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)

Liver disease causes significant morbidity and mortality from multilobular cirrhosis in patients with cystic fibrosis. Abnormal bile transport and biliary fibrosis implicate abnormal biliary physiology in the pathogenesis of cystic fibrosis-associated liver disease (CFLD), yet the mediators linking biliary events to fibrosis remain unknown. Activated hepatic stellate cells (HSCs) are the pre-eminent mediators of fibrosis in a range of hepatic disorders. The dominant stimulus for matrix production by HSCs is the cytokine transforming growth factor (TGF)-beta(1). In CFLD, the role of HSCs and the source of TGF-beta(1) have not been evaluated. Liver biopsy tissue obtained from 38 children with CFLD was analyzed. Activated HSCs, identified by co-localization of procollagen alpha(1)(I) mRNA and alpha-smooth muscle actin, were demonstrated as the cellular source of excess collagen production in the fibrosis surrounding the bile ducts and the advancing edge of scar tissue. TGF-beta protein and TGF-beta(1) mRNA expression were shown to be predominantly expressed by bile duct epithelial cells. TGF-beta(1) expression was significantly correlated with both hepatic fibrosis and the percentage of portal tracts showing histological abnormalities associated with CFLD. This study demonstrates a definitive role for HSCs in fibrogenesis associated with CFLD and establishes a potential mechanism for the induction of HSC collagen gene expression through the production of TGF-beta(1) by bile duct epithelial cells.
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PMID:The role of hepatic stellate cells and transforming growth factor-beta(1) in cystic fibrosis liver disease. 1200 Jul 22

Hepatocyte growth factor (HGF) was purified as a potent mitogen for rat hepatocytes in primary culture and is believed to be the most physiological hepatotrophic factor that triggers liver regeneration. HGF is one of the largest disulfide-linked cytokines, consisting of a 60-kDa heavy chain and a 35-kDa light chain. Human HGF is synthesized as a single polypeptide chain precursor of 728 amino acid residues that has an appreciable homology with plasminogen, and it is processed proteolytically to release an N-terminal signal peptide of 31 amino acids and to generate an active heterodimer after secretion. The novel serine protease HGF activator and urokinase-type plasminogen activator (u-PA) are responsible for the latter extracellular processing. HGF stimulates the proliferation of rat hepatocytes in primary culture at concentrations as low as 10 pM. It also stimulates the growth of various epithelial cells, endothelial cells, and some kinds of mesenchymal cells. HGF inhibits the proliferation of several tumor cell lines and induces apoptosis of some of them. It also has motogenic, morphogenic, anti-apoptotic, angiogenic, and immunoregulatory activities. The receptor of HGF is the product of c-met proto-oncogene with tyrosine kinase activity that mediates the transduction of multiple biological signals of HGF. During liver regeneration, HGF gene expression in the liver, spleen, and lung and HGF levels in the blood and liver increase prior to the induction of liver DNA synthesis. Liver regeneration is markedly inhibited by continuous administration of a neutralizing anti-HGF antibody. HGF production in cultured cells is induced by PKC-activating agents, cAMP-elevating agents, PKA-activating agents, growth factors, and inflammatory cytokines; and it is inhibited by TGF-beta, glucocorticoids, 1,25-dihydroxyvitamin D3, and retinoic acid. There are many reports on potential application of HGF as a therapeutic agent for organ diseases that are difficult to cure such as liver cirrhosis, chronic renal failure, pulmonary fibrosis, myocardial infarction, and arteriosclerosis obliterans utilizing its potent growth-stimulating activity for a wide variety of cells. ELISA kits for assays of serum and plasma HGF levels are clinically used to prognosticate the development of fulminant hepatic failure.
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PMID:[Function and regulation of production of hepatocyte growth factor (HGF)]. 1206 Nov 40

Patients with hepatitis C virus (HCV) related-liver cirrhosis (LC) often develop hepatoma. The type 1 helper T cell (Th1) response presents an antitumor effect. We evaluated the Th1 response in patients with HCV-related LC at the single-cell level and examined the influence of transforming growth factor (TGF)-beta, an immunosuppressive cytokine, on the Th1 response. We determined the ratios of Th1-type cytokine (IFN-gamma, IL-2)-producing cells to CD3-positive cells in 14 patients (LC group) and in 16 normal controls using flow cytometry and measured serum TGF-beta(1) and TGF-beta(2) levels by ELISA. We then incubated, peripheral blood mononuclear cells from seven healthy volunteers with recombinant TGF-beta(1) or TGF-beta(2) for 48 h, and determined the ratio of IFN-gamma producing cells to CD3-positive cells. The IFN-gamma ratio was significantly lower in the LC group (29.7+/-0.3 vs. 44.2+/-15.0%, P<0.01). The serum TGF-beta(2) level was significantly increased in the LC group (601+/-232 vs. 329+/-118 pg/ml, P<0.001). TGF-beta(2) significantly suppressed IFN-gamma production at the single-cell level (10.0+/-4.3 vs. 7.3+/-2.0%, P<0.05). These findings indicated that the enhanced down-regulation of Th1 by TGF-beta(2) in patients with HCV-related LC might be effective against hepatoma.
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PMID:Th1 down-regulation at the single-lymphocyte level in HCV-related liver cirrhosis and the effect of TGF-beta on Th1 response: possible implications for the development of hepatoma. 1239 30

Chronic hepatitis C progresses to cirrhosis within 20 years in an estimated 20-30% of patients, while running a relatively uneventful course in most others. Certain HCV proteins, such as core and NS5A, can induce derangement of lipid metabolism or alter signal transduction of infected hepatocytes which leads to the production of reactive oxygen radicals and profibrogenic mediators, in particular TGF-beta1. TGF-beta1 is the strongest known inducer of fibrogenesis in the effector cells of hepatic fibrosis, i.e. activated hepatic stellate cells and myofibroblasts. However, fibrogenesis proceeds only when additional profibrogenic stimuli are present, e.g. alcohol exposure, metabolic disorders such as non-alcoholic steatohepatitis, or coinfections with HIV or Schistosoma mansoni that skew the immune response towards a Th2 T cell reaction. Furthermore, profibrogenic polymorphisms in genes that are relevant during fibrogenesis have been disclosed. This knowledge will make it possible to identify those patients who are most likely to progress and who need antiviral or antifibrotic therapies most urgently. However, even the best available treatment, the combination of pegylated interferon and ribavirin, which is costly and fraught with side effects, eradicates HCV in only 50% of patients. While the suggestive antifibrotic effect of interferons (IF-gamma>alpha,beta), irrespective of viral elimination, has to be proven in randomised prospective studies, additional, well tolerated and cost-effective antifibrotic therapies have to be developed. The combination of cytokine strategies, e.g. inhibition of the key profibrogenic mediator TGF-beta, with other potential antifibrotic agents appears promising. Such adjunctive agents could be silymarin, sho-saiko-to, halofuginone, phosphodiesterase inhibitors, and endothelin-A-receptor or angiotensin antagonists. Furthermore, drug targeting to the fibrogenic effector cells appears feasible. Together with the evolving validation of serological markers of hepatic fibrogenesis and fibrolysis an effective and individualised treatment of liver fibrosis is anticipated.
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PMID:Hepatitis C and liver fibrosis. 1265 47

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

Fibrosis is the process accompanying majority of chronic diseases of liver, independent of etiological factor and leading to cirrhosis and hepatic failure. Monitoring fibrosis process by liver's biopsy is limited, so many attempts are undertaken to assess concentrations of definite proteins in blood, which could be easily accessible marker of intrahepatic process. It seems, that among others, determinations of blood concentration of aminoterminal propeptide of procollagen III--index of collagen's III synthesis and TGF-beta 1--cytokine of antiproliferative action and inhibiting hepatocytes' growth, yet inducing fibroblasts' growth and stimulating fibrosis process brings out such a possibility. The aim of the study was simultaneous determination of TGF-beta 1 and PIIINP concentration in blood of patients with chronic hepatitis B and C before interferone's therapy in comparison to healthy controls, assessment of the parameters in dependence on stage of liver fibrosis and determination of correlation between TGF-beta 1 and PIIINP. Studies were performed in 40 patients with chronic hepatitis B (CAH B) and 35 patients with chronic hepatitis C (CAH C). Significantly increased serum concentrations of TGF-beta 1 as PIIINP in both groups of patients (CAH B and CAH C; grading 2-3, staging 1-2) in comparison with control group was noted. Significant positive correlation of TGF-beta 1 and PIIINP serum concentrations in both groups of patients was observed. There was not significant changes in PIIINP serum levels in patients with hepatitis B and C in dependence on stage of liver fibrosis (staging 1 vs staging 2) but TGF-beta 1 serum levels was significantly increased in CAH B and C patients with higher stage of liver fibrosis process. On the base of obtained results, it seems that changes in TGF-beta 1 concentrations in blood reflect "grading" and "staging" and can be a marker of intensification of intrahepatic fibrosis process whereas PIIINP levels in blood have rather the relation with "grading".
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PMID:[Serum aminoterminal peptide of type III procollagen (PIIINP) and transforming growth factor-beta1 (TGF-beta1) levels in patients with chronic hepatitis B and C]. 1456 92

TGFbeta controls hepatocyte growth through cell cycle arrest and apoptosis, and resistance to TGFbeta is a mechanism of malignant transformation. The aim of this study was to assess differences in TGFbeta-mediated growth inhibition in normal and cirrhotic hepatocytes. Cirrhosis was induced in mice and normal and cirrhotic hepatocytes were isolated by collagenase perfusion and treated with or without TGFbeta (5 ng/ml). DNA synthesis, Smad protein expression, and DNA binding activity were determined. TGFbeta reduced DNA synthesis to a greater degree in normal hepatocytes than in cirrhotic hepatocytes (87% vs. 68%; p<0.05). Smad protein expression was decreased in cirrhotic hepatocytes and Smad 2/3/4 complex formation was suppressed. Furthermore, cirrhotic hepatocytes had decreased DNA binding activity at 120 min following TGFbeta treatment. In conclusion, decreased Smad protein expression may impair TGFbeta-mediated growth inhibition in cirrhotic hepatocytes.
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PMID:Cirrhotic hepatocytes exhibit decreased TGFbeta growth inhibition associated with downregulated Smad protein expression. 1469 24

The mechanisms that determine viral clearance or viral persistence in chronic viral hepatitis have yet to be identified. Recent advances in molecular genetics have permitted the detection of variations in immune response, often associated with polymorphism in the human genome. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virulence of microbial agents. Several recent advances concerning the influence of human genes in chronic viral hepatitis B and C are discussed in this article: a) the associations between human leukocyte antigen polymorphism and viral hepatic disease susceptibility or resistance; b) protective alleles influencing hepatitis B virus (HBV) and hepatitis C virus (HCV) evolution; c) prejudicial alleles influencing HBV and HCV; d) candidate genes associated with HBV and HCV evolution; d) other genetic factors that may contribute to chronic hepatitis C evolution (genes influencing hepatic stellate cells, TGF-beta 1 and TNF-alpha production, hepatic iron deposits and angiotensin II production, among others). Recent discoveries regarding genetic associations with chronic viral hepatitis may provide clues to understanding the development of end-stage complications such as cirrhosis or hepatocellular carcinoma. In the near future, analysis of the human genome will allow the elucidation of both the natural course of viral hepatitis and its response to therapy.
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PMID:The influence of the human genome on chronic viral hepatitis outcome. 1528 11

Cirrhosis, a pathological condition defined by deranged hepatic architecture resulting from progressive fibrosis, is the final common pathway through which nearly all chronic diseases of the liver produce morbidity and mortality. Historically, treatments for hepatic fibrosis have been directed against specific causes of chronic liver injury, and include corticosteroids for autoimmune hepatitis, interferon for hepatitis B and C, and iron depletion for haemochromatosis. However, there is no effective treatment for most causes of chronic liver disease. Fortunately, the past decade has witnessed great advances in our understanding of the fundamental pathophysiological mechanisms underlying fibrosis of the liver. It is now recognised that hepatic stellate cells (myofibroblast-like cells that encircle the sinusoids) are primarily responsible for hepatic fibrosis and subsequent progression to cirrhosis. In response to liver injury stellate cells undergo a phenotypic transformation that is termed activation, and characterised by chemotaxis, proliferation, contraction, fibrogenesis, and extracellular matrix degradation. Under conditions of persistent injury the behavioural responses of these stellate cells act in concert to bring about fibrosis of the liver. Recent investigations elucidating the signal transduction pathways that link hepatic injury to stellate cell function suggest novel targets at which treatment for fibrosis may be directed. For example, antagonism of TGF-beta receptor signaling has been shown to modulate fibrosis in animal models. This work, as well as other studies in both humans and animals, indicates that hepatic fibrosis may be slowed or reversed. These results suggest that a rational approach to treatment can be developed based on our detailed understanding of the molecular and cellular mechanisms underlying cirrhosis, which will have a major impact on the clinical management of patients with chronic liver disease.
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PMID:Cirrhosis--can we reverse hepatic fibrosis? 1614 8

Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver by a variety of etiological factors including viruses, alcohol and drug abuse, the metabolic syndrome, autoimmune disease and hereditary disorders of metabolism. Fibrosis is a progressive pathological process in which wound-healing myofibroblasts of the liver respond to injury by promoting replacement of the normal hepatic tissue with a scar-like matrix composed of cross-linked collagen. Until recently it was believed that this process was irreversible. However emerging experimental and clinical evidence is starting to show that even cirrhosis is potentially reversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of hepatic stellate cells (HSC) by apoptosis. Furthermore, proof-of-concept studies in rodents have demonstrated that experimental augmentation of HSC apoptosis will promote the resolution of fibrosis. Consequently there is now considerable interest in determining the molecular events that regulate HSC apoptosis and the discovery of drugs that will stimulate HSC apoptosis in a selective manner. This review will consider the regulatory role played by growth factors (e.g. NGF, IGF-1, TGFbeta), death receptor ligands (TRAIL, FAS), components and regulators of extracellular matrix (integrins, collagen, matrix metalloproteinases and their tissue inhibitors) and signal transduction proteins and transcription factors (Rho/Rho kinase, Jun N-terminal Kinase (JNK), IkappaKinase (IKK), NF-kappa B). The potential for known pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I to induce HSC apoptosis and therefore to be used therapeutically will be explored.
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PMID:The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. 1615 28


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