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)

Immunolocalization of Type I, Type III and Type IV collagens, laminin and prolyl hydroxylase (PH), a key enzyme in collagen synthesis, was examined to clarify the fibrotic process in chronic, active liver disease. In piecemeal necrosis of chronic, active hepatitis (CAH) and active liver cirrhosis (LC), fat-storing cells (FSCs) and transitional cells (TSCs), containing abundant rough endoplasmic reticulum (RER), were increased in number and stained intensely for PH. Immunodeposits of extracellular matrix (ECM) components were found in the RER, Golgi apparatus (GA) and vesicles of these cells, especially in cases with marked inflammation. On the other hand, in the periportal areas of chronic, persistent hepatitis (CPH) or inactive LC, immunoreaction of ECM components was seldom found in the RER of FSCs and TSCs. In the portal tract, immunodeposits of ECM components were seldom found in the organelles of fibroblasts, although ECM was increased there. These findings indicate that FSCs and TSCs in piecemeal necrosis might play a role in the production of ECM components in the progression of fibrosis during the development of chronic active liver disease. In addition, ECM component production by FSCs and TSCs is associated with marked inflammation.
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PMID:Extracellular matrix formation in piecemeal necrosis: immunoelectron microscopic study. 133 6

Serum type IV collagen fragment (7S collagen domain) was measured in 30 controls and 152 liver disease patients with a radioimmunoassay using a polyclonal antibody to human placenta 7S collagen. The serum concentrations of 7S collagen (mean +/- SD) were 4.2 +/- 0.9 ng/mL in controls, 5.1 +/- 2.0 ng/mL in acute hepatitis, 6.5 +/- 2.5 ng/mL in chronic inactive hepatitis, 9.5 +/- 3.8 ng/mL in chronic active hepatitis, 14.4 +/- 7.5 ng/mL in liver cirrhosis, and 14.4 +/- 6.9 ng/mL in hepatocellular carcinoma. In acute hepatitis, 7S collagen was slightly increased, whereas type III procollagen N-peptide and prolyl hydroxylase were markedly increased. In chronic liver disease, 7S collagen concentrations increased with the severity of the disease, and also reflected the degree of fibrosis. The serum 7S collagen concentrations were significantly correlated with those of type III procollagen N-peptide and prolyl hydroxylase in all subjects. These results suggest that serum 7S collagen concentration is a useful diagnostic aid for determining hepatic collagen metabolism in liver diseases.
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PMID:Clinical significance of serum 7S collagen in various liver diseases. 133 51

Administration of carbon tetrachloride to rats resulted in induction of hepatic fibrosis and a 60% reduction of hepatic S-adenosylmethionine synthetase activity without producing any significant modification of hepatic levels of S-adenosylmethionine synthetase messenger RNA. The reduction of S-adenosylmethionine synthetase activity was corrected by treatment with S-adenosylmethionine (3 mg/kg/day, intramuscularly). Administration of carbon tetrachloride also produced a 45% depletion of liver glutathione (reduced form) that was corrected by S-adenosylmethionine treatment. After the rats received carbon tetrachloride, a 2.3-fold increase in liver collagen was observed; prolyl hydroxylase activity was 2.5 times greater than that seen in controls. These increases were attenuated in animals treated with carbon tetrachloride and S-adenosylmethionine. The attenuation by S-adenosylmethionine treatment of the fibrogenic effect of carbon tetrachloride was associated with a decrease in the number of rats in which cirrhosis developed.
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PMID:S-adenosylmethionine treatment prevents carbon tetrachloride-induced S-adenosylmethionine synthetase inactivation and attenuates liver injury. 139 82

Changes in serum and hepatic levels of immunoreactive prolyl hydroxylase (IRPH) as well as cellular localization of the enzyme were studied in 2 models of hepatic fibrosis, which was induced in male rats either by subcutaneous administration of CCl4 (Group A) or by intraperitoneal injection of porcine serum (Group B). Hepatic fibrosis appeared at the 8th week in Group A and at the 12th week in Group B, and liver cirrhosis developed at the 16th week in both models. Although tissue contents of hydroxyproline (HP) and IRPH increased in both models, only HP levels correlated with the degree of fibrosis. Serum IRPH levels and serum asparate aminotransferase (AST) activities increased, showing a significant positive correlation, in group A, whereas both remained in a control range in Group B. Moreover, in another model which received a single intraperitoneal injection of CCl4, serum IRPH showed a marked increase and then a rapid decrease in parallel with the change in serum AST. Immunohistochemical analysis also showed a difference between the two fibrosis models: in group A, IRPH was positive mainly in parenchymal cells in the peripheral zone of the pseudolobulus, while in group B the staining was diffuse. These results indicate that the elevation of serum IRPH is, at least in part, due to the parenchymal cell damage, and that IRPH levels should be carefully evaluated when being used as a parameter to estimate the activity of fibrogenesis in the liver.
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PMID:Changes in serum and hepatic levels of immunoreactive prolyl hydroxylase in two models of hepatic fibrosis in rats. 165 96

Excessive accumulation of collagen in the extracellular matrix has a crucial role in fibrosis. Thus pharmacological inhibition of collagen deposition is likely to be beneficial for patients suffering from fibrotic disorders such as liver cirrhosis. Prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline in collagens and other proteins with collagen-like amino acid sequences by the hydroxylation of proline residues in -X-Pro-Gly- sequences. The reaction products, 4-hydroxyproline residues, serve to stabilize the collagen triple helices under physiological conditions. Conversely, collagen chains that contain no 4-hydroxyproline cannot fold into triple helical molecules that are stable at body temperature. The prolyl 4-hydroxylase reaction therefore seems to be a particularly suitable target for the pharmological regulation of excessive collagen formation. The reaction catalyzed by prolyl 4-hydroxylase requires Fe2+, 2-oxoglutarate, O2 and ascorbate and involves an oxidative decarboxylation of 2-oxoglutarate. The active enzyme is an alpha 2 beta 2 tetramer that consists of two types of inactive monomer and has two catalytic sites. Some parts of the catalytic sites may be built up cooperatively of both the alpha and beta subunits, but the alpha subunit appears to contribute the major part. The beta subunit contains the carboxyl-terminal tetrapeptide sequence -Lys-Asp-Glu-Leu which is essential for the retention of a polypeptide within the lumen of the endoplasmic reticulum. Since the alpha subunit lacks the carboxyl-terminal retention signal, one function of the beta subunit in the prolyl 4-hydroxylase tetramer may be to retain the enzyme within the endoplasmic reticulum.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prolyl 4-hydroxylase and its role in collagen synthesis. 166 65

The model of biliary cirrhosis by bile duct ligation was further characterized using PIIIP, 7S-collagen as well as standard enzymes in the serum, prolyl 4-hydroxylase and total hydroxyproline in the liver and light microscopical histology. Five weeks after bile duct ligation there was an increase in total collagen content of the liver to 510% of initial values accompanied by an increase of serum-PIIIP (225%) and 7S-collagen (389%). The time-course of this connective tissue proliferation was biphasic with an initial phase of cholestasis and cellular damage followed by rapidly increasing collagen accumulation. The novel prolyl 4-hydroxylase inhibitor HOE 077 reduced the accumulation of collagen in the liver over 6 weeks by 48%. There were no apparent side effects and treated animals showed a tendency towards less functional impairment. The drug's effects, however, were not dose-dependent between daily doses of two times 2 mg/kg and two times 10 mg/kg. These results emphasize the usefulness of the bile duct ligation model for studies of collagen metabolism. They show HOE 077 to be a promising agent for the inhibition of hepatic fibrosis.
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PMID:Fibrosis of the liver in rats induced by bile duct ligation. Effects of inhibition by prolyl 4-hydroxylase. 166 67

Lysyl oxidase was partially purified from serum by a diethylaminoethyl batch procedure in the presence of 6 mol/L urea and dialyzed against 3 mol/L KSCN. Using this method, we determined serum lysyl oxidase activity in 52 patients with liver disease and in 14 healthy controls, and we examined usefulness of serum lysyl oxidase in assessing liver fibrogenesis. For this purpose, serum lysyl oxidase activity in chronic liver disease was compared with serum levels of prolyl hydroxylase and laminin P1. As compared with controls, serum lysyl oxidase activity increased 1.6-fold in chronic persistent hepatitis, 4.4-fold in chronic active hepatitis and 11.8-fold in cirrhosis, indicating an increase in concert with the development of liver fibrosis. In hepatocellular carcinoma, the serum activity, although significantly increased, was lower than that in cirrhosis. Serum prolyl hydroxylase was significantly increased in chronic active hepatitis, in liver cirrhosis and in hepatocellular carcinoma. Serum laminin P1 was significantly increased in chronic active hepatitis, in cirrhosis and in hepatocellular carcinoma. Serum lysyl oxidase activity did not correlate significantly with serum levels of prolyl hydroxylase and laminin P1 in any subject or in any subgroup. The magnitude of the increase and the abnormal percentage of serum lysyl oxidase activity were larger than those for serum prolyl hydroxylase and laminin P1. These results suggest that serum lysyl oxidase activity is a more sensitive indicator of liver fibrosis than serum prolyl hydroxylase and laminin P1.
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PMID:Serum lysyl oxidase activity in chronic liver disease in comparison with serum levels of prolyl hydroxylase and laminin. 168 40

Although there is no established therapy for the fibrogenesis of hepatic cirrhosis, many potential therapies are now emerging. The requirements for the "perfect therapy" for hepatic fibrosis can be listed: (1) the pharmacologic agent should be active only in the liver; (2) its effect should be specific for collagen (or another critical extracellular matrix component); and (3) it should not be toxic. To date no agents fulfill these criteria. Of the agents we reviewed, only colchicine appears sufficiently safe for use outside of controlled clinical trials for cirrhotic patients whose underlying disease is not otherwise treatable. However, confirmation of the efficacy of colchicine in additional well-controlled clinical trials is still required. Agents such as collagen propeptides require extensive in vitro development, while trials in animal models are required for prolyl 4-hydroxylase inhibitors, proline analogues, and prostaglandins. For more developed agents, such as malotilate and gamma-interferon, there is now a need for well-designed long-term clinical trials.
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PMID:Therapy for hepatic fibrosis. 218 90

It was found that chronic intoxication of rats with ethanol results in an increase in prolyl hydroxylase activity in liver and serum of the investigated animals. Similar effects have been observed in some alcoholic patients. We hope that the assay of prolyl hydroxylase in serum or in liver biopsy samples might be useful for the diagnosis and prognosis of the tendency of some individuals to develop liver cirrhosis.
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PMID:Prolyl hydroxylase activity in liver and serum of rats and human subjects intoxicated by chronic administration of ethanol. 282 7

The concentration of serum immunoreactive prolyl 4-hydroxylase (S-IRPH) was determined in patients with various liver diseases by the radioimmunoassay developed previously. S-IRPH values were elevated in acute hepatitis (p less than 0.01), hepatocellular carcinoma (p less than 0.05), metastatic liver neoplasm (p less than 0.01) and cholestatic diseases (p less than 0.001), but no significant elevation was seen in chronic hepatitis or liver cirrhosis. The mean value of S-IRPH was highest in cholestatic diseases, and next highest in acute hepatitis. In addition to acute hepatitis, S-IRPH was increased in other conditions of hepatocellular damage such as exacerbation of chronic hepatitis or immediately after transcatheter arterial embolization of hepatocellular carcinoma. In cases of hepatocellular damage S-IRPH varied concurrent with cytoplasmic enzyme (AST, ALT and LDH) levels and in cases of cholestatic diseases with biliary enzyme (Al-P and gamma GTP) levels. These properties appear to be unique among serum enzymes. The characteristics of S-IRPH were considered to be related to its unique subcellular localization within the cell, ie the membrane of rough endoplasmic reticulum.
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PMID:Studies on serum immunoreactive prolyl 4-hydroxylase in liver diseases--its elevation both in hepatocellular damage and cholestatic diseases. 284 41


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