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

Westra, I. M., Oosterhuis, D., Groothuis, G. M. M. & Olinga, P., 15-Jan-2014, In : Toxicology and Applied Pharmacology. 274, 2, p. 328-338 11 p.

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  • Precision-cut liver slices as a model for the early onset

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DOI

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-beta 1 and the fibrosis markers Hsp47, alpha Sma 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, TGF beta-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-beta 1 was not changed. Hsp47, alpha Sma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48 h, which was further increased by PDGF-BB and TGF-beta 1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGF beta-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-beta 1 gene expression and the limited effect of the TGF beta-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. (C) 2013 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)328-338
Number of pages11
JournalToxicology and Applied Pharmacology
Volume274
Issue number2
Publication statusPublished - 15-Jan-2014

    Keywords

  • Precision-cut liver slices, Liver fibrosis, Antifibrotic drugs, Ex vivo model, Early onset of fibrosis, HEPATIC STELLATE CELLS, ANTI-FIBROTIC DRUGS, IN-VITRO, IMATINIB MESYLATE, GROWTH-FACTOR, ROSMARINIC ACID, ANGIOTENSIN-II, ENDOPLASMIC-RETICULUM, INHIBITS ACTIVATION, DERMAL FIBROBLASTS

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