Adenoviral-mediated transfer of p53 or retinoblastoma protein blocks cell proliferation and induces apoptosis in culture-activated hepatic stellate cells

Abriss, Bärbel; Hollweg, Günter; Gressner, A. M.; Weiskirchen, Ralf

doi:10.1016/s0168-8278(02)00361-6

Cited by 29 publications

(22 citation statements)

References 35 publications

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“…pRb expression in vivo was not shown in normal hepatocytes (Zhao and Zimmermann, 1998), HSC (Abriss et al, 2003), or cholangiocytes (Kang et al, 2002). Consistent with those findings, we were not able to show pRb in livers of sham-operated, BDL CTR, or BDL SIR animals and in long-term serum-deprived HEK cells.…”

Section: Sirolimus and Liver Fibrosis 959supporting

confidence: 83%

Long-Term Treatment of Bile Duct-Ligated Rats with Rapamycin (Sirolimus) Significantly Attenuates Liver Fibrosis: Analysis of the Underlying Mechanisms

Biecker¹,

Gottardi²,

Neef³

et al. 2005

J Pharmacol Exp Ther

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Rapamycin is an immunosuppressant with antiproliferative properties. We investigated whether rapamycin treatment of bile duct-ligated (BDL) rats is capable of inhibiting liver fibrosis and thereby affecting hemodynamics. Following BDL, rats were treated for 28 days with rapamycin (BDL SIR). BDL animals without drug treatment (BDL CTR) and sham-operated animals served as controls. After 28 days, hemodynamics were measured, and livers were harvested for histology/immunohistochemistry. Liver mRNA levels of transforming growth factor (TGF)-␤1, connective tissue growth factor (CTGF), plateletderived growth factor (PDGF)-␤, cyclin-dependent kinase inhibitor p27 kip (p27), and cyclin-dependent kinase inhibitor p21 WAF1/CIP1 (p21) were quantified by real-time polymerase chain reaction. Liver protein levels of p27, p21, p70 S6 kinase (p70 s6k ), phosphorylated p70 s6k (p-p70 s6k ), eukaryotic initiation factor 4E-binding protein (4E-BP1), p-4E-BP1 (Thr37/46), and p-4E-BP1 (Ser65/Thr70) were determined by Western blotting. Portal vein pressure was lower in BDL SIR than in BDL CTR animals. Volume fractions of connective tissue, bile duct epithelial, and desmin-and actin-positive cells were lower in BDL SIR than in BDL CTR rats. On the mRNA level, TGF-␤1, CTGF, and PDGF were decreased by rapamycin. p27 and p21 mRNA did not differ. On the protein level, rapamycin increased p27 and decreased p21 levels. Levels of nonphosphorylated p70 s6k and 4E-BP1 did not vary between groups, but levels of p-p70 s6k were decreased by rapamycin. Rapamycin had no effect on p-4E-BP1 (Thr37/46) and p-4E-BP1 (Ser65/Thr70) levels. In BDL rats, rapamycin inhibits liver fibrosis and ameliorates portal hypertension. This is paralleled by decreased levels of TGF-␤1, CTGF, and PDGF. Rapamycin influences the cell cycle by up-regulation of p27, down-regulation of p21, and inhibition of p70 s6k phosphorylation.

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Section: Sirolimus and Liver Fibrosis 959supporting

confidence: 83%

Long-Term Treatment of Bile Duct-Ligated Rats with Rapamycin (Sirolimus) Significantly Attenuates Liver Fibrosis: Analysis of the Underlying Mechanisms

Biecker¹,

Gottardi²,

Neef³

et al. 2005

J Pharmacol Exp Ther

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“…This resulted in HSC apoptosis as determined morphologically as well as by increases in p21 and caspase 3. 90 The second approach utilized the thymidine kinase gene with an upstream TIMP-1 promoter sequence. This was introduced into a recombinant replication-defective adenovirus that was then used to infect HSC in vitro.…”

Section: Manipulation Of Hsc Apoptosis In Vivomentioning

confidence: 99%

The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis

2005

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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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“…An alternative strategy might be to induce HSC apoptosis by adenoviral delivery of proapoptotic proteins. Abriss et al [68] , who demonstrated that transduction of p53 or retinoblastoma protein induced apoptosis of activated HSC in vitro, explored this concept recently. Suppression of I-B by the transcriptional repressor C promoter binding factor (CBF)-1 results in persistently raised activity of the transcription factor NF-B in activated HSC [69] .…”

Section: Stimulation Of Hsc Apoptosismentioning

confidence: 99%

Emerging Therapies for Liver Fibrosis

Fowell

Iredale²

2006

Dig Dis

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Liver fibrosis occurs as a result of a wide range of injurious processes and in its end-stage results in cirrhosis. This gross disruption of liver architecture is associated with impaired hepatic function, portal hypertension and significant resultant morbidity and mortality. Indeed, liver fibrosis and cirrhosis represent a major worldwide healthcare burden. Recent progress in liver transplantation, the management of portal hypertension and the treatment of chronic viral hepatitis have had an important impact. However, these approaches are not without their limitations – in particular, issues regarding organ availability for transplantation – and serve to highlight the urgent requirement to influence pharmacologically the underlying fibrotic process in many patients. Liver fibrosis has been shown to be a bidirectional process and increasing data from laboratory and clinical studies reveal that even advanced fibrosis and cirrhosis are potentially reversible. Exploration of the molecular mechanisms underlying this bi-directionality will lead to char acterisation of the essential attributes of an antifibrotic therapy. In this review, these mechanisms are highlighted and the growing number of emerging antifibrotic agents discussed.

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Adenoviral-mediated transfer of p53 or retinoblastoma protein blocks cell proliferation and induces apoptosis in culture-activated hepatic stellate cells

Cited by 29 publications

References 35 publications

Long-Term Treatment of Bile Duct-Ligated Rats with Rapamycin (Sirolimus) Significantly Attenuates Liver Fibrosis: Analysis of the Underlying Mechanisms

Long-Term Treatment of Bile Duct-Ligated Rats with Rapamycin (Sirolimus) Significantly Attenuates Liver Fibrosis: Analysis of the Underlying Mechanisms

The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis

Emerging Therapies for Liver Fibrosis

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