摘要:

AbstractThe relationship between vitamin A and liver fibrosis was studied with a CCl4‐induced fibrosis model in rats. Depending on the time of administration, vitamin A can potentiate or reduce fibrosis: when present during CCl4‐treatment parenchymal cell damage and fibrosis were enhanced, whereas vitamin A post‐treatment strongly reduced fibrosis. Enhanced fibrosis was also found in rats with low hepatic retinoid levels. Administration of ß‐carotene during CCl4‐treatment reduced several signs of fibrosis. The notion that liver retinoids play an important role in hepatic fibrogenesis is

ISSN:0815-9319    

DOI:10.1111/j.1440-1746.1995.tb01797.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractAn increasing body of experimental evidence is emerging to incriminate oxidative stress as a pivotal signal for liver fibrogenesis. This paper reviews the results from our studies testing this hypothesis. In the rat model of alcoholic liver disease, the importance of oxidative stress was supported by marked accentuation of liver fibrosis by dietary supplementation of iron, a pro‐oxidant, and the significant correlation of the liver malondialdehyde (MDA) and 4‐hydroxynonenal (4HNE) levels with the hepatic collagen accumulation. Both MDA and 4HNE adduct epitopes were detected intensely and diffusely in close association with collagen deposition. The direct cause and effect relationship between MDA/4HNE and Ito cell stimulation was indicated by the demonstration of Ito cell collagen gene induction by these aldehydes in culture. In primary cultures of rat Kupffer cells (KC), addition of antioxidants such as α‐tocopherol acetate and succinate suppressed mRNA expression and the release of interleukin (IL)‐6 and tumour necrosis factor alpha (TNFα). In rats with biliary fibrosis, an increase in the liver MDA level was accompanied by enhanced mRNA expression of procollagen α 1 (I) and transforming growth factor β 1 in Ito cells; and that of TNFα and IL‐6 in KC. Furthermore, the gel shift assay of KC nuclear extracts showed enhanced NF‐kB DNA binding activity. These results support the proposal that enhanced oxidative stress constitutes an important signal for activation of Kupffer and Ito cells in experimental li

ISSN:0815-9319    

DOI:10.1111/j.1440-1746.1995.tb01798.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractHepatic sinusoidal Ito cells (fat storing cells) are believed to play a regulatory role on hepatic sinusoidal blood flow through their contraction. The detailed mechanism of contraction of Ito cells, however, is still unknown. The present study was undertaken to clarify the effect of new myosin light chain kinase inhibitor, wortmannin, on Ito cell contraction. Ito cells prepared from rat liver were cultured for 4 days before the study. The contraction of Ito cells, which was monitored and analysed by time‐lapse video tape recording, was triggered by addition of endothelin‐1. Wortmannin pretreatment for 1 h inhibited endothelin‐induced Ito cell contraction dose‐dependently. Therefore, the integrity of the actomyosin system is essential for Ito cell contraction and normal sinusoidal blo

ISSN:0815-9319    

DOI:10.1111/j.1440-1746.1995.tb01799.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractLiver fibrosis is a dynamic process caused by changes in not only the synthesis of matrix proteins but also their degradation. Current evidence indicates that Ito cells, when activated to a myofibroblastic phenotype, play a very active role in regulating matrix degradation in liver. This is mediated via their ability to synthesize and release several members of the matrix metalloproteinase family, a class of enzymes which are responsible for degradation of matrix proteins in the extracellular space. Activated Ito cells have been demonstrated to release prostromelysin, progelatinase A and the pro‐enzyme form of interstitial collagenase. In addition, these cells can express appropriate systems for cleaving pro‐metalloproteinases to active forms (e.g. the plasminogen activator system, urokinase) as well as specific tissue inhibitors of the activated metalloproteinases (TIMP). In the early phases of liver injury, enzymes with the ability to degrade components of normal liver matrix are expressed (stromelysin and gelatinase A). In contrast, in the fibrotic phase of liver injury, during which fibrillar collagens accumulate, there is little (if any) expression of interstitial collagenase but marked expression of TIMP. These findings suggest that metalloproteinases and their inhibitors play a significant role in liver injury and fibro

ISSN:0815-9319    

DOI:10.1111/j.1440-1746.1995.tb01800.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractA choline deficient l‐amino acid defined (CDAA) diet led to the development of liver cirrhosis in male Wistar rats after 16 weeks. A new prolyl 4‐hydroxylase inhibitor, 2,4‐pyridine dicarboxylic acid bis [(2‐methoxyethyl amide)] (HOE 077), prevented liver fibrosis in a dose‐dependent manner without a reduction in increased serum alanine aminotransferase and aspartate aminotransferase in parallel with a reduction in preneoplastic enzyme‐altered lesions stained with anti‐glutathione S‐transferase placental form antibody. HOE 077 reduced the increase in serum procollagen III peptide (PIIIP) in a dose‐dependent manner and in proportion to the reduction in mRNA expression of type III procollagen in the liver of rat

ISSN:0815-9319    

DOI:10.1111/j.1440-1746.1995.tb01801.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractKupffer cells (KC) become activated in response to lipopolysaccharide (LPS) and produce a variety of mediators. Among them, TNFα is known to injure the liver. Here we report that TNFα mediates apoptosis in KC and sinusoidal endothelial cells. After stimulation for 24 h with LPS (0‐10 μg/mL), apoptosis in KC detected by TUNEL TdT‐mediated dUTP‐biotin nick end labelling (TUNEL) increased in a concentration‐dependent manner (0 μg/mL, 12 ± 4%; 0.1 μg/mL, 36 ± 11%; 1.0 μg/mL, 65 ± 9%; 10 μg/mL, 78 ± 15%). In contrast, co‐incubation of endothelial cells with LPS‐stimulated KC resulted in a marked increase in TUNEL‐positive endothelial cells. TNFα antibody blocked apoptosis in both KC and endothelial cells. Apoptosis was observed in cells adjacent to or in contact with KC. Reducing transmembrane TNFα expressed on KC also led to a decrease in endothelial cell apoptosis, suggesting that transmembrane TNFα is implicated in the cell‐to‐cell contact mechanism of induction of apoptosis. Thus, TNFα mediates apopt

ISSN:0815-9319    

DOI:10.1111/j.1440-1746.1995.tb01802.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractThe metabolic changes in a rat hepatoma cell line, AH70 cells, after co‐culture with rat Kupffer cells (KC) were visualized and analysed using a fluorescence microscope equipped with a silicon intensified target camera and a laser scanning confocal microscopic system. Kupffer cells were isolated from male Wistar rats, and cultured without any stimuli. The non‐activated KC reduced the mitochondrial energization in the cocultured AH70 cells within 2 h, which was indicated by decreased rhodamine 123 (Rh123) fluorescence. EitherNg‐monomethyl‐l‐arginine or dexamethasone significantly attenuated the KC‐induced mitochondrial dysfunction in AH70 cells, suggesting the involvement of nitric oxide (NO) derived from inducible‐type nitric oxide synthase (iNOS). Administration of monoclonal antibody (mAb) directed against rat ICAM‐1 also prevented the decrease in Rh123 fluorescence. Electron microscopy revealed that the membrane‐to‐membrane attachment between KC and AH70 cells occurred within 2 h. A laser scanning confocal microscopic observation using mAb against ICAM‐1 presented that the ICAM‐1 expression on AH70 cells and KC increased after the co‐culture. It is therefore concluded that the KC‐mediated mitochondrial dysfunction of hepatoma cells largely depends on NO production by iNOS. Furthermore, the present study supports a scenario that the NO production and release from KC is triggered by the close contact with hepatoma cells through adhesi

ISSN:0815-9319    

DOI:10.1111/j.1440-1746.1995.tb01803.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractImmunohistochemical analysis using monoclonal antibodies specific for cells of monocyte/macrophage lineage reveals that resident liver macrophages have a phenotype distinct from that of monocytes or activated liver macrophages. Liver macrophages consist of heterogeneous cell populations in maturation (matured 25F9‐positive and immature 25F9‐negative) but the ratio of two populations is constant in normal and diseased livers. The expression of CD 14 is down‐regulated in resident liver macrophages as compared to that in monocytes, while the expression of 25F9 is up‐regulated. On the other hand, the expressions of CD 14 and Fc γ RI are up‐regulated in activated liver macrophages in viral and autoimmune hepatitis.In vitroculture of monocytes in medium without cytokines induces the phenotype similar to that of resident liver macrophages. Addition of macrophage‐colony stimulating factor or interferon‐γ into the culture medium induces the expression of Fc γ RI, the phenotype of which resembles that of activated liver macrophages. These results suggest that liver macrophages consist of heterogeneous cell populations and that both phenotype and function are affected by the local mil

ISSN:0815-9319    

DOI:10.1111/j.1440-1746.1995.tb01804.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractThe expression of thrombomodulin on sinusoidal endothelial cells was studied using the immuno‐peroxidase method and both light and electron microscopy in patients with chronic viral hepatitis (type B: four cases; type C: 28 cases). Thrombomodulin was found on sinusoidal endothelial cells, especially on the surface in both type B and type C chronic hepatitis. There was no correlation between the level of thrombomodulin expression and clinical data including serum level of transaminase, and coagulating factors. The supernatant of liver tissue homogenate obtained from the patients showed a clear 80 kDa single band by western blotting. We concluded that the expression of thrombomodulin might be related to hepatic inflammatory responses in chronic viral hepatiti

ISSN:0815-9319    

DOI:10.1111/j.1440-1746.1995.tb01805.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

AbstractCirculating connective tissue macromolecules are efficiently eliminated by receptor‐mediated endocytosis in liver endothelial cells (LEC). In patients with a seriously diseased liver, for example in liver cirrhosis or when a transplanted liver is about to be rejected, dysfunctional LEC or altered blood perfusion through the liver results in significantly increased serum levels of connective tissue macromolecules and other substances that are normally taken up by LEC. With the aid of high affinity antibodies or other kinds of binding proteins it has been possible to measure a number of connective tissue macromolecules in the blood, and some of these substances have been used to diagnose serious liver disease. However, the metabolic patterns of these molecules are such that it is difficult to extrapolate directly on the basis of increased serum levels to conclude that the main underlying cause of increased serum levels is dysfunctional LEC. Elevated serum levels of many connective tissue proteins may reflect either increased synthesis, increased release from cell or tissue depots, and/or decreased removal by LEC. Therefore, to use measurement of serum connective tissue molecule levels as indicators of LEC function, it is imperative to know the catabolic routes of these substances in health and disease. Due to the fact that we presently know more about the total metabolic pattern of hyaluronan (HYA) than of other connective tissue macromolecules that are cleared solely by LEC, serum HYA should be preferentially used to monitor the function of LEC, in particular in liver transplantation and cirrhosi

ISSN:0815-9319    

DOI:10.1111/j.1440-1746.1995.tb01807.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY