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)

Fat storing-(Ito-)cells (FSC) transform into a myofibroblast-like cell type during liver fibrogenesis. A similar development can be observed in cell culture. At the moment, a definite marker to differentiate transformed FSC from smooth muscle cells (SMC) is not available. We recently found that FSC, SMC and skin fibroblasts (SF) synthesize tenascin, a novel matrix protein. As it is reported that various tissues express different tenascin forms by the mechanism of alternative pre-mRNA splicing, we analyzed the tenascin transcripts in these cell types. Total RNA extracted from cultured FSC, SMC and SF, analyzed by Northern blot hybridization, showed a 7.2 kb transcript in FSC, a 8.7 kb mRNA in SMC, whereas SF produced both messages. As the splicing pattern of FSC in primary culture did not change after passaging, this differential expression of tenascin mRNA might provide a tool to identify myofibroblast-like cells derived from FSC. The important fibrogenic mediator transforming growth factor-beta (TGF-beta) increased tenascin gene expression in each cell type. In SMC, TGF-beta additionally induced the production of the 7.2 kb transcript. Determination of tenascin transcripts will allow to examine the purity of FSC cultures and facilitate a better identification of the cells involved in liver fibrosis.
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PMID:Alternative splicing products of the tenascin gene distinguish rat liver fat storing cells from arterial smooth muscle cells and skin fibroblasts. 137 92

Transforming growth factor-beta 1 is an important cytokine in the pathophysiology of liver fibrosis, stimulating the production of extracellular matrix. Whether this cytokine can also control the degradation of matrix proteins in liver cells has not been investigated. Because plasmin is an important protease for the degradation of matrix glycoproteins, we investigated whether sinusoidal endothelial liver cells could contribute to fibrosing liver disease through the modulation of plasmin-generating enzymes in response to transforming growth factor-beta 1. Sinusoidal endothelial cells from guinea pig liver were investigated in pure monolayer culture. Using 125I-labelled transforming growth factor-beta, we demonstrated high-affinity binding sites on sinusoidal endothelial cells at a density of 9.3 x 10(2) per cell, and a dissociation constant of about 5.5 x 10(-11) mol/L. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the known three classes of membrane receptors for transforming growth factor-beta. Using biosynthetic labeling of proteins with 35S-methionine, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we showed that sinusoidal endothelial cells produce and secrete plasminogen activator inhibitor type 1 from the beginning of culture. Treatment of confluent cell cultures for 24 hr with transforming growth factor-beta 1 increased synthesis and release of plasminogen activator inhibitor type 1. The response was almost maximal at a concentration of 1 ng transforming growth factor-beta/ml and paralleled the increased synthesis of fibronectin. On reverse fibrin autography we proved that transforming growth factor-beta 1 stimulated the release of functionally active plasminogen activator inhibitor type 1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution of sinusoidal endothelial liver cells to liver fibrosis: expression of transforming growth factor-beta 1 receptors and modulation of plasmin-generating enzymes by transforming growth factor-beta 1. 840 70

Liver stellate cells (SCs) play central roles in both the storage of retinol and the development of liver fibrosis. The present study is aimed to understand the mechanism by which retinoic acid (RA, an active metabolite of retinol) enhances hepatic fibrosis in rats. We tested the effect of 9-cis-RA on several aspects in vitro rat SC cultures, including the activity of cellular plasminogen activator (PA), messenger RNA (mRNA), and protein levels of transforming growth factor-beta (TGF-beta) mRNA level of type-I procollagen, and the activity of type-I collagenase. Employing the rat liver fibrosis model produced by porcine serum, we also estimated the effect of oral administration of a stable RA analog on the progression of the fibrosis, as well as on hepatic TGF-beta contents. In vitro SC cultures, 9-cis-RA enhanced cellular PA and plasmin levels thereby induced plasmin-mediated activation of latent TGF-beta. Active TGF-beta generated self-stimulated its synthesis as well as that of collagen and suppressed the production of collagenase in an autocrine manner. In in vivo rat models, an RA analog accelerated the porcine serum-induced fibrosis by enhancing TGF-beta contents and, thus, collagen levels in the liver, although the RA analog alone was not fibrogenic. These results suggest that RA exacerbated liver fibrosis, at least in part, by inducing the activation and production of latent TGF-beta in liver SCs.
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PMID:Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-beta in liver stellate cells. 932 35

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

Cultured hepatic stellate cells (HSCs), the cell type primarily involved in the progression of liver fibrosis, secrete insulin-like growth factor-I (IGF-I) and IGF binding protein (IGFBP) activity. IGF-I exerts a mitogenic effect on HSCs, thus potentially contributing to the fibrogenic process in an autocrine fashion. However, IGF-I action is modulated by the presence of specific IGFBPs that may inhibit and/or enhance its biologic effects. Therefore, we examined IGFBP-1 through IGFBP-6 mRNA and protein expression in HSCs isolated from human liver and activated in culture. Regulation of IGFBPs in response to IGF-I and other polypeptide growth factors involved in the hepatic fibrogenic process was also assessed. RNase protection assays and ligand blot analysis demonstrated that HSCs express IGFBP-2 through IGFBP-6 mRNAs and release detectable levels of IGFBP-2 through IGFBP-5. Because IGF-I, platelet-derived growth factor-BB (PDGF-BB), and transforming growth factor-beta (TGF-beta) stimulate HSC proliferation and/or matrix production, we tested their effect on IGFBPs released by HSCs. IGF-I induced IGFBP-3 and IGFBP-5 proteins in a time-dependent manner without an increase in the corresponding mRNAs. IGFBP-4 protein levels decreased in response to IGF-I. TGF-beta stimulated IGFBP-3 mRNA and protein but decreased IGFBP-5 mRNA and protein. In contrast, PDGF-BB failed to regulate IGFBPs compared with controls. Recombinant human IGFBP-3 (rhIGFBP-3) was then tested for its effect on IGF-I-induced mitogenesis in HSCs. rhIGFBP-3 inhibited IGF-I-stimulated DNA synthesis in a dose-dependent manner, with a peak effect observed at 25 nM IGFBP-3. Because TGF-beta is highly expressed in cirrhotic liver tissue, we determined whether IGFBP-3 mRNA expression is increased in liver biopsies obtained from patients with an active fibroproliferative response due to viral-induced chronic active hepatitis. In the majority of these samples, IGFBP-3 mRNA was increased compared with normal controls. These findings indicate that human HSCs, in their activated phenotype, constitutively produce IGFBPs. IGF-I and TGF-beta differentially regulate IGFBP-3, IGFBP-4, and IGFBP-5 expression, which, in turn, may modulate the in vitro and in vivo action of IGF-I.
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PMID:Characterization and regulation of insulin-like growth factor binding proteins in human hepatic stellate cells. 942 10

Reactive oxygen species are implicated in the pathogenesis of several diseases, including Alzheimer's disease, multiple sclerosis, human immunodeficiency virus, and liver fibrosis. With respect to liver fibrosis, we have investigated differences in antioxidant enzymes expression in stellate cells (SCs) and parenchymal cells from normal and CCl(4)-treated rat livers. We observed an increase in the expression of catalase in activated SCs. Treatment with transforming growth factor-beta (TGF-beta) increased the production of H(2)O(2). Treatment with catalase decreased TGF-beta expression. Addition of H(2)O(2) resulted in increased TGF-beta production. 3-Amino-1,2,4-triazole abolished the capacity of SCs to remove H(2)O(2). A paradoxical increase in capacity was observed when the cells were pretreated with diethyl maleate. Treatment with 3-amino-1, 2,4-triazole increased TGF-beta production. A paradoxical decrease of TGF-beta production was observed with diethyl maleate. Treatment of the cells with N-acetylcysteine resulted in increased TGF-beta production. TGF-beta decreased the capacity of the SCs to remove H(2)O(2.) An increase in the capacity to remove H(2)O(2) was observed when TGF-beta was removed by neutralizing antibodies. In conclusion, our results suggest: 1) a link between cellular GSH levels and TGF-beta production and 2) that cellular GSH levels discriminate whether H(2)O(2) is the result of oxidative stress or acts as second messenger in the TGF-beta signal transduction pathway.
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PMID:Glutathione levels discriminate between oxidative stress and transforming growth factor-beta signaling in activated rat hepatic stellate cells. 1056 49

Hepatic fibrosis is a wound-healing process that occurs when the liver is injured chronically. Hepatic stellate cells (HSC) are responsible for the excess production of extracellular matrix (ECM) components. The activation of HSC, a key issue in the pathogenesis of hepatic fibrosis, is mediated by various cytokines and reactive oxygen species released from the damaged hepatocytes and activated Kupffer cells. Therefore, inhibition of HSC activation and its related subsequent events, such as increased production of ECM components and enhanced proliferation, are crucial goals for intervention in the hepatic fibrogenesis cascade. This is especially true when the etiology is unknown or there is no established therapy for the cause of the chronic injury. This review explores the rationale for choosing HSC as a target for the pharmacological, molecular, and other novel therapeutics for hepatic fibrosis. One focus of this review is the inhibition of two cytokines, transforming growth factor-beta and platelet-derived growth factor, which are important in hepatic fibrogenesis. A number of new agents, such as Chinese herbal recipes and herbal extracts, silymarin, S-adenosyl-L-methionine, polyenylphosphatidylcholine, and pentoxifylline are also discussed.
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PMID:Hepatic stellate cells: a target for the treatment of liver fibrosis. 1102 37

Redox-regulated processes are important elements in various cellular functions. Reducing agents, such as N-acetyl-l-cysteine (NAC), are known to regulate signal transduction and cell growth through their radical scavenging action. However, recent studies have shown that reactive oxygen species are not always involved in ligand-stimulated intracellular signaling. Here, we report a novel mechanism by which NAC blocks platelet-derived growth factor (PDGF)-induced signaling pathways in hepatic stellate cells, a fibrogenic player in the liver. Unlike in vascular smooth muscle cells, we found that reducing agents, including NAC, triggered extracellular proteolysis of PDGF receptor-beta, leading to desensitization of hepatic stellate cells toward PDGF-BB. This effect was mediated by secreted mature cathepsin B. In addition, type II transforming growth factor-beta receptor was also down-regulated. Furthermore, these events seemed to cause a dramatic improvement of rat liver fibrosis. These results indicated that redox processes impact the cell's response to growth factors by regulating the turnover of growth factor receptors and that "redox therapy" is promising for fibrosis-related disease.
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PMID:Regulation of cell growth by redox-mediated extracellular proteolysis of platelet-derived growth factor receptor beta. 1134 54

Pathobiological functions and metabolism of retinoids (vitamin A and its derivatives) in liver fibrosis and hepatocellular carcinoma (HCC) are discussed in the present review. Retinoic acid (RA, active metabolite) exacerbates liver fibrosis that is not accompanied by hepatic necroinflammation, in which RA acts directly on hepatic stellate cells (HSCs); RA enhances plasminogen activator/plasmin levels and thereby induces proteolytic activation of latent transforming growth factor-beta (TGF-beta), a strong fibrogenic cytokine, resulting in enhanced collagen production. We have developed a protease inhibitor, camostat mesilate, that suppresses TGF-beta activation and thereby inhibits the transformation of HSCs, leading to reduced matrix production by the cells. The compound is effective not only in preventing but also in reducing hepatic fibrosis in rats when administered orally. HCC is refractory to RA due to its local depletion in the tumors and also due to malfunction of its nuclear receptor, retinoid X receptor-alpha (RXRalpha) Oral supplementation of a synthetic retinoid named acyclic retinoid led to the disappearance of serum lectin-reactive alpha-fetoprotein (AFP-L3) and subsequently suppressed posttherapeutic recurrence of HCC in cirrhotic patients. These results suggest eradication of AFP-L3-producing latent malignant clones from the liver by the retinoid. We propose the concept of "clonal deletion" therapy for cancer chemoprevention, a new category of cancer chemotherapy.
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PMID:Retinoids in liver fibrosis and cancer. 1177 8

Biliary type liver fibrosis develops as part of the wound healing response to bile duct injury in chronic cholestatic liver diseases. The origin of myofibroblasts accumulating together with extracellular matrix around proliferating bile duct structures (referred to as ductular reaction) in the setting of cholestatic injury, has been investigated mostly in the rat bile duct ligation model. Evidence indicates that hepatic stellate cells undergo a myofibroblastic transition following bile duct ligation and that myofibroblastic hepatic stellate cells disclose chemoattraction towards bile duct structures in cholestatic liver. On the basis of morphological studies, nevertheless, the origin of peribiliary myofibroblasts has also been attributed to the activation and proliferation of portal fibroblasts. Bile duct epithelial cells of the ductular reaction actively contribute to the promotion and regulation of biliary type liver fibrogenesis. They synthesize and release a number of paracrine mediators such as transforming growth factor-beta, connective tissue growth factor, platelet-derived growth factor-BB, and endothelin-1 that target different liver cell types, including hepatic stellate cells and portal fibroblasts. Through these interactions, bile duct epithelial cells and peribiliary myofibroblasts cause periportal fibrosis in cholestatic and also probably other types of liver diseases.
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PMID:Peribiliary myofibroblasts in biliary type liver fibrosis. 1181 89


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