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

Collagen synthesis was measured in liver slices obtained from mice with hepatosplenic schistosomiasis. Enlarged fibrotic livers from these mice contained 20 times more collagen than normal. This model of hepatic fibrosis results from an inflammatory granulomatous host response to Schistosoma mansoni ova in portal tracts, rather than from direct lover cell injury as with carbon tetrachloride-induced liver fibrosis. Collagen synthesis, as measured by the formation of labeled protein-bound hydroxyproline, occurred in granulomas isolated from fibrotic livers. Labeled collagen that cochromatographed with type I collagen was extracted with neutral salt solution from liver slices incubated with labeled proline. The free proline pool of the liver was doubled in infected mice; coordinately, liver slices from these animals showed maximal collagen production when the concentration of free proline in the medium was raised to 0.4 mM, the same level measured in the fibrotic livers. Under such conditions, collagen synthesis was at a rate equivalent to the formation of 5.4 nmol of protein-bound hydroxyproline per g liver in 6 h. In comparative incubations in medium containing 0.2 mM proline, fibrotic liver slices produced 16-fold more collagen than normal slices. The proline analogue, L-azetidine 2-carboxylic acid, effectively inhibited synthesis of labeled collagen by fibrotic liver slices. These studies show the synthesis of collagen in a reproducible animal model of the most prevalent form of human liver fibrosis. Difinitition of the controlling factors in this system is of interest for the general problem of fibrosis produced by immunological responses.
 ...
PMID:Liver collagen synthesis in murine schistosomiasis. 84 55

Hepatic lipocytes (perisinusoidal, Ito cells) are the primary matrix-producing cells in liver fibrosis. During liver injury they undergo activation, a process characterized by cell proliferation and increased fibrogenesis. We and others have established a culture model in which in vivo features of lipocyte activation can be mimicked by cells grown on plastic. Additionally, we recently showed that activation is associated with new expression of smooth muscle-specific alpha-actin both in vivo and in culture. Although interferon-gamma is known to inhibit collagen production in some systems, its action as a general modulator of lipocyte activation has not been examined; this issue forms the basis for our study. In culture-activated lipocytes, interferon-gamma (1,000 U/ml) significantly inhibited lipocyte proliferation as assessed by [3H]thymidine incorporation assay and nuclear autoradiography. In time-course studies of activation, it also markedly reduced expression of smooth muscle-specific alpha-actin and its messenger RNA. In dose-response experiments, maximal inhibitory effects on smooth muscle-specific alpha-actin mRNA gene expression were achieved with as little as 10 U interferon-gamma/ml. Inhibition of cellular activation was reversible; after interferon-gamma withdrawal, messenger RNA levels of smooth muscle-specific alpha-actin returned to untreated control levels. The effect of interferon-gamma extended to extracellular matrix gene expression, with reduction of type I collagen, type IV collagen and total fibronectin messenger RNAs to 3%, 24% and 15% of untreated control levels, respectively. In contrast to the marked effects on smooth muscle-specific alpha-actin and extracellular matrix gene expression, interferon-gamma reduced total protein synthesis by only 17.7%.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Inhibition of rat hepatic lipocyte activation in culture by interferon-gamma. 150 21

Liver fibrosis was induced in rats both with carbon tetrachloride and dimethylnitrosamine. Assays were performed on steady-state levels of messenger RNAs in the liver for several collagens and basement membrane components. The results indicated marked increases in the steady-state levels of messenger RNA for type I collagen, type III collagen, type IV collagen and the B2 component of laminin. In the same animals, immunoassays were performed for serum levels of the N-terminal propeptide of type III procollagen and the 7S fragment of type IV collagen. The results demonstrated an increase in the serum levels of 7S fragment that occurred early and closely paralleled the increase in the steady-state levels of messenger RNA for the alpha 1(IV) chain of type IV collagen. In contrast, no significant increase was seen in the serum levels of the N-propeptide of type III procollagen. The results suggest that immunoassays for 7S fragment of type IV collagen in serum are a more sensitive index for liver cell damage and fibrosis than assays for the N-propeptide of type III procollagen. The results suggest that greater attention should be paid to assays of 7S fragments in assessing hepatic fibrosis in man.
 ...
PMID:Hepatic fibrosis in rats produced by carbon tetrachloride and dimethylnitrosamine: observations suggesting immunoassays of serum for the 7S fragment of type IV collagen are a more sensitive index of liver damage than immunoassays for the NH2-terminal propeptide of type III procollagen. 161 69

Incorporation rates of 14C-proline into collagen hydroxyproline in cultured Ito cells and hepatocytes isolated from chronically alcohol-treated rats were studied in order to clarify the role of Ito cells in the development of alcoholic liver fibrosis pathogenesis. In the cultured Ito cells isolated from alcohol-treated rats, prolyl hydroxylase activity significantly increased. Total collagen synthesis tended to increase in the alcohol group, and the increase in intracellular intact collagen was statistically significant. More than half of the 14C-radioactivity in intact collagen in cultured Ito cells from control rats was found in collagen other than types I and III collagen (mainly type IV collagen). In Ito cells from alcohol-treated rats, synthesis of collagen other than type I and III significantly increased and type I collagen synthesis tended to be decreased. No significant difference was found in collagen synthesis between the cultured hepatocytes from alcoholic and control rats. These results suggest that chronic alcohol consumption stimulates collagen synthesis in Ito cells, especially type IV collagen. This stimulation of Ito cells may play a role in the development of alcoholic liver fibrosis.
 ...
PMID:Collagen synthesis by cultured rat liver cells isolated from chronically alcohol-treated rats. 196 91

The dynamics of hepatic collagen biosynthesis and degradation were studied in mice infected with Schistosoma japonicum. Hepatic fibrosis, the major clinical manifestation of disease, increased during acute infection (0-15 wk). The majority of proline incorporation into hydroxyproline, which was reflective of collagen synthesis, was found within hepatic egg granulomas. As the disease became chronic (20-30 wk) there was a decrease in collagen synthesis and a maintenance of total collagenolytic activity, which resulted in decreased accumulations of both total hepatic and granuloma-associated collagen. In addition to these quantitative decreases in extracellular collagen there was a qualitative change in the type of hepatic collagen synthesized. Early in infection, type I collagen was the predominant biosynthetic product, whereas late in infection type III collagen became the dominant isotype. A similar switch was seen in the substrate specificity of the constitutive collagenolytic activity, with decreasing type I activity and increasing type III activity as the disease progressed from acute (10 wk) to chronic (30 wk). These changes in the quantity and makeup of extracellular collagen may lead to amelioration of disease and potential reversibility of fibrosis.
 ...
PMID:Dynamics of collagen accumulation and polymorphism in murine Schistosoma japonicum. 299 Oct 69

Liver fibrosis in rats was induced by repeated subcutaneous injections of carbon tetrachloride. Total collagen, soluble and insoluble collagen fractions as well as type I and type III collagen content in the liver were subsequently measured over a 3-18 week period. Liver collagen was found to increase exponentially during this time. Insoluble collagen accumulated more rapidly than soluble forms, and the accumulation of type III collagen was relatively greater than type I collagen. Changes in specific liver enzymes were also observed. Collagenase, collagenolytic cathepsin and collagen peptidase activities all increased. Levels of collagen-degrading enzymes increased rapidly during the first weeks of fibrosis-induction, and were followed by a more gradual increase during the remainder of the study.
 ...
PMID:Dynamics of collagen accumulation and activity of collagen-degrading enzymes in the liver of rats with carbon tetrachloride-induced hepatic fibrosis. 303 9

The products of the collagen-alpha 1(I) and -alpha 2(I) genes form the triple helical molecule collagen type I, which constitutes the major ECM protein in tissue fibrosis. The collagen-alpha 1(I) gene is mainly transcriptionally regulated, and its promoter activity depends on the interaction of the transcription factors NF-I and Sp1 with a tandem repeat of evolutionary conserved NF-I/Sp1 switch elements. An increased affinity of Sp1 to these elements has been observed in experimental liver fibrosis. Here, we demonstrate that the DNA binding drug mithramycin displays a high affinity binding to the GC-rich elements in the collagen-alpha 1(I) promoter as measured by DNAse I protection and gel retardation assays. Mithramycin interferes with Sp1 but not with NF-I binding to these sites. At a concentration of 100 nM, mithramycin efficiently reduces basal and TGF-beta-stimulated alpha 1(I) gene expression in human primary fibroblasts. The transcriptional activity and mRNA steady state levels of other genes, including the collagenase gene, as well as the growth rate of fibroblasts remained unchanged on exposure to this drug. Taken together, our results indicate that the transcriptional activity of the type I collagen gene highly depends on its GC-rich regulatory elements, and further, that these elements can be differentially blocked, thereby changing the balance between ECM structural and degrading gene activities in human fibroblasts.
 ...
PMID:Mithramycin selectively inhibits collagen-alpha 1(I) gene expression in human fibroblast. 1456 12

Type VI collagen is a minor but essential matrix component in the liver. In this study, we utilized an acute and a chronic injury model to clarify the process of liver fibrosis in rats by administration of carbon tetrachloride. Collagen gene expression, with particular emphasis on type VI collagen, was studied by molecular hybridization techniques. The alpha 2(VI) collagen mRNA levels were markedly elevated on day 3 of acute injury and were approximately at the same high level at 7 and 14 weeks of chronic injury, as determined by Northern hybridizations and slot-blot analyses. Marked enhancement of type I collagen gene expression was similarly noted at these time points. The activation of collagen gene expression in acute injury, as determined by in situ hybridization, was particularly prominent in the vicinity of the central veins. Indirect immunofluorescence demonstrated marked accumulation of type VI collagen protein as early as day 3 of acute injury, and the reaction appeared to be initiated in the proximity of central veins. These results indicate that type VI collagen gene expression, together with other connective tissue components, including type I collagen, is activated in the early stages of the fibrotic process. Type VI collagen accumulation may contribute to the distorted architecture and functional impairment of the liver in hepatic fibrosis.
 ...
PMID:Type VI collagen gene expression in experimental liver fibrosis: quantitation and spatial distribution of mRNAs, and immunodetection of the protein. 779 42

Hepatic fibrosis is an important morphological feature of alcohol-induced liver injury. We previously reported that acetaldehyde, but not ethanol can stimulate type I collagen and fibronectin synthesis in cultures of rat fat-storing cells (FSC) by increasing transcription of the specific genes. The effect of lactate and pyruvate was studied on collagen I, III, fibronectin accumulation by cultured rat FSCs and it was investigated whether acetaldehyde could increase procollagen I and fibronectin gene transcription through the formation of protein adducts. Lactate and pyruvate (5, 15 and 25 mmol/l) did not significantly affect collagen I, III and fibronectin production by cultured FSCs. Pyridoxal-phosphate and p-hydroxymecuribenzoate (inhibitors of acetaldehyde-protein adduct formation) blocked the stimulatory effect of acetaldehyde on procollagen I and fibronectin gene transcription. These data suggest that ethanol may act as a liver fibrogenic factor through acetaldehyde, its immediate metabolite, whereas lactate does not seem to play a role. Acetaldehyde might stimulate gene transcription of extracellular matrix components by liver FSCs through the formation of adducts with proteins.
 ...
PMID:Acetaldehyde-protein adducts, but not lactate and pyruvate, stimulate gene transcription of collagen and fibronectin in hepatic fat-storing cells. 815 Oct 99

Increased Ito cell collagen production occurs during in vivo liver fibrogenesis. Regulation of the overproduction of collagen was studied in cultured rat hepatic Ito cells, which resemble the myofibroblast associated with liver fibrosis. Previous studies suggest that the steroid hormones, retinoic acid, and glucocorticoids may have antifibrogenic properties in vitro and in vivo when used at pharmacological doses. Their potential roles at physiological levels are not well understood. The current study examined the potential regulation of the overproduction of type I collagen in cultured rat hepatic Ito cells by another steroid hormone, 3,5,3'-triiodo-L-thyronine (T3). T3 induced a 3.4-fold reduction in type I collagen production. The effect was dose dependent and was maximal with physiological levels of T3 (10(-9) M). The effect of T3 was independent of any suppression in total protein synthesis. The mechanism of the suppressive effect of T3 on collagen production was explored and was found to be at a posttranslational level. This study suggests that the inhibitory effects of T3 on type I collagen production are likely caused by enhanced intracellular turnover of type I collagen.
 ...
PMID:Posttranslational inhibition of Ito cell type I collagen production by triiodothyronine. 833 36


1 2 3 4 5 6 7 8 9 10 Next >>