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)

Ito cells play a major role in liver fibrosis but the mechanisms controlling their activation in vivo are poorly understood. Heparin-binding growth factors (HBGF) types 1 and 2 are mitogenic for cultured Ito cells. They have been found in liver extracts but their cellular localization is unknown. We have studied by immunohistochemistry HBGF-1 and -2 expression in normal rat liver and in carbon tetrachloride (CCl4)-induced fibrosis. In normal liver, HBGF-1 was present only in sinusoidal cells whereas HBGF-2 was also detected in endothelial cells lining major vessels. At the acute stage of CCl4 intoxication, HBGF-2 was expressed in centrilobular clusters of mononuclear phagocytes that were surrounded by many HBGF-2-negative Ito cells. In the later stages, HBGF-2 was expressed by Ito cells within the fibrous bands. No modulation of HBGF-1 expression was noted at any stage. These results suggest that (1) at the acute stage of CCl4 intoxication, HBGF-2 produced by mononuclear phagocytes could participate in the recruitment of Ito cells; and (2) during the CCl4-induced fibrotic process, HBGF-2 could contribute to Ito cell proliferation and the synthesis of fibrosis components. In this in vivo model of hepatic fibrosis, the hyperexpression of HBGF-2 is a relatively specific event since the expression of a structurally related molecule, HBGF-1 was not modulated.
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PMID:Immunolocalization of heparin-binding growth factors (HBGF) types 1 and 2 in rat liver. Selective hyperexpression of HBGF-2 in carbon tetrachloride-induced fibrosis. 768 79

Forty-eight rats with biliary obstruction induced by double ligation and section of the common bile duct were randomly and blindly assigned to receive subcutaneous injection of either conventional heparin sodium (1000IU kg(-1)), three already marketed low molecular weight heparin (LMWH) preparations: nadroparin (1000 anti-Xa IU kg(-1)), tinzaparin (1000 anti-Xa IU kg(-1)), enoxaparin (180 anti-Xa IU kg(-1)) or saline. Drugs were administered once a day, starting 7 days after surgery and continued for 3 weeks. At the end of the treatment period, rats were killed and analyzed for blood biochemistry and liver pathology. Liver fibrosis was assessed by image analysis. Data indicated that treatment with nadroparin decreased plasma total bilirubin, serum alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT) levels by 80.3, 70.7 and 42%, compared with bile duct ligated (BDL) control values. The reduction in plasma total protein observed in BDL controls was prevented by nadroparin. Enoxaparin-treated rats showed significant reduction in plasma total bilirubin and alanine aminotransferase levels by 32.5 and 38.4% versus BDL controls. Liver necrosis evaluated histologically was significantly reduced in the nadroparin- and enoxaparin-treated rats. Morphometric analysis showed significant reduction in fibrosis on nadroparin and enoxaparin treatment: area of fibrosis: 1.66 +/- 0.17% and 14.03 +/- 1.1% versus 18.94 +/- 2.4% (P<0.05); nadroparin and enoxaparin versus BDL control. By contrast, neither conventional heparin nor tinzaparin prevented the bile duct ligation-induced liver damage as indicated by increased plasma aminotransferases, ALP and GGT concentrations and the histological evidence of necrosis. Total serum bilirubin was increased by 27.5% in rats treated with conventional heparin, while ALP and GGT levels were 38.6 and 31.4% higher after tinzaparin treatment versus BDL controls. Significant increase in the area of fibrosis was observed after tinzaparin treatment compared to BDL control group. Results suggest a beneficial effect for nadroparin and enoxaparin in the therapy of patients with obstructive jaundice or cholestatic liver disorders. The present data from bile duct ligated rats suggest an antifibrotic effect for nadroparin and enoxaparin.
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PMID:A study of unfractionated and low molecular weight heparins in a model of cholestatic liver injury in the rat. 1551 36

Factor VII-activating protease (FSAP) circulates as an inactive zymogen in the plasma. FSAP also regulates fibrinolysis by activating pro-urokinase or cellular activation via cleavage of platelet-derived growth factor BB (PDGF-BB). As the Marburg I polymorphism of FSAP, with reduced enzymatic activity, is a risk factor for atherosclerosis and liver fibrosis, the regulation of FSAP activity is of major importance. FSAP is activated by an auto-catalytic mechanism, which is amplified by heparin. To further investigate the structural requirements of polyanions for controlling FSAP activity, we performed binding, activation and inhibition studies using heparin and derivatives with altered size and charge, as well as other glycosaminoglycans. Heparin was effective in binding to and activating FSAP in a size- and charge density-dependent manner. Polyphosphate was more potent than heparin with regard to its interactions with FSAP. Heparin was also an effective co-factor for inhibition of FSAP by plasminogen activator inhibitor 1 (PAI-1) and antithrombin, whereas polyphosphate served as co-factor for the inhibition of FSAP by PAI-1 only. For FSAP-mediated inhibition of PDGF-BB-induced vascular smooth muscle cell proliferation, heparin as well as a polyphosphate served as efficient co-factors. Native mast cell-derived heparin exhibited identical properties to those of unfractionated heparin. Despite the strong effects of synthetic polyphosphate, the platelet-derived material was a weak activator of FSAP. Hence, negatively charged polymers with a high charge-to-size ratio are responsible for the activation of FSAP, and also act as co-factors for its inhibition by serine protease inhibitors.
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PMID:High negative charge-to-size ratio in polyphosphates and heparin regulates factor VII-activating protease. 1966 58

Heparin and low molecular weight heparin (LMWH) have recently been considered useful treatment tools for inflammation. Heparin has antifibrotic activity, mediated by cellular secretion of hepatocyte growth factor (HGF). HGF has antifibrotic properties demonstrated in experimental models of lung, kidney, heart, skin, and liver fibrosis. The ability of LMWH for HGF secretion is similar to that of normal heparin. Poly (lactic-co-glycolic acid) (PLGA) is widely used for sustained drug release, because of its biocompatibility and low toxicity. LMWH-loaded PLGA microparticles are prepared by a conventional water-in-oil-in-water emulsion method. Interstitial pneumonia is a life-threatening pathological condition that causes respiratory failure when it progresses. In the present study, we investigated the therapeutic effect of LMWH-loaded PLGA microparticles in a mouse model of bleomycin-induced lung fibrosis. The ratios of fibrotic area to total area were significantly lower in mice administered LMWH-loaded microparticles than in mice administered bleomycin alone. The microparticle administration did not further enhance the gene expression for inflammatory cytokines. In a cell culture study, HGF secretion by mouse and human lung fibroblasts was significantly increased by LMWH addition. We conclude that LMWH showed anti-inflammatory activity, through the effects of LMWH-loaded PLGA microparticles on cells at sites of inflammation.
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PMID:Antifibrotic therapy by sustained release of low molecular weight heparin from poly(lactic-co-glycolic acid) microparticles on bleomycin-induced pulmonary fibrosis in mice. 3314 92