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Toxicol Appl Pharmacol. 2014 Jan 15;274(2):328-38. doi: 10.1016/j.taap.2013.11.017. Epub 2013 Dec 7.

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

Author information

1
Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, The Netherlands.
2
Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, The Netherlands.
3
Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, The Netherlands. Electronic address: p.olinga@rug.nl.

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 48h, 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 48h 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 48h, 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.

KEYWORDS:

Antifibrotic drugs; Early onset of fibrosis; Ex vivo model; Liver fibrosis; Precision-cut liver slices

PMID:
24321339
DOI:
10.1016/j.taap.2013.11.017
[Indexed for MEDLINE]

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