PMID- 24321339
OWN - NLM
STAT- MEDLINE
DCOM- 20140303
LR  - 20231213
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 274
IP  - 2
DP  - 2014 Jan 15
TI  - Precision-cut liver slices as a model for the early onset of liver fibrosis to 
      test antifibrotic drugs.
PG  - 328-38
LID - S0041-008X(13)00537-1 [pii]
LID - 10.1016/j.taap.2013.11.017 [doi]
AB  - 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-beta1 and the fibrosis 
      markers Hsp47, alphaSma 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, TGFbeta-pathway inhibitors, were determined. 
      After 48h of incubation, viability of the PCLS was maintained and gene expression 
      of PDGF-B was increased while TGF-beta1 was not changed. Hsp47, alphaSma and Pcol1A1 
      gene expressions were significantly elevated in PCLS after 48h, which was further 
      increased by PDGF-BB and TGF-beta1. The increased gene expression of fibrosis 
      markers was inhibited by all three PDGF-inhibitors, while TGFbeta-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-beta1 gene expression and the 
      limited effect of the TGFbeta-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.
CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
FAU - Westra, Inge M
AU  - Westra IM
AD  - Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, 
      University of Groningen, The Netherlands.
FAU - Oosterhuis, Dorenda
AU  - Oosterhuis D
AD  - Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, 
      University of Groningen, The Netherlands.
FAU - Groothuis, Geny M M
AU  - Groothuis GM
AD  - Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, 
      University of Groningen, The Netherlands.
FAU - Olinga, Peter
AU  - Olinga P
AD  - Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, 
      University of Groningen, The Netherlands. Electronic address: p.olinga@rug.nl.
LA  - eng
PT  - Journal Article
DEP - 20131207
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Benzamides)
RN  - 0 (Benzylisoquinolines)
RN  - 0 (CCN2 protein, rat)
RN  - 0 (Cinnamates)
RN  - 0 (Collagen Type I)
RN  - 0 (Depsides)
RN  - 0 (HSP47 Heat-Shock Proteins)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Piperazines)
RN  - 0 (Proto-Oncogene Proteins c-sis)
RN  - 0 (Pyridones)
RN  - 0 (Pyrimidines)
RN  - 0 (Serpinh1 protein, rat)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 139568-91-5 (Connective Tissue Growth Factor)
RN  - 1B56C968OA (Becaplermin)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 29EX23D5AJ (tetrandrine)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - D7NLD2JX7U (pirfenidone)
RN  - Y5GMK36KGY (Perindopril)
SB  - IM
MH  - Animals
MH  - Becaplermin
MH  - Benzamides/pharmacology
MH  - Benzylisoquinolines/pharmacology
MH  - Cinnamates/pharmacology
MH  - Collagen Type I/genetics/metabolism
MH  - Connective Tissue Growth Factor/genetics/metabolism
MH  - Depsides/pharmacology
MH  - Down-Regulation
MH  - Gene Expression
MH  - HSP47 Heat-Shock Proteins/genetics/metabolism
MH  - Imatinib Mesylate
MH  - Liver/*drug effects/metabolism
MH  - Liver Cirrhosis/*drug therapy
MH  - Male
MH  - Models, Biological
MH  - Niacinamide/analogs & derivatives/pharmacology
MH  - Organ Culture Techniques
MH  - Perindopril/pharmacology
MH  - Phenylurea Compounds/pharmacology
MH  - Piperazines/pharmacology
MH  - Proto-Oncogene Proteins c-sis/*antagonists & inhibitors/genetics/metabolism
MH  - Pyridones/pharmacology
MH  - Pyrimidines/pharmacology
MH  - Rats
MH  - Rats, Wistar
MH  - Sorafenib
MH  - Transforming Growth Factor beta1/antagonists & inhibitors/genetics/metabolism
MH  - Valproic Acid/pharmacology
MH  - Rosmarinic Acid
OTO - NOTNLM
OT  - Antifibrotic drugs
OT  - Early onset of fibrosis
OT  - Ex vivo model
OT  - Liver fibrosis
OT  - Precision-cut liver slices
EDAT- 2013/12/11 06:00
MHDA- 2014/03/04 06:00
CRDT- 2013/12/11 06:00
PHST- 2013/09/02 00:00 [received]
PHST- 2013/11/19 00:00 [revised]
PHST- 2013/11/25 00:00 [accepted]
PHST- 2013/12/11 06:00 [entrez]
PHST- 2013/12/11 06:00 [pubmed]
PHST- 2014/03/04 06:00 [medline]
AID - S0041-008X(13)00537-1 [pii]
AID - 10.1016/j.taap.2013.11.017 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2014 Jan 15;274(2):328-38. doi: 
      10.1016/j.taap.2013.11.017. Epub 2013 Dec 7.