Rapamycin inhibits hepatic stellate cell proliferation in vitro and limits fibrogenesis in an in vivo model of liver fibrosis

Zhu, Jianliang; Wu, Jian; Frizell, Edward; Liu, Shu-Ling; Bashey, Reza I.; Rubin, Raphael; Norton, Pamela A.; Zern, Mark Α.

doi:10.1016/s0016-5085(99)70406-3

Cited by 200 publications

(157 citation statements)

References 37 publications

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“…In a rodent model of hepatic fibrogenesis, the 1.5-mg/kg/d dosage of sirolimus significantly decreased fibrogenesis measured by tissue collagen content, histological analysis, and messenger RNA levels of procollagen and transforming growth factor-␤. 10 In addition, sirolimus significantly decreased platelet-derived growth factor-stimulated proliferation of stellate cells. The human dose (for a 70-kg person) equivalent to 1.5 mg/kg/d is 105 mg/d, which is more than 50 times the dose administered to our patients.…”

Section: Discussionmentioning

confidence: 96%

Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications

Dunkelberg

Trotter

Wachs

et al. 2003

Liver Transplantation

114

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Sirolimus is a new immunosuppressive agent increasingly being used in liver transplant recipients. There is concern that sirolimus may be associated with wound complications and hepatic artery thrombosis (HAT). We have used sirolimus as primary immunosuppression in 170 liver transplant recipients and therefore reviewed our experience with wound complications and HAT in our cohort of patients. Records of all 170 patients administered sirolimus as primary immunosuppression and 180 historic controls were reviewed. Numbers of wound and hepatic artery complications were recorded, as well as the prevalence of obesity, reoperation, diabetes, and OKT3 use, all of which are risk factors for wound complications. The prevalence of wound complications was 12.4% in sirolimus-treated patients compared with 13. S irolimus, a new immunosuppressive agent, is being used increasingly in liver transplantation. 1-4 Sirolimus and tacrolimus are structurally related macrolides that bind the same intracellular receptor (FK506-binding protein-12 [FKBP12]) and potently inhibit T-cell proliferation. 5,6 The tacrolimus-FKBP12 complex, like the cyclosporine-cyclophilin complex, binds to and inhibits the Ca 2ϩ -dependent serine-threonine phosphatase calcineurin, thereby inhibiting cytokine-induced T-cell gene transcription and G 0 to G 1 transition. Conversely, the sirolimus-FKBP12 complex inhibits the target of rapamycin kinase, thereby inhibiting protein synthesis, G 1 to S transition, and cytokinedriven T-cell proliferation.Sirolimus has shown benefit in renal transplant recipients and therefore was approved for use in renal transplantation by the Food and Drug Administration in 1999. In two recent studies, a fixed dose of 2 or 5 mg/d of sirolimus in combination with cyclosporine decreased the acute rejection rate in the first year by 50% without an increase in immunosuppressant-related side effects. 7,8 Wound infection rates were not increased with sirolimus.Two recent trials have shown that liver transplantation may be performed successfully with minimal use of corticosteroids by using sirolimus and either tacrolimus or cyclosporine A. Low-dose sirolimus in the absence of prednisone in liver transplant recipients at our center was associated with a 50% decreased incidence of rejection, and the incidence of steroid-resistant rejection was decreased by 90% (compared with historic controls). 4 Similar efficacy was reported by McAlister et al 2 in an open-label report of 56 patients administered low-dose tacrolimus and sirolimus with prednisone up to 6 months after transplantation. The acute cellular rejection rate was 14%, which was approximately 50% lower than the historic rejection rate. None of the patients had steroid-resistant rejection.The well-established side-effect profile of sirolimus includes dose-dependent hyperlipidemia, thrombocytopenia, anemia, and leukopenia with an absence of neurotoxicity, nephrotoxicity, and diabetogenesis. There are anecdotal reports from some centers that sirolimus is associated with an increased incid...

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Section: Discussionmentioning

confidence: 96%

Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications

Dunkelberg

Trotter

Wachs

et al. 2003

Liver Transplantation

114

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“…mTOR modulates hepatic fibrosis, as demonstrated by evidence that rapamycin inhibits HSC proliferation and fibrinogenesis. 66 In this regard, HSC resemble dermal fibroblasts in which transfection with small interference RNA targeted at mTOR significantly decreases collagen gene expression. 67 These findings are pertinent to our work because the mTOR pathway is sensitized by Gli1, 68 a known signaling component and transcriptional target of Hh signals.…”

Section: Discussionmentioning

confidence: 99%

Role for Hedgehog signaling in hepatic stellate cell activation and viability

Sicklick

Choi

et al. 2005

Laboratory Investigation

170

150

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Hepatic stellate cells (HSC) have a complex phenotype that includes both neural and myofibroblastic features. The Hedgehog (Hh) pathway has been shown to direct the fate of neural and myofibroblastic cells during embryogenesis and during tissue remodeling in adults. Therefore, we hypothesized that Hh signaling may regulate the fate of HSC in adults. In this study, we find that freshly isolated stellate cells from adult PatchedlacZ transgenic mice exhibit b-galactosidase activity, indicating Hh pathway activity. Transcripts of Hh ligands, the Hh pathway receptor, and Hh-regulated transcription factors are expressed by stellate cells from mice, rats, and humans. Transfection experiments in a cell line using a Hh-inducible luciferase reporter demonstrate constitutive Hh pathway activity. Moreover, neutralizing antibodies to Hh increase apoptosis, while viability is restored by treatment with Hh ligand. In vitro treatment of primary stellate cells with cyclopamine (Cyc), a pharmacologic inhibitor of the Hh pathway, inhibits activation and slightly decreases cell survival, while a single injection of Cyc into healthy adult mice reduces activation of HSC by more than 50% without producing obvious liver damage. Our findings reveal a novel mechanism, namely the Hh pathway, that regulates the activation and viability of HSC.

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“…Determination of Hepatocyte Proliferation and tTG Activity-The cells seeded on 24-well Costar® plates were treated with phenylephrine at concentration indicated under "Results" for 24 h. After the cells were incubated with phenylephrine overnight, methyl-[ 3 H]thymidine (Amersham Pharmacia Biotech) was added to reach a concentration of 1 Ci/ml in the culture medium, and the cells were incubated for an additional 4 h. [ 3 H]Thymidine incorporation was determined according to the method described previously (17). The hepatocytes seeded on 6-well Costar® plates were used for determination of tTGase activity.…”

Section: Methodsmentioning

confidence: 99%

Roles of Tissue Transglutaminase in Ethanol-induced Inhibition of Hepatocyte Proliferation and α1-Adrenergic Signal Transduction

Wu¹,

Liu²,

Zhu³

et al. 2000

Journal of Biological Chemistry

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The mechanisms by which ethanol inhibits hepatocyte proliferation have been a source of some considerable investigation. Our studies have suggested a possible role for tissue transglutaminase (tTG) in this process. Others have shown that tTG has two distinctly different functions: it catalyzes protein cross-linking, which can lead to apoptosis and enhancement of extracellular matrix stability, and it can function as a G protein (G␣ h ). Under that circumstance, we speculated that the cross-linking activity would be decreased and that it would function to enhance hepatocyte proliferation in response to adrenergic stimulation. Ethanol treatment inhibited hepatocyte proliferation and led to enhanced tTG crosslinking activity, whereas treatment of hepatocytes with an ␣1 adrenergic agonist, phenylephrine, enhanced hepatocyte proliferation while decreasing tTG cross-linking. However, phenylephrine treatment of several hepatoma cell lines had no effect on cellular proliferation or tTG cross-linking activity, and of note, Northern blot analysis demonstrated that whereas primary hepatocytes had high levels of the ␣1␤ adrenergic receptor (␣1BAR) mRNA, the hepatoma cell lines did not have this mRNA. When the Hep G 2 cell line was stably transduced with an expression vector containing the ␣1BR cDNA, the cell line responded to phenylephrine treatment with enhanced proliferation and with decreased tTG cross-linking activity. Ethanol treatment of the ␣1BAR-transfected cells suppressed the phospholipase C-mediated signaling pathways, as detected in the phenylephrine-induced Ca 2؉ response. These results suggest that phenylephrine stimulation of hepatocyte proliferation appears to be occurring through the ␣1BAR, which is known to be coupled with the tTG G protein moiety, G␣ h , and that tTG appears to play a significant role in either enhancing or inhibiting hepatocyte proliferation, depending on its cellular location and on whether it functions as a cross-linking enzyme or a G protein.

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Rapamycin inhibits hepatic stellate cell proliferation in vitro and limits fibrogenesis in an in vivo model of liver fibrosis

Cited by 200 publications

References 37 publications

Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications

Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications

Role for Hedgehog signaling in hepatic stellate cell activation and viability

Roles of Tissue Transglutaminase in Ethanol-induced Inhibition of Hepatocyte Proliferation and α1-Adrenergic Signal Transduction

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