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)

Based on the finding that prolyl hydroxylase, a key enzyme in collagen biosynthesis, is a constituent of the hepatic parenchymal cell, we have suggested that the hepatocyte may synthesize collagen (Exp. Cell Res. 123: 269-279, 1979). We now report that, consistent with this idea, collagen formation has been detected in primary nonproliferating cultures of isolated rat hepatocytes prepared from either normal liver or regenerated liver four days after partial hepatectomy. The characteristics of the radiolabeled collagen formed in two-day old cultures incubated for 24 hours in the presence of either [3H]-proline or [35S]-cystine were its resistance to pepsin and its susceptibility to degradation by highly purified, protease-free bacterial collagenase. The presence of fibroblasts in the hepatocyte cultures was excluded as an explanation for these results because we detected no type I collagen, a universal product of the cultured fibroblast. The initial low rates of synthesis of collagen relative to total cellular protein (0.1-0.4 percent) increased dramatically upon continued incubation of the cells reaching 0.31 and 0.81 percent in nine-day old cultures of normal or regenerated hepatocytes, respectively. This change was accompanied by the synthesis of an additional 100,000 molecular weight from of collagen, possibly type I or A, B. Morphologically, the hepatocytes progressively flattened and overlapped adjacent cells with time in culture. However, their identify as hepatocytes was confirmed by the fact that synthesis of fibrinogen, a liver-specific function, was maintained above initial levels throughout the experiment. We conclude that synthesis of collagen is a constitutive function of the hepatocyte. This function is linked to hepatocyte replication, is subject to phenotypic change in culture, and may be important in the pathogenesis of hepatic fibrosis or cirrhosis.
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PMID:Collagen synthesis by the hepatocyte: studies in primary cultures of parenchymal cells from adult rat liver. 734 23

Changes in the synthesis of type I collagen, a major extracellular matrix component in skin and bones, are associated with both normal growth or repair processes and with several pathological conditions such as lung fibrosis and liver cirrhosis. The expression of the alpha 1(I) collagen gene is regulated by transcriptional and post-transcriptional mechanisms. Regulation at both these levels are usually utilised when extensive changes occur in collagen synthesis. We constructed plasmids carrying the whole or partially deleted 3'-UTR sequences of the alpha 1(I) collagen gene, fused to two hGH exons and to the promoter of the alpha 1(I) collagen gene. A control plasmid contained the 3'-UTR of the hGH gene. In transient transfections into Rat-1 fibroblasts, no significant differences between plasmids were found, which suggests that although 3'-end of the gene has been shown in previous studies to contain DNaseI hypersensitive sites and to bind sequence-specific nuclear proteins it does not seem to function as a transcriptional regulator. This was further supported by the finding that TGF-beta treatment induced a 2.5-fold expression of hGH mRNA from plasmids containing collagen promoter and either hGH or alpha 1(I) collagen 3'-UTR. In stable transfections, mRNAs using the first polyadenylation site were not as stable as those transcribed from the endogenous alpha 1(I) collagen gene. We suggest that the 3'-UTR alone may not be sufficient to determine the stability of the shorter alpha 1(I) collagen mRNA species.
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PMID:Effect of the 3'-untranslated region on the expression levels and mRNA stability of alpha 1(I) collagen gene. 787 3

Cirrhosis is characterized by a marked increase in the deposition of type I collagen and in the expression of the type I collagen genes alpha 1(I) and alpha 2(I). Although alpha 1(I) gene regulation has been extensively studied in cultured cells, these results may not be applicable to hepatic fibrogenesis in vivo. Therefore the regulation of the alpha 1(I) endogenous gene and an alpha 1(I) transgene was studied in a transgenic mouse model that has a single copy of a human alpha 1(I) gene segment containing the structural gene and 1.6 Kb of 5' DNA and 20 Kb of 3' DNA. To initiate hepatic fibrogenesis, we treated mice with the hepatotoxin carbon tetrachloride, either in a single dose or in biweekly doses for a period of 3 to 8 wk. Subsequently, hepatic alpha 1(I) messenger RNA levels were determined by a species-specific RNase protection assay. Carbon tetrachloride injections coordinately increased the messenger RNA levels of the alpha 1(I) endogenous gene and the transgene, both immediately and after 8 wk. These experiments demonstrate that this alpha 1(I) transgene fragment contains information sufficient for appropriate basal and carbon tetrachloride-stimulated hepatic expression. They further demonstrate that sufficient homology exists between the human and mouse regulatory elements for the recognition of human cis-acting elements by mouse trans-acting factors. Thus transgenic mice provide a unique model in which to characterize the collagen alpha 1(I) regulatory elements that are required in vivo for pathophysiological responses.
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PMID:Stimulation of the collagen alpha 1 (I) endogenous gene and transgene in carbon tetrachloride-induced hepatic fibrosis. 842 27

Cirrhosis is characterized by an increased deposition of extracellular matrix proteins, including type I collagen. Type I collagen is a product of two genes, alpha 1(I) and alpha 2(I), which are generally coordinately regulated. Since expression of type I collagen genes is increased during cirrhosis, understanding the structure and function of the regulatory components of the type I collagen genes should provide insight into the molecular pathogenesis of cirrhosis. This review will analyze the collagen alpha 1(I) gene with respect to chromatin structure, DNA methylation, regulation by agonists, and DNA-protein interactions.
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PMID:Type I collagen gene regulation and the molecular pathogenesis of cirrhosis. 847 45

We examined 60 patients with various chronic liver diseases for cellular sensitivity to native human type I and IV collagens using an in vitro leucocyte migration inhibition test. Mononuclear cells from 7 (33%) of 21 patients with chronic active hepatitis, 14 (52%) of 27 patients with liver cirrhosis and 11 (92%) of 12 patients with primary biliary cirrhosis exhibited cellular sensitivity to type IV collagen, although cells from almost all patients responded to type I collagen. None except one for type I collagen of 25 normal controls showed positive response to both collagens. In chronic active hepatitis and liver cirrhosis, cellular sensitivity to type IV collagen was significantly lower than to type I collagen (p < 0.01). Patients with primary biliary cirrhosis showed significantly higher cellular sensitivity to type IV collagen when compared to patients with other chronic liver diseases (p < 0.01). Cellular sensitivity to type IV collagen was significantly correlated with serum levels of the 7S domain of type IV collagen in all 85 subjects (r = +0.462, p < 0.001). These findings suggest that cellular sensitivity to type IV collagen as well as to type I collagen exists in chronic liver disease, especially in primary biliary cirrhosis, and may reflect the accelerated metabolism of the perisinusoidal and peribiliary basement membranes.
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PMID:Cellular sensitivity to native type IV collagen in primary biliary cirrhosis. 848 75

Type I collagen synthesis and deposition is generally indicative of irreversible damage in alcohol-induced cirrhosis in humans. However, in rodents, ethanol alone does not readily cause hepatic fibrosis. To determine whether this is because of a lack of ethanol-responsive elements, an artificial enhancer construct controlling rat type I collagen gene transcription was prepared in transgenic mice. The gene construct, ColCAT3.6, was a chimeric sequence containing the marker chloramphenicol acetyltransferase (CAT) gene linked to 3.5 kb of the rat alpha 1(I) 5'-flanking DNA, and 115 base pairs (bp) of transcribed collagen gene. Groups of transgenic mice were given 4 g/kg ethanol orally, twice daily for 4 weeks. As a positive control for hepatic fibrosis, transgenic mice were given intraperitoneal injections of CCl4, twice weekly for 4 weeks. Livers were assayed for CAT activity. Endogenous mouse collagen alpha 1(I) messenger RNA (mRNA) and transgene CAT mRNA were measured by RNase protection assays. Collagen synthesis in livers from the transgenic mice treated with ethanol were increased over controls, but the levels were not significantly different. Endogenous collagen alpha 1(I) steady-state mRNA levels in ethanol-treated mice were not significantly different compared with saline-treated controls. However, the transgene mRNA levels in ethanol-treated animals increased approximately 21-fold compared with saline-treated controls, as measured by RNase protection assays. Furthermore, the transgene product as measured by CAT activity in ethanol-treated mice was significantly increased threefold over saline-treated controls. We conclude that the 5'-flanking region of the rat alpha 1(I) collagen gene does contain regulatory elements that are strongly responsive to ethanol administration.
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PMID:A collagen enhancer-promoter construct in transgenic mice is markedly stimulated by ethanol administration. 859 57

Previous results of our group revealed that mebendazole, a broad spectrum anthelmintic drug with antimicrotubular properties, used for the treatment of liver cirrhosis, decreased total collagen content and biosynthesis in liver upon treatment. In the present study, we have evaluated the effects of mebendazole (5-50 micrograms/mL) on protein synthesis, secretion, and deposition in human-derived fibroblast cultures. The results showed a decrease in cell viability (18.5 +/- 0.9%) at 50 micrograms/mL. [3H]Thymidine incorporation diminished gradually with increasing mebendazole concentrations, reaching a plateau (53.67%) between 30 and 50 micrograms/mL. In late logarithmic phase cultures, the drug caused a decrease of [3H]proline incorporation (43.10%) and collagen biosynthesis (58.61%) in the extracellular matrix. This correlated with an increase in radioactivity in total proteins (51.28%) of the intracellular fraction. Similar results were obtained when mebendazole was assayed in post-confluent fibroblast cultures. The electrophoretic patterns of the extracellular matrix showed a decrease of radioactive collagenous components (alpha chains and beta dimers). By contrast, in the intracellular fraction an increase of radioactive collagen precursors (pro alpha chains) was observed. Immunofluorescence studies and immunotransfer analysis, using polyclonal anti-type I collagen antibodies, revealed an accumulation of intracellular collagen which included: collagen pro alpha chains, alpha chains, and low molecular weight peptides. The results obtained suggest that mebendazole interferes with the transcellular mobilization of proteins, resulting in a decrease of secretion and deposition of extracellular matrix proteins, and an accumulation of intracellular collagenous components. The intracellular accumulation of newly synthesized proteins could cause a feedback regulation in fibroblast cultures.
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PMID:Effects of mebendazole on protein biosynthesis and secretion in human-derived fibroblast cultures. 869 54

The collagen-binding activity of plasma vitronectin was measured in 15 control subjects and 64 subjects with chronic liver disease. The assay of collagen-binding vitronectin was performed by an enzyme immunoassay using a monoclonal antibody to human vitronectin and type I collagen from human placenta. The plasma collagen-binding vitronectin concentration (mean +/- S.D.) was 5.6 +/- 1.9 micrograms/ml in the controls, 8.3 +/- 1.1 micrograms/ml in chronic persistent hepatitis, 8.3 +/- 2.9 micrograms/ml in chronic active hepatitis, 7.8 +/- 2.9 micrograms/ml in liver cirrhosis and 8.2 +/- 2.1 micrograms/ml in hepatocellular carcinoma with cirrhosis. The percent collagen-binding vitronectin to total plasma vitronectin was 2.2 +/- 0.8% in the controls, 3.9 +/- 2.2% in chronic persistent hepatitis, 3.9 +/- 1.2% in chronic active hepatitis, 5.8 +/- 3.3% in liver cirrhosis and 4.1 +/- 1.2% in hepatocellular carcinoma with cirrhosis. The plasma collagen-binding vitronectin also correlated with the serum levels of 7S collagen and hyaluronic acid. These findings suggest that vitronectin may play an important role in the progression of liver disease and/or in hepatic fibrosis through its collagen-binding domain.
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PMID:Collagen-binding activity of plasma vitronectin in chronic liver disease. 881 65

Patients with alcoholic hepatitis have several manifestations of the acute phase response (APR) and have elevated blood levels of interleukin-1, interleukin-6 and tumor necrosis factor-alpha. We have previously shown that liver stellate cells express interleukin-6 mRNA and protein and respond to this cytokine with increased expression of alpha1(I) procollagen mRNA. We further showed that the production of an APR episode stimulates a transient expression of alpha1(I) procollagen mRNA in the liver. In this communication we demonstrate that the concomitant induction of a weekly APR episode in rats with a schedule of CCl4 to produce cirrhosis, accelerates the development of liver fibrosis. We show that the enhancement of liver fibrosis is due, in part, to further upregulation in the expression of alpha1(I) procollagen and tissue inhibitor of metalloproteinases-1 mRNAs above values observed in control rats receiving only CCl4. The effect of the APR appears to have specificity since not all the mRNAs measured were equally affected. Altogether, these results suggest that increased blood or liver levels of APR cytokines, whether induced by APR episodes, endotoxin or other unrelated causes, may contribute to the development of liver fibrosis by enhancing the expression of type I collagen and of tissue inhibitor of metalloproteinases-1 mRNAs.
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PMID:Accelerated development of liver fibrosis in CCl4-treated rats by the weekly induction of acute phase response episodes: upregulation of alpha1(I) procollagen and tissue inhibitor of metalloproteinase-1 mRNAs. 930 Jul 99

Plasma collagen-binding vitronectin was assayed in 62 patients with chronic liver disease and 14 healthy control subjects. It was measured by an enzyme immunoassay using type I collagen and monoclonal antibody to vitronectin before and after treatment with heparin or dextran sulfate in vitro. The pretreatment level of plasma collagen-binding vitronectin (mean +/- S.E.M.) was 5.5 +/- 0.5 micrograms/ml in the controls, 8.2 +/- 0.3 micrograms/ml in chronic persistent hepatitis, 8.3 +/- 0.7 micrograms/ml in chronic active hepatitis, 7.9 +/- 0.7 micrograms/ml in liver cirrhosis, and 8.2 +/- 0.5 micrograms/ml in hepatocellular carcinoma with cirrhosis. After treatment with heparin, the percent collagen-binding vitronectin to total vitronectin was 20.6 +/- 2.0% in the controls, 24.7 +/- 4.1% in chronic persistent hepatitis, 28.6 +/- 2.5% in chronic active hepatitis, 42.6 +/- 4.5% in liver cirrhosis, and 31.8 +/- 2.3% in hepatocellular carcinoma. All percents were significantly increased compared to the pretreatment percent. The same pattern was also found after dextran sulfate treatment. Compared to that in the pretreatment state, the collagen-binding vitronectin after these treatments was more closely correlated with the serum levels of 7S collagen and hyaluronic acid. These results suggest that the collagen-binding activity of vitronectin may play an important role in the progression of liver disease and/or fibrosis through its activation with some glycosaminoglycans.
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PMID:Plasma collagen-binding vitronectin activated by heparin and dextran sulfate in chronic liver disease. 938 91


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