Expression of collagens type I and IV, osteonectin and transforming growth factor beta-1 (TGFβ1) in biliary atresia and paucity of intrahepatic bile ducts during infancy

Lamireau, T.; Bail, Brigitte Le; Boussarie, Liliane; Fabrè, Monique; Vergnes, P; Bernard, Olivier; Gautier, Frédéric; Bioulac‐Sage, Paulette; Rosenbaum, Jean

doi:10.1016/s0168-8278(99)80221-9

Cited by 45 publications

(29 citation statements)

References 23 publications

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“…In our model of cultured PCLS, processes depending on inflammation or biliary pressure cannot be involved; we thus propose that bile acid treatment induces biliary epithelial cell stimulation leading to portal fibroblast proliferation and activation. This is supported by previous results indicating that biliary epithelial cells synthesize a series of relevant cytokines such as monocyte chemotactic protein-1 (MCP-1), 39 PDGF, 12,40 transforming growth factor-b, 41,42 and connective tissue growth factor. 43 The expression of all these cytokines is increased in either experimental or human cholestatic diseases (for review, see 44 ).…”

Section: Bile Acids and Portal Fibrosissupporting

confidence: 86%

Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices

Clouzeau-Girard

Guyot

Combe

et al. 2006

Laboratory Investigation

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During cholestasis, bile acids accumulate in the liver, and induce cellular alterations. Cholestasis is a major cause of liver fibrosis. We have used precision-cut liver slices (PCLS) in culture to investigate the effects of bile acids on hepatic cells. Rat PCLS were placed on an insert in a vial containing culture medium, and gently agitated on a roller platform. PCLS were treated with 100 lM taurolithocholate (TLC), taurodeoxycholate (TDC) or taurocholate (TC) for 24 or 48 h. PCLS viability was measured, and immunohistochemistry was performed with antibodies against active caspase 3, platelet-derived growth factor (PDGF) receptor-b and ED-A fibronectin. TDC and TLC, two hydrophobic bile acids, induced hepatocyte necrosis and apoptosis, whereas TC, an hydrophilic bile acid, improved slice viability as compared with controls. Both TDC and TC induced biliary epithelial cell proliferation, together with portal fibroblast proliferation and activation, as shown by PDGF receptor-b and ED-A fibronectin expression. TLC induced biliary epithelial cell apoptosis. Our results indicate that individual bile acids induce cell type-specific effects in a complex liver microenvironment. The fact that PCLS support biliary epithelial cell and portal fibroblast proliferation will make this model very useful for the study of the mechanisms involved in portal fibrosis.

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Section: Bile Acids and Portal Fibrosissupporting

confidence: 86%

Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices

Clouzeau-Girard

Guyot

Combe

et al. 2006

Laboratory Investigation

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“…27 In chronic biliary diseases of childhood, the expression of proteins such as MCP-1, TGF-␤, and PDGF by ductal epithelial cells has been postulated to underlie the portal fibrosis that develops. 13,28,29 The ductular reaction occurring in submassive hepatic necrosis has also been shown to have increased expression of profibrogenic factors and to intimately localize with activated stellate cells or myofibroblasts. 30 This study does not prove that the ductular reaction directly promotes portal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis

et al. 2005

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The mechanisms for progressive fibrosis and exacerbation by steatosis in patients with chronic hepatitis C (HCV) are still unknown. We hypothesized that proliferative blockade in HCVinfected and steatotic hepatocytes results in the default activation of hepatic progenitor cells (HPC), capable of differentiating into both biliary and hepatocyte lineages, and that the resultant ductular reaction promotes portal fibrosis. To study this concept, 115 liver biopsy specimens from subjects with HCV were scored for steatosis, inflammation, and fibrosis. Biliary epithelium and HPC were decorated by cytokeratin 7 immunoperoxidase, and the replicative state of hepatocytes was assessed by p21 and Ki-67 immunohistochemistry. A ductular reaction at the portal interface was common. There was a highly significant correlation between the area of ductular reaction and fibrosis stage (r ‫؍‬ 0.453, P < .0001), which remained independently associated after multivariate analysis. HPC numbers also correlated with fibrosis (r ‫؍‬ 0.544, P < .0001) and the ductular area (r ‫؍‬ 0.624, P < .0001). Moreover, steatosis correlated with greater HPC proliferation (r ‫؍‬ 0.372, P ‫؍‬ .0004) and ductular reaction (r ‫؍‬ 0.374, P < .0001) but was not an obligate feature. Impaired hepatocyte replication by p21 expression was independently associated with HPC expansion (P ‫؍‬ .002) and increased with the body mass index (P < .001) and lobular inflammation (P ‫؍‬ .005). In conclusion, the strong correlation between portal fibrosis and a periportal ductular reaction with HPC expansion, the exacerbation by steatosis, and the associations with impaired hepatocyte replication suggest that an altered regeneration pathway drives the ductular reaction. We believe this triggers fibrosis at the portal tract interface. This may be a stereotyped response of importance in other chronic liver diseases. (HEPATOLOGY 2005;41: 809-818.)

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“…SPARC is upregulated in aHSCs (5) and in cirrhotic livers from rats and humans (14,23,24). We have recently demonstrated that SPARC expression levels correlate with the severity of liver fibrosis and shown that inhibition of SPARC by an adenovirus encoding an antisense mRNA (AdasSPARC) ameliorates hepatic fibrosis in rats (6).…”

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confidence: 99%

SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β₁and PDGF

Atorrasagasti

Aquino

Hofman

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Liver fibrosis is an active process that involves changes in cell-cell and cell-extracellular matrix (ECM) interaction. Secreted protein, acidic and rich in cysteine (SPARC) is an ECM protein with many biological functions that is overexpressed in cirrhotic livers and upregulated in activated hepatic stellate cells (aHSCs). We have recently shown that SPARC downregulation ameliorates liver fibrosis in vivo. To uncover the cellular mechanisms involved, we have specifically knocked down SPARC in two aHSC lines [the CFSC-2G (rat) and the LX-2 (human)] and in primary cultured rat aHSCs. Transient downregulation of SPARC in hepatic stellate cells (HSCs) did not affect their proliferation and had only minor effects on apoptosis. However, SPARC knockdown increased HSC adhesion to fibronectin and significantly decreased their migration toward PDFG-BB and TGF-β1. Interestingly, TGF-β1 secretion by HSCs was reduced following SPARC small interfering RNA (siRNA) treatment, and preincubation with TGF-β1 restored the migratory capacity of SPARC siRNA-treated cells through mechanisms partially independent from TGF-β1-mediated induction of SPARC expression; thus SPARC knockdown seems to exert its effects on HSCs partially through modulation of TGF-β1 expression levels. Importantly, collagen-I mRNA expression was reduced in SPARC siRNA-transfected HSCs. Consistent with previous results, SPARC knockdown in aHSCs was associated with altered F-actin expression patterns and deregulation of key ECM and cell adhesion molecules, i.e., downregulation of N-cadherin and upregulation of E-cadherin. Our data together suggest that the upregulation of SPARC previously reported for aHSCs partially mediates profibrogenic activities of TGF-β1 and PDGF-BB and identify SPARC as a potential therapeutic target for liver fibrosis.

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Expression of collagens type I and IV, osteonectin and transforming growth factor beta-1 (TGFβ1) in biliary atresia and paucity of intrahepatic bile ducts during infancy

Cited by 45 publications

References 23 publications

Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices

Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices

Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis

SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β₁and PDGF

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Expression of collagens type I and IV, osteonectin and transforming growth factor beta-1 (TGFβ1) in biliary atresia and paucity of intrahepatic bile ducts during infancy

Cited by 45 publications

References 23 publications

Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices

Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices

Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis

SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1and PDGF

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SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β₁and PDGF