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Title: Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs

Abstract

Induction of fibrosis during prolonged culture of precision-cut liver slices (PCLS) was reported. In this study, the use of rat PCLS was investigated to further characterize the mechanism of early onset of fibrosis in this model and the effects of antifibrotic compounds. Rat PCLS were incubated for 48 h, viability was assessed by ATP and gene expression of PDGF-B and TGF-β1 and the fibrosis markers Hsp47, αSma and Pcol1A1 and collagen1 protein expressions were determined. The effects of the antifibrotic drugs imatinib, sorafenib and sunitinib, PDGF-pathway inhibitors, and perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone, TGFβ-pathway inhibitors, were determined. After 48 h of incubation, viability of the PCLS was maintained and gene expression of PDGF-B was increased while TGF-β1 was not changed. Hsp47, αSma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48 h, which was further increased by PDGF-BB and TGF-β1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGFβ-inhibitors showed marginal effects. The protein expression of collagen 1 was inhibited by imatinib, perindopril, tetrandrine and pirfenidone. In conclusion, the increased gene expression of PDGF-B and the down-regulation of fibrosis markers by PDGF-pathway inhibitors, together with the absence of elevatedmore » TGF-β1 gene expression and the limited effect of the TGFβ-pathway inhibitors, indicated the predominance of the PDGF pathway in the early onset of fibrosis in PCLS. PCLS appear a useful model for research of the early onset of fibrosis and for testing of antifibrotic drugs acting on the PDGF pathway. - Highlights: • During culture, fibrosis markers increased in precision-cut liver slices (PCLS). • Gene expression of PDGF-β was increased, while TGFβ was not changed in rat PCLS. • PDGF-pathway inhibitors down-regulated this increase of fibrosis markers. • TGFβ-pathway inhibitors had only minor effects on fibrosis markers. • Rat PCLS can be used to study the early onset of fibrosis.« less

Authors:
 [1];  [2];  [1];  [2]
  1. Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen (Netherlands)
  2. Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen (Netherlands)
Publication Date:
OSTI Identifier:
22285584
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 274; Journal Issue: 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ATP; DRUGS; FIBROSIS; GENES; LIVER; RATS

Citation Formats

Westra, Inge M., Oosterhuis, Dorenda, Groothuis, Geny M.M., and Olinga, Peter. Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2013.11.017.
Westra, Inge M., Oosterhuis, Dorenda, Groothuis, Geny M.M., & Olinga, Peter. Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs. United States. https://doi.org/10.1016/J.TAAP.2013.11.017
Westra, Inge M., Oosterhuis, Dorenda, Groothuis, Geny M.M., and Olinga, Peter. 2014. "Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs". United States. https://doi.org/10.1016/J.TAAP.2013.11.017.
@article{osti_22285584,
title = {Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs},
author = {Westra, Inge M. and Oosterhuis, Dorenda and Groothuis, Geny M.M. and Olinga, Peter},
abstractNote = {Induction of fibrosis during prolonged culture of precision-cut liver slices (PCLS) was reported. In this study, the use of rat PCLS was investigated to further characterize the mechanism of early onset of fibrosis in this model and the effects of antifibrotic compounds. Rat PCLS were incubated for 48 h, viability was assessed by ATP and gene expression of PDGF-B and TGF-β1 and the fibrosis markers Hsp47, αSma and Pcol1A1 and collagen1 protein expressions were determined. The effects of the antifibrotic drugs imatinib, sorafenib and sunitinib, PDGF-pathway inhibitors, and perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone, TGFβ-pathway inhibitors, were determined. After 48 h of incubation, viability of the PCLS was maintained and gene expression of PDGF-B was increased while TGF-β1 was not changed. Hsp47, αSma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48 h, which was further increased by PDGF-BB and TGF-β1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGFβ-inhibitors showed marginal effects. The protein expression of collagen 1 was inhibited by imatinib, perindopril, tetrandrine and pirfenidone. In conclusion, the increased gene expression of PDGF-B and the down-regulation of fibrosis markers by PDGF-pathway inhibitors, together with the absence of elevated TGF-β1 gene expression and the limited effect of the TGFβ-pathway inhibitors, indicated the predominance of the PDGF pathway in the early onset of fibrosis in PCLS. PCLS appear a useful model for research of the early onset of fibrosis and for testing of antifibrotic drugs acting on the PDGF pathway. - Highlights: • During culture, fibrosis markers increased in precision-cut liver slices (PCLS). • Gene expression of PDGF-β was increased, while TGFβ was not changed in rat PCLS. • PDGF-pathway inhibitors down-regulated this increase of fibrosis markers. • TGFβ-pathway inhibitors had only minor effects on fibrosis markers. • Rat PCLS can be used to study the early onset of fibrosis.},
doi = {10.1016/J.TAAP.2013.11.017},
url = {https://www.osti.gov/biblio/22285584}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 274,
place = {United States},
year = {Wed Jan 15 00:00:00 EST 2014},
month = {Wed Jan 15 00:00:00 EST 2014}
}