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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic lipocytes which are activated to a myofibroblastic phenotype synthesize many of the metalloproteinases and their inhibitors, particularly TIMP-1. The available evidence suggests that this enzyme/inhibitor system for regulating matrix degradation is important in liver in two respects; (i) degradation of the normal liver matrix by the gelatinases (A and B) and stromelysin and the role this has in the pathogenesis of liver injury, and (ii) failure of matrix degradation consequent upon the relative expression of interstitial collagenase and TIMP-1 by hepatic lipocytes and the role this has in the progression of liver fibrosis. Recent progress in this field provides a clear indication that liver fibrosis is dynamic, involving a balance between matrix synthesis and regulated matrix degradation. These observations offer opportunities for the development of new therapeutic strategies in the management of liver fibrosis.
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PMID:Collagenases and liver fibrosis. 766 49

Hepatic fibrosis occurs as a consequence of net accumulation of matrix proteins (particularly collagen types I and III) in liver. Current concepts of the pathogenesis of liver fibrosis place major emphasis on the activation of hepatic lipocytes (fat-storing or Ito cells) to a myofibroblast-like phenotype with a consequent increase in their synthesis of matrix proteins. While this is an important factor, there is increasing evidence to indicate that liver fibrosis is a dynamic pathologic process in which altered matrix degradation may also play a significant role. Extracellular degradation of matrix proteins is regulated by a family of enzymes called the matrix metalloproteinases, which is subdivided into three groups; collagenases which degrade interstitial collagens (types I, II and III), type IV collagenases/gelatinases which degrade basement membrane (type IV) collagen and gelatins and stromelysins which degrade a broad range of substrates including proteoglycans, laminin, gelatins and fibronectin. The extracellular activity of these enzymes is regulated by several mechanisms which include alterations in gene transcription and proenzyme synthesis, cleavage of secreted proenzymes to active forms, and specific inhibition of activated forms by tissue inhibitor(s) of metalloproteinases (TIMPs). In liver, current evidence indicates that activated hepatic lipocytes and Kupffer cells play a central role in synthesis of matrix metalloproteinases. Under defined conditions they synthesize interstitial collagenase, 72 kDa and 95 kDa type IV collagenase/gelatinase and possibly stromelysin. Moreover, lipocytes also contribute to regulation of the extracellular activity of these enzymes by secretion of TIMP-1 and alpha 2-macroglobulin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Degradation of matrix proteins in liver fibrosis. 789 31

To explore the functional role of TIMP-2 in liver, we determined TIMP-2 mRNA levels in primary rat hepatocytes and in total rat liver. Rat hepatocytes constitutively express TIMP-2 mRNA at a low level. Incubation with dexamethasone, prostaglandin E2 and a combination of inflammatory cytokines leads to an up-regulation of TIMP-2 mRNA. In rats in vivo we found a dramatic increase of TIMP-2 expression after intraperitoneal injection of lipopolysaccharide. Compared to our previous findings on TIMP-1 we conclude that TIMP-2 mRNA expression is regulated in a distinct and partially opposite manner. Over-production of TIMP-2 could inhibit the activity of metalloproteinases and thus lead to matrix accumulation. Dysregulation of TIMP-2 synthesis might be involved in the development of liver fibrosis.
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PMID:Tissue inhibitor of metalloproteinases-2 (TIMP-2) in rat liver cells is increased by lipopolysaccharide and prostaglandin E2. 800 73

Degradation of extracellular matrix proteins is performed by metalloproteinases which are inhibited by tissue inhibitors of metalloproteinases (TIMP). We expressed the murine TIMP-1 protein in E. coli and prepared a polyclonal antiserum against the recombinant protein. Using this antiserum we studied the biosynthesis and glycosylation of murine TIMP-1 protein in COS-7 cells transfected with a TIMP-1 expression plasmid by metabolic labeling and indirect immunofluorescence studies. In primary rat hepatocytes we show for the first time that TIMP-1 protein expression is up-regulated upon stimulation with IL-1 beta and IL-6. Since TIMP-1 is induced during the acute phase reaction it could possibly be involved in the pathogenesis of liver fibrosis.
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PMID:TIMP-1 protein expression is stimulated by IL-1 beta and IL-6 in primary rat hepatocytes. 804

Hepatic fibrosis, a consequence of most forms of chronic liver disease, is a dynamic process involving complex interactions between several cell types, the net result of which is accumulation of several distinct extracellular matrix (ECM) proteins. The resultant disruption of intrahepatic blood flow contributes to the development of portal hypertension. The effects, however, are not merely a space-occupying phenomenon; by changing the composition of the ECM, fibrosis may also alter hepatocyte function via cellular integrins. The principal source of ECM proteins in normal and fibrotic liver is the perisinusoidal cells which lie in the space of Disse. The response of this cell population to acute and chronic liver injury has been studied in detail. Perisinusoidal cells proliferate and become activated following hepatocyte necrosis. This phenomenon is transient in acute injuries, but in chronic liver disease, continued activation is associated with phenotypic modulation of perisinusoidal cells to myofibroblasts. This process is mediated by various cytokines including TGF-beta and PDGF. Some of the growth factors involved are derived from activated Kupffer cells and there is evidence of a complex interplay between mediators; injured sinusoidal endothelial cells and platelets are possible additional sources. Accumulation of ECM proteins in fibrosis can be explained not only by increased synthesis, but also by decreased degradation. There is growing evidence that in fibrotic liver there is decreased interstitial collagenase activity. This is, at least in part, due to expression of a tissue inhibitor of metalloproteinase, TIMP-1, by activated perisinusoidal cells.
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PMID:C. L. Oakley Lecture (1993). Cellular and molecular aspects of hepatic fibrosis. 834 6

Liver fibrosis and its end stage sequelae cirrhosis represent a major worldwide health problem. By definition progressive fibrosis occurs when the rate of matrix synthesis exceeds matrix degradation. Considerable evidence suggests that the hepatic stellate cell is central to the fibrotic process. During liver injury these cells transform from a quiescent retinoid filled phenotype to a proliferative myofibroblast like cell. In this 'activated' phenotype the HSC is the major source of the interstitial collagens, which characterize fibrosis. Recent work suggests that the HSCs are also a source of matrix degrading metalloproteinase (MMPs), indicating that, together with other cells, hepatic stellate cells (HSC) could participate in matrix remodelling. However, HSC activation in tissue culture models and in vivo is also associated with expression of the powerful MMP inhibitors: tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2). TIMP expression has also been demonstrated in fibrotic human liver disease and animal models of liver fibrosis. TIMPs 1 and 2 may therefore promote progression of hepatic fibrosis through inhibition of matrix degradation.
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PMID:Tissue inhibitors of metalloproteinases in liver fibrosis. 907 40

Liver fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSC), which proliferate during fibrotic liver injury. We have studied a model of spontaneous recovery from liver fibrosis to determine the biological mechanisms mediating resolution. Livers were harvested from rats at 0, 3, 7, and 28 d of spontaneous recovery from liver fibrosis induced by 4 wk of twice weekly intraperitoneal injections with CCl4. Hydroxyproline analysis and histology of liver sections indicated that the advanced septal fibrosis observed at time 0 (peak fibrosis) was remodeled over 28 d of recovery to levels close to control (untreated liver). alpha-Smooth muscle actin staining of liver sections demonstrated a 12-fold reduction in the number of activated HSC over the same time period with evidence of HSC apoptosis. Ribonuclease protection analysis of liver RNA extracted at each recovery time point demonstrated a rapid decrease in expression of the collagenase inhibitors TIMP-1 and TIMP-2, whereas collagenase mRNA expression remained at levels comparable to peak fibrosis. Collagenase activity in liver homogenates increased through recovery. We suggest that apoptosis of activated HSC may vitally contribute to resolution of fibrosis by acting as a mechanism for removing the cell population responsible for both producing fibrotic neomatrix and protecting this matrix from degradation via their production of TIMPs.
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PMID:Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. 969 Oct 91

Hepatic stellate cells (HSC) play a central role in the pathogenesis of liver fibrosis. Following liver injury, these cells proliferate and are activated to a profibrogenic myofibroblastic phenotype. In addition to increased matrix protein synthesis, there is evidence to indicate that these cells are able to regulate matrix degradation. In the early phases of their cellular activation, HSC release matrix metalloproteinases with the ability to degrade the normal liver matrix. When HSC are fully activated, there is a net down-regulation of matrix degradation mediated by increased synthesis and extracellular release of tissue inhibitors of metalloproteinase (TIMP)-1 and -2. These studies in cell culture have been complemented by in vivo studies of hepatic TIMP-1 and TIMP-2 gene expression. In advanced human liver disease of various aetiologies, there is increased TIMP-1-mRNA and protein and increased TIMP-2-mRNA in fibrotic liver compared with control liver. Temporal studies of progressive rat liver fibrosis caused by bile duct ligation or by carbon tetrachloride, indicate an important role for increased TIMP-1 and TIMP-2 expression in pathogenesis. Moreover, in a rat model of reversible liver fibrosis, matrix remodelling and resolution of liver fibrosis is closely associated, temporally, with a marked decrease in TIMP-1 and TIMP-2 expression. These combined cell culture and in vivo findings have led us to investigate the mechanisms of regulation of TIMP-1 gene expression in hepatic stellate cells. Our recent data indicate that transcriptional regulation of TIMP-1 gene expression in HSC is mediated via a mechanism which differs considerably from that previously identified in skin fibroblasts. We conclude that increased TIMP-1 and TIMP-2 expression by HSC plays an important role in the pathogenesis of liver fibrosis. This may represent an important therapeutic target in the design of anti-fibrotic strategies for chronic liver disease.
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PMID:Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis. 979 32

Tissue inhibitors of metalloproteinases (TIMPs) are involved in liver fibrosis through impaired matrix degradation. Previous studies showed that the serum level of TIMP-1 was increased in patients with chronic liver disease, reflecting the liver TIMP-1 level, and that it is useful for assessing liver fibrosis. An enzyme immunoassay for TIMP-2 is now available. In this study, we examined the clinical usefulness of this serum TIMP-2 test for liver fibrosis in patients with chronic liver disease, in comparison with the serum TIMP-1 test. The serum TIMP-2 concentration was 61 +/- 13 ng/ml in healthy controls (n = 32), and 18% higher in the group of chronic active hepatitis (CAH) patients (n = 34), 64% higher in the liver cirrhosis (LC) group (n = 33) and 44% higher in the hepatocellular carcinoma (HCC) group (n = 61), and similar to the control level in the chronic persistent hepatitis (CPH) group (n = 23). In contrast, the serum TIMP-1 concentration was 155 +/- 17 ng/ml in the healthy controls, 18% higher in CPH, 35% in CAH, 63% higher in LC and 92% higher in HCC. The serum TIMP-2 level was related to the histological degrees of both periportal necrosis and liver fibrosis, as well as to the serum TIMP-1 level. However, the relationships for TIMP-2 were weaker compared to those of serum TIMP-1. These results suggest that compared to the serum TIMP-1 level, changes in the serum TIMP-2 level in chronic liver disease are less liver-specific, and the serum TIMP-2 level is less useful in the assessment of liver fibrosis in chronic liver disease.
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PMID:Clinical usefulness of serum tissue inhibitor of metalloproteinases (TIMP)-2 assay in patients with chronic liver disease in comparison with serum TIMP-1. 1021 32

In liver fibrosis, activated hepatic stellate cells (HSC) play a major role in the deposition of excess extracellular matrix, including fibrillar collagens type I and type III. In addition to matrix protein synthesis, HSC regulate matrix degradation in the liver. This is mediated via a combination of synthesis of matrix (pro)metalloproteinases, which activate these zymogens via specific mechanisms and by inhibiting the active matrix-degrading enzymes via expression of tissue inhibitors of metalloproteinases (TIMPs). There are currently four members of the TIMP family described and of these, both TIMP-1 and TIMP-2 are synthesised by HSC. These observations have led to the suggestion that inhibition of matrix degradation mediated by a change in HSC-expression of TIMPs relative to metalloproteinases, such as interstitial collagenase, may contribute to progression of liver fibrosis. This hypothesis is supported by studies of human liver disease in which TIMP-1 expression is upregulated 5-fold in cirrhotic compared with normal liver. TIMP-1 and TIMP-2 expression is also upregulated in animal models of progressive fibrosis, whereas expression of collagenase is unchanged. In a model which is characterized by natural resolution of liver fibrosis, degradation of the deposited fibrillar liver matrix is accompanied by rapid down-regulation of TIMP-1 expression. In alcoholic liver disease, the role of TIMPs has not been studied exhaustively, but the evidence currently available supports a role for inhibition of matrix degradation by TIMPs in this progressive fibrotic liver disease.
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PMID:Tissue inhibitors of metalloproteinases: role in liver fibrosis and alcoholic liver disease. 1037 19


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