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)

The demonstration that fibroblastic cells acquire contractile features during the healing of an open wound, thus modulating into myofibroblasts, has open a new perspective in the understanding of mechanisms leading to wound closure and fibrocontractive diseases. Myofibroblasts synthesize extracellular matrix components such as collagen types I and III and during normal wound healing disappear by apoptosis when epithelialization occurs. The transition from fibroblasts to myofibroblasts is influenced by mechanical stress, TGF-beta and cellular fibronectin (ED-A splice variant). These factors also play important roles in the development of fibrocontractive changes, such as those observed in liver cirrhosis, renal fibrosis, and stroma reaction to epithelial tumours.
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PMID:The myofibroblast in wound healing and fibrocontractive diseases. 1284 17

Previous studies have showed that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of liver cirrhosis. The localization of angiotensin II receptor in hepatic stellate cells opens up a new research direction of RAS in the regulation of liver fibrosis. However, the potential role of angiotensin II on Kupffer cells remains unexplored. As Kupffer cells are actively involved in the fibrotic process, the present study aimed, specifically, to demonstrate the presence of key RAS components, with particular reference to the AT(1) receptor, and its potential role in hepatic Kupffer cells. The expression of key RAS components in rat liver and isolated hepatic Kupffer cells was analyzed by RT-PCR. The expression and precise localization of AT(1) receptors in hepatic Kupffer cells were investigated by Western blot analysis and immunofluorescent double staining, respectively. The effect of angiotensin-stimulated Kupffer cells on the expression of the fibrogenic factors, i.e. transforming growth factor-beta (TGF-beta) and fibronectin, was examined by semi-quantitative RT-PCR. RT-PCR analysis showed that mRNA of several key RAS components-angiotensin II receptors, angiotensinogen, renin and angiotensin-converting enzyme, particularly the AT(1) receptors, was expressed in the liver and isolated hepatic Kupffer cells. The AT(1) receptor protein was consistently expressed in hepatic Kupffer cells as evidenced by Western blot analysis. Double immunostaining confirmed that the AT(1) receptors were specifically localized to the Kupffer cells from the liver and isolated hepatic Kupffer cells. On the other hand, angiotensin II stimulated mRNA expression of TGF-beta and fibronectin, which could be inhibitable by saralasin and losartan, the nonselective and specific antagonists for AT(1) receptors, respectively. The present findings clearly demonstrated the expression, localization and potential role of local RAS components with particular emphasis on the AT(1) receptors in hepatic Kupffer cells. The intimate interaction of angiotensin II with its AT(1) receptor located in the Kupffer cells and its fibrogenic action may represent a regulatory mechanism in the development of liver fibrosis such as inflammation and cirrhosis.
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PMID:Expression and localization of AT1 receptors in hepatic Kupffer cells: its potential role in regulating a fibrogenic response. 1459 16

Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is accompanied by inflammation and fibrosis eventually leading to cirrhosis. The chemokine CXCL12 is involved in chronic inflammatory conditions. The role of the CXCL12/CXCR4 pathway in HCV- and HBV-associated liver inflammation and fibrosis was therefore studied. The levels and tissue localization of CXCL12 in liver and plasma of HCV and HBV patients were tested using immunohistochemistry and ELISA. The expression and function of CXCR4 on liver-infiltrating lymphocytes (LIL) were tested by FACS and transwell migration assays. We found that CXCL12 is expressed by bile duct epithelial cells in normal liver tissue. Bile duct proliferation and liver fibrosis in chronic HCV and HBV infection result in the anatomical re-distribution of CXCL12 in the liver. Moreover, CXCL12 is up-regulated in the endothelium of neo-blood-vessels formed in active inflammatory foci and is significantly elevated, compared with controls, in the plasma of patients with advanced liver fibrosis. Complementing these observations were others indicating that over 50% of LIL express CXCR4 and, in response to CXCL12, migrated and adhered to fibronectin. These observations suggest an important role for the CXCL12/CXCR4 pathway in recruitment and retention of immune cells in the liver during chronic HCV and HBV infection.
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PMID:Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus. 1504 28

The development of fibrosis and cirrhosis during chronic hepatitis B virus (HBV) infection correlates with the persistent expression of HBV x antigen (HBxAg), which acts in part, by stimulating selected signal transduction pathways, including nuclear factor kappa B (NF-kappa B). To identify NF-kappa B responsive genes that are differentially expressed in HBxAg-positive cells, HepG2 cells were stably transfected with HBxAg, and then with pZeoSV2 or pZeoSV2-I kappa B alpha. When RNAs from each culture were compared by PCR-select cDNA subtraction, fibronectin (FN) mRNA was shown to be strongly down-regulated by I kappa B alpha. Up-regulated expression of FN and co-expression between FN and HBxAg were observed in liver sections from HBV carriers that were stained for HBxAg and analysed for FN mRNA by in situ hybridization (ISH). In liver cell cultures, HBxAg increased the levels of FN mRNA and protein. This was because of the HBxAg-mediated trans-activation of the FN promoter, which was NF-kappa B-dependent. HBxAg also antagonized the repression of the FN promoter by the tumour suppressor, p53. Hence, the FN gene may be a natural target for HBxAg trans-activation, perhaps through activation of NF-kappa B and inactivation of p53, thereby contributing to the accumulation of FN in the liver over the course of chronic HBV infection.
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PMID:Activation of fibronectin gene expression by hepatitis B virus x antigen. 1523 Aug 56

Liver cirrhosis is caused by a relative imbalance between synthesis and degradation of collagens. Arg-Gly-Asp (RGD) peptide is a major adhesive domain of several extracellular matrix (ECM) components, such as that involved in the binding of fibronectin to the alpha5beta1 integrin receptor. We previously reported that RGD peptide increased the expression of matrix metalloproteinase in hepatic stellate cells (HSCs) which play a major role in hepatic fibrosis. We evaluated whether RGD-peptides inhibit the progression of liver fibrosis in an animal model of carbon tetrachloride-induced hepatotoxicity. RGD peptide (GRGDS) (1 mg/kg body weight) was injected intraperitoneally (i.p.) 3 times a week for one month. The group treated with control peptide (GRGES) showed pathologically typical hepatic fibrosis, while the RGD-treated group showed minimal fibrotic changes. The liver contents of collagen and hydroxyproline in the RGD-treated group was significantly lower than that of the control group. Collagenase activity measured in liver homogenates was significantly higher in the treated group than in the control group. In an in vitro study using TWNT-4 cells derived from human HSCs, RGD peptide (100 mug/ml) reduced the expression of type I collagen and tissue inhibitor of matrix metalloproteinase-1, and increased that of matrix metalloproteinase-1. These results indicated that RGD peptides inhibited liver fibrosis associated with both decreased collagen production and increased collagenase acitivity, and suggested that RGD peptide might be useful for the therapy of hepatic fibrosis.
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PMID:Arg-Gly-Asp (RGD) peptide ameliorates carbon tetrachloride-induced liver fibrosis via inhibition of collagen production and acceleration of collagenase activity. 1554 72

Liver fibrosis is the end result of an imbalance between synthesis and degradation of extracellular matrix proteins of the liver. The extracellular matrix of the liver is complex. It comprises multiple components of three major types of macromolecules: proteins, glycoproteins and proteoglycans. The normal liver contains limited amounts of extracellular matrix composed of elastin, fibronectin, collagen, proteoglycans and other macromolecules. These molecules have specific structure-function properties. In the liver they provide a structural framework and modulate tissue repair. The fibrogenesis is a reaction to liver injury, it leads to marked impairment of hepatic sinusoidal blood flow and ultimately to cirrhosis associated with portal hypertension and hepatocyte dysfunction. The process of fibrosis is the result from complex interactions between extracellular matrix macromolecules, hepatic cells, cytokines and growth factors, that activate the stellate cells of the liver to induce the synthesis of extracellular matrix components that deposit into the local extracellular matrix and to produce the inhibitor of metalloproteinase. The end result of these activities is an imbalance in the synthesis/degradation homeostasis of the liver, that is, liver fibrosis.
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PMID:[The physiopathological mechanism of hepatic fibrosis]. 1649 97

Hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells in liver fibrogenesis. The excessive synthesis of ECM proteins deteriorates hepatic architecture and results in liver fibrosis and cirrhosis. This study investigated the role of bone morphogenetic protein 7 (BMP7) as a member of the transforming growth factor (TGF)-beta superfamily in chronic liver disease. Plasma levels of BMP7 were significantly elevated in patients with chronic liver disease compared with healthy controls. Immunohistochemistry of cirrhotic human liver demonstrated upregulated BMP7 protein expression in hepatocytes as compared with normal human liver. Because gene expression for all putative BMP7 receptors was induced during the culture activation process of primary human HSCs, we studied the effects of BMP7 on hTERT immortalized human HSCs in vitro. BMP7, as expressed and secreted after infection with adenoviruses encoding BMP7 (AdBMP7), increased proliferation of HSCs. The mRNA and protein expression of type I collagen and fibronectin was increased in BMP7-stimulated HSCs. Elevated systemic and hepatic levels of BMP7 in patients with chronic liver disease may contribute to progression of liver fibrogenesis in vivo.
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PMID:Bone morphogenetic protein 7 is elevated in patients with chronic liver disease and exerts fibrogenic effects on human hepatic stellate cells. 1741 33

Liver fibrosis and cirrhosis are common sequelae to diverse liver injuries in the tropics or Nigeria. The development of hepatic fibrosis or cirrhosis is due to increased synthesis, deposition, and possibly reduced degradation of hepatic extracellular matrix components, especially collagens, such as interstitial type I and III, basement membrane type IV, microfibrillar type VI, and pericellular type V, non-collagenous proteins, such as laminin, fibronectin, undulin, etc., and various types of proteoglycans, such as hyaluronan, etc. In Nigeria, the common approach for diagnosing or assessing the activity of connective tissue in this organ is the histological examination of a biopsy, if one is performed by a specialist physician. The liver biopsy provides a static picture of the changes that have already taken place in the liver. Another possible method is (where the facilities are available) a quantitative assessment of the liver biopsy by biochemical determination of total collagen via hydroxyproline. Biopsy is an invasive method and cannot be repeated often enough in the bid to ensuring an intensive follow-up of the changes taking place during the course of antifibrotic treatment or therapy. Thus, serum or other biological fluid assays for connective tissue proteins, such as the aminoterminal propeptide of type III Procollagen PIIINP, or the dimeric carboxyterminal domain of type IV collagen known as NCl or PIVCP, laminin, and others are essentially non-invasive and can be carried out repeatedly. In addition, the measurement of certain enzymes of connective tissue proteins in serum may the reflect activity of liver fibrogenesis. They offer the potential for diagnosis and therapeutic control. However, it is very important to note that circulating biochemical markers of fibrogenesis, fibrolysis or both may not reflect hepatic fibrosis or cirrhosis, since they are not liver-specific. Thus, the best diagnostic approach would be the identification and measurement in serum of the driving force of fibrogenic process.
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PMID:Biochemical markers, extracellular components in liver fibrosis and cirrhosis. 1768 72

Embryonic stem cell-derived endoderm is critical for the development of cellular therapies for the treatment of disease such as diabetes, liver cirrhosis, or pulmonary emphysema. Here, we describe a novel approach to induce endoderm from mouse embryonic stem (mES) cells using fibronectin-coated collagen gels. This technique results in a homogeneous endoderm-like cell population, demonstrating endoderm-specific gene and protein expression, which remains committed following in vivo transplantation. In this system, activin, normally an endoderm inducer, caused an 80% decrease in the Foxa2-positive endoderm fraction, whereas follistatin increased the Foxa2-positive endoderm fraction to 78%. Our work suggests that activin delays the induction of endoderm through its transient precursors, the epiblast and mesendoderm. Long-term differentiation displays a twofold reduction in hepatic gene expression and threefold reduction in hepatic protein expression of activin-treated cells compared with follistatin-treated cells. Moreover, subcutaneous transplantation of activin-treated cells in a syngeneic mouse generated a heterogeneous teratoma-like mass, suggesting that these were a more primitive population. In contrast, follistatin-treated cells resulted in an encapsulated epithelial-like mass, suggesting that these cells remained committed to the endoderm lineage. In conclusion, we demonstrate a novel technique to induce the direct differentiation of endoderm from mES cells without cell sorting. In addition, our work suggests a new role for activin in induction of the precursors to endoderm and a new endoderm-enrichment technique using follistatin.
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PMID:Activin alters the kinetics of endoderm induction in embryonic stem cells cultured on collagen gels. 1806 98

Under most circumstances, hepatitis B virus (HBV) is noncytopathic. However, hepatocellular regeneration that accompanies each bout of hepatitis appears to be associated with increased integration of HBV DNA fragments expressing the virus encoded hepatitis B x antigen (HBxAg). Intrahepatic HBxAg staining correlates with the intensity and progression of chronic liver disease (CLD), and additional work has shown that HBxAg blocks immune mediated killing by Fas and by tumor necrosis factor alpha (TNFalpha). This is not only associated with the blockage of caspase activities by HBxAg, but also by the constitutive stimulation of hepatoprotective pathways, such as nuclear factor kappa B (NF-kappaB), phosphoinositol 3-kinase (PI3K), and beta-catenin (beta-catenin). HBxAg also appears to promote fibrogenesis, by stimulating the production of fibronectin. HBxAg also stimulates the production and activity of transforming growth factor beta1 (TGFbeta1) by several mechanisms, thereby promoting the profibrogenic and tumorigenic properties of this important cytokine. In addition, HBxAg appears to remodel the extracellular matrix (ECM) by altering the expression of several matrix metalloproteinases (MMPs), which may promote tumor metastasis. Hence, HBxAg appears to promote chronic infection by preventing immune mediated apoptosis of infected hepatocytes, by promoting the establishment and persistence of fibrosis and cirrhosis preceding the development of HCC, and by promoting the remodeling of EMC during tumor progression.
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PMID:Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver disease. 1920 Oct 80


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