生的中心环节。     

重视肝纤维化与肝硬化的防治研究

肝纤维化(Hepatic Fibfosis)是指肝细胞发生坏死及炎症刺激时，肝内纤维结组织增生的病理过程。轻者称为肝纤维化，重者假小叶及结节形成，称为肝硬化。慢性肝病的重要病理基础是肝纤维化，通过纤维化的发展走向肝硬化。肝纤维化是各种原因引起的慢性肝损害导致的病理状态过程，是发展为肝硬化形成的基础和必要阶段。现已证实肝纤维化的第一步是炎症反应和肝星状细胞(HSC)的激活。     

肝纤维化病程中Kupffer细胞与HSC的相互关系（综述）

肝纤维化（HF）是诸多慢性肝病共同的病理过程,也是各种慢性肝病向肝硬化转归的中转站。肝星状细胞（HSC）是细胞外基质（ECM）的主要来源,在肝纤维化形成中起关键性作用。枯否细胞（KC）是肝脏内重要的非实质细胞,KC通过分泌一系列细胞因子参与HSC的活化。参与肝纤维化的发生与发展。在肝纤维化的恢复阶段,KC可抑制HSC活性,促进其凋亡从而发挥抗纤维化作用。因此,深入研究Kupffer细胞与HSC的Cross-talk在肝纤维化的发生与发展中的作用和机制,对于临床工作中防治肝脏损伤,提高患者生存率具有实际意义。     

靶向结缔组织生长因子siRNA对肝纤维化影响研究进展

肝纤维化是肝脏对各种原因所致肝损伤的创伤愈合反映,是组织发生修复反映时细胞外基质(ECM)合成、降解与沉积不平衡而引起的病理过程,肝纤维化的形成涉及多种细胞、细胞因子以及ECM的变化.其中肝星状细胞(HSCs)激活并转化为肌成纤维细胞是肝纤维化发生、发展的核心环节、各种致纤维化因素均把HSCS作为最终靶细胞,促使其转化为肌成纤维细胞而导致肝纤维化的发生.影响肝纤维化形成的因素很多,至今尚未完全阐明.结缔组织生长因子(connective tissue growth factor,CTGF)是一种非结构性基质蛋白,能直接介导肝星状细胞(HSCs)的活化、合成及分泌细胞外基质(ECM),该因子的研究为探索肝纤维化的发病机制及新的治疗方案注入了新思想,现就CTGF在肝纤维化中研究讲展作一综述.     

肝纤维化中细胞因子的作用

肝纤维化是继发于各种形式慢性肝损伤之后的组织修复过程中的代偿反应,它也是慢性肝病发展为肝硬化的必经病理过程.各种病因所引起的慢性肝病绝大多数都有肝纤维化,其中25%～加%最终发展为肝硬化乃至肝癌.因此,肝纤维化的发生机制成为目前慢性肝病的研究热点之一.肝纤维化的形成是一个多因素、多细胞参与的复杂过程,涉及多种细胞因子和蛋白成分表达的改变,细胞因子在肝星形细胞的活化、表型改变中扮演重要角色.此文对部分细胞因子在肝纤维化中的作用作一简要综述.     

Recent advances in the study of the mechanisms of silica-induced pulmonary fibrosis

A review was made on the recent advances in the study on the pathogenesis of silica-induced pulmonary fibrosis. Alveolar macrophages which ingest silica particles liberate a fibrogenic factor, which stimulates the production of collagen of cultured fibroblasts. Silica deposited in the alveoli augments the demand of macrophages, the supply of which is maintained by monocytes recruited from the bone marrow. Attempts to demonstrate in vitro the presence of a fibrogenic factor in the supernatant of macrophages have been made in many laboratories, and an in vivo model utilizing diffusion chambers implanted in mice has been used by some investigators. A fibrogenic factor has been isolated and purified from the medium of silica-treated macrophages. Recent advances in immunological studies have demonstrated that silica stimulates macrophages to release monokines such as interleukin 1 (IL-1) and that IL-1 has chemical properties identical to the fibrogenic factor, which enhances the level of collagen production by modulating the proliferation of fibroblasts. Silica inhibits the suppressive effects of macrophages on fibroblasts. The increased protein synthesis in the fibroblasts is due partly to increase in mRNA. Collagen synthesis is stimulated not only by the fibrogenic factor released from silica-treated macrophages but also by the inhibition of macrophage ribonuclease activity. Information on the number of cells, collagen content and protease activity in the lung as well as in the bronchopulmonary lavage fluid has provided us a better understanding of the mechanisms involved in silica-induced pulmonary fibrosis.     

Iron-induced oxidant stress in alcoholic liver fibrogenesis.

Iron is an essential micronutrient. However, because human beings have no means to control iron excretion, excess iron, regardless of the route of entry, accumulates in parenchymal organs and threatens cell viability. Indeed, when iron-buffering capability is overwhelmed, oxidative stress-induced cell damage and fibrogenesis may arise, mainly in the liver, the main storage site for iron in the body. Results of recent studies have clearly shown that these pathologic events are induced by iron-generated reactive oxygen species and lipid peroxidation by-products. Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix components in the liver, is a dynamic process, from chronic liver damage to end-stage liver cirrhosis. Iron-induced oxidant stress is involved in this process (1) as the primary cause of parenchymal cell necrosis or (2) as activator of cells that are effectors [e.g., hepatic stellate cells, (myo)fibroblasts] or key mediators (e.g., Kupffer cells) of hepatic fibrogenesis (or through both mechanisms). Beyond their effect as direct cytotoxic agents, iron and free radicals may trigger increased synthesis of collagen in myofibroblast-like cells as well as activate granulocytes and Kupffer cells, resulting in an increased formation of cytokines and eicosanoids and further reactive oxygen species. This may constitute a cascade of amplifying loops, which perpetuate the fibrogenic process. The fibrogenic potential of iron is even more dramatic when iron acts in concert with other hepatotoxins such as alcohol. In this instance, even if tissue iron levels are only slightly elevated, the toxic effect of alcohol or its metabolites may be amplified and propagated with rapid acceleration of the liver disease. At the molecular level, the presence of catalytically active "free iron" may (1) contribute directly to the hepatotoxicity of alcohol or (2) enhance the generation of cytokine and fibrogenic mediators from resident Kupffer cells (or be involved in both ways). A challenge for future research is to develop therapeutic tools able to block "redox-active" free iron in the cell.     

矽肺相关蛋白的纯化,鉴定及其促成纤维细胞增殖作用

目的分离、鉴定与矽肺发生、发展过程相关的几种蛋白质,并测定其促成纤维细胞增殖的活性。方法采用高压液相色谱技术包括凝胶过滤柱层析、离子交换柱层析、反相Ｃ４高压液相色谱柱层析,分别对矽肺大鼠肺泡灌洗液（ＢＡＬＦ）、肺泡巨噬细胞冻融物（ＡＭＥ）及其条件培养液（ＡＭＣＭ）进行分离纯化,并通过Ｎ末端氨基酸序列的测定来鉴定这些蛋白质。结果（１）染尘２１天后,矽肺大鼠ＢＡＬＦ中白蛋白含量明显升高;（２）从ＢＡＬＦ、ＡＭＥ和ＡＭＣＭ中除纯化到相对分子质量为１５４００的溶菌酶外（其刺激成纤维细胞增殖的活性为１４０％）,还纯化到一种新的具有明显促成纤维细胞增殖的细胞因子（Ｆｉｂｒｏｂｌａｓｔｇｒｏｗｔｈｐｒｏｍｏｔｉｎｇｆａｃｔｏｒ,ＦＧＰＦ）,其最适作用浓度为２．０～６．０μｇ／ｍｌ。结论巨噬细胞分泌的ＦＧＰＦ和溶菌酶在矽肺纤维化过程中可能有重要作用。     

Observations on the Pathogenesis of Silicosis by Means of the Diffusion Chamber Technique

An attempt has been made to determine whether the diffusion chamber technique can be used to decide the validity of the silica solubility theory of the pathogenesis of silicosis. Small chambers were constructed from membranes of a pore size which allowed free passage of colloidal silicic acid and tissue fluids but which prevented the entry of host cells and the exit of the larger silica particles. Significant fibrosis failed to develop around chambers containing five different forms of silicon dioxide when inserted subcutaneously and intraperitoneally in rats and rabbits. All five forms of silica were actively fibrogenic when brought into direct contact with peritoneal tissues. However, in vitro experiments suggest that colloidal silicic acid, the form which may be involved in silicotic fibrosis, does not escape from the chambers. Thus the biological results obtained by this technique do not necessarily invalidate the silica solubility theory of the pathogenesis of silicosis.     

An assessment of the fibrogenic potential of very short 4T30 chrysotile by intratracheal instillation in rats

Three groups of five rats each received, respectively, a single intratracheal instillation of saline (control), 5 mg of UICC chrysotile B asbestos, and 5 mg of a preparation of very short chrysotile fibers (4T30, 100% less than 8 micron) isolated by a sedimentation procedure. At various intervals after the treatment (1 to 60 days), assessment of lung morphology was performed on each animal. Although the two types of chrysotile fibers have similar chemical composition, structure, and surface charge, the lung tissue reaction differed considerably. Lungs of animals exposed to UICC chrysotile B showed significant pathological alterations as early as 7 days following treatment. The lesions were localized in and around terminal bronchioles and consisted of inflammatory cells, fibroblasts and collagen deposition which distorted and obstructed small airways. Reaction to very short 4T30 chrysotile fibers was quite distinct. Seven days after treatment, lungs of these animals showed alveolar and interstitial accumulation of inflammatory cells. The alveolitis persisted 60 days after treatment and no fibrosis was apparent. It appears that very short 4T30 chrysotile fibers are much less fibrogenic than UICC chrysotile B and that intratracheal instillations in rats may represent a useful mean of rapidly assessing the fibrogenic potential of various dusts. These observations support the concept that fiber length is an important factor for fibrogenicity of asbestos.     

Pulmonary function in workers inhaling iron oxide dust

Summary Lung function studies (static lung volumes, FEV_1.0, transfer factor, blood oxygen tension) in fourteen workers (mean age 43 years) exposed (average length 10 years) to pure iron oxide dust did not reveal abnormalities compatible with pulmonary fibrosis, although nodular opacities were present in the chest radiographs. The results seem to support the opinion that pure iron oxide is not fibrogenic in the lung.     

Exposure of diamond polishers to cobalt

Interstitial pulmonary fibrosis due to 'hard metal' exposure is well known, and the presence of cobalt has always been considered as the causative factor. Recently interstitial pulmonary fibrosis has been described in diamond polishing workers. In this study the dust composition in different polisher's workplaces where diamond disks are in use has been determined. Careful investigation showed that the exposure to respirable dust was comparable to that of 'hard metal' workers. The dust consists mainly of iron and cobalt particles and small amounts of silica. No 'hard metals' have been found, and other fibrogenic agents such as beryllium have been excluded. These observations lend support to the hypothesis that crystalline cobalt particles can be responsible for pulmonary fibrosis even in the absence of carbides.     

Pulmonary fibrogenic response of guinea pigs to amosite dust

Summary The fibrogenic response of amosite variety of asbestos was studied in lungs of guinea pigs over a period of 300 days. Histologically there was marked reticulin fibrosis but the maturation into collagen was slow. Biochemical estimation revealed significant increase of hydroxyproline and glycosamine contents. Total lung protein was also found to be higher in the amosite treated animals reaching maximum at 90 days. The significance of these findings have been discussed.     

搪瓷喷花粉尘致肺纤维化的实验研究

目的：研究搪瓷喷花粉尘的致肺纤维化作用。方法：３组ＳＤ大鼠气管内分别注入搪瓷喷花（白下底料）粉尘、石英石粉尘和生理盐水,染尘后６０ｄ和１８０ｄ宰杀,称取肺鲜重,测定肺胶原含量,肺组织病理学改变。结果：熟料粉尘组大鼠的肺鲜重和肺胶原含量高于生理盐水组,但明显低于石英尘组。病理观察结果显示,熟料粉尘能在肺内形成异物结节及周围轻度纤维增生。结论：一定量的搪瓷喷花粉尘进入肺内不至引起进行性肺纤维化,而是引     

The effects of silica on lymph nodes and vessels--a possible mechanism in the pathogenesis of non-filarial endemic elephantiasis

Non-filarial tropical elephantiasis, which occurs in certain volcanic areas of the world, has been postulated to be an obstructive lymphopathy due to the fibrogenic effects of silica absorbed through the plantar skin of bare-footed people. Animal experiments involving the direct intralymphatic injection of fine silica particles have been carried out in order to assess the extent to which this substance can engender lymphatic obstruction and to determine its main site of action. Intralymphatic silica provoked an immediate and intense macrophage reaction with later fibrosis both within lymph vessels and to a lesser extent within lymph nodes. Lymphography indicated that the consequent obstruction resulted more from the effects of silica on vessels than on nodes.