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)

Processes that result in either normal peritoneal tissue repair of fibrous adhesion formation have until recently been largely unexplored at the molecular level. Our group is investigating the molecular events underlying peritoneal healing and hypothesizes that peptide growth factors, cytokines, and their receptors, which are expressed by various cell types at the site of injury and are present in the peritoneal fluid, play key roles in regulating tissue repair processes. This regulation is highly complex, involving the individual action of and/or synergistic interactions among many substances. These include various members of the growth factor family, such as transforming growth factors alpha and beta (TGF-alpha and TGF-beta), and of the cytokine family. These growth factors and cytokines are synthesized and released by activated macrophages in the peritoneal fluid and in the wound and by other major cell types in the wound, suggesting that they have a role in an autocrine/paracrine mechanism. For normal peritoneal healing to occur, the availability of these signaling substances must be optimal, precise, and synchronized. Inhibition, interruption, or excess expression of these signals seems to be responsible for failure in normal healing, either impairment (nonhealing) or excess tissue formation (adhesion development). Evidence of the key role of TGF-beta in peritoneal healing and adhesiogenesis falls into four main categories: 1) the characteristics of TGF-beta in other settings; 2) the presence and 3) activity of TGF-beta and/or its receptors in peritoneal wounds and fluid; and 4) the effects of the application of excess TGF-beta and anti-TGF-beta antibody on adhesion formation. TGF-betas are chemotactic for fibroblasts and inflammatory cells and promote cell proliferation and differentiation and angiogenesis. They also regulate the expression of various components of extracellular matrix. In mice, subcutaneous TGF-beta induces the formation of granulation tissue, and in several animal models and in humans, excess TGF-beta activity has been linked to the development of kidney and liver fibrosis. TGF-betas and their receptors are expressed by various cells in peritoneal wounds and fluid and are present at higher levels in injured compared with uninjured tissues. In vitro studies in peritoneal wounds and fluid show that TGF-beta 1 significantly upregulates its own expression and the expression of several extracellular matrix components and of tissue inhibitors of matrix metalloproteinases (TIMPs) but downregulates the expression of matrix metalloproteinases (MMPs). Following uterine horn injury, rats given TGF-beta daily for five days developed adhesions in significantly greater number and severity than did untreated controls. Although anti-TGF-beta neutralizing antibody in rats failed to significantly reduce adhesion formation, it did reduce cellularity of fibrous tissue. Antisense oligonucleotides to TGF-beta effectively blocked macrophage expression of TGF-beta, indicating the possible use of this technique in adhesion prevention. Another potential clinical application of some of our findings includes targeted delivery of an anti-TGF-beta preparation by means of a suitable biodegradable barrier during the first five to seven days following peritoneal injury.
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PMID:The role of growth factors in peritoneal healing: transforming growth factor beta (TGF-beta). 907 48

Activated hepatic stellate cells (HSC) participate in matrix remodeling and deposition in liver fibrosis. The present study demonstrates that interleukin (IL)-10 is expressed by HSC upon activation in vitro or in vivo and that autocrine effects of this cytokine include inhibition of collagen production. Culture activation of HSC caused a distinct increase in IL-10 mRNA level compared with freshly isolated quiescent HSC. Treatment of cultured HSC with tumor necrosis factor-alpha, transforming growth factor-beta, or lipopolysaccharide further increased IL-10 mRNA by 2-fold and resulted in the release of IL-10 protein into the medium. HSC isolated from rats after bile duct ligation (BDL) showed prominent increases in IL-10 mRNA (x 100) and protein (x 30) levels at 7 days after BDL, but such induction disappeared in advanced liver fibrosis (19 days after BDL). IL-10 expression correlated positively with mRNA expression of interstitial collagenase and inversely with that of alpha1(I) collagen. Addition of anti-IL-10 IgG to cultured HSC caused enhanced collagen production under a basal or stimulated condition with TGF-beta, tumor necrosis factor-alpha, or lipopolysaccharide. These effects were associated with increased alpha1(I) collagen mRNA and reciprocally reduced collagenase mRNA levels. Co-transfection of HSC with an IL-10 expression vector and collagen reporter genes showed a 40% inhibition of alpha1(I) collagen promoter activity. These results demonstrate that activation of HSC causes enhanced autocrine expression of IL-10 which possesses a negative autoregulatory effect on HSC collagen production mediated at least in part by alpha1(I) collagen transcriptional inhibition and stimulation of collagenase expression. These findings, along with the demonstrated early induction of HSC IL-10 expression and its late disappearance during biliary liver fibrosis, suggest its in vivo role in matrix remodeling and a possibility that failure for HSC to sustain IL-10 expression underlies pathologic progression to liver cirrhosis.
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PMID:Expression of interleukin-10 by in vitro and in vivo activated hepatic stellate cells. 941 80

Transforming growth factor (TGF)-beta 1 is an important cytokine involved in the pathobiology of tissue fibrosis through its stimulation of the production of, and inhibition of the degradation of, extracellular matrix proteins. We examined the clinical usefulness of plasma TGF-beta 1 concentration as a marker of fibrogenesis in patients with chronic viral hepatitis. Thirty-five patients, 11 with minimal chronic hepatitis, 14 with mild chronic hepatitis and 10 with moderate chronic hepatitis and 20 healthy subjects were studied. Transforming growth factor-beta 1 concentrations in platelet-poor plasma were measured with a TGF-beta 1 enzyme-linked immunosorbent assay system kit after acid-ethanol extraction. Plasma TGF-beta 1 levels were significantly elevated in patients with mild and moderate chronic hepatitis, but not in those with minimal chronic hepatitis, compared with the levels in the controls. Plasma TGF-beta 1 levels were increased in parallel with the histological degree of necroinflammation and of liver fibrosis. Plasma TGF-beta 1 levels were positively correlated with blood levels of procollagen type III N-peptide, and 7S fragment and central triple-helix of type IV collagen. These results suggest that plasma TGF-beta 1 level is a useful marker in assessing the situation of liver active fibrogenesis in patients with chronic viral hepatitis.
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PMID:Plasma transforming growth factor-beta 1 concentrations in patients with chronic viral hepatitis. 971 17

We eliminated type beta transforming growth factor (TGF-beta) signaling by adenovirus-mediated local expression of a dominant-negative type II TGF-beta receptor (AdCATbeta-TR) in the liver of rats treated with dimethylnitrosamine, a model of persistent liver fibrosis. In rats that received a single application of AdCATbeta-TR via the portal vein, liver fibrosis as assessed by histology and hydroxyproline content was markedly attenuated. All AdCATbeta-TR-treated rats remained alive, and their serum levels of hyaluronic acid and transaminases remained at low levels, whereas all the AdCATbeta-TR-untreated rats died of liver dysfunction. The results demonstrate that TGF-beta does play a central role in liver fibrogenesis and indicate clearly in a persistent fibrosis model that prevention of fibrosis by anti-TGF-beta intervention could be therapeutically useful.
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PMID:Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. 1005 44

Liver fibrosis is commonly observed in chronic liver disease. However, the immunological mechanisms underlying hepatic fibrosis due to chronic inflammation are not well defined, mainly because suitable experimental models have not been established. We have found that weekly i.v. administration of concanavalin A (Con A) in BALB/c mice brought about a striking alanine aminotransferase increase, resulting in piecemeal necrosis with bridging fibrosis in the parenchyma. Using this fibrosis model, we demonstrated the kinetics of cytokine mRNA expression in liver. Transforming growth factor (TGF)-beta1, TGF-alpha, basic fibroblast growth factor (bFGF) and hepatocyte growth factor mRNAs were up-regulated after each Con A administration. Furthermore, either anti-IFN-gamma, anti-tumor necrosis factor (TNF)-alpha or anti-TGF-beta mAb given together with Con A markedly inhibited the development of hepatic fibrosis. Treatment with either anti-IFN-gamma or anti-TNF-alpha mAb also completely prevented hepatic injury; in contrast, treatment with anti-TGF-beta mAb did not. The treatment with anti-TGF-beta mAb did not affect the levels of hepatic mRNAs for either IFN-gamma or TNF-alpha after Con A injection. Treatment with either anti-IFN-gamma or anti-TNF-alpha did not affect the expression levels of TGF-beta in the liver. In conclusion, the continuous presence of both severe liver damage and up-regulation of TGF-beta synthesis is necessary to induce hepatic fibrosis in this model.
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PMID:Immunopathogenesis of hepatic fibrosis in chronic liver injury induced by repeatedly administered concanavalin A. 1046 70

We demonstrated that local expression of a dominant-negative type II TGF-beta receptor prevents live fibrogenesis and dysfunction in dimethylnitrosamine-treated rats. Using the same model, we have now tested whether a soluble TGF-beta receptor expressed in skeletal muscle can effectively suppress TGF-beta signaling in a remote organ (the liver). We constructed an adenovirus expressing an entire ectodomain of human TGF-beta type II receptor fused to the Fc portion of human IgG (AdTbeta-ExR). This soluble receptor secreted from AdTbeta-ExR-infected cells bound TGF-beta and blocked TGF-beta-signaling in vitro. After intramuscular injection of AdTbeta-ExR in rats, the soluble receptor protein was detectable in the blood for at least 3 weeks. When such rats were treated with dimethylnitrosamine, liver fibrosis was markedly attenuated without apparent systemic or local side effects. The hepatic hydroxyproline content was reduced to a level indistinguishable from that achieved by local expression of the dominant-negative TGF-beta receptor. Since a qualitatively and quantitatively similar suppression was achieved by the two methods, it may be concluded that the new strategy can achieve a complete inhibition of TGF-beta signaling under pathophysiological conditions in vivo. This strategy should facilitate clarification of the role of TGF-beta in vivo in various organs where direct gene transfer seems to be difficult.
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PMID:A soluble transforming growth factor beta receptor expressed in muscle prevents liver fibrogenesis and dysfunction in rats. 1064 37

Hepatitis B, one of the most common infectious diseases in the world, is closely associated with acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Many clinical investigations have revealed that hepatic fibrosis is an important component of these liver diseases caused by chronic hepatitis B. TGF-beta signaling plays an important role in the pathogenesis of fibrosis in chronic hepatitis and cirrhosis. As these diseases are associated with hepatitis B virus (HBV) infection, we examined the possibility that the HBV-encoded pX oncoprotein regulates TGF-beta signaling. We show that pX enhances transcriptional activity in response to TGF-beta, BMP-2, and activin by stabilizing the complex of Smad4 with components of the basic transcriptional machinery. Additionally, confocal microscopic studies suggest that pX facilitates and potentiates the nuclear translocation of Smads, further enhancing TGF-beta signaling. Our studies suggest a new paradigm for amplification of Smad-mediated signaling by an oncoprotein and suggest that enhanced Smad-mediated signaling may contribute to HBV-associated liver fibrosis.
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PMID:The hepatitis B virus encoded oncoprotein pX amplifies TGF-beta family signaling through direct interaction with Smad4: potential mechanism of hepatitis B virus-induced liver fibrosis. 1123 Jan 53

Chronic diseases of the liver, pancreas, intestine, kidneys, skin and lungs are usually accompanied by scarring. Loss of organ function is often progressive despite the use of immunosuppressive, antiviral or antiinflammatory agents. Therefore, well tolerated antifibrotic therapies are urgently needed. The targets for such therapies are activated mesenchymal cells that synthesize an excess of matrix proteins and resemble the myofibroblasts of healing wounds. These cells derive from normally quiescent fibroblasts or smooth muscle cells and from stellate cells of liver and pancreas. Their activation is triggered and maintained by mechanical stress and several fibrogenic modulators and cytokines. Some agents inhibit myofibroblast proliferation and collagen synthesis in vitro, but only few of them are effective in vivo. Potential antifibrotic drugs have been tested mainly in models of liver fibrosis. In the suitable rat model of biliary fibrosis, an antifibrotic effect was demonstrated for silymarin, a defined mixture of flavonoids, and to a lesser degree for pentoxifylline. A spin-off of the large multicenter trials for hepatitis C is the finding that interferon-alpha given for 6-12 months may halt or reverse fibrosis, even in virological non-responders. This has to be proven in prospective randomized trials. Specific inhibitors of the endothelin-A-receptor which are orally available can suppress liver collagen accumulation by 40-60%. Other strategies aim at inhibition of the profibrogenic cytokines TGF-beta or connective tissue growth factor. Effective drug targeting to the fibrogenic liver cells is now possible by use of cyclic peptides that bind to receptors which are specifically upregulated on activated stellate cells. Blockade of such activation receptors can induce stress-relaxation which reverts the fibrogenic cells to a fibrolytic, collagen degrading phenotype. Fibrosis has been discovered as a novel target for the pharmaceutical industry. This implies the use of combinatorial chemistry and an automatized screening machinery, greatly speeding up the design and selection of specific antifibrotic agents. Combined with the rapidly evolving validation of serological markers of fibrogenesis and fibrolysis unforeseen progress in the treatment of organ fibrosis can be expected.
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PMID:Fibrosis of liver, pancreas and intestine: common mechanisms and clear targets? 1123 19

Decorin is a small extracellular matrix proteoglycan. It binds and modulates transforming growth factor (TGF)-beta 1 action, the major stimulator of fibrogenesis. Its role in the pathogenesis of human liver cirrhosis is unknown. Therefore, we studied the relationship of the 2 proteins in normal human liver and in 43 chronic hepatitis and liver cirrhosis specimens. To understand the mechanism that maintains matrix deposition in stage IV hepatitis, we studied expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, as well as the activities of type IV collagenases. Gene expression was analyzed on messenger RNA and protein level by morphologic and biochemical approaches. Decorin proved to be an early marker of fibrogenesis, and its deposition increased parallel to that of TGF-beta 1 and to inflammatory activity. Liver fibrosis progressed despite high temporospatial expression of decorin with TGF-beta 1. Neither decorin nor TGF-beta 1 protein deposition increased further in cirrhosis with low inflammatory activity, suggesting that impaired extracellular matrix catabolism rather than active production plays a role in this stage. This possibility was supported by high message levels of metalloproteinase inhibitors, no 72-kd collagenase activities, and low 92-kd collagenase activities.
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PMID:Expression of decorin, transforming growth factor-beta 1, tissue inhibitor metalloproteinase 1 and 2, and type IV collagenases in chronic hepatitis. 1134 37

Biliary atresia is a unique disorder in pediatric surgery. The incidence is 1 in 3,500 to 20,000 live births, but the disorder accounts for more than half of the patients requiring liver transplantation. After Kasai operation, the 5- and 10-year survival rate without the need of transplantation are 37-48% and 18-28%, respectively. An infectious pathogen, particularly the virus, has long been implicated as the causative agent of biliary atresia, but none has ever been identified. Ductal plate malformation is likely to be important in the pathogenesis of biliary atresia. Earlier diagnosis is associated with a better prognosis and biliary atresia should be considered in the differential diagnosis of prolonged jaundice in any infants older than 2 weeks of age. The experience of the surgeon and surgical decade are determinant in achieving success of the Kasai operation. Postoperative cholangitis affects more than 45% of the patients receiving Kasai operation and the afflicted patients are at risk of cessation of bile flow and exacerbation of preexisting liver cirrhosis. Hepatic fibrosis starts at the moment when biliary atresia develops and the ongoing inflammation will end up with liver cirrhosis and hepatic failure in most patients, including some with adequate bile drainage. The inhibition of liver cirrhosis in mice or rats by gene therapy, such as telomere gene delivery, transduction with the hepatocyte growth factor gene or blockade of TGF-beta signaling, may provide a new strategy to rejuvenate the ailing liver associated with biliary atresia in the future.
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PMID:Biliary atresia at the dawn of a new century. 1141 79


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