Article: article from journal or magazin.
Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term
Journal of Hepatology
Comparative Study Journal Article Research Support, Non-U.S. Gov't --- Old month value: Jan
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 alpha1(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% (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. 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.
Administration, Oral Animals Biological Markers/metabolism Collagen Type I/genetics/metabolism Disease Progression Follow-Up Studies Liver Cirrhosis, Experimental/*drug therapy/metabolism/pathology Male Mass Spectrometry Matrix Metalloproteinase 2/metabolism Piperazines/*administration & dosage/pharmacokinetics/therapeutic use Procollagen/genetics/metabolism Protein Kinase Inhibitors/*administration & dosage/pharmacokinetics/therapeutic use Protein-Tyrosine Kinases/*antagonists & inhibitors Pyrimidines/*administration & dosage/pharmacokinetics/therapeutic use RNA, Messenger/genetics Rats Rats, Wistar Reverse Transcriptase Polymerase Chain Reaction Time Factors Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism Treatment Outcome
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