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)

Hepatocarcinogenesis is closely related to hepatic fibrosis. In this study, we investigated the relationship of type II transforming growth factor-beta receptor (T beta RII) to hepatic fibrosis and hepatocellular carcinoma (HCC). In vivo: liver tissues were obtained from 30 patients (10 chronic hepatitis, 7 cirrhosis, 13 HCC). Protein expression and immunolocalization of T beta RII were examined by Western blot analysis and immunohistochemistry. In vitro: T beta RII protein expression in hepatoma cell lines (HepG2, Hep3B, HLE, HLF and Huh7) was examined by Western blot analysis. Next, we transfected T beta RII cDNA to Huh7, and compared the change of cell number and observed the induction of apoptosis after TGF-beta1 treatment using a FACScan flow cytometer. In vivo: T beta RII immunolocalization in liver tissues was significantly decreased in patients with HCC compared with that of patients with chronic hepatitis or liver cirrhosis. In Western blot analysis, T beta RII expression in tissues attenuated in comparison with that in non-tumor tissues in some patients with HCC. In vitro: T beta RII protein expression in HLE, HLF and Huh7 cells was weaker than that in HepG2 and Hep3B cells. In Huh7 cells transfected T beta RII cDNA, cell arrest and apoptosis were obviously induced. These results indicated that human HCC has a reduced expression of T beta RII for TGF-beta1. This may provide a selective growth advantage to HCC to escape the inhibitory growth signals of TGF-beta1, and may be linked with critical steps in the growth of hepatoma cells.
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PMID:Relation of type II transforming growth factor-beta receptor to hepatic fibrosis and hepatocellular carcinoma. 1111 38

Cells termed myofibroblasts are prominent in the injury response of all epithelial tissues. They exhibit proliferation, migration, production of collagen and other extracellular matrix (ECM) molecules, and contraction, all for containing the injury and closing the wound. When the injury is limited in time, the final stage of the repair involves a dismantling of the cellular apparatus and restoration of normal tissue structure. With multiple cycles of repair, however, there is net accumulation of ECM, to the detriment of tissue structure and function. Repair-related ECM coalesces into fibrous bundles and, over time, undergoes changes that render it resistant to degradation. The result is a scar. In the skin, a scar may have cosmetic importance only. In the liver, however, extensive scarring is the setting for unregulated growth and neoplasia; also, fibrous bands disrupt normal blood flow, leading to portal hypertension and its complications. With regard to therapy for fibrosis, the first consideration is elimination of the injury factor. However, given that many liver diseases do not have effective therapies at present, strategies targeting fibrogenesis per se are under development. The main source of myofibroblast-like cells and ECM production in the liver is the perisinusoidal stellate cell, which responds to injury with a pleiotypic change termed activation. Activation is orchestrated by cytokines and the ECM itself. Among the cytokines involved in this process, transforming growth factor-beta (TGF-beta) is particularly prominent. The early changes in ECM include de novo production of a specific "fetal" isoform of fibronectin, which arises from sinusoidal endothelial cells. It is stimulated by TGF-beta and acts directly on stellate cells to promote their activation. Based on these and other advances in understanding the fundamentals of the injury response, several strategies now exist for altering fibrogenesis, ranging from agents that block TGF-beta to traditional Chinese herbal extracts. Arrest of fibrogenesis, even with underlying cirrhosis, is likely to extend life or prolong the time to transplant. Whether it reduces the risk of hepatocellular carcinoma remains to be proven. Although TGF-beta antagonists are effective anti-fibrogenic agents, they will require detailed safety testing because of the finding that several forms of epithelial neoplasia are associated with altered regulation of TGF-beta.
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PMID:Chronic liver injury, TGF-beta, and cancer. 1179 78

Smad expressions, signaling mediators of transforming growth factor-beta (TGF-beta) superfamily of cytokines, were investigated in paraffin-embedded tissue sections of liver cirrhosis due to the hepatitis C virus infection and in the hepatic stellate cell (HSC) line in vitro. Smad 2/3, 4 and 7 was expressed in the nucleus of the HSC in the cirrhotic liver, while the expression was weak in the non-cirrhotic liver. TGF-beta1 expression in the HSC of the cirrhotic liver was strong, while the expression was weak in the non-cirrhotic liver. In situ hybridization also demonstrated the Smad signalings in the HSC of the cirrhotic liver, which confirmed the results of the Smad expressions by immunohistochemistry. The HSC line showed a cytoplasmic and a weak nuclear expression of Smads without TGF-beta1 stimulation, while these cells showed a strong Smad expression in the nucleus by TGF-beta1 stimulation. Immunocytochemical assay demonstrated that the TGF-beta1 stimulation induced the increase of the Smad expressions and the decrease of the autocrine TGF-beta1 in the HSC line. In situ hybridization assay also demonstrated an increase of the Smad mRNA signalings by TGF-beta1 stimulation in vitro. These observations suggest that the Smad expressions increase in the nucleus of the HSC in the cirrhotic liver and that the TGF-beta1 stimulation induces the Smad expression.
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PMID:Smad expression of hepatic stellate cells in liver cirrhosis in vivo and hepatic stellate cell line in vitro. 1255 65

The capacity for the liver to regenerate after injury or resection has long been recognized, as implied by the legend of Prometheus. Resections of up to 70% of the liver are followed by a sequence of events that generally result in complete restitution of hepatic mass and function. Hypertrophy of hepatocytes begins within hours, with accumulation of amino acids and triglycerides and activation of enzymes that are associated with proliferative activity. Increased DNA synthesis is associated initially with hyperplasia of hepatocytes, and then other cells, which begins in the periportal region and spreads in a wave-like fashion to the pericentral region of the lobule. Quiescent hepatocytes are primed to enter the cell cycle and then proceed through the G1/S and G2/M restriction points, under the influence of a variety of proteins, growth factors (especially hepatocyte growth factor) and cycle dependent kinases. At each stage there is interplay between growth promoters and inhibitors, including transforming growth factor-beta and GABA. Factors that initiate hepatic regeneration are unknown, and might include hepatic depolarization, increases in blood flow, destruction of liver matrix (with release of growth factors), and increased production or expression of growth promoters compared to inhibitors. Regenerative activity increases with the amount of resection to a point, and then relatively declines. Uncontrolled proliferation of liver tissue after resection or injury is not necessarily beneficial, because it could lead to a diversion of resources from the maintenance of hepatic function and to an increased risk of neoplasia. Therefore, it is unclear whether clinicians should attempt to enhance hepatocyte regeneration. Since both hepatic regeneration and metabolic function require energy from high-energy nucleotide triphosphates, especially adenosine triphosphate (ATP), a reasonable strategy might be to augment energy delivery and ATP production. Mortality rates after limited (fewer than 70%) resections and mild or moderate injuries of previously normal livers are low, and supportive care is often sufficient. The prognosis is unclear; however, in cases of more massive resection, resections in the setting of underlying liver disease or cirrhosis, and fulminant hepatic failure, and liver transplantation is still an important option.
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PMID:Hepatic regeneration: If it ain't broke, don't fix it. 1291 14

Macrophage inflammatory peptide-1 (MIC-1)/growth/differentiation factor-15 (GDF-15) is a divergent member of the transforming growth factor-beta superfamily cloned by others and us. MIC-1/GDF-15 is expressed in the liver, breast, and colon. Studies have demonstrated a growth-inhibiting effect of MIC-1/GDF-15 on colon and breast cancer cell lines in vitro and on tumor growth in vivo. We previously reported that MIC-1 expression is rapidly induced after a wide variety of murine acute and chronic liver injuries including aniline dye administration. I hypothesized, therefore, that MIC-1/GDF-15 may be a mediator of biliary tract injury and could play a role in regulation of bile duct proliferation. C57BL/6 mice underwent surgical ligation of the common bile duct. Northern blot analysis revealed a time-dependent induction of MIC-1/GDF-15 mRNA in the liver. In situ hybridization of liver sections for MIC-1/GDF-15 expression after bile duct ligation demonstrated a zone 1 or periportal expression pattern, consistent with expression of MIC-1 in periductular hepatocytes. Northern blot analysis of liver mRNA from patients with sclerosing cholangitis or cirrhosis also demonstrated enhanced expression of MIC-1/GDF-15. MIC-1/GDF-15 is expressed after bile duct injury in mice and humans. Taken together with the previously demonstrated growth inhibitory effects of MIC-1/GDF-15 on normal and transformed cells, MIC-1/GDF-15 may play a role in regulation of bile duct proliferation and biliary tumor formation.
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PMID:Induction of MIC-1/growth differentiation factor-15 following bile duct injury. 1459 65

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

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States for which there is no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentration levels of TNF-alpha and TNF-alpha-inducible cytokines/chemokines, such as IL-6, -8, and -18, have been reported in patients with alcoholic hepatitis and/or cirrhosis, and levels correlated with markers of the acute phase response, liver function, and clinical outcome. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. Cytokines, such as transforming growth factor-beta, play a critical role in the fibrosis of ALD. Multiple new strategies are under investigation to modulate cytokine metabolism as a form of therapy for ALD.
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PMID:Recent advances in alcoholic liver disease. IV. Dysregulated cytokine metabolism in alcoholic liver disease. 1533 49

Tetrathiomolybdate, an anticopper drug, has been shown to protect mice against pulmonary fibrosis from bleomycin. Our hypothesis is that it does so by inhibiting fibrosis-inducing cytokines. Indeed, we have good evidence, not yet published, that tetrathiomolybdate inhibits pulmonary levels of transforming growth factor-beta and tumor necrosis factor-alpha expression in these bleomycin experiments. Herein, we evaluate tetrathiomolybdate's effectiveness in mitigating hepatitis and fibrosis in mice from the hepatotoxins, concanavalin A and carbon tetrachloride, and its inhibition of cytokines as a possible mechanism. In short-term experiments, concanavalin A elevated serum amino leucine transferase levels several fold, and tetrathiomolybdate completely prevented this increase. In additional experiments, tetrathiomolybdate therapy reversed the elevated serum transaminase levels despite continued concanavalin A injections, with nearly significant serum interleukin-1beta inhibition. Concanavalin A given for 12 weeks produced mild fibrosis, whereas concomitant tetrathiomolybdate treatment resulted in normal histology. Carbon tetrachloride given for 12 weeks resulted in very high serum amino leucine transferase levels, high serum transforming growth factor-beta levels, cirrhosis as seen histologically, and increase in liver hydroxyproline, a measure of fibrosis. Concomitant tetrathiomolybdate partially and significantly protected against increases in amino leucine transferase and transforming growth factor-beta, fully protected against the increase in hydroxyproline, and resulted in normal histology. In conclusion, tetrathiomolybdate protects against the hepatitis and fibrosis produced by these hepatotoxins, probably by inhibiting the excessive increase in inflammatory and fibrotic cytokines.
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PMID:Tetrathiomolybdate therapy protects against concanavalin a and carbon tetrachloride hepatic damage in mice. 1533 42

Hepatitis C virus (HCV) is one of the major causative agents of liver diseases, such as liver inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Using an efficient HCV subgenomic replicon system, we demonstrate that transforming growth factor-beta (TGF-beta) suppresses viral RNA replication and protein expression from the HCV replicon. We further show that the anti-viral effect of this cytokine is associated with cellular growth arrest in a manner dependent on Smad signaling, not mitogen-activated protein kinase (MAPK) signaling. These results suggest a novel insight into the mechanisms of liver diseases caused by HCV.
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PMID:Suppression of hepatitis C virus replicon by TGF-beta. 1562 83

Liver fibrosis and cirrhosis involve multiple cellular and molecular events that lead to deposition of an excess of extracellular matrix proteins and increase the distortion of normal liver architecture. Etiologies include chronic viral hepatitis, alcohol abuse and drug toxicity. Degradation of these matrix proteins occurs predominantly as a result of a family of enzymes called metalloproteases (MMPs) that specifically degrade collagenous and non-collagenous substrates. Matrix degradation in the liver is due to the action of at least four of these enzymes: MMP-1, MMP-2, MMP-3 and MMP-9. In the fibrinolytic system, MMPs can be activated through proteolytic cleavage by the action of urokinase plasminogen activator; a second mechanism includes the same metalloproteases. This activity is regulated at many levels in the fibrinolytic system. The main regulator is the PAI-1. This molecule blocks the conversion of plasminogen into plasmin, and the MMP cannot be activated. At a second level, the inhibition is possible by binding to inhibitors called TIMP that can inhibit the proteolitic activity even when the MMPs had been previously activated by plasmin. During abnormal conditions, overexpression of these inhibitors is directed by the transforming growth factor-beta that in a fibrotic disease acts as an extremely important adverse factor.
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PMID:[Hepatic fibrosis: role of matrix metalloproteases and TGFbeta]. 1616 29


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