Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term.

Details

Serval ID
serval:BIB_FB0ED134A39B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term.
Journal
Journal of hepatology
Author(s)
Neef M., Ledermann M., Saegesser H., Schneider V., Widmer N., Decosterd L.A., Rochat B., Reichen J.
ISSN
0168-8278 (Print)
ISSN-L
0168-8278
Publication state
Published
Issued date
01/2006
Peer-reviewed
Oui
Volume
44
Number
1
Pages
167-175
Language
english
Notes
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Transactivated hepatic stellate cells (HSCs) represent the key source of extra cellular matrix (ECM) in fibrotic liver. Imatinib, a potent inhibitor of the PDGF receptor tyrosine kinase, reduces HSC proliferation and fibrogenesis when treatment is initiated before fibrosis has developed. We tested the antifibrotic potential of imatinib in ongoing liver injury and in established fibrosis.
BDL-rats were gavage fed with 20 mg/kg/d imatinib either early (days 0-21) or late (days 22-35) after BDL. Untreated BDL-rats served as controls. ECM and activated HSCs were quantified by morphometry. Tissue activity of MMP-2 was determined by gelatin zymography. mRNA expression of TIMP-1 and procollagen alpha1(I) were measured by RT-PCR. Liver tissue concentration of imatinib was measured by tandem mass spectrometry.
Early imatinib reduced ECM formation by 30% (P=0.0455) but left numbers of activated HSCs and procollagen I expression unchanged. MMP-2 activity and TIMP-1 expression were reduced by 50%. Late imatinib treatment did not alter histological or molecular markers of fibrogenesis despite high imatinib tissue levels.
The antifibrotic effectiveness of imatinib is limited to the early phase of fibrogenesis. In ongoing liver injury other mediators most likely compensate for the inhibited PDGF effect.
Keywords
Administration, Oral, Animals, Benzamides, Biomarkers/metabolism, Collagen Type I/genetics, Collagen Type I/metabolism, Disease Progression, Follow-Up Studies, Imatinib Mesylate, Liver Cirrhosis, Experimental/drug therapy, Liver Cirrhosis, Experimental/metabolism, Liver Cirrhosis, Experimental/pathology, Male, Mass Spectrometry, Matrix Metalloproteinase 2/metabolism, Piperazines/administration & dosage, Piperazines/pharmacokinetics, Piperazines/therapeutic use, Procollagen/genetics, Procollagen/metabolism, Protein Kinase Inhibitors/administration & dosage, Protein Kinase Inhibitors/pharmacokinetics, Protein Kinase Inhibitors/therapeutic use, Protein-Tyrosine Kinases/antagonists & inhibitors, Pyrimidines/administration & dosage, Pyrimidines/pharmacokinetics, Pyrimidines/therapeutic use, RNA, Messenger/genetics, Rats, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Tissue Inhibitor of Metalloproteinase-1/genetics, Tissue Inhibitor of Metalloproteinase-1/metabolism, Treatment Outcome
Pubmed
Web of science
Create date
25/01/2008 8:47
Last modification date
20/02/2025 7:12
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