Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liver fibrogenesis is a delicately balanced process, in which mainly the non-parenchymal liver cells are implicated. Either increased synthesis or decreased catabolism of matrix proteins results in the enhancement of ECM. As further consequence the formation of continuous diffusion and filtration barriers along the Disse space will hinder the bidirectional exchange of macromolecules. Normal structure of ECM is necessary to the normal function of hepatocytes. The quantitative and qualitative changes of ECM observed in liver fibrosis are able to inhibit the liver specific functions of hepatocytes. The mechanisms involved in this effect are not yet clearly understood. In animal experiments liver cirrhosis is reversible and theoretically the chance is open for humans, as well if we will be able to influence the specific steps of fibrogenesis.
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PMID:[Fibrogenesis in the liver--fibrosis, cirrhosis]. 841 83

Hepatic necrosis is a common reaction to liver injury of various etiologies. The response is regeneration. As reviewed earlier, reconstitution of liver mass may proceed via two mechanisms: (1) re-entry of surviving, functionally intact differentiated liver cells into the cell cycle, where they may remain for several rounds of replication, and (2) recruitment of hepatic progenitor cells, whereby the liver mass is replaced by extensive proliferation and differentiation of more primitive cell types. Although both mechanisms appear to share a number of regulatory factors, distinct differences exist that are reflected in the complex and intricate networks of interacting cells, cytokines, and ECM molecules constituting the regenerative process. The development of liver fibrosis or cirrhosis is probably an unwanted but frequent byproduct of the regenerative process, similar to scar formation in any other tissue following extensive damage. Although intensive research in recent years has yielded a wealth of information about regenerative processes, a better understanding of the elements regulating the regenerative process is crucial for effective intervention to prevent or minimize fibrosis while providing optimal conditions for regeneration. Because our only experimental tool is observation in human studies, we must continue the use of experimental animal models including those of transgenic mice to further elucidate the complex interactions of cytokines, ECM, and target cells in the development of liver fibrogenesis, cirrhosis, and cancer.
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PMID:Hepatic regeneration. The role of regeneration in pathogenesis of chronic liver diseases. 879 75

The liver undergoes pathogenic changes such as hepatitis, fibrosis and cirrhosis under continuous stimulation by hepatitis virus or alcohol intake, leading to the development of hepatocellular carcinoma. The metastatic potential of HCC can be positively or negatively regulated by pathogenic alterations of liver. We investigated whether the metastatic abilities of HCC after orthotopic implantation can be influenced in the fibrotic liver by continuous injection of carbon-tetrachloride (CCl4) for seven weeks. The incidence of lung metastasis after orthotopic implantation of murine HCC (CBO140C12) fragments into CCl4-treated livers was higher than into normal livers. The amount of mRNA for MMP-2 increased in the CCl4-treated livers as compared with normal livers, and CBO140C12 cells constitutively expressed mRNA for MT1-MMP in early amplification cycles by RT-PCR. In addition, we found that the culture of CBO140C12 cells on the substrates pre-coated with ECM components increased the expression of MMP-2 mRNA. Thus, enhanced incidence of lung metastasis in the fibrotic liver might be partly due to: i) over-expression of MMP-2 in the fibrotic liver in cooperation with MT1-MMP on the CBO140C12 cell surface, ii) over-expression of MMP-2 in CBO140C12 cells, possibly mediated by the interaction of tumor cells (surface integrins) with accumulated ECM in the fibrotic liver. This is the first report showing that increase of MMP-2 in the fibrotic liver can influence the metastatic potential of HCC cells.
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PMID:Accumulation of extracellular matrix in the liver induces high metastatic potential of hepatocellular carcinoma to the lung. 1140 24

Proteoglycans are macromolecules formed by a protein core to which sugar chains are covalently attached. They are present on the cell surface and in the ECM of living things. In normal liver syndecan-1 is the dominant transmembrane proteoglycan, trace amounts of ECM proteoglycans are in the stromal components. The amounts of proteoglycans we studied increase in liver cirrhosis. In liver cancer abnormal localization of syndecan-1 and stroma rich in agrin was characteristic. The core proteins as well as the sugar chains of proteoglycans interact with and modulate the effect of regulatory factors. This implies that structural alterations of proteoglycans contribute to the development of malignant phenotype. Heparan sulfate chains of liver cancer are undersulfated with decreased or altered biological activity. Their binding capacity for transcription factor decreases, and they do not inhibit topoisomerase I enzyme. Truncated form of syndecan-1 lacking the extracellular domain of the molecule induces differentiation of hepatoma cell line and inhibits the shedding of syndecan-1. This phenomenon calls attention to the importance of syndecan-1 shedding in the regulation of cell behavior.
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PMID:[Proteoglycans in the liver]. 1552 Aug 70

In the present study, we found collagenolytic and gelatinolytic activity in the supernatants of hepatocyte cultures from rats with experimental CCl(4)-induced liver cirrhosis, in levels significantly higher than in comparable supernatants of hepatocyte cultures from normal rats. In addition, we clearly detected the messenger ribonucleic acids (mRNA) of four matrix metalloproteinases (MMP-2, MMP-3, MMP-10, and MMP-13) and of two tissue inhibitors of matrix metalloproteinases (TIMP-1 and TIMP-2) in hepatocytes from both normal and cirrhotic rats by RT-PCR and by in situ hybridization. Finally, we demonstrated MMP-2, MMP-3, and MMP-13 and TIMP-1 and TIMP-2 proteins in the same hepatocyte preparations by immunostaining. We conclude that rat hepatocytes produce the major enzymes and inhibitors involved in liver ECM modulation and therefore suggests that they might participate actively in the pathophysiology of liver cirrhosis in rats.
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PMID:Hepatocyte production of modulators of extracellular liver matrix in normal and cirrhotic rat liver. 1633 68

Fibrotic progression of chronic liver diseases of different aetiology to the common advanced-stage of cirrhosis can be envisaged as a dynamic and highly integrated cellular response to chronic liver injury. Liver fibrosis is accompanied by perpetuation of liver injury, chronic hepatitis and persisting activation of tissue repair mechanisms, leading eventually to excess deposition of ECM components. Liver fibrogenesis (i.e., the process) is sustained by populations of highly proliferative, pro-fibrogenic and contractile MFs that, according to current literature, originate by a process of activation involving perisinusoidal HSC, portal fibroblasts and even bone marrow-derived MSC. In this short review emerging concepts in hepatic fibrogenesis and related molecular mechanisms, as provided by recent experimental and clinical studies, are presented.
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PMID:Myofibroblast - like cells and liver fibrogenesis: Emerging concepts in a rapidly moving scenario. 1802 82

Liver fibrosis (LF), where the chronic HCV infection is a major cause, is a characteristic of chronic liver diseases. LF results from chronic damage to the liver in conjunction with the accumulation of ECM proteins. Matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs) are thought to play an essential role in the hepatic lesions. The available data concerning the circulating levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in chronic hepatitis C are not conclusive. Therefore, the present study was designed to seek the relationship between serum MMP-9, and TIMP-1 to liver status in chronic liver disease in fifty patients divided into three groups (chronic hepatitis, liver cirrhosis and hepatocellular carcinoma). MMP-9 and TIMP-1 were analyzed by the enzyme linked immunosorbent assay (ELISA). The results showed that the lowest serum level of MMP-9 was found in chronic hepatitis patients compared to the control ( P < 0.05). Serum MMP-9 is decreasing during progression of chronic hepatitis to cirrhosis showing the least level in the cirrhotic group. Serum TIMP-1 was significantly higher in the cirrhotic group compared to chronic hepatitis ( P < 0.05) and controls ( P < 0.001). MMP-9 was negatively correlated to both TIMP-1 and the histological severity in chronic hepatitis. There was a positive correlation between TIMP-1 and the degree of fibrosis (r = 0.73, P < 0.001). Lastly, there was a statistically significant increase of MMP-9 ( P < 0.001) and TIMP-1 ( P < 0.05) in HCC patients compared with the other groups. In conclusion, these findings raise the possibility of using serum TIMP-1 as a non-invasive assay in liver fibrosis. Further, the altered balance between circulating MMP-9 and TIMP-1 during HCV infection may play an important role in aggravating liver injury progression in chronic liver diseases.
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PMID:Significance of serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in chronic hepatitis C patients. 2035 Aug 77

In any chronic liver disease (CLDs), whatever the aetiology, reiteration of liver injury results in persisting inflammation and progressive fibrogenesis, with chronic activation of the wound healing response in CLDs, representing a major driving force for progressive accumulation of ECM components, eventually leading to liver cirrhosis. Cirrhosis is characterized by fibrous septa dividing the hepatic parenchyma into regenerative pseudo-lobules, as well as by extensive changes in vascular architecture, the development of portal hypertension and related complications. Liver fibrogenesis (i.e., the dynamic process leading to increased deposition of ECM and much more) can lead to different patterns of fibrosis and is sustained by myofibroblast-like cells (MFs) of different origin, with activated hepatic stellate cells (HSC/MFs) being the major cell type involved. Major pro-fibrogenic mechanisms also include oxidative stress, as well as derangement of epithelial-mesenchymal interactions and, as recently suggested, the process of epithelial to mesenchymal transition (EMT). Liver fibrosis has been considered traditionally as an irreversible process but experimental and clinical literature data published in the last decade have suggested that both the removal of the aetiological agent or condition, as well as an effective therapy, can result in significant regression of liver fibrosis. This is usually associated, particularly in animal models, with induction of apoptosis in MFs but, unfortunately, human HSC/MFs are much more resistant to apoptosis than murine MFs. However, clinical studies provided no unequivocal evidence for a complete reversal of cirrhosis or a significant reversal of vascular changes in conditions of established cirrhosis.
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PMID:Liver fibrosis: a dynamic and potentially reversible process. 2055 56

Fibrosis is characterized by balance disorders between syntesis and degradation ECM (Extracellular Matrix) by myofibroblasts. Activated by inflammation factor HSC cells transform in myofibroblasts. This changes are caused and assisted by number of mediators: cytokines, growth factors, kinases. All this stimulus we call fibrosis factors. This paper compose second part of object-article: Liver fibrosis and cirrhosis - causes.
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PMID:[Liver fibrosis and cirrhosis--selected cytokines, growth factors and proteins. Part II]. 2185 79

Hepatitis C virus (HCV) infection is a leading cause of liver fibrosis, especially in developing countries. The process is characterized by the excess accumulation of ECM that may lead, over time, to hepatic cirrhosis, liver failure and also to hepatocarcinoma. The direct role of HCV in promoting fibroblasts trans-differentiation into myofibroblasts, the major fibrogenic cells, has not been fully clarified. In this study, we found that HCV derived from HCV-infected patients infected and directly induced the trans-differentiation of human primary fibroblasts into myofibroblasts, promoting fibrogenesis. This effect correlated with the activation of GLI2, one of the targets of Hedgehog signaling pathway previously reported to be involved in myofibroblast generation. Moreover, GLI2 activation by HCV correlated with a reduction of autophagy in fibroblasts, that may further promoted fibrosis. GLI2 inhibition by Gant 61 counteracted the pro-fibrotic effects and autophagy inhibition mediated by HCV, suggesting that targeting HH/GLI2 pathway might represent a promising strategy to reduce the HCV-induced fibrosis.
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PMID:HCV derived from sera of HCV-infected patients induces pro-fibrotic effects in human primary fibroblasts by activating GLI2. 2747 57


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