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)

The relationship between alpha 1-acid glycoprotein (alpha 1-AG) and liver fibrosis was studied. Immunoperoxidase staining of liver specimens from patients with chronic hepatitis showed large amounts of alpha 1-AG to be located primarily in hepatocytes adjacent to areas of piecemeal necrosis, bridging fibrosis and fibrous septa. In patients with severe chronic active hepatitis, hepatocytes throughout the liver stained similarly to those adjacent to areas of piecemeal necrosis. In cell cultures of human embryonal lung (HEL) fibroblasts, addition to the culture medium of alpha 1-AG promoted cell growth. It is known that alpha 1-AG is also produced in the liver. It thus appears likely that alpha 1-AG is a promoter of hepatic fibrosis in chronic hepatitis.
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PMID:Alpha 1-acid glycoprotein and hepatic fibrosis. 305 64

The first part of this review describes the chemistry, the occurrence and the metabolism of extracellular connective tissue components in the liver. The normal liver contains typical connective tissue proteins (collagens, structural glycoproteins and proteoglycans) not only in vessel walls, perivascular areas and in the capsule, but they occur also in small amounts in the parenchyma, mainly in the space of Disse along the sinusoidal walls. The "interstitial" collagens type I and III represent the major amount of collagen in the normal as well as in fibrotic liver, showing a relative increase of type III in fibrosis. Basement membrane collagens type IV and V as well as the cysteine-rich collagenous components "7 S collagen" and "short chain collagen" have been shown to occur in extracts prepared after limited pepsin digestion. In the normal liver, basement membrane collagen can hardly be detected within the parenchyma by immunofluorescence microscopy; increased occurrence, however, can be shown along the sinusoids even in early stages of chronic liver diseases. The glycoprotein fibronectin was shown to be distributed very similarly to collagens type I and III, whereas the basement membrane specific glycoprotein laminin is restricted to vessel walls and the epithelial layer of bile ductuli in the normal liver but is also found in the parenchyma in fibrosis. Occurrence of proteoglycans is increased in fibrosis: a change in the composition of glycosaminoglycans from mainly heparan sulfate in the normal to dermatan- and chondroitin sulfate in the fibrotic liver was observed. It is not yet clear which cell type is mainly responsible for increased connective tissue synthesis in fibrosis. The occurrence of cells resembling smooth muscle cells ("myofibroblasts") in connective tissue septa of fibrotic livers and the fact that similar cells which actively synthesize collagen grow from explants of fibrotic livers may indicate the significance of this cell type in the process of liver fibrosis.
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PMID:Connective tissue components of the normal and fibrotic liver. I. Structure, local distribution and metabolism of connective tissue components in the normal liver and changes in chronic liver diseases. 702 93

Diffuse and chronic liver damage leads to scar formation of the liver structure accompanied with a disproportionate increase of the extracellular matrix (ECM) constituents. Therapeutic intervention in fibrogenesis with its serious clinical consequences requires analysis of structure and cellular sources of ECM. Fibronectin (FN) is a high molecular weight glycoprotein and increases first among ECM proteins during liver fibrosis. The following report summarizes the crucial aspects of FN during fibrogenesis. Besides its controvertible role as initiator or regulator of fibrogenesis FN plays an important role as a scaffold for other matrix proteins.
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PMID:[Fibronectin--a key substance in pathogenesis of liver cirrhosis?]. 830 39

Extrahepatic cholestasis is one of the main factors causing liver fibrosis. Surgical biopsies of six patents were studied: one with normal liver (control patient), and five with different degrees of extrahepatal cholestasis with hepatocellular degenerative and necrotic changes. Monospecific antibodies directed against type IV collagen and fibronectin were localized by light microscopical immunohistochemistry. Type IV collagen was found in all basement membranes: ductal, vascular, neural, Intensive, almost continuous deposits of it were found along the entire length of the sinusoid. Fibronectin, the structural glycoprotein, was codistributed with type IV collagen in portal matrix and in perisinusoidal location. It did not decorate the basement membranes of bile ducts and stained more intensely than type IV collagen at the border between portal stroma and parenchyma. The intensity of the two antibodies increased corresponding with the heaviness of parenchymal deterioration. There was weaker staining behavior of the extracellular matrix regarding collagen IV and fibronectin in the area of heavy bilirubin impregnation. The sinusoid morphology in the regions with fibrosis and increased extracellular matrix formation in periportal areas was reported. Disses's space was distended and occupied by collagen bundles, amorphous matrix, swollen hepatocyte microvilli, and basement membrane-like material. Ito cells transformed into transitional cells or myofibroblast-like cells. Sinusoidal changes and increased collagen IV as well as perisinusoidal fibronectin formation coincided with the aggravation of cholestasis.
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PMID:Electron microscopic investigation on Ito cells and Disse's space in patients with extrahepatic cholestasis. Immunohistochemistry of collagen type IV and fibronectin in hepatic sinusoids. 870 81

Laminin is a major basement membrane-associated, non-collagenous glycoprotein of the extracellular matrix and is deposited in the space of Disse during sinusoidal capillarisation. Laminin P1, a pepsin-resistant fragment originating from the central portion of the cross-shaped laminin molecule, is detectable in serum and has been related to liver fibrosis and portal hypertension. In this study we investigated the behaviour of serum laminin P1, measured by radioimmunoassay, in a homogeneous group of 95 patients suffering from chronic viral hepatitis, types C or B, in order to determine the relationships between serum laminin P1 and each of the main histological aspects of the disease process (i.e. portal-periportal activity, lobular activity and fibrosis), which were assigned numerical scores. Moreover, we computed, at several cut-off levels, the sensitivity, specificity and positive and negative predictive values of laminin P1 in detecting both necroinflammatory activity and fibrosis in the liver. The results show that serum laminin P1 levels parallel the severity of liver disease, the highest laminin concentrations being observed in cirrhotic patients. They suggest also that serum laminin P1 should be considered a marker of the liver disease process as a whole, rather than a marker exclusively linked to fibrosis. Nevertheless, the usefulness of serum laminin P1 measurement, as investigated in this study, seems too limited to be recommended for routine clinical practice.
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PMID:Serum laminin P1 in chronic viral hepatitis: correlations with liver histological activity and diagnostic value. 885 64

Osteonectin/SPARC is a glycoprotein involved in the regulation of cell shape, adhesion, migration, and proliferation. It also has complex effects on extracellular matrix synthesis and turnover. We found that osteonectin mRNA was very abundant in a human liver myofibroblast library. Using Northern and Western blot, immunoprecipitation, and radioimmunoassay, we found that cultured liver myofibroblasts actively secreted osteonectin. Myofibroblasts are very rare in normal liver but proliferate during liver fibrosis where they synthesize extracellular matrix components. Thus, we studied the distribution of osteonectin in normal and fibrotic human liver using in situ hybridization. Osteonectin mRNA expression was weak in normal liver but very high in fibrotic liver within fibrous septae and scattered sinusoidal cells. Serial sectioning and double staining experiments with an antibody to smooth muscle alpha-actin showed that osteonectin transcripts were mostly co-localized with myofibroblasts. In conclusion, osteonectin is highly expressed in human liver myofibroblasts in culture as well as in human liver fibrosis in vivo. The many biological properties of osteonectin make it a candidate effector of human liver fibrogenesis.
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PMID:Osteonectin (SPARC) expression in human liver and in cultured human liver myofibroblasts. 928 12

Dystroglycan is a membrane component of the dystrophin-glycoprotein transmembrane complex. Its expression is required for the spatial organization of laminin on the cell surface and for basement membrane assembly. In view of the constitution of a perisinusoidal basement membrane during liver fibrosis, we studied dystroglycan expression in liver fibrosis. Dystroglycan mRNA and protein expression were investigated by immunofluorescence, Western blot, and quantitative RT-PCR (TaqMan) in normal human and rat liver and in isolated rat hepatic stellate cells. On Western blot, a 43-kd band corresponding to beta-dystroglycan was observed in protein extracted from normal and fibrotic human and rat livers. The specific 43-kd protein was also detected in lysates from rat hepatic stellate cells but not from hepatocytes. By immunofluorescence, patchy deposits of beta-dystroglycan were detected on membrane of hepatic stellate cells in culture. On Western blot and quantitative RT-PCR, an up-regulation of beta-dystroglycan was shown during spontaneous activation of hepatic stellate cells in culture. Direct evidence for the role of dystroglycan in laminin-hepatic stellate cell interaction was shown because specific antibody directed against alpha-dystroglycan inhibited partially hepatic stellate cell adhesion on laminin-coated plates. This mechanism was calcium dependent because EDTA inhibited cell/laminin adhesion, an effect reversed by addition of Ca(2+). This study shows that dystroglycan is expressed on the membrane of hepatic stellate cells and is up-regulated during liver fibrosis. Dystroglycan interaction with laminin should be implicated in the concentration of pericellular laminin and in the constitution of a perisinusoidal basement membrane during liver fibrosis.
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PMID:Dystroglycan expression in hepatic stellate cells: role in liver fibrosis. 1217 44

Congenital disorders of glycosylation (CDG) represent a newly delineated group of inherited multisystem disorders characterized by defective glycoprotein biosynthesis. In the present study we report and discuss the clinical and neuropathological findings in a newborn with CDG type Ia (CDG-Ia). The patient presented mild dysmorphic facial features, inverted nipples, progressive generalized edema, hypertrophic cardiomyopathy, hepatosplenomegaly, muscular hypotonia and had severe hypoalbuminemia. Deficiency of phosphomannomutase (PMM)-2 activity was detected. Molecular analysis showed V231M/T237R mutations of the PMM2 gene. Muscular biopsy, disclosed myopathic alterations with myofibrillar disarray by electron microscopy. The patient died at 1 month of age of circulatory and respiratory failure. Autopsy showed liver fibrosis and renal abnormalities. Neuropathological abnormalities were mainly confined to the cerebellum. Histological and immunocytochemical examination of cerebellar tissue showed partial atrophy of cerebellar folia with severe loss of Purkinje cells, granular cell depletion and various morphological changes in the remaining Purkinje cells and their dendritic arborization. Autopsy findings confirm the complexity of the CDG-Ia syndrome, and indicate that CDG-Ia is a distinct disease entity, which can be differentiated from other neurological disorders and other types of CDG, not only clinically, but also based on unique pathological findings. The data proved useful in determining the underlying disease process associated with a defective N-glycosylation pathway.
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PMID:Congenital disorder of glycosylation type Ia: a clinicopathological report of a newborn infant with cerebellar pathology. 1571 16

Targeting of antifibrotic drugs to hepatic stellate cells (HSC) is a promising strategy to block fibrotic processes leading to liver cirrhosis. For this purpose, we utilized the neo-glycoprotein mannose-6-phosphate-albumin (M6PHSA) that accumulates efficiently in HSC during liver fibrosis. Pentoxifylline (PTX), an antifibrotic compound that inhibits HSC proliferation and activation in vitro, was conjugated to M6PHSA. We employed a new type of platinum-based linker, which conjugates PTX via coordination chemistry rather than via covalent linkage. When incubated in plasma or in the presence of thiol compounds, free PTX was released from PTX-M6PHSA at a sustained slow rate. PTX-M6PHSA displayed pharmacological activity in cultured HSC as evidenced by changes in cell morphology and reduction of collagen I production. PTX-M6PHSA and platinum coupled PTX did not induce platinum-related toxicity (Alamar Blue viability assay) or apoptosis (caspase activation and TUNEL staining). In vivo distribution studies in fibrotic rats demonstrated specific accumulation of the conjugate in nonparenchymal cells in the fibrotic liver. In conclusion, we have developed PTX-M6PHSA employing a novel type of platinum linker, which allows sustained delivery of the drug to HSC in the fibrotic liver.
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PMID:Selective targeting of pentoxifylline to hepatic stellate cells using a novel platinum-based linker technology. 1646 67

Hepatitis B and C viruses are major causative agents of liver fibrosis, cirrhosis, and liver cancer. Using comparative glycoproteomics, we identified a glycoprotein that is altered both in amount and in glycosylation as a function of liver fibrosis and cirrhosis. Specifically, this altered glycoprotein is an immunoglobulin G (IgG) molecule reactive to the heterophilic alpha-Gal epitope [Galalpha-1-3Galbeta1-(3)4GlcNAc-R]. While similar changes in glycosylation have been observed in several autoimmune diseases, the specific immunoglobulins and their antigen recognition profiles were not determined. Thus, we provide the first report identifying the specific antigenic recognition profile of an immunoglobulin molecule containing altered glycosylation as a function of liver disease. This change in glycosylation allowed increased reactivity with several fucose binding lectins and permitted the development of a plate-based assay to measure this change. Increased lectin reactivity was observed in 100% of the more than 200 individuals with stage III or greater fibrosis and appeared to be correlated with the degree of fibrosis. The reason for the alteration in the glycosylation of anti-Gal IgG is currently unclear but may be related to the natural history of the disease and may be useful in the noninvasive detection of fibrosis and cirrhosis.
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PMID:Increased levels of galactose-deficient anti-Gal immunoglobulin G in the sera of hepatitis C virus-infected individuals with fibrosis and cirrhosis. 1804 39


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