Precision-cut fibrotic rat liver slices as a new model to test the effects of anti-fibrotic drugs in vitro.
OBJECTIVE
Current cell culture models contributed significantly to the study of liver fibrosis and the testing of anti-fibrotic drugs but mimic the complex in vivo milieu poorly. Therefore, we evaluated fibrotic rat liver slices as a new, more physiologic in vitro model to test anti-fibrotic compounds.


METHODS
Precision-cut slices (8 mm diameter, 250 microm thickness) were prepared from fibrotic rat livers three weeks after bile-duct ligation and incubated for 0-48 h, during which viability and progression of the fibrotic process was evaluated. In addition, the effects of pentoxifylline, gleevec, and dexamethasone on mRNA expression of markers for fibrosis were determined.


RESULTS
Fibrotic liver slices remained viable during 48 h of incubation, with increasing alphaSMA and pro-collagen 1a1 mRNA expression, and alphaSMA and collagen protein content after prolonged incubation. Addition of pentoxifylline, gleevec, or dexamethasone during incubation dose-dependently inhibited pro-collagen-1a1 and alphaSMA mRNA expression after 24h of incubation without influencing slice viability.


CONCLUSIONS
Fibrotic liver slices are a promising tool to test anti-fibrotic drugs in vitro in a multicellular, fibrotic milieu, which cannot be achieved in vitro using other models. Importantly, this method may provide the opportunity to study anti-fibrotic compounds not only in animal but also in fibrotic human liver tissue.
van de Bovenkamp
Marja
M
Department of Pharmacokinetics and Drug Delivery, University Center for Pharmacy, Groningen, The Netherlands. M.van.de.Bovenkamp@rug.nl
Groothuis
Geny M M
GM
Meijer
Dirk K F
DK
Olinga
Peter
P
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001549:Benzamides; D015415:Biomarkers / Q000032:analysis; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D024042:Collagen Type I / Q000187:drug effects / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003907:Dexamethasone / Q000494:pharmacology; D016591:Histocytological Preparation Techniques; D000068877:Imatinib Mesylate; D008099:Liver; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy*; D008297:Male; D023421:Models, Animal; D010431:Pentoxifylline / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000199:Actins; D001549:Benzamides; D015415:Biomarkers; D003094:Collagen; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D003907:Dexamethasone; D000068877:Imatinib Mesylate; D010431:Pentoxifylline; D010879:Piperazines; D011743:Pyrimidines; C498862:Acta2 protein, rat