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)

Since the authors reported the presence of collagenase in the liver as well as its increased activity in the early stage of hepatic fibrosis and its reduced activity in advanced fibrosis in rats induced by chronic CCl4 intoxication, in baboons fed alcohol chronically and in patients with alcoholic fibrosis, other investigators have demonstrated the same tendency of collagenase activity biologically and histochemically. Very recently, the authors demonstrated definite gene expression of collagenase during the recovery from experimental hepatic fibrosis using Northern blotting and in situ hybridization. The findings of in situ hybridization not only demonstrated the cells expressing collagenase, but also suggested much information on the mechanism of the recovery from fibrosis. Hepatic stellate cells play a key role not only in fibrogenesis but also in fibrolysis. The authors' recent observation revealed that collagenase (matrix metalloproteinase-13 (MMP-13)) gene expression appears very early in the process of recovery from liver fibrosis, and that both stellate cells and hepatocytes express MMP-13. Recovery from liver cirrhosis requires the gene expression of collagenase, increased production of the collagenase enzyme, and activation of the enzyme balanced with the specific inhibitors of collagenase. The understanding of molecular mechanisms of MMP-1 gene expression which is under investigation in our laboratory may provide us a new strategy for the treatment of liver fibrosis including the possibility of gene therapy.
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PMID:Reversibility of hepatic fibrosis: from the first report of collagenase in the liver to the possibility of gene therapy for recovery. 1145 May 93

Following liver injury, hepatic stellate cells (HSCs) become activated and express a combination of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs). In the early phases of liver injury (and primary cell culture), HSCs transiently express MMP-3, MMP-13, and uroplasminogen activator (uPA) and exhibit a matrix-degrading phenotype. In the later stages of liver injury and HSC activation, the pattern changes and the cells express a combination of MMPs that have the ability to degrade normal liver matrix, while inhibiting degradation of the fibrillar collagens that accumulate in liver fibrosis. This pattern is characterized by the combination of pro-MMP-2 and membrane type 1 (MT1)-MMP expression, which drive pericellular generation of active MMP-2 and local degradation of normal liver matrix. In addition there is a marked increase in expression of TIMP-1 leading to a more global inhibition of degradation of fibrillar liver collagens by interstitial collagenases (MMP-1/MMP-13). These pathways play a significant role in the progression of liver fibrosis. Following cessation of liver injury, the pattern reverses and TIMP-1 in particular is rapidly downregulated. This phase is characterized by increasing activity of collagenases, degradation of liver matrix, and regression of liver fibrosis.
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PMID:Extracellular matrix degradation and the role of hepatic stellate cells. 1158 66

The activated hepatic stellate cell (HSC) is central to liver fibrosis as the major source of collagens I and III and the tissue inhibitors of metalloproteinase-1 (TIMP-1). During spontaneous recovery from liver fibrosis, there is a decrease of TIMP expression, an increase in collagenase activity, and increased apoptosis of HSC, highlighting a potential role for TIMP-1 in HSC survival. In this report, we use tissue culture and in vivo models to demonstrate that TIMP-1 directly inhibits HSC apoptosis. TIMP-1 demonstrated a consistent, significant, and dose-dependent antiapoptotic effect for HSC activated in tissue culture and stimulated to undergo apoptosis by serum deprivation, cycloheximide exposure, and nerve growth factor stimulation. A nonfunctional mutated TIMP-1 (T2G mutant) in which all other domains are conserved did not inhibit apoptosis, indicating that inhibition of apoptosis was mediated through MMP inhibition. Synthetic MMP inhibitors also inhibited HSC apoptosis. Studies of experimental liver cirrhosis demonstrated that persistent expression of TIMP-1 mRNA determined by PCR correlated with persistence of activated HSC quantified by alpha smooth muscle actin staining, while in fibrosis, loss of activated HSC correlated with a reduction in TIMP-1 mRNA. We conclude that TIMP-1 inhibits apoptosis of activated HSC via MMP inhibition.
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PMID:Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. 1179 25

AIM:To study the mechanism of Fuzhenghuayu (FZHY) decoction on anti-liver fibrosis.METHODS:FZHY 10% decoction sera was incubated with rat normal subcultured hepatic stellate cells (HSC) and fibrotic primarily cultured HSC, normal and fibrotic hepatocytes and subcultured skin fibroblasts seperately. Cell intracellular and extracellular collagen synthesis rates were measured by the method of (3)H Proline impulse and collagenase digestion.RESULTS:For primarily cultured HSC and hepatocytes, both of intracellular and extracellular collagen synthesis rates decreased in the drug sera group. For the normal subcultured HSC and primarily cultured hepatocytes, the extracellular collagen secretion was decreased obviously by the drug sera, and intracellular collagen synthesis rates were inhibited to some extents.For fibroblasts, both intracellular and extracellular collagen synthesis rates were inhibited somewhat, but no significant differences were found.CONCLUSION:The mechanism of FZHY decoction on anti-liver fibrosis may be associated with inhibition of liver collagen production.
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PMID:Effects of Fuzhenghuayu decoction on collagen synthesis of cultured hepatic stellate cells, hepatocytes and fibroblasts in rats. 1181 68

AIM:To investigate the mechanisms of salvianolic acid A (SA-A) against liver fibrosis in vitro.METHODS:NIH/3T3 fibroblasts were cultured routinely, and incubated with 10(-4) mol/L-10(-7)mol/L SA-A for 22h. The cell viability was assayed by (3)H proline incorporation, cell proliferation by (3)H TdR incorporation, cell collagen synthetic rate was measured with (3)H proline impulse and collagenase digestion method.The total RNA was prepared from the control cells and the drug treated cells respectively, and alpha(1) I pro-collagen mRNA expression was semi-quantitatively analyzed with RT-PCR.RESULTS:10(-4)mol/L SA-A decreased cell viability and exerted some cytotoxiciy,while 10(-5)mol/L -10(-7)mol/L SA-A did not affect cell viability, but inhibited cell proliferation significantly, and 10(-6)mol/L SA-A had the best effect on cell viability among these concentrations of drugs. 10 (-5)mol/L -10(-6)mol/L SA-A inhibited intracellular collagen synthetic rate, but no significant influence on extracellular collagen secretion. Both 10(-5)mol/L and 10(-6)mol/L SA-A could decrease alpha(1)I pro-collagen mRNA expression remarkably.CONCLUSION:SA-A had potent action against liver fibrosis. It inhibited NIH/3T3 fibroblast proliferation, intracellular collagen synthetic rate and type I procollagen gene expression, which may be one of the main mechanisms of the drug.
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PMID:Effects of salvianolic acid-A on NIH/3T3 fibroblast proliferation, collagen synthesis and gene expression. 1181 98

Dietary nucleotides reportedly promote functionality and repair in fibrotic liver. Liver fibrosis is characterized by an excessive accumulation of extracellular matrix components, which lead to the impairment of the hepatic function. The aim of this work was to evaluate the influence of dietary nucleotides on liver fibrosis induced by thioacetamide and to elucidate the mechanism by which nucleotides exert their protective effects. Rats consumed ad libitum 300 mg/L thioacetamide in drinking water and were pair-fed diets with (group TN) or without nucleotides (group TS) for 4 mo. Liver histology and extracellular matrix components, liver collagenase and prolyl 4-hydroxylase activities, and tissue inhibitor of metalloproteinases-1 were assessed. The degree of fibrosis was lower in group TN than in group TS. Group TN had lower hepatic concentration of hydroxyproline (P < 0.05), collagen type I (P = 0.12) and type III (P = 0.20), fibronectin (P = 0.05), laminin (P = 0.11) and desmin (P = 0.07), higher collagenolytic activity (P < 0.05), lower prolyl 4-hydroxylase activity (P < 0.05) and lower prolyl 4-hydroxylase (P = 0.10) and tissue inhibitor of metalloproteinase-1 (P = 0.06) expression than group TS. Moreover, expression of tissue inhibitor of the metalloproteinases-1 gene was lower in group TN than in group TS (P < 0.05). These data indicate that the reduction of liver fibrosis in nucleotide-supplemented rats may rely on the enhancement of collagenase activity and the reduction of collagen content and maturation.
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PMID:Dietary nucleotide supplementation reduces thioacetamide-induced liver fibrosis in rats. 1192 56

In studies of the pathogenesis of pancreatic fibrosis, pancreatic stellate cells (PSCs) have recently gained attention. In the present study, we established a new collagenase perfusion method through thoracic aorta cannulation to isolate PSCs, and we studied gene expression of TGF-beta1, type I collagen, and connective tissue growth factor using primary cultured PSCs. Our method facilitated PSC isolation, and by our new method, 4.3 +/- 1.2 x 10(6) PSCs were obtained from a rat. In comparing the expression of these genes with that of hepatic stellate cells (HSCs), we observed a similar pattern, although PSCs expressed type I collagen gene earlier than did HSCs. These results suggest that PSCs may play an important role in fibrosis of the pancreas, as HSCs do in liver fibrosis; in addition, PSCs may exist in a preactivated state or may be more easily activated than are HSCs. We also isolated the PSCs from a WBN/Kob rat, the spontaneous pancreatitis rat, and compared the gene expression with that from a normal rat.
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PMID:Establishment of a novel collagenase perfusion method to isolate rat pancreatic stellate cells and investigation of their gene expression of TGF-beta1, type I collagen, and CTGF in primary culture or freshly isolated cells. 1219 27

Transplanted hepatocytes are ideal carriers for exogenous genes in liver gene therapy. The present study investigated the anti-fibrogenic effects of intrasplenically transplanted hepatocytes modified with interferon gamma (IFN-gamma) gene on cirrhotic rats. Hepatocytes isolated from normal Sprague-Dawley (SD) rats were transfected with an adenoviral vector encoding human IFN-gamma gene (AdCMVhIFN-gamma) and transplanted into the spleens of syngenic recipients with ongoing liver fibrosis induced by carbon tetrachloride (CCl(4)). Histology was assessed, and liver hydroxyproline was detected. Additionally, serum procollagen type III (PIIINP) levels and hepatic collagenase activity were measured to determine hepatic collagen synthesis and degradation. Transplantation with AdCMVhIFN-gamma transfected hepatocytes ameliorated the histological outcome of liver fibrosis by reducing liver collagen content and decreasing hepatic hydroxyproline. Additionally, IFN-gamma transfected hepatocytes reduced serum PIIINP levels and increased hepatic collagenase activity. Our data suggest that transplantation of IFN-gamma transfected hepatocytes may reduce the pace of liver fibrosis by inhibiting the synthesis and enhancing the degradation of hepatic collagen.
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PMID:Intrasplenic transplantation of syngenic hepatocytes modified by IFN-gamma gene ameliorates hepatic fibrosis in rats. 1238 79

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

Hepatic fibrosis is a common feature of many chronic liver diseases. Given the ethical considerations of studies with humans and the limited availability of liver biopsies, there is a need for in vitro models to understand the molecular events involved in hepatic fibrosis. The aim of this work was to compare the behavior of two hepatic cell types involved in fibrogenesis: a liver stellate cell line (CFSC-2G) and primary hepatocytes, both in single and mixed cultures. Cell proliferation was measured as DNA synthesis, protein content, and cell cycle study; functionality as adenylate charge, metabolic rate, and albumin content; and extracellular matrix production as type I collagen content, total collagen synthesis/degradation, metalloproteinase-13 content, and interstitial collagenase activity. Protein content and DNA synthesis were higher in CFSC-2G than in cocultures. Adenylate charge, metabolic rate, and albumin content were impaired in cocultures. Type I collagen content and total collagen synthesis were similar in CFSC-2G and cocultures. Metalloproteinase-13 content was higher in CFSC-2G and cocultures compared with hepatocytes, whereas collagenase activity was only detectable in cocultures. These results suggest that the presence of hepatocytes in the cocultures affects negatively the cell proliferation, functionality, and extracellular matrix production. Cocultures of activated CFSC-2G and healthy hepatocytes are a useful model to study fibrogenesis in vitro since various functional alterations found in this pathology are reproduced.
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PMID:Proliferation, functionality, and extracellular matrix production of hepatocytes and a liver stellate cell line: a comparison between single cultures and cocultures. 1287 Aug 5


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