Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The "very late activation" (VLA) subgroup of the integrin superfamily of adhesion molecules plays a central role in cell-cell and cell-matrix interactions. The six different VLA dimers known so far consist of a common beta subunit and a variable alpha (1 to 6) subunit. They serve as receptors for laminin, collagen, and fibronectin or function as adhesion molecules for leukocytes and are therefore of great significance in embryogenesis, growth and repair, and in leukocyte recirculation. The distribution of the common beta and the variable alpha chains of the VLA were studied in normal, inflammatory, and cholestatic liver biopsy samples. In normal liver tissue, vascular endothelia express alpha 1, 2, 3, 5, and 6; bile duct epithelium alpha 2, 3, 5, and 6; connective tissue stroma alpha 1 and 2; hepatocytes alpha 1 and 5; sinusoidal lining cells alpha 1, 2, and 5; and mononuclear cells alpha 4. Whereas bile ducts and vascular endothelia do not show relevant changes in alpha chain expression in liver diseases, hepatocytes de novo express membranous alpha 3 and 6 in inflammatory liver diseases. In view of the role of the VLA-3 and VLA-6 as laminin receptors, this finding is in line with the production of laminin in active liver disease. Moreover, de novo expression of "bile duct type" alpha 2, 3, and 6 on periportal hepatocytes in cholestatic liver disease likely illustrates a phenotypic switch of hepatocytes towards bile duct epithelium during cholestasis.
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PMID:Distribution of the VLA family of integrins in normal and pathological human liver tissue. 204 8

Collagens (I, III, and IV), fibronectin, and laminin were localized using the indirect immunoperoxidase technique 14 days after bile duct ligation, i.e., when extensive fibrosis and numerous neoformed bile ducts were observed. Extensive fibrous septa in enlarged portal spaces were stained for collagens I, III and IV, fibronectin, and laminin. Collagen IV and laminin were abundant around proliferative bile ducts. In addition, collagen IV was nearly continuous in the sinusoids. At the ultrastructural level, antigens were localized in the endoplasmic reticulum of several liver cell types. In portal spaces, bile duct cells and cells that form the transitional canal of Hering were strongly labelled for basement membrane components, particularly laminin, but not for collagens I and III and fibronectin, which were abundant in fibroblast-like cells. Inside the lobule, only Ito cells and, to a lesser extent, endothelial cells contained collagens, fibronectin, and laminin. Ito cells were found to be heavily stained for collagens III and IV, and laminin. Except for fibronectin, which was always abundant, precursors of extracellular matrix proteins were only slightly detectable in the endoplasmic reticulum of some hepatocytes, particularly those located close to altered areas. This study demonstrates that experimental extrahepatic cholestasis in the rat induces periportal fibrosis and continuous deposition of collagen IV in the sinusoids. Several cell types participate in the formation of extracellular matrix components, particularly bile duct cells and Ito cells, with a possible involvement of hepatocytes, thus suggesting that cholestasis provokes changes in the pattern of matrix protein production in liver cells.
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PMID:Cellular sources of matrix proteins in experimentally induced cholestatic rat liver. 207 16

The reversibility of hepatic fibrosis was investigated in an experimental model of extrahepatic cholestasis in the rat after common bile duct ligation for 2 weeks, followed by bilioduodenal anastomosis for 3 weeks. Bile duct ligation resulted in a transitory marked elevation in the serum concentration of 5'-nucleotidase, alkaline phosphatase, and bilirubin during the first 3 days. Then these levels decreased to threefold, twofold, and 100-fold the normal values, respectively, during the following 4 weeks. Histologic examination of the liver disclosed extensive bile duct proliferation and the formation of periportal fibrosis, with only slight inflammation and necrosis. The distribution of the major components of the hepatic extracellular matrix was analyzed 2 weeks after bile duct ligation, using the indirect immunoperoxidase method. Fibrous septa were found to be strongly stained for collagens I, pro-III, III and IV, fibronectin, and laminin. The most intense staining was found in enlarged periportal areas, collagen IV and laminin being particularly abundant around newly formed bile ducts. These changes paralleled high steady-state levels of alpha 1(I) and alpha 1(IV) collagen and B2 chain laminin mRNAs. Relief of the obstruction for 2 weeks resulted in a shift in the serum concentration of 5'-nucleotidase, alkaline phosphatase, and bilirubin toward normal values. A dramatic resorption of bile duct proliferations and periportal fibrosis were observed. Three weeks after bile duct repermeabilization, immunohistochemical study showed that the pattern of distribution of extracellular matrix components was almost normal, except for collagen IV, which remained abundant in the sinusoids when compared with the normal liver. In parallel, the steady-state B2-chain laminin mRNA level became lower than in cholestatic livers, whereas alpha 1(I) and alpha 1(IV) mRNAs were almost undetectable. These results show that hepatic fibrosis induced by experimental extrahepatic cholestasis in rat disappears in less than 3 weeks after relief of bile duct obstruction, suggesting that an active degradation of matrix protein occurs, except for collagen IV in the sinusoid.
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PMID:Reversibility of hepatic fibrosis in experimentally induced cholestasis in rat. 226 Jun 23

The determination of fibronectin (FN) concentration in plasma has been performed in the group of 77 patients (60-with various chronic liver diseases, 6-with AIDS IVc, 11-healthy patients). The purpose of this study was: evaluation of the value of plasma FN determination in assessment the degree of liver fibrosis and the degree of liver damage. The obtained results were compared with routine biochemical tests and histopathological picture of liver sections. Among patients with liver diseases, we observed that plasma FN concentration was significantly lower only in the group with decompensated liver cirrhosis, in relation to control group. Non significant lower values of FN was observed in the group of patients with chronic hepatitis, as well as non significant higher ones in the group with cholestasis and fibrosis. It has been concluded that determination of plasma FN concentration has not any importance in evaluation of degree of liver fibrosis and its only one from many functional liver tests.
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PMID:[Plasma fibronectin in chronic liver disease--marker of fibrosis?]. 763 58

This study was carried out to evaluated the role of the fibronectin (FN) in chronic liver diseases. For these reasons FN plasmatic concentration was assayed in patient with different degrees of chronic liver disease. For these reasons FN plasmatic concentration was assayed in patient with different degrees of chronic liver disease; the correlation between FN and the most common parameters of liver function was also evaluated. Moreover we also correlated FN plasma levels with laminin and the N-terminale peptide of type III procollagen, serum levels, that are through to be markers of fibrogenesis. 172 patients were studied: twenty-one patients suffering from chronic persistent hepatitis (CPH), 45 from chronic active hepatitis (CAH) and 106 from liver cirrhosis (LC). Last patients were also divided according the Child-Pugh's classification. Control group was composed of 74 healthy blood donors. Significant reduction of plasmatic levels of FN was found in the LC groups in comparison with control group (p < 0.0001) and also with CPH group (p < 0.01) and with CAH group (p < 0.0001). Lower values of FN were found in the LC group at advanced stage (Child-Pugh's B and C classes). In the group of CAH significant correlations with the parameters of cholestasis (GGT, APh, Tot. Bil. p < 0.005) were found, while in the group of LC significant correlations both with the parameters of synthesis (Alb. and Protr. time p < 0.01) and necrosis (AST/ALT p < 0.001). A negative correlation was also found between FN and spleen volume (p < 0.05). No correlation between FN and the parameters of fibrosis was found.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Plasma fibronectin in chronic liver diseases]. 821 Jun 24

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

The extracellular matrix (ECM) expression is subject to distinct changes during ontogeny, and the natural course of liver fibrosis in neonates is thought to differ from that in adults. We compared the expression and distribution of main ECM components between neonatal and adult liver fibrosis. Liver biopsies from infants with neonatal cholestasis and fibrosis were compared to adult biopsies exhibiting an equivalent stage of fibrosis. All biopsies were examined by immunohistochemistry (indirect ABC method) for the ECM proteins, collagens I, III, IV, and VI, laminin, and fibronectin. Infants (aged 1-8 months) with neonatal hepatitis (n = 3), extrahepatic biliary atresia (EHBA) (n = 5), and normal histology (n = 2) were compared with 9 adults (aged 17-70 years) with chronic hepatitis (n = 3), primary biliary cirrhosis (PBC) (n = 4), and normal histology (n = 2). Collagens I, III, and IV and fibronectin were significantly increased in neonatal hepatitis with mild fibrosis (score < or = 4) compared to adults with an equivalent fibrosis stage. This increase was particularly notable in perisinusoidal spaces. Laminin expression was increased in portal and perisinusoidal spaces both in neonatal hepatitis and extrahepatic biliary atresia with mild fibrosis. In infants with moderate to severe fibrosis (score > or = 6), only collagen I was increased in comparison to adults, whereas collagen VI expression was identical in all groups, irrespective of the degree of fibrosis. Expression of matrix proteins was not different in infants and adults without fibrosis. The increased perisinusoidal deposition of certain ECM components in infants with active hepatitis and mild fibrosis may point to an underlying difference in the mechanism or stimulus of fibrogenesis in neonates as compared to adults.
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PMID:Divergent patterns of extracellular matrix protein expression in neonatal versus adult liver fibrosis. 1469 30

During cholestasis, bile acids accumulate in the liver, and induce cellular alterations. Cholestasis is a major cause of liver fibrosis. We have used precision-cut liver slices (PCLS) in culture to investigate the effects of bile acids on hepatic cells. Rat PCLS were placed on an insert in a vial containing culture medium, and gently agitated on a roller platform. PCLS were treated with 100 microM taurolithocholate (TLC), taurodeoxycholate (TDC) or taurocholate (TC) for 24 or 48 h. PCLS viability was measured, and immunohistochemistry was performed with antibodies against active caspase 3, platelet-derived growth factor (PDGF) receptor-beta and ED-A fibronectin. TDC and TLC, two hydrophobic bile acids, induced hepatocyte necrosis and apoptosis, whereas TC, an hydrophilic bile acid, improved slice viability as compared with controls. Both TDC and TC induced biliary epithelial cell proliferation, together with portal fibroblast proliferation and activation, as shown by PDGF receptor-beta and ED-A fibronectin expression. TLC induced biliary epithelial cell apoptosis. Our results indicate that individual bile acids induce cell type-specific effects in a complex liver microenvironment. The fact that PCLS support biliary epithelial cell and portal fibroblast proliferation will make this model very useful for the study of the mechanisms involved in portal fibrosis.
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PMID:Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices. 1640 30

IN THE LAST YEARS THERE HAS BEEN AN INCREASED AWARENESS REGARDING THE ALTERATIONS OF BONE METABOLISM AS A COMMON COMPLICATION OF CHRONIC LIVER THAT OCCURS REGARDLESS OF THE ETIOLOGY: alcoholic, viral, autoimmune, whether or not associated with cholestasis.The aim of this paper was to summarize the current understanding of bone metabolism and to point out the new discoveries that have been made in this field.Bone density is maintained constant due to the equilibrium between bone formation bone resorbtion, under the control of hormonal and proinflammatory cytokines. The influence of sex hormones, parathyroid hormone, growth hormone, and insulin-like growth factor-1 and 2 on bone metabolism is discussed. The role of proinflammatory cytokines, CSF1-RANKL system, leptin and oncofetal fibronectin are also discussed.Although the physiological mechanism of bone metabolism has been established, when it comes to pathological conditions, the hormones and cytokines have different new roles, or are associated with other factors having different influences.
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PMID:Hormonal and cytokine implications in the pathophysiology of osteoporosis occurring in chronic liver diseases. 2348 75

Cholangiocyte proliferation is regulated in a coordinated fashion by many neuroendocrine factors through autocrine and paracrine mechanisms. The renin-angiotensin system (RAS) is known to play a role in the activation of hepatic stellate cells and blocking the RAS attenuates hepatic fibrosis. We investigated the role of the RAS during extrahepatic cholestasis induced by bile duct ligation (BDL). In this study, we used normal and BDL rats that were treated with control, angiotensin II (ANG II), or losartan for 2 wk. In vitro studies were performed in a primary rat cholangiocyte cell line (NRIC). The expression of renin, angiotensin-converting enzyme, angiotensinogen, and angiotensin receptor type 1 was evaluated by immunohistochemistry (IHC), real-time PCR, and FACs and found to be increased in BDL compared with normal rat. The levels of ANG II were evaluated by ELISA and found to be increased in serum and conditioned media of cholangiocytes from BDL compared with normal rats. Treatment with ANG II increased biliary mass and proliferation in both normal and BDL rats. Losartan attenuated BDL-induced biliary proliferation. In vitro, ANG II stimulated NRIC proliferation via increased intracellular cAMP levels and activation of the PKA/ERK/CREB intracellular signaling pathway. ANG II stimulated a significant increase in Sirius red staining and IHC for fibronectin that was blocked by angiotensin receptor blockade. In vitro, ANG II stimulated the gene expression of collagen 1A1, fibronectin 1, and IL-6. These results indicate that cholangiocytes express a local RAS and that ANG II plays an important role in regulating biliary proliferation and fibrosis during extraheptic cholestasis.
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PMID:Activation of the renin-angiotensin system stimulates biliary hyperplasia during cholestasis induced by extrahepatic bile duct ligation. 2567 5


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