肝纤维化的发病机制

1.肝纤维化的概念：1978年世界卫生组织专家组将纤维化定义为胶原的过度形成,因为当时认为胶原是纤维化肝脏最突出的结缔组织成分,经过20多年的研究,目前认为肝纤维化是指各种原因引起的动态创伤-愈合过程,在这个过程中,肝脏中的多种ECM成分含量不断增加。有研究表明,肝硬化时肝脏Ⅰ、Ⅲ、Ⅳ、Ⅴ、Ⅵ型胶原分别为正常肝脏的8、4、14、8和10倍,[第一段]     

HSC凋亡与肝纤维化逆转的研究进展

肝星状细胞(HSC)在肝纤维化形成中起核心作用,其凋亡是肝纤维化逆转的主要机制之一.深入研究HSC凋亡的调控机理及HSC凋亡在肝纤维化逆转中的作用,对肝纤维化的防治具有重要意义.     

肝纤维化发病机制与临床诊断的研究进展

肝纤维化是机体对各种病因引起的慢性肝损伤后的一种损伤修复反应,慢性肝病发展至最后将发展成为肝硬化,肝硬化及其并发症威胁着全球居民的生命健康.在过去的几十年中,人们在肝纤维化的发生机制方面已经取得了很大的进展.HSC的激活是肝纤维化发生过程中的一个重要事件,同时各类细胞因子与其对应受体;以及各类炎症细胞均在纤维化发展过程...     

肝纤维化基因治疗的研究进展

肝纤维化仍缺少有效的治疗措施。本文将围绕近年来对肝纤维化形成机制的认识,对采用基因治疗防治肝纤维化的相关探索性研究作一综述。     

肝纤维化的基因治疗研究进展

肝纤维化是各种慢性肝病发展至肝硬化的必经阶段,以纤维组织大量增生和肝小叶结构无序化为特征.近年来随着分子生物学的发展,肝纤维化的分子机制逐渐得以阐明,从而使肝纤维化的基因治疗成为可能,肝纤维化的基因治疗主要起到阻止纤维化发展、刺激肝细胞再生和肝组织结构重建三方面的作用.目前,常用的方法一般是通过抑制肝星状细胞(HSC)的活化,抑制HSC的增殖,及对HSC的靶向治疗等,达到延缓和治愈肝纤维化的目的.     

肝星状细胞与肝纤维化的研究进展

一、ＨＳＣ的增殖活化及凋亡 当肝脏受到物理、化学及生物因素的刺激时,ＨＳＣ增殖并激活,转变为“肌成纤维细胞（ｍｙｏｆｉｂｒｏｂｌａｓｔ, ＭＦＢ）”,表达ａ－平滑肌动蛋白（ａ－ｓｍｏｏｔｈ ｍｕｓｃｌｅａｃｔｉｎ, ａ—ＳＭＡ）、合成ＥＣＭ等。Ｇｒｅｓｓ一ｆｉｅｒ等［１］根据已有的研究结果,提出了ＨＳＣ激活的“三步级联反应”模式。（１）炎症前期阶段,肝细胞受损后释放丝裂原,旁分泌作用于ＨＳＣ从而引起ＨＳＣ增殖,且肝细胞丧失接触抑制。（２）炎症阶段,活化的ｋｕｐｆｆｅｒ细胞、巨噬细胞及血小板释放细胞因…     

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。     

神经生长因子与肝纤维化的研究进展

神经生长因子(NGF)不仅对神经元与其前体细胞的生长、分化、再生与修复起着重要作用,而且具有更广泛的生物学作用。NGF能通过抑制肝脏炎症反应,诱导活化的肝星状细胞凋亡,促进细胞外基质降解来影响肝纤维化的进展,为肝纤维化的预防与治疗提供了重要的思路。     

肝细胞生长因子与肝纤维化的研究进展

肝细胞生长因子是一种具有多种生物活性的细胞因子,其在促进肝细胞增殖、抑制肝星状细胞活化等方面有重要作用.肝纤维化进展过程中,各种因素引起肝细胞持续损伤,使损伤部位肝细胞再生,肝星状细胞激活,细胞外基质大量沉积,从而导致肝纤维化形成.此文就肝细胞生长因子的生物学特性及其在肝纤维化中发挥的作用作一综述.     

Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options

Despite intensive studies, the clinical opportunities for patients with fibrosing liver diseases have not improved. This will be changed by increasing knowledge of new pathogenetic mechanisms, which complement the "canonical principle" of fibrogenesis. The latter is based on the activation of hepatic stellate cells and their transdifferentiation to myofibroblasts induced by hepatocellular injury and consecutive inflammatory mediators such as TGF-β. Stellate cells express a broad spectrum of matrix components. New mechanisms indicate that the heterogeneous pool of (myo-)fibroblasts can be supplemented by epithelial-mesenchymal transition (EMT) from cholangiocytes and potentially also from hepatocytes to fibroblasts, by influx of bone marrow-derived fibrocytes in the damaged liver tissue and by differentiation of a subgroup of monocytes to fibroblasts after homing in the damaged tissue. These processes are regulated by the cytokines TGF-β and BMP-7, chemokines, colony-stimulating factors, metalloproteinases and numerous trapping proteins. They offer innovative diagnostic and therapeutic options. As an example, modulation of TGF-β/BMP-7 ratio changes the rate of EMT, and so the simultaneous determination of these parameters and of connective tissue growth factor (CTGF) in serum might provide information on fibrogenic activity. The extension of pathogenetic concepts of fibrosis will provide new therapeutic possibilities of interference with the fibrogenic mechanism in liver and other organs.     

Influences of reactive oxygen species and nitric oxide on hepatic fibrogenesis.

BACKGROUND/AIMS: This study determined the roles of NAD(P)H oxidase, which generates reactive oxygen species (ROS), and of inducible nitric oxide synthase (iNOS), which generates nitric oxide (NO) on the development of hepatic fibrosis in mice. METHODS: Hepatic fibrosis was produced by carbon tetrachloride administered for 12 weeks in wild-type (WT) mice and in mice with knockout of either the gp91phox subunit of the NAD(P)H complex (gp91phox-/-) or of iNOS (iNOS(-/-)). RESULTS: Liver fibrosis and hydroxyproline after carbon tetrachloride was lower in gp91phox-/- and in iNOS(-/-) mice than in WT mice. The increase in alpha2(I) collagen mRNA was absent in the gp91phox-/- but not in the iNOS(-/-) mice. Transformation growth factor beta (TGF-beta) mRNA was increased more in the gp91phox-/- than in the WT mice, while in the iNOS(-/-) mice there was no increase in TGF-beta mRNA. 3-Nitrotyrosine was similarly increased by carbon tetrachloride in gp91phox-/- and WT mice, while there was no increase in the iNOS(-/-) mice. CONCLUSIONS: Deficiencies in NAD(P)H oxidase and in iNOS separately reduce, but do not eliminate carbon tetrachloride-induced liver fibrosis. Likely causes for this inhibitory effects are decreases in the production of ROS in NAD(P)H deficiency and of peroxinitrite radicals in iNOS deficiency.     

New concepts in reactive oxygen species and cardiovascular reperfusion physiology

Increasingly complex behavior of free radicals and reactive oxygen species (ROS) are noted within biological systems. Classically free radicals and ROS were considered injurious, however current mechanisms describe both protective and deleterious effects. A burst of ROS has been well described with the first moments of reperfusion and is associated with injury. However ROS can also be protective as signal preconditioning protection and induce stress responses that lead to survival. ROS generation is appreciated to occur during ischemia despite the low oxygen tension, from a likely mitochondria source, and ROS-induced ROS release may amplify its signal. The burst of ROS seen during reperfusion may originate from a different cellular source than during ischemia and is not yet fully identified. ROS and cellular redox conditions regulate a large number of vital pathways (energy metabolism, survival/stress responses, apoptosis, inflammatory response, oxygen sensing, etc). While cellular systems may demonstrate reperfusion injury, whole organ and animal models continue to report contradictory results on reperfusion injury and the role of antioxidants as a therapy. Collectively, these data may offer insight into why clinical trials of antioxidants have had such mixed and mostly negative results. Future antioxidant therapies are likely to be effective but they must become: more specific for site of action, not have deleterious effects on other signaling pathways, be targeted to a specific reactive oxygen species or cellular compartment, and be "time sensitive" so they deliver the correct therapy at precisely the correct time in ischemia and reperfusion.     

线粒体反应氧体系与脂肪肝

线粒体是真核细胞的重要细胞器,是生成ATP的主要场所,在脂质氧化中起重要作用。近年大量研究发现线粒体尤其是线粒体反应性氧体系(reactive oxygen species,ROS)与脂肪肝的发生密切相关。现就线粒体ROS和脂肪肝的关系及其作用机制进行阐述。 一、线粒体ROS与线粒体损伤 线粒体是细胞内ROS的主要来源,线粒体功能失常可导致肝细胞线粒体ROS泄漏,使体内氧自由基增加。研究发现:脂肪性肝炎患者存在线粒体超微结构损伤,表现为肿胀线粒体内     

Evolving concepts in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) represents a particular aetiology of systolic heart failure that frequently has a genetic background and usually affects young patients with few co‐morbidities. The prognosis of DCM has improved substantially during the last decades due to more accurate aetiological characterization, the red‐flag integrated approach to the disease, early diagnosis through systematic familial screening, and the concept of DCM as a dynamic disease requiring constant optimization of medical and non‐pharmacological evidence‐based treatments. However, some important issues in clinical management remain unresolved, including the role of cardiac magnetic resonance for diagnosis and risk categorization and the interaction between genotype and clinical phenotype, and arrhythmic risk stratification. This review offers a comprehensive survey of these and other emerging issues in the clinical management of DCM, providing where possible practical recommendations.     

Evolving patterns of reactive arthritis

Clinical Rheumatology - To characterize rheumatologists’ perspectives on evolving trends of reactive arthritis (ReA). After ethics approval, 548 members of the Canadian Rheumatology...     

Evolving concepts in primary sclerosing cholangitis

Patients suffering from primary sclerosing cholangitis (PSC) show considerable differences regarding clinical manifestations (i.e. large duct versus small-duct PSC, presence or absence of concomitant inflammatory bowel disease), disease progression, risk for malignancy and response to therapy, raising the question whether PSC may represent a mixed bag of diseases of different aetiologies. The growing list of secondary causes and diseases 'mimicking' or even overlapping with PSC (e.g. IgG4-associated sclerosing cholangitis), which frequently causes problems in clear-cut discrimination from classic PSC and the emerging knowledge about potential disease modifier genes (e.g. variants of CFTR, TGR5 and MDR3) support such a conceptual view. In addition, PSC in children differs significantly from PSC in adults in several aspects resulting in distinct therapeutic concepts. From a clinical perspective, appropriate categorization and careful differential diagnosis are essential for the management of concerned patients. Therefore, the aim of the current review is to summarize current and evolving pathophysiological concepts and to provide up-to-date perspectives including future treatment strategies for PSC.     

Evolving concepts regarding transient ischemic attacks

Transient ischemic attack (TIA) represents one end of the spectrum of focal brain ischemia, the other being completed infarction or ischemic stroke. The evolving technologic advancements in neuroimaging continue to change and sharpen the definition, epidemiology, and management of TIA. As a powerful risk factor for ischemic stroke, TIA deserves widespread public and physician education, urgent attention and investigation, and rapid management. The recognition and treatment of TIA provides an excellent opportunity for stroke prevention that is often missed or poorly recognized among physicians.