Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In progressive liver fibrosis, the rate [corrected] of extracellular collagen deposition exceeds its rate of degradation. Collagen and related proteins are synthesised in the fat-storing liver cells (lipocytes). When injured, these cells proliferate and change into myofibroblast-like cells, secreting even more collagen into the extracellular space. The degradation of collagen is accomplished by metalloproteinases, whose activity is reduced by tissue inhibitors (TIMPs). Injured lipocytes produce an excess of these inhibitors. The final result of lipocyte injury is thus progressive liver fibrosis. There is evidence that TIMPs also play a role in progressive fibrosis in other tissues.
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PMID:Hepatic lipocytes, TIMP-1 and liver fibrosis. 3066 87

Liver fibrosis is a complex process characterized by two major events: fibroproliferation and increased collagen synthesis. The exact role of cytokines in the pathogenesis of hepatic fibrosis remains to be established, but platelet-derived growth factor clearly stimulates proliferation of fibroblasts and increases collagen synthesis. In in vitro studies, pentoxifylline, a methylxanthine, significantly reduced platelet-derived growth factor-driven proliferation of fibroblasts. Platelet-derived growth factor has also been identified as a fibroproliferative factor produced spontaneously by monocytes obtained from patients with liver disease. Long-term administration of pentoxifylline (16 mg/kg orally, 5 days/wk for 12 wk) in an animal model of liver fibrosis prevented elevations in gamma-glutamyl transpeptidase and alkaline phosphatase levels and prevented the reduction in serum albumin level normally observed in this animal model of liver disease. The animal model used was a long-term, low-dose yellow phosphorus--induced model in pigs that reproducibly results in extensive fibrosis after 10 to 12 wk of treatment. Long-term administration of pentoxifylline also prevented the histological changes characteristic of fibrosis in this animal model. Collagen concentration was significantly elevated in liver sections obtained from animals receiving yellow phosphorus, compared with controls. Long-term pentoxifylline treatment resulted in significantly lower collagen concentrations in liver sections from animals receiving yellow phosphorus than in sections from animals receiving yellow phosphorus alone; this was supported by histological observation. Therefore administration of pentoxifylline prevented the biochemical and histological changes associated with an animal model of liver disease. Pentoxifylline will likely have an important therapeutic role in liver fibrosis.
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PMID:Pentoxifylline prevents fibrosis in an animal model and inhibits platelet-derived growth factor-driven proliferation of fibroblasts. 809 47

Interferon gamma (IFN-gamma) inhibits in vitro the activation of hepatic stellate cells (HSC), the primary extracellular matrix-producing cells in liver fibrosis. This study was undertaken to determine in vivo the effect of IFN-gamma in the rat model of liver fibrosis induced by dimethylnitrosamine (DMN), where HSC activation represents an early response to cell injury. Rats were killed after 1 or 3 weeks of treatment with DMN, IFN-gamma, DMN + IFN-gamma, or saline. Immunohistochemistry was used to identify proliferating (desmin-positive/bromodeoxyuridine (BrdU)-positive cells) and activated (alpha-smooth-muscle actin [alpha-SMA]-positive cells) HSCs. Collagen deposition was determined colorimetrically and by morphometry. The parenchymal extension of desmin- and actin-positive cells and of fibrotic tissue was measured by point-counting technique and expressed as a percentage of area. Western blot was used to determine laminin and fibronectin accumulation. The levels of messenger RNA (mRNA) for procollagen type I, fibronectin, and laminin were evaluated by Northern blot. No differences were observed in rats treated with either saline or IFN-gamma alone. IFN-gamma reduced HSC activation induced by liver injury, as shown by the decreased number of proliferating HSC and the reduction of parenchymal area occupied by alpha-SMA-positive cells observed in DMN + IFN-gamma-treated animals compared with the DMN group. This was associated with reduced collagen, laminin, and fibronectin accumulation and lower levels of mRNA for procollagen type I, fibronectin, and laminin in the DMN + IFN-gamma group. Thus, this study indicates that IFN-gamma reduces extracellular matrix deposition in vivo by inhibition of HSC activation.
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PMID:Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis. 862 Nov 53

Glucocorticoids have been shown to suppress collagen synthesis and gene expression by fibroblasts. However, little is known about their effects on fat-storing cells, the major matrix-producing cells in liver fibrosis. In this study we investigated the effect of dexamethasone on the extracellular matrix expression by cultured rat fat-storing cells. Fat-storing cells were isolated from male Wistar rats by collagenase/pronase digestion and purified by density gradient centrifugation. Fat-storing cells in early primary culture (3-day-old, representing a relatively quiescent phenotype) and in subculture (one passage, about 2-week-old, representing an activated phenotype) were treated with 10(-6) mol/L dexamethasone for messenger RNA (mRNA) study or with 10(-8) to 10(-6) mol/L dexamethasone for protein study. Expression of collagen type I, III, IV, fibronectin, and laminin was analyzed at the mRNA level by Northern hybridization, and at the protein level by metabolic labeling and immunoprecipitation. Dexamethasone had a variable effect on the expression of collagen alpha1(I) mRNA level. While a tendency for modest suppression was observed (5%-50%) in primary cells, the difference was not statistically significant. Variable response was observed in subcultured cells. Collagen alpha1(III) mRNA level showed a tendency for stimulation. Dexamethasone stimulated the expression of collagen alpha1 (IV), fibronectin, and laminin B1 mRNA levels by 1.4-, 2.4-, and 1.6-fold respectively, in primary fat-storing cells. Subcultured cells showed a similar response, but the magnitude of stimulation was more variable than that of primary cells. Unexpectedly, at the protein level dexamethasone had no effect on the expression of these proteins. Our results indicate that glucocorticoids do not possess a net suppressive effect on extracellular matrix synthesis by fat-storing cells. Beneficial effects of glucocorticoids may be attributable to other mechanisms of action, such as their anti-inflammatory effect.
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PMID:Dexamethasone alters messenger RNA levels but not synthesis of collagens, fibronectin, or laminin by cultured rat fat-storing cells. 867 92

The model of liver cirrhosis was induced by CCl4 and alcohol in rats, which were subjected to splenectomy or given Tuftsin. The isolated and purified liver parenchymal, Kupffer and Ito cells were cultured with CCl4 and splenic conditional fluid or Tuftsin. The RNA isolated from the liver tissues of cirrhosis animals were hybridized with five kinds of cDNA probes. In this study we explored the mechanism of spleen's promoting effects on the liver cirrhosis formation at the whole body, cellular and molecular levels. The result showed that in cirrhosis model, the levels of IL1, IL6 and TNF alpha in serum of rats in imitative splenectomy or Tuftsin group were significantly increased compared to those in splenectomy group (P < 0.05). Cell culture showed that if medium contained CCl4 and splenic conditional fluid or Tuftsin, its cells can secrete more fibronectin, laminin and collagen I than those cultured in medium only contained CCl4 (P < 0.05). Slot blot hybridization showed that the RNA isolated from liver of rats in imitative splenectomy or Tuftsin group hybridized with probes of TNF alpha, IL1 beta, TGF beta and Collagen I had a more high density picture of X-ray than that isolated from liver of rats in the splenectomy group. Should be it a complex process for spleen to promote liver cirrhosis formation, in which the TGF beta gene expression enhancement may be the key of splenic effects on liver fibrosis.
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PMID:[The mechanism for splenic promoting effects on liver cirrhosis]. 869 73

Interferons have been utilized widely in chronic liver diseases for their antiviral properties. In addition, there is evidence for their antifibrogenic actions. In this work we studied effects of various doses of interferon-alpha 2b on experimental liver fibrosis and cholestasis induced in the rat by biliary obstruction. Collagen was measured as hepatic hydroxyproline content. Cholestasis was determined by serum alkaline phosphatase and gamma-glutamyltranspeptidase activities and by bilirubin content. Glycogen was measured in the liver. Interestingly, the best effects (antifibrotic and anticholestatic) were observed in the group receiving the lowest dose of interferon. These results suggest that interferon-alpha 2b may be used at low doses, thereby decreasing side effects and costs.
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PMID:Dose-response studies of interferon-alpha 2b on liver fibrosis and cholestasis induced by biliary obstruction in rats. 921 63

Reactive biliary hepatitis is a defined morphological entity, which is a result of chronic diseases of the gall bladder, biliary ducts or pancreas. The aim of the present study was to describe the morphology of reactive biliary hepatitis and its significance for progression of liver fibrosis, and in particular Ito cell (fat storing cell) transformation and occurrence of collagen type III and IV in the liver. Liver tissue from 19 patients with reactive biliary hepatitis was investigated light microscopically and immunohistochemically. Histologically, the liver showed features of mild to severe portal and lobular inflammation. The number of Ito cells increased periportally and pericentrally. Deposition of collagen type III and IV was increased in portal tracts, septa and perisinusoidal spaces, mainly in periportal zones of the lobules. Ultrastructurally, collagen type III immunoreactive fibrillar networks were found to be increased in the space of Disse around transitional cells. Collagen type IV immunoreactive deposits were detected around newly proliferating bile ducts in portal stroma and in the space of Disse. Ito cells were mainly transformed into transitional and myofibroblast-like cells. We discuss here the role of Ito cells and certain cytokines in the process of fibrosis of the liver in the course of reactive biliary hepatitis. It is proposed that bile acid retention in bile ducts during non-specific reactive inflammation or a gut endotoxin may cause transformation of Ito cells and increased collagen type III and IV in this type of hepatitis.
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PMID:Immunohistochemical detection of collagen type III and IV in relation with transformation of Ito cells in liver sinusoids of patients with reactive biliary hepatitis. 1033 64

Hepatic fibrosis is characterized by abnormal collagen deposition resulting from increased collagen synthesis and decreased collagen degradation. Cytochrome P450 mediates major drug metabolizing enzyme activity in the liver and this activity is reduced in hepatic fibrosis. In this study we assess cytochrome P450 and CYP 1A mRNA in livers of animals that have been induced to hepatic fibrosis using the heterologous serum induced model of fibrosis in rats compared to controls. Fibrosis was confirmed by assessing the collagen in liver sections as quantified by Sirius red/Fast green staining, a quantitative measure of fibrosis as well as by visualization of the hepatic fibrosis. Collagen levels in the liver sections of heterologous serum induced fibrotic rats was increased by 33% compared to controls and a typical fibrotic pattern was seen. Messenger RNA was prepared from heterologous serum induced fibrotic rats and compared to controls. CYP 1A2 was assessed using a specific probe and the CYP 1A2 level was significantly reduced in the heterologous serum induced fibrotic rats compared to controls. These results further suggest that cytochrome P450 is reduced in the presence of hepatic fibrosis. Thus, in three well established experimental models of hepatic fibrosis which had clearly developed hepatic fibrosis (as shown by Sirius red/Fast green staining), cytochrome P450 mediated enzyme activity, or specifically, CYP 1A messenger RNA is decreased. We then investigated a transgenic mouse, deficient in the arylhydrocarbon hydroxylase receptor (AHR), which has undetectable levels of CYP 1A messenger RNA. We quantitated the collagen in liver sections obtained from AHR knockout mice compared to controls, as an indication of the presence of hepatic fibrosis. Collagen concentration was significantly increased by 53% (P<0.0005) in sections from Ahr-/- (knockout) mice compared to wild-type controls. Collagen in livers of the Ahr+/- heterozygous mice was not different from wild-type controls. The increase in collagen concentration in liver sections is an indication of fibrosis in Ahr-/- mice. Collagen protein deposition was also elevated in liver sections from bile duct ligated rats (by 44%) compared to sham operated controls, was elevated in liver sections from heterologous serum induced fibrosis in rats (33%) compared to controls, and was elevated in liver sections from yellow phosphorous induced hepatic fibrosis (74%) compared to vehicle treated controls. In conclusion, these results indicate that cytochrome P450 and specific subtypes of P450, the CYP 1A subgroup, are significantly reduced in three experimental models of hepatic fibrosis when there is evidence of increased collagen deposition in the livers. These results also indicate that mice that are deficient in CYP 1A have elevated levels of hepatic collagen protein, an indication of hepatic fibrosis.
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PMID:Hepatic fibrosis and cytochrome P450: experimental models of fibrosis compared to AHR knockout mice. 1070 5

Collagen-I, which predominates in the neomatrix of fibrotic liver, regulates hepatocyte and hepatic stellate cell (HSC) phenotypes. Recovery from liver fibrosis is accompanied by hepatocyte regeneration, matrix degradation, and HSC apoptosis. Using mice bearing a mutated collagen-I gene (r/r mice), which confers resistance to collagenase degradation, we have investigated the hypothesis that collagen-I degradation is critical to HSC apoptosis and hepatocyte regeneration during recovery from liver fibrosis. During a 28-day recovery period after 8 wk of CCl4 treatment, wild-type (WT) livers had significantly (43%) decreased hydroxyproline (OHP) content. In r/r livers, however, OHP content remained elevated at peak fibrosis levels. Expressed markers of activated HSC (alpha-smooth muscle actin, collagen-I), elevated at peak fibrosis, dropped to control levels in WT livers after 28 days but remained raised in the r/r livers. Moreover, relative to WT livers, r/r livers had significantly reduced stellate cell apoptosis and hepatocyte regeneration during the recovery period. Using extracted collagen-I from each genotype as culture substrata, relative to r/r, we show that WT collagen-I promotes hepatocyte proliferation via stimulation of integrin alpha(v)beta3. Failure to degrade collagen-I critically impairs HSC apoptosis and may prevent the effective restoration of hepatocyte mass in liver fibrosis.
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PMID:Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration. 1247 3

Collagen degradation by matrix metalloproteinases is the limiting step in reversing liver fibrosis. Although collagen production in cirrhotic livers is increased, the expression and/or activity of matrix metalloproteinases could be normal, increased in early fibrosis, or decreased during advanced liver cirrhosis. Hepatic stellate cells are the main producers of collagens and matrix metalloproteinases in the liver. Therefore, we sought to investigate whether they simultaneously produce alpha1(I) collagen and matrix metalloproteinase-13 mRNAs. In this communication we show that expression of matrix metalloproteinase-13 mRNA is reciprocally modulated by tumor necrosis factor-alpha and transforming growth factor-beta1. When hepatic stellate cells are co-cultured with hepatocytes, matrix metalloproteinase-13 mRNA is up-regulated and alpha1(I) collagen is down-regulated. Injuring hepatocytes with galactosamine further increased matrix metalloproteinase-13 mRNA production. Confocal microscopy and differential centrifugation of co-cultured cells revealed that matrix metalloproteinase-13 is localized mainly within hepatic stellate cells. Studies performed with various hepatic stellate cell lines revealed that they are heterogeneous regarding expression of matrix metalloproteinase-13. Those with myofibroblastic phenotypes produce more type I collagen whereas those resembling freshly isolated hepatic stellate cells express matrix metalloproteinase-13. Overall, these findings strongly support the notion that alpha1(I) collagen and matrix metalloproteinase-13 mRNAs are reciprocally modulated.
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PMID:Reciprocal modulation of matrix metalloproteinase-13 and type I collagen genes in rat hepatic stellate cells. 1275 35


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