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

Autor: Nicolas Widmer, Markus Neef, Bertrand Rochat, M. Ledermann, Juerg Reichen, Vreni Schneider, H. Saegesser, Laurent A. Decosterd
Rok vydání: 2006
Předmět:
Male
medicine.medical_specialty
Time Factors
Cirrhosis
Platelet-derived growth factor
Administration
Oral
Liver Cirrhosis
Experimental
Collagen Type I
Mass Spectrometry
Piperazines
chemistry.chemical_compound
Fibrosis
Internal medicine
Animals
Medicine
RNA
Messenger
Rats
Wistar
Protein Kinase Inhibitors
Liver injury
Tissue Inhibitor of Metalloproteinase-1
Hepatology
biology
Reverse Transcriptase Polymerase Chain Reaction
business.industry
Imatinib
Protein-Tyrosine Kinases
medicine.disease
Rats
Procollagen peptidase
Pyrimidines
Treatment Outcome
Endocrinology
chemistry
Benzamides
Disease Progression
Imatinib Mesylate
Hepatic stellate cell
Cancer research
biology.protein
Matrix Metalloproteinase 2
business
Biomarkers
Procollagen
Platelet-derived growth factor receptor
Follow-Up Studies
medicine.drug
Zdroj: Journal of Hepatology. 44:167-175
ISSN: 0168-8278
Popis: Background/Aims: 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. Methods: 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 a1(I) were measured by RT-PCR. Liver tissue concentration of imatinib was measured by tandem mass spectrometry. Results: Early imatinib reduced ECM formation by 30% (PZ0.0455) 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. Conclusions: 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. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Databáze: OpenAIRE
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